FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly, the Food and Drug
Administration makes no representation as to its accuracy.
85th Meeting of:
BLOOD PRODUCTS
ADVISORY COMMITTEE
November 3, 2005
Holiday Inn
Gaithersburg, Maryland
Reported By:
CASET Associates
10201 Lee Highway, Suite 180
Fairfax, Virginia 22030
(703) 352-0091
TABLE
OF CONTENTS
Page
Welcome, Statement of Conflict of Interest, 1
Committee
Updates:
- West Nile Virus Update - Hira Nakhasi 10
Theresa Smith 17
- Draft Guidance on NAT for HIV-1 and HCV - Paul
Mied 27
- Summary of the TSEAC Meeting of October 31, 2005 37
- David Asher
- Summary of DHHS Advisory Committee on Blood Safety
and 50
Availability - Jerry Holmberg
- Re-entry of Donors Deferred Based on anti-HBc Test
Results - Gerardo Kaplan 61
- Susan Stramer 64
Approaches to Over-the-Counter Home-Use HIV
Test Kids
- Introduction and Questions to the Committee 77
-
Elliott Cowan
- Proposal for an OTC Home-Use HIV Test Kit 101
-
Sue Sutton-Jones
- Changes in HIV Test Practices and Counseling 139
Recommendations - Bernard Branson
- Role of Quality Systems for Diagnostic Tests 172
-
Devery Howerton
- Psychological/Social Issues Associated with HIV 187
Testing and OTC Home-Use HIV Tests - Joseph
Inungo
- Human Factors in OTC Testing - Arleen Pinkos 205
- Open Public Hearing 224
- Elliott Millenson 225
- Wesley Rodriguez 232
- Patrick Keenan 238
- Freya Spielberg 242
- Waheed Khan 252
- Patricia Charache 255
- Tracy Powell 261
- Ernest Hopkins 266
- Tom Donahue 271
- Duralba Munoz 276
- Richard Cizik 285
- Tom Myers 288
- Shawn Fay 291
- Damen Dozier 298
- James Sykes 303
- Bill Parra 306
- Neeraj Vats 308
- Terry Anderson 311
- Questions to the Committee and Committee
Discussion 315
COMMITTEE
MEMBERS:
JAMES
ALLEN, MD, MPH, Chair. President and CEO, American Social Health Administration,
Research Triangle Park, NC
DONNA
M. DI MICHELE, MD, Chair (Topic I only). Associate
Professor of Pediatrics and Public Health, Weill Medical College and Graduate
School of Medical Science, Cornell University, New York, New York
MATTHEW
KUEHNERT, MD, CDR,
U.S. Public Health Service, Assistant Director for Blood Safety, Division of
Viral and Rickettsial Diseases, CDC, Atlanta, Georgia
CATHERINE
S. MANNO, MD, Professor
of Pediatrics, The Children's Hospital of Philadelphia, University of
Pennsylvania School of Medicine, Philadelphia, Pennsylvania
KEITH
QUIROLO, MD, Hemoglobinopathy
Pediatrician, Clinician Director, Apheresis, Transfusion Medical Director, Sibling
Donor Cord Blood Program, Department of Hematology, Children's Hospital and
Research Center, Oakland, California
GEORGE
C. SCHREIBER, ScD, Vice
President, Health Studies, Westat, Rockville, Maryland
DONNA
S. WHITTAKER, PhD, Director,
Robertson Blood Center, Fort Hood, Texas
CONSUMER
REPRESENTATIVE:
JUDITH
BAKER, MHSA, Regional
Coordinator, Federal Hemophilia Treatment Centers, Children Hospital, Los
Angeles, CA
NON-VOTING
INDUSTRY REPRESENTATIVE
LOUIS
KATZ, MD, Executive
Vice President, Medical Affairs, Mississippi Valley Regional Blood Center,
Davenport, Iowa
ACTING
NON-VOTING INDUSTRY REPRESENTATIVE
WILLIAM
H. DUFFELL, PhD, Director
of Government Affairs, Regulatory Affairs Quality Systems, Gambro BCT Lakewood,
CO
TEMPORARY
VOTING MEMBERS:
HENRY
M. CRYER, III, MD, PhD, Chief, Trauma and Critical Care, Division of General Surgery,
University of California, Los Angeles, California
ADRIAN
M. DI BISCEGLIE, MR, Professor
of Medicine, Chief of Hepatology, St. Louis University School of Medicine, St.
Louis, Missouri
SAMUEL
H. DOPPELT, MD, Chief,
Department of Orthopedic Surgery, The Cambridge Hospital, Cambridge,
Massachusetts
HARVEY
KLEIN, MD,
Chief, Department of Transfusion Medicine, National Institutes of Health,
Warren G. Magnuson Clinical Center, Bethesda, Maryland
ROSHNI
KULKARNI, MD, Professor
and Chief, Pediatric and Adolescent Hematology/Oncology, Michigan State
University, East Lansing, Michigan
SAMAN
LAAL, PhD, Assistant
Professor, Department of Pathology, New York University School of Medicine, New
York, New York
KENRAD
NELSON, MD, Professor,
Department of Epidemiology, Johns Hopkins University School of Hygiene and
Public Health, Baltimore, Maryland
THOMAS
QUINN, MD, Professor
of Medicine and Deputy Director, Infectious Disease Division, The Johns Hopkins
University, Baltimore, Maryland
FREDERICK
SIEGAL, MD, Medical
Director, Comprehensive HIV Center, St. Vincent's Catholic Medical Center, St.
Vincent's Manhattan, New York, New York
GORDON
SNIDER, MD, Towson,
Maryland
IRMA
O.V. SZYMANSKI, MD, Professor
of Pathology, Emeritus, University of Massachusetts Medical Center, Department
of Pathology, Worcester, Massachusetts
EXECUTIVE
SECRETARY:
DONALD
JEHN, Executive
Secretary, Blood Products Advisory Committee, Division of Scientific Advisors
and Consultants, CBER, FDA
COMMITTEE
MANAGEMENT SPECIALIST:
PEARLINE
MUCKELVENE, Division
of Scientific Advisors and Consultants, CBER, FDA
STAFF:
SUSAN
ZULLO, PhD, Acting
Associate Director for Policy, Office for Blood Research and Review, CBER, FDA
RHONDA
DAWSON, Policy
Analyst, Office for Blood Research and Review, CBER, FDA
P R O C E E D I N G S (8:20 a.m.)
Agenda Item:
Welcome, Statement of Conflict of Interest, Announcements.
MR. JEHN: I am
going to go ahead and begin here. Mr.
Chairperson, members of the committee, invited guests, consultants and public
participants, I would like to welcome you to the 85th meeting of the Blood
Products Advisory Committee. I am
Donald Jehn, the executive secretary for this meeting.
The entire meeting is open to the public today. At this
time, I would like to introduce the individuals seated at the head table for
today's first session.
Starting over to my right here, and going counterclockwise
around the table, we have Dr. Kenrad Nelson, professor of epidemiology from
Johns Hopkins. Dr. Quinn will be seated
next to him when he arrives. He is also from Johns Hopkins.
Dr. Samuel Doppelt is the chief of the department of
orthopedic surgery, Cambridge Hospital. Dr. Henry Cryer III, chief of trauma
and critical care, UCLA.
Dr. Schreiber, vice president of health studies, Westat.
Dr. Roshni Kulkarni, professor and director of pediatric and adolescent
hematology oncology, Michigan State University. Dr. William Duffell, Jr., director of government affairs,
regulatory affairs, quality systems, Gambro.
Coming over to this side now, we have Judith Baker,
consumer representative, regional coordinator, federal hemophilia treatment
center, region IX, Children's Hospital, Los Angeles.
Next to her, Dr. Adrian Di Bisceglie, professor of
medicine, chief of hepatology at St. Louis University School of Medicine.
Dr. Suman Laal, assistant professor, department of
pathology, New York University School of Medicine, Dr. Frederick Siegal,
medical director, comprehensive HIV center, St. Vincent's Hospital, Manhattan.
Dr. Catherine Manno, professor of pediatrics, Children's
Hospital, Philadelphia. Dr. Matthew
Kuehnert, assistant director for blood safety, division of viral and
rickettsial diseases, CDC.
Dr. Donna Whittaker, director of Robertson Blood Center,
Fort Hood, Texas. Dr. Irma Szymanski,
here to my immediate right, professor of pathology emerita, University of
Massachusetts Medical Center. Dr. Harvey Klein, chief of the department of
transfusion medicine, NIH.
Dr. Donna DiMichele, she will be acting chair for topic I
discussion. She is the assistant professor of pediatrics and public health,
Weill Medical College and Graduate School of Medical Science, Cornell.
Our regular BPAC chair, Dr. James Allen, president and CEO,
American Social Health Administration, Research Triangle.
There are two committee members not present for the
meeting, Dr. Quirolo and Dr. Katz. I would like to thank the members and
consultants for attending this meeting.
Before we begin, Dr. Epstein, can I have you forward? There are four retiring members of the
committee that we are going to recognize these individuals.
Could we have Dr. DiMichele, Dr. Doppelt, Dr. Klein
and Dr. Laal to step forward? Thank
you.
DR. EPSTEIN: Let me
just remark that it is a bittersweet honor to give these awards to our outgoing
committee members.
We deeply appreciate the effort that each of you have
provided on our behalf, and in the
interests of the public health.
We know that this participation represents a certain degree
of personal sacrifice, reading long documents, sitting in a chair long hours,
and scratching your brain for all of us.
So, these are small tokens of our appreciation, which I am very pleased
to hand to you. So, I guess one at a
time.
First, to Dr. Harvey Klein, with our deep
appreciation. [Award given, photograph
taken, applause.]
This is to Dr. Donna DiMichele, again, with our great
thanks. [Award given, photograph taken,
applause.]
Dr. Samuel Doppelt, again, thank you very much. [Award given, photograph taken, applause.]
Dr. Laal will receive hers later. Thank you.
MR. JEHN: Before I
turn the meeting over to the chair, I have a conflict of interest statement to
read. Bear with me. It is a little lengthy.
The Food and Drug Administration, FDA, is convening today's
meeting of the Blood Products Advisory Committee under the authority of the
Federal Advisory Committee Act of 1972.
With the exception of the industry representative, all
members and consultants of the committee are special government employees or
regular federal employees from other agencies, and are subject to federal
conflict of interest laws and regulations.
The following information on the status of this advisory
committee's compliance with federal ethics and conflict of interest laws,
including, but not limited to, 18 USC Section 201, and 21 USC Section 355(n)(4)
has been provided to participants in today's meeting, and to the public.
FDA has determined that members of this advisory committee
and consultants to the committee are in compliance with the federal ethics and
conflict of interest laws, including but not limited to, 18 USC Section 208,
and 21 USC, Section 355(n)(4).
Under 18 USC Section 208, applicable to all government agencies,
and 21 USC Section 355(n)(4) applicable to certain FDA committees, congress has
authorized FDA to grant waivers to special government employees who have
financial conflicts, when it is determined that the agency's need for a
particular individual's services outweighs his or her potential financial
conflict of interest, section 208, and where participation is necessary to
afford special expertise, section 355.
Members and consultants of the committee who are special
government employees at today's meeting, including special government employees
appointed at temporary voting members, have been screened for potential
financial conflicts of interest of their own, as well as those imputed to them,
including those of their employer, spouse or minor child related to discussions
of approaches to over-the-counter home use HIV test kits, and the discussions
of alpha-1 protease inhibitor products.
These interests may include investments, consulting, expert
witness testimony, contracts, grants, CRADAs, teaching, speaking, writing,
patents and royalties, and primary employment.
Today's agenda for topic I includes review and discussion
of the approaches of over-the-counter home use HIV test kits. For topic II, the
committee will review and discuss alpha-1 protease inhibitor products.
In accordance with 18 USC Section 208(b)(3), waivers have
been granted to the following special government employees: Dr. Donna DiMichele, topics one and two, Dr.
Catherine Manno, topic two.
In addition, Dr. James Allen has recused himself from the
discussion of topic one related to HIV home test kits.
A copy of the written waiver statement may be obtained by
submitting a written request to the agency's freedom of information office,
Room 12-A-30 of the Parklawn Building.
With regard to FDA's guest speakers, the agency has
determined that the information provided by these speakers is essential.
The following information is being made public to allow the
public to objectively evaluate any presentation and/or comments made by the speakers.
Dr. Mark Brantly is professor of medicine, molecular
genetics and microbiology and alpha-1 research professor, University of
Florida, Gainesville.
Dr. Bernard Branson is associate director for laboratory
diagnostics, division of HIV/AIDS prevention, CDC, Atlanta.
Dr. Devery Ann Howerton is chief, laboratory practice,
evaluation and genomics branch, coordinating center for health information and
services, CDC, Atlanta.
Dr. Joseph Inungo is professor, school of health sciences,
Central Michigan University.
Dr. Hans Peter Schwarz is associate professor of medicine,
vice president, global preclinical research and development, Baxter Bioscience,
Vienna, Austria.
Dr. Sue Sutton-Jones is senior vice president, regulatory
affairs and quality assurance, OraSure Technologies.
Any guest speakers will not participate in the committee
deliberations, nor will they vote. In addition, there may be regulated industry
and other outside organization speakers making presentations.
These speakers may have financial interests associated with
their employer and with other regulated firms.
The FDA asks, in the interests of fairness, that they
address any current or previous financial involvement with any firm whose
product they may wish to comment upon.
These individuals were not screened by FDA for conflicts of interest.
Dr. William Duffell, Jr., is serving as the industry
representative, acting on behalf of all related industry, and is employed by
Gambro BCT. Industry representatives are not special government employees and
do not vote.
This conflict of interest statement will be available for
review at the registration table. We would like to remind members and
consultants that, if the discussions involve any other products or firms not
already on the agenda, for which an FDA participant has a personal or imputed
financial interest, the participants need to exclude themselves from such
involvement, and their exclusion will be noted for the record.
FDA encourages all other participants to advise the
committee of any financial relationships that you may have with any sponsor,
products, direct competitors and firms, that could be affected by the
discussions. Thank you. Dr. Allen, I turn it over to you.
DR. ALLEN: Thank
you, Mr. Jehn. I would like to add my
welcome to all the committee members, and my thanks to the retiring members. It
has been wonderful working with you, and we will miss you.
We have a very full agenda today. We are going to do one more retirement here.
DR. EPSTEIN: I
would like to call Dr. Suman Laal up at this time and, once again, please step
forward, to thank you personally for your service to this committee and, again,
this is an expression of appreciation on behalf of all of us and the public
health. [Award given, photograph taken,
applause.]
DR. ALLEN: Jay, I
think we will have to come up with another name for retirement, because there
are no retiring members on this panel.
We do have a very busy schedule today. During topic one,
from which I will recuse myself, we have got a number of open hearing speakers,
as well as our regularly scheduled speakers.
I would just like to remind everyone today, please keep to
your allotted time. It is essential that we have adequate time for the
committee to have full discussion and to ask questions, and to seek the
information that we need in order to provide the proper advice to the Food and
Drug Administration.
For the updates this morning, rather than running through
each of the updates in sequence and then having time for discussion, I am going
to allow time for discussion immediately after each one, because each topic is
so different.
So, we will move straight into the first discussion item,
which is a west nile virus update by Dr. Hira Nakhasi of the FDA and Dr.
Theresa Smith of the CDC.
Agenda Item:
Committee Updates: West Nile
Virus Update.
DR. NAKHASI: Good
morning, everybody. The first speaker
always has to be on time, I guess. So, I will try my best to be on time, and
also just to give you a quick update on the epidemic of 2005, the west nile
virus epidemic of 2005, and our efforts to see how things are moving. Also, Dr. Theresa Smith will talk from the
CDC perspective.
Now, the background here, if you were not here for the last
three years, then I think you should be looking at this slide.
However, if you were here for the last three years, at
every BPAC, I have been talking the same thing. I just want to briefly say that
West Nile is a single stranded RNA virus, a flavivirus.
It is mosquito borne.
Eighty percent of infection is asymptomatic, 20 percent develop mild
fever, and approximately one in 150 infections result in meningitis or
encephalitis.
Old people like me are at risk for neurological diseases
for a period two weeks prior to symptoms, and can last more than a month, which
was a new revelation during the course of this epidemic.
In 2002, when the first outbreak -- not the first outbreak,
the first transmission cases -- occurred, and in that time we realized that
west nile can be transmitted through blood and transplantation and other
sources. However, the magnitude of risk is still unknown through the
transmission. Virus titers of this blood is much lower than the other known
viruses, like HIV, HCV, and IgM can persist, that antibody can persist, up to
two years. However, there is no chronic stage.
This is the progression of the epidemic, west nile
epidemic, in the Americas. You can see
the United States started in 1999, Canada 2000, spread to Mexico in 2002, and
Central American in 2003, and then to the Caribbean.
This just gives you the overall human cases over the period
of time. What you see is here, that the epidemic started in 1999 and reached a
peak in 2003, and the last two years it has sort of plateaued here.
You will hear more about the epidemic from Theresa. This is
year, 2005, as of now, most of the states in the lower 48 states, they are
human cases, but still, Washington, northeastern and some places in Virginia
you still have only avian activity but not the human activity.
This is to give you an idea of how many cases of the blood
donors this years. As of November 374
cases in blood donors that were detected by testing. Again, you can see it is
spread out all over the place.
This just gives you an idea how we progressed since we
started testing the blood as of July 1, 2003, using Genprobe and Roche tests.
The first year, in 2003, we found 880 donors who had
reported to the CDC arbonet and, at that time, there were six confirmed
transfusion transmitted cases. However, out of six, four out of six had very
low viremia.
In 2004, we saw a dramatic decrease in the number of cases
from approximately 880 to 224. Again, I want to emphasize that this is
mini-pool NAT and, during this season, we started to also, in certain areas,
where the incidence and prevalence of these cases was much higher, the industry
introduced the individual NAT testing.
Last year we found one reported case of transfusion
transmitted cases. However, that was only detected by ID NAT and it happened in
a situation right before the ID Nat was instituted in that area.
This area, as of now, October 1, 2005, we saw a little bit
of an increase in the number of cases, 374 so far, and it has already petered
out. In the last couple of weeks we see one or two cases every week. Again, the
peak was between late August, early September.
Again, this year, mini-pool NAT and ID NAT was instituted
in mild cases, where the high cases, where the prevalence was much higher, the
ID NAT was started right away.
Fortunately, so far we have no reported transfusion
transmitted cases this year. However, there were three cases of transmission
through transplantation.
As you know, we have issued several guidances over a period
of time in 2002 and 2003, and now this year we issued a revised guidance,
basically to update what is happening with the epidemic, and to keep on
changing the donor deferral periods.
This year we show, under the new revised guidance of 2005,
basically says the epidemic season starts between May 1 and November 30.
The reason I am saying May 1, for the last several years we
have seen it coming earlier and earlier, except this year, where it started a
little bit late, and last year it started toward the middle of April, end of
April kind of a thing.
So, we said, if the cases are during that epidemic season,
donors of suspected west nile infection, or diagnosed with west nile infection,
should be deferred for 120 days.
What we found out is that the studies showed last year
that, in some of the donors during the epidemic period, could be up to 104.
Mind you, it was only one case, but there were some cases that were beyond 28
days, and the earlier guidance said 28 days, because that was based on the
studies in the 1950s.
We found out that in some cases -- again, mind you, this is
low level of virus in the presence of antibodies. So, we do not know whether
that is infectious or not.
So, we decided that it would be 120 days deferral, would be
fine. Donors would be deferred on the
basis of investigational tests, and blood establishments, at their own
discretion, may enter such donors after 120 days after the reactive donation,
i.e., that they may not have to test them again before entering.
Earlier we had suggested that, before re-entering, they
should be tested. However, the FDA recommends that we still would like to be
tested those who are re-entered, be tested by ID NAT on a follow up sample
during the 120 days, which will provide useful additional scientific
information on the duration of west nile viremia.
Still it is evolving. The first year we thought it was only
28 days, the next year we found out 49, 50 days. Last year we found that one of
the cases was 104 days.
So, it will be important to find out how long the viremic
period is, because this is an evolving situation. If such a follow up sample is
reactive for west nile virus, the FDA recommends that the donor be deferred for
an additional 120 days from the day the sample was taken.
So, we still are continuing working closely with the test
kit manufacturers to expedite the licensure, and we still are having the
meetings bi-weekly during the season with the AABB task force, and I am really
thankful for them, in collaboration with CDC and NIH. So, we monitor the epidemic and then make a course correction if
that is needed.
So, in having this story told so far, there are still gaps
in knowledge, which we in the FDA are working on. A couple of things, one is the genetic variation in west nile
strains.
Even though there is limited data, I will show you some
data that there may be some variation, but the question is, why are we studying
that? Is it important because it may
have impact on the west nile assays?
Then also, an important issue still remains whether there
is any residual risk of west nile infection in the presence of antibodies. That
means, those people who have low titer virus by mini-pool or ID NAT, and are
having antibodies, are they infectious.
I think those studies, we want to ask those questions. So,
Maria Rios' lab in FDA has collected several of these isolates, 25 in total,
from various periods of the epidemic, and sequenced the structural gene, and
five of them have completely sequenced the complete genome.
What she found out, and others found out, was that there
was a genetic shift between 1999 and 2001 and 2002 in the sequences, at least
in the structural regions. So, there was a major shift there, that 55 percent
of the oral isolates in 2002 had changes, whereas 85 percent had a different
group of isolates in 2003.
However, between 2005 and 2002, the majority of the
nucleotide changes were in U to C and A to G, and a small number of mutations
also have so far not affected the testing.
So, thank God for that.
She also did in vitro infective study samples, which were
mini-pool NAT positive or ID NAT positive and antibody positive or mini-pool
NAT negative or ID NAT positive.
What she found out, 10 out of 16 samples, when she infected
these blood samples onto viral or macrophage cells, she could see the virus
replication.
That doesn't mean that virus is infectious, and it doesn't
mean that it can be transmitted, but it tells you that it is infectious.
Although in vitro infective does not imply infective in
vivo, it demonstrates the presence of live virus and, therefore, raises some
concerns about a potential risk for transfusion transmission.
I should hasten to say that, so far, we have not seen any
transfusion transmitted cases from samples, if they were antibody positive
samples. So far, in real life, we have not seen that.
There remains a potential for that, even though it is low.
So, what we are trying to do now is doing it in non-human primate studies as
well as small animals, to see whether these samples are infectious.
With that, I think I will acknowledge my colleagues at CDC,
the AABB task force, other organizations -- ABC, ARC, BSL, Roche, GenProbe, Department
of Defense and FDA colleagues. Thank
you very much.
We are doing a tag team, and Theresa can talk and if you
have any questions, then we can come together.
Agenda Item:
West Nile Virus Update.
DR. SMITH: Thank
you for letting me tell you about the west nile virus epidemiology and
surveillance update for 2005.
I will skip virology this year, since Dr. Nakhasi covered
it so well but, like last year, I will go ahead and discuss the epidemiology of
west nile in the United States quickly from 1999 and then, more fully, a brief
review of last year and how things have gone this year. Then we will discus what we have seen in
blood donations. As marked on this
slide, all data, including 2005, was in Arbonet as of 11-1-05.
The data that we are going to be looking at is from
Arbonet, a national arbovirus surveillance system. It is a web based passive
system begun in 2000 in response to the new epidemic in the United States.
It includes 57 area health departments that report over the
internet to the division of vector borne infectious diseases.
It includes both animal and environmental data in the form
of mosquito, bird, horse and other animal surveillance, and human cases.
Human cases have a great deal of information collected,
including age, sex, race, ethnicity, residence, clinical illness, onset date
and outcome, blood or organ donation or receipt.
You may have seen some of these maps over time. This gives
a sense of when we first saw this virus, and when we have seen activity in
environment versus activity in humans.
You will notice we have something like areas in our country
where we only see transmission in the environment and not yet any human cases,
and the rest of the country has experienced human cases.
In 2004, we saw a great deal of activity down in the
southwest. While it had been there before, it was the first time that we saw a
lot of human cases.
During this year, we see that area continues to have quite
a few human cases, and it is becoming a little denser in terms of the counties
that become affected by west nile.
This is a quick reminder that all the data that you are
looking at revolves around reports that come in, and that is always going to
lag behind the actual onset.
So, in orange you see the onset of cases. In green you see
the reporting of cases. So, what you see today is not going to look the same
when we finalize this year's data.
Here you can again see that we have started with relatively
few cases in 1999. Our peak year was in
2003. The last two years have been fairly
level.
So far this year, we have had 2,581 case reports in 42
states. Of those, 1053 have been neuroinvasive disease.
West nile fever has accounted for 1,368. There have been 83
deaths. Of those 83 deaths, we have information on the age of those people in
78 cases. The median age was 78 with an
age range of 36 to 98.
There were six states with cases that were greater than 100
in number. California has 824 so far, Arizona has 102. These together account
for nearly two thirds of all the cases in the United States.
We have been collecting data on screened blood since 2003,
when 6.2 million units were screened.
Eight hundred eighteen presumptive viremic donors were recognized.
Of those, six ultimately developed west nile non-invasive
disease, 137 developed west nile fever, and six were related to transfusion
associated transmission of west nile.
In 2004, 8.2 million units were screened, 224 presumptive
viremic donors were recognized, of which four developed west nile neuroinvasive
disease, 66 developed west nile fever, and there was one transfusion associated
transmission.
In this year, we of course don't know how many will be
screened by the end of the year. So
far, we have seen 375 presumptive viremic donors. Three have developed west
nile neuroinvasive disease, 82 have developed west nile fever, and there have
been no transfusion associated transmissions this year.
Here is the map from 2003 showing that the predominance of
the presumptive viremic donors were in the midwestern and high plains states.
Last year, where we see a little more scattering of where
the presumptive viremic donors were found, although some of the highest density
areas were where the newest activity was in the southwest.
This year, you again see some scattering, but there also
are some little clusters. It looks like the Missouri valley, Texas and
California would be the areas that we have seen the most activity in.
In 2004, again, 224 cases were reported in 29 states --
California, Arizona, Colorado and Texas being the most common places to find
presumptive viremic donors last year.
This year, we have had more presumptive viremic donors --
374 -- in 30 states, with California, Texas, Nebraska and Louisiana being the
most common places to find presumptive viremic donors this year.
During this year we have had six investigations. As of last
night, four are now negative and two are pending plasma return from
Switzerland.
We did have one organ transplantation transmission. In the
past, organ transplantation transmission has also been associated with
transfusion associated transmission.
This year it was likely to be a mosquito borne infection in the donor.
There was potentially a febrile illness in that person, but
that was a history that was not obtained prior to their donation.
Later, again, after there was recognized to be a problem,
it was found that the day before donation, this person was IGM positive for
west nile, although PCR negative.
Three of the four organ recipients became PCR positive, and
two became ill. Here is a quite time line of what occurred.
On the top you see information that was available at these
dates. So, on August 16 there were known to be west nile positive mosquitoes in
a park in the area where this person lived.
On the 23rd, this person was injured and required surgery.
On the 26th, they were declared brain dead, and on the 28th organ recovery and
transplantation occurred.
On the bottom you see information that was available only
after an investigation occurred. It was found that there was a possibility of a
febrile illness before this gentleman's injury, and blood that was recovered
from the 27th of August was found to be PCR negative and IGG positive for west
nile.
In summary, west nile activity has continued over most of
the continental United States. It has continued its westward expansion insofar
as it has increased its presence in many of the counties in the southwest.
The full season of transmission in California occurred for
the first time in this last year. Now human cases have been reported from all
states except Alaska, Hawaii, Maine and Washington.
The risk of west nile virus transfusion associated transmission
remains unknown. We continue to
investigate possible transfusion associated transmissions, as we will next
year. We have only two pending this
year.
As we have seen from this last occurrence, the transfusion
associated transmission is less likely to cause organ transplant related west
nile virus transmissions than it was before we started our work in looking at
the blood.
I would also like to point out that there are some areas of
the United States that appear to be remaining important spots for transmission.
Here the Missouri Valley appears to be a consistent area
since it first became involved in west nile. This may be something that we need
to continue watching.
Each year we learn more about where this organism wants to
live and transmit the most. Thank you. Any questions?
DR. ALLEN:
Questions or comments for either Dr. Nakhasi or Dr. Smith?
MS. BAKER: A
question. Is there any west nile transmission surveillance activity in the U.S.
Pacific jurisdictions?
DR. SMITH: I am
sorry, I don't think I understood that question.
MS. BAKER: We have
the territory of Guam, and there are two other Pacific jurisdictions that are
affiliated with the United States, and three others that are less affiliated. I
wondered if they were involved in surveillance.
DR. SMITH: Puerto Rico is. The others have not been very
active, simply because there is little evidence that it is going to get across
that ocean again very quickly.
Over time, we are going to need to be able to make sure
that they have the capacity for surveillance, but right now, no.
DR. CRYER: Is there
a clinical difference in the course of the disease in the transplant patient
that is immunosuppressed?
DR. SMITH: It
appears so, but it is a little hard to tell because we have had so few to look
at. There is no reason to believe that
all four people didn't receive an organ that was capable of transmitting west
nile virus, yet only three actually seemed to have any evidence that the
transmission occurred.
Of those three, only two people got sick, but one of the
people that did not get sick had a rather prolonged course of having at least
PCR positive blood, and that may not be something that is due to their
transplant, per se.
Just as the blood donor had long-term PCR positive blood,
it is hard to tell whether or not that had to do with transplant or just some
people are capable of having a little longer term viremia. I wish I could tell you more than that.
Those are the things we are looking at, though.
DR. ALLEN: Are
organ donors, at this point, routinely tested for west nile virus in most
circumstances or not?
DR. SMITH: No, the
test that we have been using on blood has only been given an IND for that
purpose at this point, is my understanding.
DR. DUFFELL: I am
curious about your thoughts about the drop in numbers from 2003. Is this an indication that this was almost
like a medical fad at the moment, that people were looking for this, noticing
it and reporting it, and then the interest in it has dropped off? Has the reporting system changed in some way
that might account for the dramatic drop in numbers?
DR. SMITH: It is
difficult to tell, but there does appear to be a point at which west nile
becomes entrenched in an area in a way that it has covered a certain geography,
it is capable of being in the mosquitoes, in the birds, in the humans, but the
majority of people have never seen it.
The majority of birds have never seen it. So, all are susceptible.
Why that decreases, whether it is a change in the
mosquitoes, the birds or the humans is a little difficult. There is certainly
evidence that, once west nile virus is introduced into an area, that people are
much more careful about using mosquito sprays when they go out to garden, and
wearing long sleeves and long pants.
It is also possible that birds become resistant to the
transmission, making it impossible, then, for the mosquitoes to continue the
cycle as efficiently each year.
I don't think it is merely a surveillance artifact. I think
this is a matter of the rather complex work that goes into supporting a
transmission cycle like this in nature.
DR. NAKHASI: I just wanted to make another point here. I
don't think it is that interest in the surveillance has dropped.
I think as you see in the blood area, the testing has been
going on year round, in most of the blood centers. You can see, when you did
the number of cases in 2003 were more than 800, and last year were 224, and
this year a little bit more.
Obviously, it is fluctuating, but what was happening, I
think what Theresa said, that was the first time it was a full blown epidemic
going through mosquitoes, a new population of mosquitoes were being infected
and, once it established, and birds were infected, birds were dying.
It is known in the literature that, once the birds and
other people get infected, they may develop resistance, and therefore you may
see a drop in the human cases.
DR. ALLEN: Other
questions? If not, we do need to move
on. Thank you very much. Our next
presentation, by Dr. Paul Mied, Food and Drug Administration Draft Guidance on
NAT testing for HIV-1 and hepatitis C viruses, testing, product disposition,
donor deferral and reentry.
Agenda Item:
Draft Guidance on NAT for HIV-1 and HCV: Testing, Product Disposition
and donor Deferral and Re-entry.
DR. MIED: Thank you, Dr. Allen. This morning, I would like
to very briefly provide an update on comments FDA has received to the docket
for our draft guidance on NAT for HIV-1 and HCV, testing, product disposition,
and donor deferral and reentry.
This draft NAT guidance for industry was published on July
27, 2005, for comment purposes only. The 90-day comment period closed on
October 25, 2005.
This guidance provides recommendations to blood and plasma
establishments that have implemented, or are implementing, a licensed HIV-1 and
HCV NAT method for source plasma or whole blood.
This guidance contains generalized testing algorithms, to
be used when NAT reactive results are obtained on a pool of samples, or on
individual samples of source plasma or plasma from whole blood donations.
Now, these testing recommendations deal with a NAT reactive
result only, and they are independent of those for serology testing that were
in the 1992 HIV memo, and the 1993 HCV memo to blood establishments.
Currently approved tests on master pools of donor samples,
or on individual donor samples for HIV-1 RNA and HCV RNA may be either
multiplex NAT for the simultaneous detection of HIV-1 RNA, and/or HCV RNA, or
separate NAT tests for the RNA of the two viruses.
Now, the draft guidance includes six different testing
algorithms that cover all of these testing situations.
The recommendations on testing, product disposition and
donor deferral address the actions to be taken when an individual donor sample
is reactive on a multiplex HIV-1 HCV NAT, after a negative antibody screening
test, and when a master pool is reactive on a multiplex HIV-1 HCV NAT, and that
reactive master pool is then resolved down to the level of the reactive
individual donation by testing sub-pools and/or by testing individual donor
samples.
The recommendations also address the actions to be taken
when an individual donor sample is reactive on a separate HIV-1 or HCV NAT
after a negative antibody screening test, and when a master pool is reactive on
a separate HIV-1 or HCV NAT, and that reactive master pool is then resolved
down to the level of the reactive individual donation by testing sub-pools,
and/or by testing individual donor samples.
Now, in the guidance, we refer to an individual NAT for the
separate viruses HIV-1 and HCV, but one of the comments that we received was to
change this terminology to separate NAT, and I found it helpful to do that, at
least for this presentation.
Some of the highlights of the recommendations in the draft
guidance on testing and donor and unit management are, we recommend actions to
be taken regarding the unit and the donor and for look back, product retrieval
and recipient notification, at each point in the testing algorithm.
When an individual donor sample is reactive on a multiplex
HIV-1 HCV NAT, we are recommending deferral of the donor whether or not one of
the discriminatory NAT tests is reactive.
In accordance with a previous recommendation by the blood
products advisory committee, we recommend that a non-reactive NAT on subpools
or on individual donations be definitive for release on all units in those
non-reactive subpools, or for release of those non-reactive individual
donations.
For look back, the recommendations indicate, for product
retrieval only, or recipient notification also, should be done.
Now, here is a generalized algorithm for using the
multiplex NAT, that combines all the testing algorithms that are in the draft
guidance into one algorithm.
It refers to a situation in which, whether you are
resolving a reactive master pool down to the reactive subpool, and then down to
the individual donation level, or you are screening individual donations in the
first place, and you have a reactive individual donation on the multiplex NAT.
Units in all non-reactive subpools and all non-reactive
individual donations may be released, and we recommend running discriminatory
NAT tests on the individual donation, and discarding the unit, and deferring
the donor when one or both of those discriminatory NAT tests is reactive.
When both discriminatory NAT tests are non-reactive -- that
is, when there is a NDR or a non-discriminated reactive result -- we are
offered the option of performing an additional NAT at this point, and
discarding the unit and deferring the donor, regardless of the results of that
additional NAT.
The result does indicate whether you should perform product
retrieval and also initiate transfusion recipient notification when the result
is reactive, or just do product retrieval when the result is non-reactive.
Now, some of the major comments to the docket that we have
received that address the testing and unit and donor management recommendations
in the guidance include a question about the need to investigate each occurrence
of a NAT reactive unresolved master pool, that is, when all of the subpools or
the individual donations subsequently test non-reactive.
Also, a question about the need to defer donors with NAT
reactive results of the individual donation, when both of the discriminatory
NAT tests are non-reactive.
These are the donors with an NDR or a non-discriminated
active result. The argument being made
here is that the vast majority of these NDRs are false positive. There is
also a request for us to define the time frame for look back for HIV and
HCV in this document.
Now, this draft guidance also contains algorithms for donor
reentry for HIV and HCV that combine NAT and serologic test results obtained on
the donor.
This is the recommended reentry algorithm for the three
classes of donors deferred because of HIV-1 test results.
Here is the first class of donors who were individual
donation NAT reactive but serology negative, the second class of donors who
were not non-reactive, HIV-1, 2, combi-EIA repeatedly reactive, western blot or
IFA indeterminate or negative, and the third class of donors, who were negative
on the other tests, but were repeatedly reactive on the HIV-1 P24 EIA, with a
neutralization test that was positive or indeterminate.
We are recommending that, after eight weeks, you conduct
non-donation testing on a follow up sample from the donor, using an HIV-1 NAT
and an anti-HIV-1, 2 EIA.
If the HIV-1 NAT is non-reactive and the anti-HIV-1, 2 EIA
is negative, the donor may be reentered. That is, the donor is eligible to
donate in the future, provided, of course, the donor meets all donor
eligibility criteria.
Some of the major comments to the docket that we have
received that address the recommendations for donor reentry for HIV in the
guidance include the suggestion that there be an additional waiting period for
a donor who tests NAT reactive during that eight week deferral period. We had recommended that that donor be
permanently deferred.
That we clarify the conditions for reentry of donors who
were deferred because of their HIV-2 test results.
That we clarify the requirements for Group O sensitivity
for the individual sample NAT, and for the EIA on the follow up sample, and
that we permit reentry for donors who initially had an invalid or an unreadable
western blot.
This is the recommended reentry algorithm for the two
classes of donors deferred because of HCV test results. Here is the first class of donors, who were
NAT reactive, serology negative, and the second class of donors, who were NAT
non-reactive, HCV EIA repeatedly reactive, RIBA indeterminant or negative.
We are recommending that, after six months, you conduct
non-donation testing on a follow up sample from the donor using an HCV NAT and
anti-HCV EIA.
If the HCV NAT is non-reactive, and the anti-HCV EIA is
negative, the donor may be reentered. That is, the donor is eligible to donate
in the future, provided all other criteria are met.
Lastly, some of the major comments to the docket that we
have received that address the recommendations for donor reentry for HCV in the
guidance include the suggestion that there be an additional waiting period for
a donor who tests NAT reactive during that six month deferral period.
That we clarify the requisite sensitivity for the HCV EIA
used to test that follow up sample, and that an additional six-month waiting
period be permitted for donors who are anti-HCV EIA repeatedly reactive on the
follow up sample, and for whom the RIBA test is persistently indeterminant.
We will carefully consider and discuss these and other
comments submitted to the docket, and it is FDA's intention to revise the draft
guidance and to issue final guidance as soon as possible. I think I will stop
there and take any questions you might have.
DR. CRYER: How many
are we talking about? How many donors
in the donor pool would this affect?
DR. MIED: How many
would be re-enterable? The estimate I
have is about three years old, and it comes from one of the blood
organizations.
We are talking about, assuming eight million different
donors per year, possibly re-entering with these HIV and HCV algorithms, on the
order of 14,000.
For NAT false positivity, it is at about one to 20,000. So,
we are talking about maybe reentering 400 false positive NAT donors out of
those eight million. Again, those are three or four year old estimates.
DR. ALLEN: My
comment, as I have followed this, I think you have done a superb job. It is a very logical sequence.
One can argue about the parameters somewhat, which I think
are reflected in the comments that have come into the docket.
My concern is, have you received comments from people at
the working level within blood collection centers, who are going to have to
apply these, because it is an extraordinarily complex algorithm.
As you go through the process of finalization, I would hope
that would be a consideration that you would seek from the blood collection
industry.
Certainly, one would hope also that the software
manufacturers would try to write this algorithm into the computer based
software that is used in the blood collection centers, that would help simplify
this. I am just concerned with the
complexity of the algorithm.
DR. MIED: Yes, Dr.
Allen, most of the major comments that I showed this morning are from the blood
organizations themselves.
DR. DI MICHELE: I
just have one question. I am just looking at the algorithm for the multiplex
screening that is reactive.
Then we go on to do discriminatory NATS. If they are
non-reactive, it just seems that, if they are reactive, we go on to destroy,
relabel units, notify donors and do look back.
Then, if they are non-reactive for both HIV and HCV, you
either destroy and relabel the units anyway, or perform another sample. Then, whether the sample is reactive or not,
you go on to do the same thing anyway?
Is that correct?
DR. MIED: The
difference there, on the additional NAT, the difference -- the additional NAT,
which they have the option of performing, if that is reactive, they are
performing the full look back, whereas, if they are non-reactive, we only
recommend retrieval of prior collections, and not recipient notification. The difference there also is that a donor who
is reactive on the additional NAT is no eligible for reentry.
DR. DI MICHELE: So,
whether or not they are non-reactive on discriminatory tests, they are still
removed.
DR. MIED: Yes, that
is correct. This is a point of discussion, as I mentioned. The argument is that
the vast majority of these are false positives.
However, we have in the guidance the conservative approach
to defer all of those donors, but they are re-enterable, with the exception of
those who have a reactive additional NAT.
DR. ALLEN: Other
questions or comments? Well, we look
forward to hearing how this continues, and to having another update in the
future.
Our third update topic will be presented by Dr. David
Asher, the FDA summary of the transmissible spongiform encephalopathy advisory
committee, which met on Halloween.
Agenda Item:
Summary of the TSEAC Meeting held on October 31, 2005.
DR. ASHER: And a
frightening experience it was. I was just asked to do this talk on Tuesday, and
I can't summarize eight hours of action-packed committee meeting in 10 minutes.
What I tried to do was put as much of the salient
information as possible into a handout that was provided to the committee.
Unfortunately, I only made 75 copies and I was so tired I
couldn't figure out how to reload the electric stapler, but this will be -- the
other thing I have to warn you is that this is not a cleared presentation. So,
it really shouldn't be cited as authoritative information. A cleared version will be appearing on the
web site.
We had the 18th meeting of the TSE advisory committee on
Monday. There were four issues covered, two interesting informational issues
that time doesn't permit discussing, and two decisional issues.
One is asking advice on further development of a risk
assessment for variant CJD and plasma derived factor 8, an extension of an
assessment that was done for factor 11 in the year.
The second was a discussion of validation criteria and
possible label claims for devices purported to remove TSE infectivity from
blood components.
What I propose to do is to concentrate on the first few
slides, which may need some explanation, whereas the last slide summarizing the
advice of the committee should be reasonably self explanatory from the handout.
What prompts both of these issues, of course, is the
striking observation in the United Kingdom that variant CJD has almost
certainly been transmitted by transfusions of non-leukoreduced red blood cell
concentrates to two of a very small number of recipients, a difference that is
quite striking between this and sporadic CJD, which has never been convincingly
documented as transmitted by blood, although the fear of that exists.
I do want to point out right at the outset that there is no
case of variant CJD in the United Kingdom or anywhere else that has been
attributed to use of a plasma derivative, human plasma derivative, regardless
of the amounts of product used.
There are now 185 cases of variant CJD, the vast majority
of them in the United Kingdom. The concern is that five or six of those cases
have occurred in people in other countries who acquired the infection in the
United Kingdom, one of whom was only there for about 26 or 27 days, and three
days in France.
In addition, there are other BSE countries where exposure
might occur, particularly France, where there have now been 15 cases, several
of whom have been blood donors.
These travelers, of course, carry their infections with
them to their home countries, where they pose some risk of transmitting disease
to recipients of their blood.
As you know, there are deferral policies in place to reduce
that risk for people who spent considerable periods of time in the United
Kingdom and longer periods of time in France and other countries.
In addition, we know that we have had a very small BSE risk
in our own country. There has only been
one native borne cow, over 500,000 sick cows screened.
So, we think the risk of endogenous BSE in this country
must be very small indeed. The main
risk is from people who were exposed in those countries where there has been a
lot of BSE.
To evaluate these risks, Steve Anderson, our risk assessor,
with Hong Yang, has set up a risk assessment breaking down the elements of risk
into four modules.
Two of them involve the source of plasma, the second, the
ability of processing to reduce the infectivity, and the third exposure from
the use of the product.
It turns out that each of these elements is surrounded by
considerable uncertainty and is very difficult to model, and it was to improve
the information to be used in the assumptions for this model that we asked for
advice from the committee.
The prevalence of variant CJD in U.S donors is largely
controlled by the prevalence of CJD in the United Kingdom.
There are problems in evaluating both that prevalence and
our own prevalence. That is, however, a
critical driver of risk.
A second driver of risk is reduction by processing. Plasma pool size does not appear to be a
highly important factor, but reduction by the manufacturing process and, to a
somewhat lesser extent, the amount of infectivity potentially present in the plasma
are important.
In addition, it has been very difficult to estimate --
surprisingly difficult to estimate -- the amount of plasma derivative that an
individual patient has used.
There are two sources of risk in the donor population in
the United States. One is those people who should have been deferred but, for
some reason, were not. The second is those people who are suitable blood
donors, but nonetheless might have been infected.
We know that, if you defer for people who are in the United
Kingdom for three months, that it is possible to be infected in considerably
less than three months. Yet, we can't defer everybody who has ever visited the
United Kingdom, because we would be deferring perhaps 25 percent of blood
donors, and even more in east coast areas.
So, there is an analysis of prevalence in the United States
relative to the United Kingdom.
Estimating prevalence in the United Kingdom turns out to be surprisingly
difficult.
There are two methods that have been used to estimate it,
and they give quite disparate estimates.
One is predictive models based on the number of UK cases actually
observed, and the other is an estimate based on a survey of appendices removed
from patients in the United Kingdom.
The models of the first sort have estimated a maximum, in
more recent estimates, an estimate of, oh, 2,500 cases in the entire United
Kingdom, tops.
Studies looking for the accumulation of abnormal prion
protein in lymphoid tissue of the appendix have predicted about 13,000 cases
incubating variant Creutzfeld Jakob's disease in the United Kingdom.
Those are possibly low estimates, because we know that
earlier in infection the appendix is likely to be negative.
We know that blood of these patients contains the agent as
long as three years before onset of signs, clinical signs, but we don't know
how much longer, and we don't know the exact incubation periods for most
people. Nine to 12 years seems to be a
reasonable number. We don't know the maximum.
We don't know how many people with less susceptible
genotypes might be infected, but we think that some of them surely are
infected, and their blood probably contains the infectious agent as well.
The advice from the committee was to use empirical
prevalence values based on the tissue survey, allowing for preclinical and
subclinical infectious status in donors of all prion protein encoding
genotypes.
Our second source of uncertainty has to do with screening
out unsuitable donors. Estimates from analogous donor screening situations,
like the HIV risk donors, suggested that questionnaires might be as high as 99
percent sensitive, perhaps 90 percent more conservative, but the committee was
quite uneasy about that, and recommended considering only 85 percent
sensitivity of the screening.
They were concerned, as we are, that we have no direct data
about travel histories of source plasma donors. We have been using
extrapolations from a travel survey for doors of whole blood.
Donors of source plasma are younger, give more plasma, are
thought to be poorer, and it would be desirable to have specific data.
Another area of uncertainty is in how much infectivity to
consider potentially present in the blood of donors.
All the information for that comes from animal models. Our
proposal was to consider a minimum of .1 infectious dose per ml -- that is one
dose per 10 mls -- more likely 10 doses per ml, with a maximum of 310, because
that is the highest value in the published literature.
The published literature shows models all over, and to
assume that the blood was infectious from the time that the donor became
infected until the donor died.
Estimates of the actual amount of infectivity in the blood
of rodents, however, tend to cluster together somewhere between two and 30
infectious doses per ml.
This study was from mice, this study from hamsters, that
showed a mean of 10 infectivity appeared about halfway through the incubation
period.
The committee agreed that, based on rodent data, 10 doses
per ml of blood was most likely, and a minimum of 1.1 prudent. They offered mixed advice on upper levels of
infectivity.
Pool size, bimodal with a peak at 20,000, a peak at 60,000,
the committee agreed, and agreed that we use three different ranges for the
reduction in infectivity by different classes of products, anywhere from a
minimum of two log reduction to a maximum of nine log reduction, although that
would be overkill for removing infectivity.
They agreed that the CDC data bases for factor eight use
are the best available data, but they encourage, especially for von
Willobraun's disease, collecting better data, and FDA has a plan for doing
that.
They shared our concern that some experimental data
suggests that cumulative, repeated exposures to small amounts of infectivity
may increase the risk of infection, and of course they could be considered a
model for those users of plasma derivatives who use them repeatedly. They agreed with our plan to estimate a risk
per year rather than a risk per dose.
A special concern to the committee as well as to us is risk
communication. The risk of transmission by plasma derivatives, of course, is
entirely theoretical.
It is very difficult to communicate small and highly
uncertain risks of this sort, and a concern that the notification itself might
cause patient anxiety and health care provider anxiety.
It would be terrible if dentists started refusing to take
care of people with a history of the use of plasma derivatives, simply because
we had told them they were at some small, uncertain risk of this disease, and it
was felt that participation of the patient groups in setting plans for risk
communication would be helpful.
There won't be time to go through the plasma filtration. We
had a very interesting presentation from UK authorities who are going to do
independent evaluation of any European, Council of Europe, marked plasma
component filtration device that is going to be marketed there with a claim for
reduction of TSE infectivity.
They are going to require at least three log reduction in a
spiking study, evidence that at least red cells maintain their functionality.
Three manufacturers, one with a Council of Europe marked
filer, and two with interesting matrices, presented promising results.
The committee suggested a few modifications to our
criteria, greater than three log reduction of spiked infectivity, removal of
all detectable infectivity from endogenously infected animal blood, at least
two animal models using two strains of agents.
One of those should be derived from either a cow with BSE
or a human with variant CJD rodent adapted, and functionality of filtered
components should be demonstrated.
They also noted that it would be desirable to demonstrate
that any device would remove all endogenous infectivity from whole units of
blood from large animals.
At the moment, the sheep is the only large animal
demonstrated to have infected blood, although I think primates will eventually
become available, since bioassays in sheep are generally not feasible.
They felt that, if sensitivity of transgenic mice to sheep
infectivity were demonstrated, they would be an acceptable, although a huge
number of mice would be required, and the expense would be considerable. I
think that I can stop there. Thank you.
DR. ALLEN: Thank
you, Dr. Allen. Questions or comments on this topic? For anyone who is not following it, it is a very complex and
confusing area, but one in which a lot of new data continues to emerge rapidly.
Just one comment quickly. With the order of presentations
to the advisory committee, it should be noted that, already with the
presentation of data on efficacy of filtration to remove the prions from units
of blood or plasma, the work that is being done there, we may have a device
being presented that would claim to reduce risk, before there is any test to
identify risk in the potential units of blood or plasma. So, this presents an
interesting conundrum in terms of regulatory issues.
DR. SZYMANSKI: A
questions about travelers to the United Kingdom who are going to be refused as
donors. If that traveler is a vegetarian, is that considered at all?
DR. ASHER: Yes, the
question is, is a question of vegetarianism considered in suitability of blood
donors. First, let me say that travel
to the United Kingdom after 1996 is no longer considered a deferral factor,
because the agency is convinced that a full range of food chain protections put
into place then should be effective in protecting against significant exposure
to BSE agent.
The answer about vegetarianism is no, it is not considered.
The reason for that is that dietary histories, particularly long after the
fact, have to be considered relatively unreliable.
Also, people have different understandings of what it means
to be a vegetarian. Many people who are self proclaimed vegetarians have, in
the past, consumed beef.
One of the patients in North America came from a family
that, I believe, were practicing vegetarians. So, vegetarianism is a sometimes
thing, and it just can't be evaluated critically in the setting of a blood
program.
DR. NELSON: How
many cases were in the United Kingdom in the last year of the 158?
DR. ASHER: In the
last year, just a handful. The cases are dropping in the United Kingdom.
DR. NELSON: So, the
numbers are still going down, and it seems that the estimate of 12,000 is
perhaps too high.
DR. ASHER: It is
reassuring as far as it goes. The problem is that all the cases in the United
Kingdom, all the clinical cases, have been in people who were homozygous for
methionine at codon 129 of the prion protein encoding gene.
Now, that genotype is known in other forms of CJD to
increase susceptibility in shortened incubation period. The problem is that
people with other genotypes are susceptible to other types of CJD.
The second transfusion transmitted case, who died -- well,
it was a woman who died at, I think, 81 of a ruptured aortic aneurism, had
evidence of preclinical CJD.
The most likely scenario is, had she lived longer, she
would have come down with symptomatic disease, which is what happens with other
forms of CJD in people with those genotypes.
I understand that the last case of kuru was seen in New
Guinea in 1999, and then suddenly they start reporting cases in people of the
less susceptible genotype almost 15 years after the exposure.
How long the blood is infectious in variant CJD in those
people during that period of time is not clear, just another example of the
extreme uncertainties surrounding this.
DR. NELSON: About
40 percent of the population has a susceptible genotype, as I understand it.
DR. ASHER: Has the
most susceptible genotype. The advice of the committee and of the UK
authorities, is to consider all persons potentially susceptible to infection.
Hopefully, the attack rate will be lower and the incubation period will be
longer, but we still have the problem of what to do with infectious blood from
people who are clinically normal. So, it is a mixed picture.
DR. ALLEN: Okay,
any other questions or comments? We
will move on then. Dr. Jerry Holmberg, executive secretary of the advisory
committee on blood safety and availability, will present a summary of the
department's recent meetings.
Agenda Item:
Summary of the DHHS Advisory Committee on Blood Safety and Availability.
DR. HOLMBERG: As
Dr. Asher mentioned, it is difficult to cram a two days presentation into 10
minutes. So, I will try to move as fast as possible.
Just a point of clarification, Mr. Chair. I understand you
wanted a little update on the hurricane response. Is that still desirable, or
should I move forward?
DR. ALLEN: Go ahead
and move forward.
DR. HOLMBERG: Some
of the issues that were discussed at the most recent Advisory Committee for
Blood Safety and Availability were issues relating to the varicella zoster
immune globulin, immune globulin intravenous, and a strategic plan for
improving the blood safety against known and unknown transfusion transmitted
complications in the 21st Century.
As far as the issue with the VZIG, there is a potential
shortfall. There is a use rate of about
200 vials per month, which should probably take us through the end of January.
Also, one of the things that most recently the Advisory
Committee on Immune Practices has recommended, recommendations may lead to the
use of IGIV as an alternate product until there is an availability of VZIG.
That leads me to the next issue that was discussed, and
that is the IGIV issue. I hope you like my slide here. I thought this front
coming in here was a good analogy to what is happening. Is this a perfect storm, or is this just a
market adjustment to the MMA, the Medicare Modernization Act.
I would like to dwell a lot of time on the waterfall here.
This was a picture taken during my trip to Puerto Rico this summer, but I just
put that in there as an analogy of what is really happening in the market
place.
That is one thing, that the BPAC usually doesn't get
involved, or isn't permitted to get involved with the issue of economics, and
basically your charge is to look at the science attributed to the various
products that are put before you.
The Secretary's advisory committee can look at different
aspects, including the ethical use and the economics.
One of the things that we have found -- and I like to put
this as a waterfall or a cascade, is that we have the manufacturers
contributing their products.
We have seen, over the last couple of years, a
consolidation of the manufacturers and also, with the manufacturers, they have
also consolidated the number of distributors.
So, you also have primary and secondary distributors and
then, at the hospital level, you have the distribution of that, to either the
hospital, which is under the reimbursement as the DRGs, the physicians offices,
which are under the part B, and then the hospital outpatient.
Well, if we look at how reimbursement is handled, what we
have is, we have the manufacturers reporting their wholesale and their sales
prices to CMS, and this is on a regular basis, that they are reporting to CMS
for a recalculation.
IGIV is one of the very few drugs that actually is monitored
on a regular basis for price, and it is adjusted on a quarterly basis. Unfortunately, that adjustment lags behind
the quarter.
Most recently, in the medicare modernization act that took
place in January of this year, the calculation was changed to average sales
price plus six percent. As of this
quarter, that is going for a -- liquid is going for $56 a gram.
However, right at the present time, hospitals, outpatients,
are being reimbursed at average wholesale price at 83 percent, which is about $80
a gram.
So, you can see that there is a disparity there and, what
happens, there is going to be a shift in service. So, we have seen a shift in
service.
One of the things also that we identify is that the
distributor in the calculation that is mandated by congress -- and this is a
statutory requirement -- is that the MMA look at the price coming from the
manufacturer and not the distributor.
This is where the problem exists, in that the distributors
are not part of the calculation for reimbursement.
As a consequence, you have the primary distributor for the
manufacturer who is selling under contract and the secondary and gray market
that is selling in a spot market scenario.
If I can put it in a different way, we have the
manufacturers who have been very diligent at increasing their inventories.
In the past, the manufacturers have had months and months
of inventory. In an economic move, they cut back and, for a while, we were
under a yellow light system, meaning that there was about a five week supply of
IGIV.
However, in the last two months, since August, we have
actually had a green light situation, meaning that there is a greater than five
week supply of IGIV.
We also have the reimbursement issue which, as of October
28, the lyophilized was about $45.57, and the liquid was at $56.30. This is for
doctor office reimbursement.
So, as I mentioned before, in the last slide, there is a
shift in service. So, we have seen a shift in service from the physician
offices to the outpatient setting.
Then, on the other side, we have the demand issue. We have
the labeled use of the product. We have the evidence based use, that CMS has
about 30 different evidence based clinical entities that they will reimburse
for, and then you have the non-evidence based use of the product.
We have quite a problem here, trying to address all those
issues. What we have seen, just to quickly go through this -- I have talked
about all of this -- is that the industry has consolidated, there has been a
change in business practice, there has been a market correction, reduction in
inventory, a smaller number of distributors.
What we have found is that there are sufficient supplies of
IGIV for patients who need treatment. I was on the phone quite a bit this week
tracking the various complaints of availability.
Every place that I called said, yes, there is product
available. It is just that when you get it from the secondary or the gray
market, some of the physicians' offices are paying up to $160 a gram.
What we also found was is that it suggests that, under the
allocation system, that the physicians might best serve the patients by
communicating their supply needs directly to the manufacturer, and also ensure
that IVIG treatment is prioritized toward FDA labeled use, and those diseases
are clinical conditions that have been shown to benefit from the use of IVIG
based on evidence of safety and efficacy.
What we have done within the department is we have looked,
or we actually have posted -- this is my web site if you would like to go to
the advisory committee for blood safety and availability.
We do have a statement there on the IGIV. We also have posted the CBER number and a
place where you can report shortages to CBER.
Also, if there is denial of medicare coverage, then that
can be reported directly to medicare. What we also have posted there is a page
from PPTA that lists all five manufacturers with their 800 numbers, and that
will -- each one of the manufacturers has agreed to have an emergency supply
inventory of IVIG.
So, if there is a need, the physician can call directly to
the medical director at the manufacturer, and discuss the case, and request the
product.
As I just mentioned, hot lines have been established. The
department has also looked at the possibility of doing an evidence based
medicine study, and that is still under investigation.
However, we are looking at the CMS reimbursement. We are monitoring the cost. Once again, I
have to say that this is an issue that is statutory.
Congress has said, these are the calculations that you will
use to determine the rate of reimbursement. So, there is very little that we
can do as far as the reimbursement, and right now we are just constantly
monitoring what is the situation.
However, there is an IG assistance in looking at the
problem and trying to identify areas where we can step in.
Well, the committee looked at all that and, after new input
from patients, medical professionals, distributors and manufacturers, the
committee remained highly concerned that persistent disruption in access to
IGIV, which includes a progressive shift to treatment in a hospital, continues
to compromise quality of care to many patients.
In particular, the committee believes the transfer to a
hospital may impair continuity of care by their usual medical provider and may
add otherwise unnecessary cost, logistical complexity, and nosocomial
infectious risk.
The committee further is concerned that a change to the
hospital outpatient reimbursement to ASP plus eight, effective January 2006,
will further aggravate an already difficult situation, and that this shift will
not be sustainable.
They recommended to the secretary that an increased
reimbursement for non-hospital IGIV therapy, to a level consistent with current
marketing practice.
Consider and reclassify IGIV as a biological response
modifier, consider declaring a public health emergency to address short term
problems.
Modify the current plan to change hospital outpatient
reimbursement to ASP plus eight in January 2006, in such a way as to prevent
any sudden or large decrease in reimbursement.
Reexamine whether the current IGIV supplies are meeting
patient needs, and work with congress to establish a long term stable and
sustainable structure.
We are continuing to investigate this. Areas where we can
have impact we are looking at. However, there are some areas, such as what
congress is willing to do, and what congress has already put in the MMA. Whether the MMA is going to be opened up
again for discussion this year is debatable.
The other thing that we looked at was a strategic plan for
the 21st Century. The committee recognized that blood is a critical element of
modern medical care, and ensuring an adequate supply of safe blood is a
national responsibility.
Although there have been dramatic improvements in blood
safety and availability in the United States in the last two decades, the
committee finds that there are compelling needs for improvement in some areas:
Minimizing destruction of the supply, and the supply of
access to blood products and their analogs;
Meeting the product development needs for patients with
rare disorders;
Timely funding to ensure appropriate utilization of new
technologies;
Integrating presently fragmented systems for monitoring
blood safety and availability;
Aligning reimbursement and funding policies with product
approvals and other decisions intended to optimize blood safety and
availability;
Modifying reimbursement policies, as needed, to sustain
access to blood products and their analogs for all patient groups, e.g., IGIV;
Reassessing policies and their related interventions based
on the evaluation of their impacts;
Intensifying efforts -- the committee recommended doing
these things to intensify efforts to influence clinical practices related to
blood transfusion and alternate therapies based on scientific evidence.
Accelerating responses to threats -- patient specimen/unit
misidentification -- for which there are available interventions.
Utilizing formal risk communication strategies targeted to
blood donors, patients and care providers, to enhance scientific comprehension
and public trust.
Also, pursuing opportunities to enhance public health in
the management of blood donors.
Promoting comprehensive disaster planning,including
sustaining the inventories necessary for an effective crisis response.
Establishing a proactive, prioritized and goal-oriented
research agenda, utilizing formal assessment tools more routinely in policy
development and decision making.
Further clarifying the respective roles of government
agencies and the private sector in management and oversight of the blood system.
The plan should include and encompass: structured process for policy and decision
making; integration of blood systems within the public health infrastructure;
surveillance of adverse events related to blood donations and transfusions;
risk communication; error prevention in blood collection centers, transfusion
services and in clinical transfusion settings; donor recruitment and retention;
clinical practice standards for transfusion; strategic research agenda;
disaster planning; stable and sustainable reimbursement; funding for promising
new technology.
I believe I will call it there, but these recommendations
have been forwarded to the secretary for consideration.
If these are approved by the secretary, we will be working
within the department to put together a strategic plan to encompass the
recommendations that the secretary approves.
Are there any questions?
DR. ALLEN: Thank
you, Dr. Holmberg. Questions or
comments? It is an ambitious plan. I assume it is unfunded.
DR. HOLMBERG:
Unfunded and, right now, we have 94 years to accomplish that.
DR. ALLEN: Thank
you very much for the update. Our final
update for this morning will be reentry of donors deferred based on
anti-hepatitis B cor test results.
Dr. Gerardo Kaplan from the FDA will start, and Dr. Susan Stramer
from the American Red Cross will provide a brief statement also.
Agenda Item:
Re-entry of Donors Deferred Based on anti-HBc Test Results.
DR. KAPLAN: Good
morning. I will give you an update on reentry of donors deferred on anti-hepatitis
B cor test results.
The issue here is that the FDA would like to update the
committee on the proposed algorithms that will allow reentry of donors deferred
for testing repeatedly reactive for antibodies to hepatitis B cor antigen on
more than one occasion.
As a historic perspective, the 1991 guidance indicated that
donations for transfusions should be tested for anti-hepatitis B cor antigen.
Only negative units should be transfused.
The donor should be indefinitely deferred when they tested reactive
more than once, and that reentry algorithms were not recommended at that time,
because there was no supplemental test for anti-hepatitis B cor.
One of the main consequences of the screening was that
anti-hepatitis B donors contribute to the safety of the blood supply.
However, many donors have been indefinitely deferred
because of potential false positive anti-hepatitis B results.
The considerations for reentry is that reentry will be
permitted only on the premise that historical tests for anti-hepatitis B cor
antigens were false positives, and that there is no evidence for past or
present hepatitis B virus infection.
In a 1999 BPAC presentation, the FDA and AABB presented to
BPAC similar reentry algorithms, based on negative test results for surface,
anti-cor and anti-hepatitis B surface antigens.
The committee did not recommend reentry because some of the
American Red Cross data showed that there were some hepatitis B surface antigen
and hepatitis B cor negative samples with hepatitis B DNA reactives, using an
experimental NAT.
There was another BPAC presentation in a 2004 meeting,
where FDA presented to BPAC the following reentry algorithm, based on test
results for surface, anti-cor, and hepatitis B NAT.
The committee did not vote on the proposed reentry because
there was a lack of data to evaluate its use. This algorithm basically said
that, although the donor has been indefinitely deferred because of having
tested repeated reactive for anti-cor on more than one occasion, there may be
reentry if, after a minimum of eight weeks subsequent to the lest repeat
reactive anti-cor test, a new sample is collected from the donor and these
samples test negative for the three markers, basically surface antigen,
anti-cor, and hepatitis B NAT in FDA licensed assays.
When a donor presents at the blood center to donate,
subsequent to the negative test for, again, the three markers -- surface
antigen, anti-cor and hepatitis B NAT, and all donor suitability criteria for
donors of whole blood and components are fulfilled.
The good news is that companies have developed two key
tests, and the FDA has approved them.
There was an approval in April of 2005 of the Roche Cobas AmpliScreen
hepatitis B NAT for screening donations in mini-pool and individual donation format.
Roche also presented some data to BPAC indicating that it
is possible to enhance the sensitivity of the ID test.
FDA also, in October 2005, the Abbott PRISM anti-cor test
for screening donations was approved. This test uses a different technology
than other currently licensed assays, and could be used for the reentry
algorithm.
So, the FDA is looking forward to reviewing that data to
validate the proposed reentry algorithm for anti-hepatitis cor repeat reactive
donors, and the good news is that today we are going to hear a talk by Dr.
Susan Stramer from American Red Cross, and she will provide some of this data. This concludes my presentation.
DR. ALLEN: Very
quickly, any questions for Dr. Kaplan at this point? Okay.
Agenda Item:
Re-entry of Donors Deferred Based on anti-HBc Test Results.
MS. STRAMER: Good
morning. While my handouts are being handed out and we are loading my
presentation, I will thank the committee for this opportunity to present an
update of what I presented at the October 21, 2004 BPAC, and also to declare my
conflicts of interest.
I am a current employee of the American Red Cross, and I am
a former employee of Abbott Laboratories and, as such, I still have Abbott
stocks, but that shouldn't influence my judgement of scientific data.
I would like to first acknowledge my collaborators at
National Genetics Institute, NGI, and Abbott Laboratories. As I mentioned, this is an update from the
October 21 meeting of last year, about a year ago.
So, the questions -- so, relative to what I presented in
October, the historical and current repeat reactive rates for FDA licensed
anti-cor tests range from .4 to 1.6 percent. This is basically a historical
number.
False positivity, as already mentioned, is high on these
tests, ranging from 25 to 87 percent reported, varying depending on the
specificity of the test used.
As mentioned, there is no confirmatory or supplemental test
available, and as such, we have a two time allowance for donors to donate and
be repeat reactive before they are permanently deferred.
I presented last time the impact of a repeat reactive
notification on first time donors, and whether this prevents them from
returning for their second donation.
If you look at what the Red Cross has in our data base for
the numbers of anti-cor deferred donors, who lack other markers for deferral,
from the period of time that we have formal tracking, it is greater than
200,000.
If you go back to the numbers since February 1987, and try
to estimate a nationwide number, we know there is probably greater than a half
million.
So, the question is, can an algorithm be validated to
reenter deferred donors who are falsely anti-cor reactive. If so, what would be
the yield of such a reentry algorithm.
BPAC, last October, did provide unanimous support for the
validation of the reentry algorithm as provided by FDA and outlined by Dr.
Kaplan.
We will test a follow up sample greater than or equal to 56
days by a highly sensitive HBV NAT, or DAN assay, having less than or equal to
10 copies per ml.
We also would retest the sample by a second or more
specific anti-cor assay. We would, of course, also do an FDA licensed, HBSAG
assay, and all tests must be non-reactive and the donor have no other causes
for deferral, and the donor would then be eligible for reentry.
What I showed at the last BPAC, relative to how successful
reentry would be based on the same test, what I used was a model saying how
many donors were one time reactive, and then came back a second time and were
reactive again.
So, looking at a data base from the year 2000 that included
6.5 million donations from about four million donors, the overall repeat
reactive rate at that time was 6.4 percent.
The important point here is that 75 percent of donors who
were reactive one time because two times reactive on their next donation, with
another 13 percent accrual over the next three years.
That doesn't bode very well for the efficacy of the two
times reentry algorithm based on the same test. If you look at the split
between first time and repeat donors, one would assume that, in these first
time donors, most of these represent true HBV infection.
These represent probably an overall mixture of false
positivity as I mentioned, and true positive HBV infection.
So, what we -- the AABB and the industry -- had recommended
was that an anti-cor reentry algorithm would be projected to have a higher
yield if a different test was introduced.
The blood system would then have to convert to that new
test, rather than testing these donors over and over again with the same tests,
and finding the same false positives.
This slide shows you the repeat reactive rate over about
the last 10 years at the Red Cross. We are running now at about a .4 percent
repeat reactive rate. That is for all donors.
Over time, the repeat reactive rates have come down
significantly. So, we have culled out
the true positive donors and, since most of our donors are repeat donors, that
is possible.
Now, one interesting piece of information is, if you switch
tests, how much of your false positivity will be reduced.
So, this slide was provided to me by Hema-Quebec, courtesy
of Dr. Gile Delage. It shows you here
that, when they introduced HBC screening in Quebec, they introduced it on the
Ortho platform.
Then, in April, they converted to the Abbott PRISM platform
What you can see, if you take an overall mean, after a first culling period and
then a stabilized repeat reactive rate of just under one percent, they convert
it to PRISM and then they stabilized it just under .6 percent for .4 or 40
percent decrease.
You can see that there was quite an impact by changing
tests, and this is actually the test, the European version of PRISM that does
not contain the reducing agent that eliminates false positivity.
So, what we did, in 2001, to look at the possibility and to
follow up, do anti-cor donors really have DNA associated with them, we took
3,000 anti-cor repeat reactive unlinked donations, and we tested them for HBV
DNA and NGI.
These were surplus NAT samples. So, they were handled under
proper conditions, and to limit contamination. The criteria for inclusion was
non-reactive by all other test methods.
There was no pre-selection for first time or two time
anti-cor repeat reactives. We just took the tubes out of our NAT laboratories.
From projections of numbers of donors who were two times
reactive, of this 3,000 -- which is why I chose a large number -- it was to
enrich the population so we would have enough donors in here who represented
truly deferred donors, and we would project 708 of these 3,000 were actually
two time cor-deferred donors.
So, when we tested these samples on the NGI net, ultraqual
assay, the eight reaction test -- that is, the sample is extracted and
processed eight times.
We used a .2 ml input and, if there is reactivity in any of
the eight tests, the test is interpreted as positive.
The sensitivity was 9 IUs per ml, which converts to 31
copies per ml. We saw 19 of 3,000, or just under one percent, samples reactive.
The samples had low reactivity for DNA. Eleven of the 19 had less than 100 copies
per ml. With an average of the eight
reactions, how many were positive? An
average of just under two.
Eight of the 19 samples had viral loads between 100 and 500
copies per ml, with about a 300 copy per ml mean, and the average number of
reactions of the eight reactive was just about five.
So, in red, this slide is shown frequently. It shows you
how this data, the .3 percent anti-cor positive rate, compares with other
published studies, either the Roche clinical trial or a rat study showing what
the frequency of DNA positivity is in isolated anti-cor reactives.
So, the purpose of me standing here today is to tell you
the updated results when we tested these 3,000 samples which were characterized
by DNA testing.
When we tested them by the Abbott PRISM anti-cor assay,
using the licensed lots -- that is, post-licensure, which Gerardo said just
happened, so these data are hot off the press, I just got the data last night.
The study was initiated following the qualification of the
samples and PPTs, which hadn't been qualified on the PRISM system previously,
and availability, as I mentioned, of licensed lots.
The assumption going into the testing is that the 19 HPV
DNA positives that I mentioned would all be PRISM anti-cor reactive.
Also, what we wanted to know was, how many eligible donors
we would yield for reentry after testing the anti-cor non-reactive. That is, how many samples would be anti-cor
nonreactive by the PRISM and were DNA negative.
This testing, as I mentioned, is completed. We are doing
further studies to investigate anti-cor IGM reactivity of the cor reactives,
and to look at anti-surface for scientific interest, as sample volume allows.
So, these are the results. If you look at the NGI sample
tests, we tested 3,000 samples. Actually, it came out to 2,999. I am off by
one. Seven were QNS for the PRISM
testing, leaving a total in this table of 2,992.
In red are the NGI DNA positive results, and all 19 were
positive on PRISM cor. All 19 were
strongly positive for anti-cor antibodies on the PRISM assay. The mean S to CO
was a .14.
I should mention, in the PRISM test, which is a competitive
inhibition assay, sample S to COs less than or equal to one are reactive.
Sample S to COs greater than one are negative. So, here you look for a low
signal to cut off ratio.
So, a .14 is a very strong mean, and the range of these 19
samples, their PRISM reactivity ranged from .02 to .49.
Of the samples that tested DNA negative, what were the
PRISM results? Eighty percent of the
total actually retained reactivity by PRISM.
So, using the Ortho test, as we do, in combination with the
PRISM test, we only have 21 percent of donors who were deferred due to anti-cor
reactivity, who would be predicted to be eligible for re-entry if they passed
the follow up testing.
These are the 19 samples. Although you might not be able to
see this, I highlighted in red -- these are the triplicate signal to cut off
ratios, initial reactives are repeated in duplicated.
The values are very consistent, and the values above .14,
which was the mean, are highlighted in blue, and there were only five such
samples.
So, in summary and to conclude -- and then I just have one
more slide after this -- preliminary data indicate the feasibility of an
anti-cor reentry algorithm.
That is, all 19 HBV DNA positive samples were detected as
reactive by PRISM anti-cor assay. All 19 of these samples were strongly
anti-cor reactive, and I already highlighted their reactivities.
The caveat of this study is that the yield of reentry is
probably dependent on the prior assay. I showed you, for our 1X, 2X anti-cor
deferral study, that we only yielded 25 percent for going from Ortho to Ortho.
In this pilot study, I only showed you a 21 percent yield.
Then, from the Hema Quebec study, I showed you a 40 percent yield going from
Ortho to PRISM.
I don't have any data, if you were using the prior Abbott
EIA called Corzon, what that yield would be going forward, going to PRISM.
I would like to just end with subsequent studies other than
completing the study I just described. Currently we are doing a study of
anti-cor repeat reactive samples with the National Genetics Institute, that is
testing them all for HBV DNA.
Of approximately 5,000 deferred donors that we had over the
last year -- that is, 2X cor reactive with anti-cor as their only deferral
criterion -- we have invited these 5,000 donors to provide a follow up sample
under NGI's HBV IND.
This was before the FDA had the proposed algorithm. So, we tested these by HBV DNA, HB SAG
anti-cor, Ortho, anti-cor, and the PRISM anti-cor results are pending, as well
as anti-HBS.
A study similar to this we will convert to the Roche's IND
using the more sensitive method that Gerardo presented.
Of these study results to date, only 10 percent -- again,
relatively low yield -- of these 5,000 deferred donors have provided a follow
up sample.
Sixty-six percent, or numbers that are consistent with
those I have shown, do have evidence of past HBV infection, leaving 44 percent
eligible for reentry, assuming they don't show reactivity on the PRISM test.
Due to low participation rates, if you multiply out all the
numbers, our yield of these 5,000 donors has only been a reentry rate of 4.4
percent. That is all the comments I
have. Thank you.
DR. ALLEN: Thank
you, Dr. Stramer. Questions or comments either for Dr. Kaplan or Dr.
Stramer? This is certainly good to have
this data, and I think at least I am a little surprised by the results that you
just presented.
DR. STRAMER: The
relatively low yield?
DR. ALLEN:
Yes. As you said, the science is
the science. So, that is very good, and we continue to learn more about
hepatitis B infection.
DR. NELSON: Are
donors now being screened for cor using PRISM?
DR. STRAMER: No,
the PRISM cor test was just licensed on October 13.
DR. NELSON: So,
presumably they will be.
DR. STRAMER: Yes,
some blood centers are gearing up. The
first date of implementation that I heard was December 5, but you know,
validation, et cetera, et cetera, is required.
DR. ALLEN: Other
questions on this topic?
DR. SZYMANSKI: I
just wanted to point out that anti-surface hepatitis B surface antibody is not
a reason for deferral, whereas the cor antibody is, I guess, because then you
have more infectivity present if you have anti-cor antibody.
I just have noticed that sometimes our donors who have been
recently vaccinated for hepatitis B also converted to anti-cor positivity.
DR. STRAMER: That
is probably because they were vaccinated having had prior HBV infection, and
this is a secondary or amanastic response to the vaccine. That has been seen
before.
DR. SCHREIBER:
Another elegant presentation, thank you, Susan. What the time between them being invited
back for the re-testing and their initial tests?
DR. STRAMER: For
the 5,000 in the last slide I showed?
DR. SCHREIBER: Yes.
DR. STRAMER:
Immediately. Certainly, when we are inviting them back for a study, the
message we can give them is not as strong as saying, if you come back for the
study you may be re-enterable.
So, moving forward, hopefully after we do the validation
studies and we are doing this real time, hopefully our yields will
improve. The regions, to do a study,
aren't that excited, as they would be to get their donors back.
DR. NELSON: I wonder if anybody has ever done a study where they do repeated DNA testing
on a cor? In other words, the levels
may be fairly low, but I wondered if they bounce around, those that are PRISM
positive.
DR. STREAMER: Most
likely they do, but in the reentry algorithm, they would have to be
nonreactive, by the anti-cor.
DR. ALLEN: That is probably
a study that is more likely to be done in the future than to have been
accomplished in the past, and perhaps could be done on the reds data or other
sources.
DR. NELSON: There
may be some PRISM false positives as well.
DR. STRAMER: Of
course there will be. There is no test
without false positivity.
DR. ALLEN: An
important object lesson to take on. Okay, we will bring this committee update
session to a close. We are, at this point, running almost a half an hour
behind. Good discussion.
I am going to turn the gavel over to Dr. DiMichele for the
next session after a 10-minute biological break. Please keep your discussions
to a minimum. Back in here ready to start in 10 minutes.
[Brief recess.]
DR. DI MICHELE:
Good morning, everyone. My name is Donna DiMichele. I am a committee
member and serving as the chair for this particular session.
In that capacity and without further ado, I would like to
ask Dr. Elliott Cowan to provide the introduction and the questions to the
committee on our topic for this morning, which is approaches to
over-the-counter home use HIV test kits.
Agenda Item:
Approaches to Over-the-Counter Home-Use HIV Test Kits. Introduction and
Questions to the Committee.
DR. COWAN: Thank
you very much. I think I am stating the
obvious when I say there has been considerable expectation surrounding this
meeting, and for good reason.
Knowledge of one's HIV status is one of the most important
weapons we have against the epidemic, and HIV tests and testing are at its
core.
As we begin what promises to be an extraordinary session, I
wanted to make clear from the outset why we are here.
Within the past several months, a sponsor approached FDA to
market its HIV test kit for home use. In response, FDA is taking a carefully
measured approach.
As a first step, the agency felt that input on what
information should be provided to validate a home use HIV test kit is critical
to our decision making process, and that input is necessary before we consider
over-the-counter claims for HIV home use test kits.
For that reason, we are bringing those issues before the
BPAC in this public forum. Let me be clear, however, that consideration of HIV
test kits for home use is a multi-step process.
Contrary to what you may have seen or heard recently, we
are not going to be evaluating an HIV test for approval today.
An evaluation will come in the future only after we have
established the criteria by which to evaluate these tests for their intended
use, and when a company decides to apply for over-the-counter status.
At that point, the FDA will determine if the test kit meets
the statutory and regulatory requirements for approval, determining that the
device is safe and effective for its intended use. That analysis will be a determination of whether the benefits
outweigh the risks.
Let me turn, then, to the matters at hand. The purpose of
this session is that FDA is seeking advice regarding the conditions necessary
to support the approval of a home use HIV test kit.
In particular, we are asking the committee to consider what
studies are needed to validate test accuracy, test interpretation and medical
follow up based on the provision of informational material in place of a
trained test operator and counselor.
My role is to provide an introduction to this session to
orient you, the committee. To do this,
I am going to give you information on prior public discussions of home use HIV
tests, a history of point-of-care testing for HIV, concentrating on rapid HIV
testing, issues to be addressed for home use HIV test kits, an overview of this
session, and finally the questions that you will be considering at the end.
Let me start with some definitions. Home use tests are
tests that are used at home by untrained persons without the help of a health
care professional.
There are two types of home use tests. The first is a home use collection kit, in
which you take your own sample, mail it to a laboratory and get your result
over the phone.
There are also home use test kits, and these are those in
which you take your own sample, test the sample, and read your own test result.
There are some currently approved home collection kits, and
those include tests for detection of hepatitis C infection as well as HIV. I
will come back to the HIV in just a couple of minutes.
There are home use test kits which are for fecal occult
blood, glucose, cholesterol, pregnancy, prothrombin time, just as a few
examples.
At the same time, I need to let you know that there are no
previously approved home use test kits for infectious diseases.
Again, home use test kits are different from home use HIV
collection kits. For the home use collection kit, the specimen is collected by
the test subject, the test is performed and interpreted by a trained operator
in a certified laboratory, and the individual asking for testing receives live
counseling.
In contrast, with a home use test kit, the specimen is
collected by the test subject and, in this case, the test is performed and
interpreted by the test subject.
So, there is a lack of trained operator, there is lack of
live pre-test counseling and post-test counseling at the time that the test
result is provided, and there is a lack of medical referral.
Let me turn now to some of the previous discussions that we
have had in considerations of home use tests.
Starting in 1986 -- you can see there is some history here
-- companies first expressed interest in developing and marketing home use
blood collection kits for HIV testing.
At that time, FDA and AIDS advocacy groups raised public health
concerns about test accuracy in the hands of untrained individuals, and the way
users would be notified of their test results, particularly centering around
areas of patient confidentiality, and adequacy of telephone counseling.
Counseling is a central issue. It is deemed critical to
ensure that HIV infected people understand what HIV infection means, and
receive important information about recommended treatment and coping methods.
In March of 1988, FDA notified, by letter, manufacturers
and other interested parties, of requirements for the approval of these test
systems, and this was based on consultation with U.S. public health agencies,
our sister agencies, and public sector advisory groups.
This led, in February 1989, February 17, 1989, to a Federal
Register Notice, in which FDA published its criteria for HIV specimen
collection systems, and stated that these systems would be available only for
professional use, and that results of testing should be reported to public
health care providers for reporting an interpretation of the test result to the
person requesting the test, as well as counseling the individual. In other words, the test result was not to
be reported directly to the individual.
There were other requirements as well, such as use of licensed HIV tests
and some other requirements.
In this Federal Register notice, there was also an
announcement of a public meeting to discuss the collection and shipping of
blood specimens by lay persons, return of results directly to the person from
whom the sample was collecting, counseling outside of the medical health care
environment, availability of blood collection systems over the counter, as well
as kits for collection and home testing of blood for evidence of HIV infection.
The meeting was held on April 6, 1989. At this session, invited speakers spoke to
the issues of regulatory issues.
We heard from CDHR, the Center for Devices and Radiologic
Health, their experience in home testing, speakers on counseling, ethical
issues, as well as experience among the states.
There was extensive discussion on risks and benefits of
blood collection kits and home use test kits, which I will get to in more
detail a little bit later.
This led, in turn, to a Federal Register notice on July 30,
1990, in which FDA had stated that they had considered the data and comments
from the April 1989 meeting and, on the basis of that, decided that HIV
specimen collection kits should remain for professional use only.
At the same time, we stated our willingness to work with
manufacturers on requirements for premarket approval application to review data
for home collection kits, opening a door.
That same month, BPAC met to consider the approval of a
premarket approval application from a sponsor for its home collection system.
The committee recommended against the approval of that
particular application, citing the fact that the application lacked sufficient
data, and the questions remained regarding possible problems with a variety of
issues, including confirmatory testing, the counseling issues, as well as
compliance with state requirements in maintaining confidentiality.
Between 1990 and 1994, FDA discussed over-the-counter
specimen collection kits extensively with other public health service agencies,
and also with product sponsors.
During that time, there was a change in circumstances. We
saw advances in technology which translated into a potential for improved
accuracy of these tests.
We saw a change in treatment methods. We saw the
availability of therapy for asymptomatic individuals, so that people who had a
reactive test result have the ability to be treated and to maintain a life with
infection.
We also saw the public's increasing desire for greater
involvement in personal health care decisions.
In June of 1994, BPAC met again to reexamine home use specimen
collection systems, and there was an agreement that there was a benefit to
having alternative means of reaching previously unreachable populations for HIV
testing, and that that outweighed the potential risks of such a system.
At the same time, concerns were expressed about
accessibility of a home use specimen collection kit for target groups, adequacy
of counseling, while maintaining confidentiality. and effectiveness of
education and follow up.
There was a recommendation from BPAC At the time for pilot
studies to evaluate these studies. One
more Federal Register notice.
On February 23, 1995, FDA notified the public that it was
revising its guidance for specimen collection kits labeled for HIV antibody
testing set forth in the February 1989 notice, that over-the-counter specimen
collection kit systems may be approvable, and listed specific kinds of data
that sponsors would need to submit for the review of the safety and
effectiveness of these products.
However, it did not address kits for home testing, home
test kits, in other words, for evidence of HIV infection.
This notice led eventually to the approval of two home
specimen collection kits in 1996, one of which was the original test that BPAC
had considered in 1990.
So, what has changed since 1995? One is the technology. We now have tests that have an extremely
low risk of an incorrect result, and tests that are unaffected by changes in
operating conditions or conditions that could affect the integrity of the
specimen.
These tests are simple to use. They don't require special
storage conditions. The results are available within 20 minutes and, in one
case, uses an oral fluid specimen, which would eliminate concerns that were
previously expressed concerning biohazardous conditions. In other words, there
is no blood to be collected and no sharps.
We also have more experience with these tests in non-traditional testing
settings.
There is the concept that early detection translates into
better outcomes. Again, with the increased availability of treatment regimens,
early identification before the onset of symptoms can translate into better
outcomes. Finally, there are changes in
social awareness of HIV infection.
Let me turn now to some nuts and bolts of HIV testing.
Traditional HIV testing requires two visits to a clinic or health care
provider, one to provide the sample and the other to receive the test result,
normally about a week later. It could be a little bit less, or it could be up
to two weeks.
CDC has estimated that each year approximately 8,000
positive individuals do not return to receive their test results.
Contrast this with point of care testing, in which the test
provides a test result in a relatively short time, so that only a single visit
is required.
These tests come under the category of what we refer to as
rapid HIV tests, again, tests that provide results within 20 minutes, require
few steps to perform, have a visual readout, no special storage conditions or
instrumentation is required. They detect antibodies to HIV, and these tests are
used for diagnostic purposes only, not for blood donor screening. At this point in time, FDA has approved four
tests in this category.
The performance standards for rapid HIV tests were
discussed at yet another BPAC meeting on June 15, 2000. Performance standards,
and the clinical trial and non-clinical requirements were discussed and
concurred upon by BPAC at that time.
In terms of performance, it was determined that the
sensitivity of these tests should be 98 percent, as well as a specificity of 98
percent.
The important consideration here is that this is a
statistical number. Ninety-eight percent is the lower bound of the 95 percent
confidence interval. It is not a point estimate.
This translates into tests that are very accurate. The next two slides are going to give you
some examples regarding the four tests that are available now.
So, the four tests that are available are OraQuick from
OraSure, Reveal from Admira, Unigold from Trinity Biotech, and Multispot from Biorad.
Looking at the numbers here, with the different types of
specimens that could be analyzed using these tests -- whole blood, plasma,
serum, oral fluid -- you can see greater than 99 percent sensitivity, and these
figures are point estimates from clinical trial data that were submitted in
support of the product approval.
Likewise, for specificity, the numbers are exceptionally
good, specificity being the ability of the test to tell someone he or she is
not infected when that is truly the case.
Regarding the interpretation of these tests, a non-reactive
rapid test result is considered to be a negative result or, as a reactive
result, is considered to be preliminary positive.
That is, all reactive results should be confirmed using an
appropriate supplemental test, and this is consistent with the concept that FDA
has abided by over the years that, although screening test results are highly
accurate, the test results should be confirmed by supplemental testing.
In discussions on the role of rapid HIV tests in
facilitating HIV testing, it was recognized that, even though these tests were
simple to use, it is critical that a quality management system be in place to
assure that testing was being performed properly, and you will be hearing more
about this later from one of our speakers.
With an eye to this, and with concerns that rapid HIV tests
could be used improperly, FDA approved rapid HIV tests with a series of sales
and use restrictions.
The first is that sale is restricted to clinical
laboratories that have an adequate quality assurance program, and where there
is assurance that operators will receive and use the instructional materials.
Secondly, the test is approved for use only by an agent of
the clinical laboratory, that is, they are not approved for self testing.
Test subjects must receive a subject information pamphlet
and pretest counseling prior to specimen collection, and appropriate counseling
when test results are provided.
These tests are not approved to screen blood or tissue
donors, and a customer letter is included with all kits that are purchased
which states, by purchasing this device, you are doing so as an agent of a
clinical laboratory and agree that you or any of your consignees will abide by
the restrictions on the sale, distribution and use of the device.
Access to rapid HIV test has been an issue that has been
discussed also over the years, and the central question here is who is
permitted to use these rapid HIV tests.
This is governed by something referred to as CLIA, the Clinical
Laboratory Improvement Amendments of 1988.
What CLIA does is, it categorizes tests on the basis of their
complexity.
So, tests can fall into one of three categories, high
complexity, moderate or waived. Waive tests are free of many of the requirements
under CLIA for oversight, when these tests are run.
To perform CLIA waived tests, the entity must do one of
only a few things. One is, enroll in the CLIA program, obtain a certificate of
waiver, pay a biennial fee, follow the manufacturer's instructions, and meet
state requirements.
Contrast that with moderate and high complexity tests in
which there are requirements for training for each of the individuals who are
running the tests, as well as a number of other requirements, including
inspections of the facility.
The sponsor must apply for CLIA waiver. It is not granted
automatically. An application is made to FDA after initial approval, and
results of studies must be supplied to demonstrate that the device is simple
and accurate in the hands of intended users.
By the way, CMS, the Center for Medicare and Medicaid
Services, is also involved in the CLIA and is involved in the inspections and
much of the program as well.
As far as the HIV testing goes, what is the impact of CLIA
waiver? What it has the potential to do
is that, again, subjects can be notified of their test result without the need
to be recontacted or the need for a second visit, and fewer laboratory
restrictions permit potentially wider use.
BPAC discussed this issue on June 14, 2001. There are now two tests that have received
CLIA waiver, each of the two tests for two different types of specimens.
OraQuick has received a CLIA waiver for its use with whole
blood, which was granted on January 31, 2003.
Subsequently, for use with oral fluid, on June 25, 2004.
The Trinity Uni-Gold test was granted a CLIA waiver for use
with venepuncture and finger stick specimens as well. On your handouts, there
is a bit of a typo. The second Uni-Gold
reference should read finger stick, instead of another venepuncture.
I should also make mention of the fact that the sales and
use restrictions, which I was discussing before, also apply to the CLIA waive
tests.
Now, turning to some of the recurring themes that we have
heard over the years -- and you will be hearing more about this, I am sure,
over the course of the day.
There are a number of benefits. Number one is, anonymous
testing potentially leads to more people knowing their HIV status.
Secondly, earlier diagnosis can translate into earlier
intervention and better outcomes for the patient. The home use test kit would
empower consumers in making their own health are decisions.
There is the potential impact on behavior and public
health. In other words, knowledge of HIV status can lead to change in behaviors
that would have resulted in infections, thereby limiting the spread of the
virus and having a potentially significant impact on public health.
There are also, of course, a number of risks that have been
repeatedly coming up over the years regarding home use HIV test kits.
Inappropriate use of the test or test result. It is
absolutely critical to understand the limits of HIV tests.
In tests that we are discussing here, these are tests that
detect the presence of antibodies to HIV.
These antibodies are a response to the infection by the immune system of
the individual, and this response can take about two months.
Therefore, an individual concerned about a possible HIV
exposure within a week could very well be infected with HIV, but would test
negative.
Actually, there is no approved or licensed HIV test that
has the ability to detect infection within a week after exposure.
Continued high risk behavior with a false sense of security
of the negative test result would then result in transmission of the virus to
others.
There is a potential for adverse outcomes obtaining a test
result without live counseling. Concerns have been expressed over the years
about the psychological effects of receiving a positive HIV test result without
the benefit of live counseling. The
biggest issue that has come up repeatedly is suicidal tendencies.
Follow up. Testing
in the home leaves the decision to seek confirmatory testing and medical care
up to the individual, rather than facilitate it through a counselor. Also critical is the need to notify partners
so that they can be tested as well.
There is the issue of coercive testing. Concerns have been
expressed about testing people against their will, for example, by insurance
companies or employers. Also, forced
testing by abusive spouses or family members could potentially lead to violent
back lashes.
Another issue is testing by minors. This is not testing of minors, but testing
by minors, the ability of a minor to go out and purchase a test, and the
question is whether a minor is able to handle the test result, or properly
interpret the test result when it is achieved.
A few additional issues, obtaining a test result without a
supplemental test. The false positive
rate is very significant in low prevalence populations or when there is little
risk present.
The availability for those who need the test the most, and
a potential conflict with state and/or federal health reporting requirements.
As I close my introductory remarks, I would like to set the
stage for you, so that you will know what you are about to hear.
What we have done is arrange for speakers to address issues
that FDA feels are key to considering HIV test kits for home use.
You will first hear a proposal by OraSure Technologies for
an over-the-counter claim for its OraQuick Advance Rapid HIV-1, 2 Antibody
Test, for use with oral fluid specimens, including proposed studies to validate
adequate performance in the hands of intended users.
What will also be addresses is the populations that would
be studied, and will they be reflecting intended users of the tests, as well as
the ability of informational materials to provide counseling and other
information in a comprehensible manner by intended users, addressing such
issues as accuracy of testing, correct test interpretation, management of
psychological and social issues, and medical referral.
You will be hearing a discussion of changes in HIV testing
practices and counseling recommendations from Dr. Bernard Branson from
CDC.
You will be hearing from Dr. Devery Howerton, also from
CDC, who will speak to the role of quality systems for diagnostic tests.
You will be hearing from Dr. Joseph Inungu from Central
Michigan University, who will address psychological and social issues
associated with HIV testing and HIV home use tests.
You will be hearing an overview of the over-the-counter
review process and human factors consideration by Arleen Pinkos from our sister
center, the Center for Devices and Radiological Health, and the Office of In
Vitro Diagnostics.
Finally, you will be hearing from the public. You will, no doubt, hear passionate
arguments on all sides of these issues.
I ask that, while considering all of the information that
you will be presented with today, you do so keeping in mind the need to address
the following questions:
Number one: Are
FDA's previously established criteria for sensitivity and specificity for rapid
HIV tests also appropriate to support OTC use for home use HIV test kits.
Number two: Please
comment on the design of clinical studies necessary to validate the safety and
effectiveness of an over-the-counter home use HIV test kit.
Finally, number three: Please comment on the proposed
content of the informational materials and the steps that should be taken to
validate the adequacy of the informational materials to communicate or provide
pathways to adequately address issues including: accuracy of testing; correct test interpretation; the importance
of supplemental testing for confirmation of positive results; management of
psychological and social issues; the availability of counseling; and medical
referral.
I am going to be returning to these questions, of course,
later -- it may be much later -- to assist you in addressing these questions,
which the heart of these questions is, what is needed for the validation of
these systems. Thank you very much in advance for your input.
DR. DI MICHELE:
Thank you, Dr. Cowan. Do the committee members have questions? I actually have one. In reading the Federal
Register document from 1995, regarding the licensing of collection HIV test
kits for home use, there was a recommendation that the manufacturers follow up
with post-marketing surveillance on the psychological and social impact of home
collection kits.
Is that some of what we will be hearing later? I guess, did that ever happen, and is that
some of what we will be hearing later?
DR. COWAN: I am not
aware of any formal studies that have been done. However, the speaker who will
address the psychological social issues will cite various references in the
literature, at which these sorts of things were examined.
As far as formalized studies to address the psychological
and social issues, in a phase IV type study, I am not aware of any results that
came out of those.
DR. QUINN: Although
it is very different, there are parallels to what the FDA probably went through
with OTC pregnancy testing being used by young people, the counseling that is
inherent with knowing one is pregnant or not, and so forth.
Will we hear, or would it be appropriate, to hear the steps
that the FDA had to go through in those considerations and how they were dealt
with, and the type of information and so forth? I don't know how far back that actually goes, as to when that was
approved.
There is a big long track record and, if there are some
parallels, at least -- different, but parallels -- we might be able to learn
from some of those experiences.
DR. COWAN: I
believe that Arleen Pinkos will be addressing some of those issues in her talk,
and it is her center which was actually involved in those studies, and there
are other folks here from CDRH who could help address some of those, if
questions remain, after her talk as well.
DR. SCHREIBER: One
of the things that we continue to see are these sensitivity specificity issues.
We all know that, in blood testing anyway, the EIA is not particularly accurate
in terms of the number of repeat reactives that confirm.
In fact, the rate is probably somewhere around 10 percent
or so, so that 10 percent of the repeat reactives confirm positive.
Whatever we look at in sensitivity and specificity is a
function of the population that it was tested on. If you look at only the high
risk populations, you are probably going to get a much higher sensitivity and
specificity.
The sensitivity is only a function of the number of
positives that are picked up, true positives, not a function of the false
positives.
If you look through the information that we have, it
appears that there is still the chance for a fairly substantial false positive
rate, probably in the literature that we saw, somewhere on the order of 10
percent, and we have a letter here that indicates a 50 percent false positive
rate.
I think that, when we review these presentations, I think
we really have to keep in -- at least I have to keep in mind how many people
are tested repeat reactive, that would never confirm, and those people probably
wouldn't go back and seek a confirmatory test, I am afraid.
DR. COWAN: I think
it is also important to keep in mind -- to separate the ideas of sensitivity
and specificity from positive predictive value and negative predictive value.
These are concepts that I alluded to a bit, where I
referred to the fact that someone who has few risk factors -- a low risk
person, a low risk group of people -- who are going to be taking this test are
most likely going to have a false positive result, again, in the absence of any
risk factors.
These are statistical epidemiological considerations that
need to be taken into account. Sensitivity and specificity are more absolute
numbers, whereas positive predictive value and negative predictive value take
into account the group of people that are being tested at the time.
MS. BAKER: Thank
you for your presentation. In the course of today's hearings, will we learn
about the experience of other countries with infectious disease testing, over
the counter?
DR. COWAN: That is
not on the agenda at this time. We had considered that briefly, but -- I take
that back. You will be hearing some
data, I believe, from Dr. Inungu, on some studies that were done abroad as
far as psychological testing goes, and there is a variety of experience around
the world with over-the-counter testing.
At the same time, there are cultural differences from
country to country, what our society is willing to accept versus what other
societies are willing to accept.
We felt that it was most relevant to restrict our
discussions to what we would expect to find in the American public.
DR. KULKARNI: I
just also wanted to know if there is any data available on the impact of these
home use test kits that are currently available on adolescents and minors. That
is one of the issues that was raised with this particular kit.
DR. COWAN: Dr.
Branson may be able to better address issues like that, and I believe you will
be hearing something to that effect from him when he speaks.
DR. DUFFELL: I
noted that your second point that you want the committee to consider deals with
the design of clinical studies.
Can you tell me right now whether or not there are any such
studies that have already been undertaken by a manufacturer and, if the answer
is yes, are they going to speak to us about the design that they chose and the
logic behind it?
DR. COWAN: I will
speak to you as an FDA person and say that any questions regarding what a
manufacturer is doing should be addressed to the manufacturer. The information
is considered confidential and proprietary.
I am not being cagey. I believe that the OraSure people
will be able to address issues like that, and you should certainly feel free to
question them on any concerns that you have regarding what they are presenting
as far as the clinical trial data goes, or as far as anything goes. That is
really the point of our questions.
DR. DI MICHELE: Are
there any further questions? Okay, I
would then like to thank you, Dr. Cowan, for a very, very clear presentation. I
think we understand what we are about to hear and the decisions we will be
faced with.
I would like to invite Sue Sutton-Jones to the podium. She
will speak on the proposal for an OTC home use HIV test kit, on behalf of
OraSure Technologies.
Agenda Item: Proposal for an OTC Home-Use HIV Test Kit.
MS. SUTTON-JONES:
Hi, good morning. On behalf of OraSure Technologies, I want to express
our appreciation just to be here.
We have been very pleased with the adoption of our product
in the market since 2002 by public health and other agencies, and we are very
encouraged by the results and the feedback we have gotten from that.
To be able to be here and participate in the meeting,
listen and learn from all the discussions today, is just a great opportunity
for us. So, we are really excited to be here with you today. Hopefully, we will answer all your
questions.
Briefly, I just want to go over the agenda. During the
talk, what I will do is just elaborate on some of the key points that we feel
are important, the intended use of the device as an OTC.
I just want to show you the device very briefly. We have a
slide that shows you how easy the sample is to collect, we will talk about the
test system itself as it exists now, and how it supports the validation of an
over-the-counter application.
Then, what OraSure would propose is needed for studies to
further validate an over-the-counter application for this product, our consumer
labeling, messaging and packaging, and then a very brief conclusion and recap
at the end.
I won't go over all the information on the slides. So, if
you have any questions about a specific slide, feel free to stop me. Otherwise,
I will just keep moving through them. There is a lot of information on them.
Our proposed intended use statement is very
straightforward. It focuses a target or an intended user on the following,
which is, it is a single-use device. It is a qualitative test.
The user won't have to worry about calculations or number
ranges, as you do with some other tests. It is also a test that will detect
antibodies to both HIV-1 and 2, which is important, and it is an oral fluid
test.
So, there is no finger sticking, no blood collection that
is going to be required by the user in their own home.
Now, this is the collection device. As you see in the
picture here, it is very easy to use. You simply go around the gum line once,
around the region of the gum, and then it is going to be inserted into a
developer bottle, and that is it.
What it does here is, this is the flat pad, and there are
no parts or anything that can harm someone with that. Then the results are simply ready to read in 20 minutes.
Now, materials in our test kit for a consumer will be
especially configured for use by a consumer and not a laboratory person.
So, we are going to have pre-test and post-test counseling
information in the package. We will also have a risk assessment pamphlet. We
will have other printed materials in there as well.
We are also going to have pictorial based collection
testing and interpretation materials in there. So, even if they don't read
everything, they will be able to see it graphically.
Then they will encounter the single use device. They are
going to see the developer vial, and then the test stand, which we propose will
be built into the package itself.
It is also important to note that there are no hazardous
components in this kit. So, disposal is simply household waste or trash. There
is no special handling that will be required either with this test for the user
to deal with.
Now, the device contains an internal control. It is easy to
interpret. What it will do is let the
consumer know that the test is functioning properly.
They will know if the sample has flowed through -- well,
they will know if the sample has been collected, and then they will know
whether it has flowed through the device after they have put it into the
developer vial, because of this C triangle, where there is a line that appears
here. That will indicate to the user
that it is a valid test. So, they will
see that.
The technology behind that is basically the antibody
conjugate complex is captured on an immobilized protein line that is on that
pad. All the consumer will have to know
is simply to look for the C triangle here.
Using the same view, once the user has actually performed
the test, what they will do is interpret it after 20 minutes.
For a negative, there is only going to be that single line.
So, a line will appear here, they will know it is a valid test, at that C or
control triangle.
If it is a preliminary positive, what the user will see is
two lines. They will see, again, the control line that is going to tell them
that it is valid, and then they will see a line here at the T.
This may indicate the presence of antibodies to HIV. The negative result indicates that there are
no antibodies to HIV-1 or 2 in the sample tested. So, it is just a very simple two step process that an individual
would go through.
Next, I would like to briefly describe some of the clinical
studies that have already been performed with oral fluid.
There is a question raised today about the specificity and
sensitivity, lower confidence boundaries of 98 percent, and whether that is
appropriate or not but, as you saw, we do meet and exceed, with greater than 99
percent, the recommendations by FDA for rapid tests at this point.
So, our sensitivity, specificity and ease of use have been
demonstrated through many of these CLIA studies that we have done here.
These studies were also conducted with sufficient
statistical power and followed the recommendations of FDA for the population
demographics and size.
So, we generated our claims for sensitivity and specificity
based on the negative, positive and high risk populations that you see here on
the slide.
We based the specificity of the test on all the negative
samples that were determined from all three population groups and, of course,
their sensitivity was calculated using positives we found within our high risk
population, as well as known positive populations that we sourced from known
infected individuals.
Now, here in this study, all of these samples were
collected, self collected by the subject, and the test performed by them.
Here, again, it shows, one, it is able to be used very
easily, and the results of all these studies are well within, again, the
sensitivity and specificity claims so far in place for rapid HIV tests.
This is our CLIA waiver study. It was granted based on demographics in a population from a lot
of different areas in our target users.
This slide here demonstrates that we had male and female,
we had varying ages, as well as a fairly diverse population.
In the next slide, we also considered their educational
backgrounds and experience, as well as their professional experience.
You will notice, down here on the bottom of the slide,
actually none of them -- 99 percent, not none -- but 99 percent of them had no
experience with our device or with rapid tests prior to participating in the
study.
In this study, users were actually given a panel to
use. There were negative, low positive,
and high positive samples that they were to test and interpret.
This study validated the safety and efficacy of our device
in those untrained user hands, as well as the accuracy of that test
interpretation by an untrained user.
Now, here we also performed studies to just determine the
impact of common household substances on performance of our test.
What we found was, there was actually no influence there at
all, no effect. We also realized that this is going to be performed under
varying environmental conditions, and so, to evaluate that, what we did was
focus on these changing environments, perform the testing there, and we found
no effect on performance of the test as well.
All of these results, as here on the bottom of this slide,
were accurate, and they were concordant with the true serostatus of the
specimen that was tested.
Now, in these slides, what we have shown you are studies
that have already been done. So, we feel that the technical performance of the
test actually does validate this application as an OTC.
However, what we would like to do now is go through slides
where we are going to propose some of the studies that we would like to do in
order to fully validate it as an OTC application.
This is just a summary slide here. What we have proposed to do is, we want to
demonstrate that, with the instructions for use, the messaging, the labeling of
the device, that an individual that is untrained is able to perform the test
correctly, and that they are also able to interpret the test correctly and
accurately.
We want to validate that the labeling and printed materials
provided communicate effectively the importance of linkage to care and
counseling to the user, and also communicate the options that are out there and
available to them for those.
Lastly, we see a need to perform post-market surveillance
studies, which were mentioned earlier, to estimate the number of individuals
that are taking the test, and then also which options did those individuals
actually choose from those available to them.
So, the first study here, the objective is simply, the
study will be designed to test the ability of the untrained user to actually
collect the sample correctly which, again, is just very simple, one time around
the gum line, and then into the developer vial.
They will do this after they read the instructions for
themselves, and then also interpret the results. Again, can they do it
accurately based on the labeling and instructions for use that we provide to
them.
Now, as expected in any study, the population will reflect
the demographics of the expected or intended users. We will have untrained
users, again, as I said, collect these samples themselves, read the
instructions, and perform the test.
The devices will be interpreted by them. They will look for
that C or control triangle which, to us, will indicate that it was a valid test
and performed properly.
We will develop design or acceptance criteria prior to the
study, in order to assure verification of the efficacy of the collection of the
sample by the untrained user.
The size of the study population will be sufficient enough
to supply statistical verification of these results.
We propose to perform another study, to validate the
ability of an untrained or lay person to interpret the results accurately after
reading the instructions and performing the test.
It is very similar to the previous study that I just talked
about. The difference here is, these individuals will be given a positive and
negative specimen panel that they will use to test and interpret.
We will have parallel interpretation of the devices by a trained
reader, so that we will have a comparison between trained and untrained users,
and then the size and the statistical validity of the study will be
established, just as it was in the previous studies, and the ones we have done
in the past.
Now, understanding the importance of counseling referral to
care, or show or validate the ability of the labeling and printed material to
ensure that important linkage to care.
The same rationale will apply for sample size, population
demographics, and for statistical validity, as it did in the other studies.
The key objectives that I want to point out in this study
is that, the ability of a user to understand will be evaluated.
What we want to know is, they understand the options for
pre and post-counseling based on the labeling and instructions for use in the
product.
We also want to look at key messaging. That would be messaging such as risk
factors, risk behaviors, the potential for false positive and negative results,
and then also the important window period where the disease may not be detected
if they are tested too soon.
Now, we have not developed fully our labeling that we would
use within these clinical studies. That is one of the reasons we are here
today, is to hear from the audience, as well as from the advisory committee,
what we should include in there.
So, this is just an example of the information or the type
of information we would expect to include in our labeling and packaging
material. So, it is not intended to be all inclusive, but it is one of the
approaches and one aspect of it.
The linkage to care and counseling is very important. With
this in mind, we are keenly aware that the clarity of the printed materials, as
well as the messaging, is essential to this process.
Because of the criticality of this information, though, we
are very eager to partner with other organizations that have experience within
this area.
We also will solicit input and recommendations from FDA and
Public Health Service during our development process as well.
Now, continuing on with labeling, our general approach
again would be to provide pre and post-counseling options that are very clearly
defined, so that the consumer can understand them very easily, as well as act
upon them.
By establishing a comprehensive support network, the
consumer will be enabled to make decisions they are comfortable with and,
therefore, reduce their risk of HIV.
Our emphasis is going to be on the numerous choices an
individual may make in order to reduce the risk of HIV in the general
population.
Now, the post-marketing studies, the last piece of the
keystone. Everyone recognizes that an over-the-counter HIV self test kit can
play a very vital role in testing where both positive and negative individuals
are actually linked to appropriate care, and also to risk reduction counseling.
We intend to partner with public health authorities in
order to disseminate and capture some of this information.
By collecting and sharing this information, we can assess
which options are the most successful in linking an individual to the multiple
resources that are out there now for their use.
In this context, our packaging is a key and critical
component to it. So, we have talked a little bit about the labeling and the
concepts that we have about what belongs in that.
We actually want to go into now the physical package
itself. We have come up with a prototype design based on the following.
We recognized early on that the packaging is an important
opportunity for us to communicate key concepts and understanding to the user of
the product.
So, we focused on the items here. We want to take the user through a step by step, very methodical
procedure on how to use the kit, as well as introduce them to the packaging and
printed material within, and the labeling and instructions for use.
We also wanted to enable multiple visual cues. So, again,
if they don't read everything, they will see how to collect the sample and how
to process it.
Important, it is to minimize missteps, as well as go
through procedure sequencing by the user. So, the following is just one concept
of how that might be accomplished.
There is our package. It is a prototype. So, it is not a
fancy one here. What you are seeing is that the package will be opened by the
user.
The lid will come off and then multiple layers, where we
have an opportunity to message how to use the kit, message about risk factors,
pre and post counseling options with it.
So, as the layers come out, it is intended to be provision
of educational materials. There will be graphical representations, as we just
spoke about. They are pictorial based, and will provide an individual with
visual cues as to how to perform the test and interpret it.
So, now it is revealed here. What you are seeing is that you are now going to see the
package. The smaller one is the
developer vial.
What they will do is, they will take it out. They will open
it up, and they will place it in the test stand. They will open it up. So, that
is the developer vial opened.
This is actually this collection device. They will open it,
once around, and then insert it immediately into that developer vial, and that
is it.
So, it is just a two step process, very simple, and in 20
minutes they will be able to read their results as well.
So, in conclusion, the technical performance of our
approach for an over-the-counter HIV-1, 2, oral fluid antibody test, we
believe, has already been proven through studies that we have done in the past
and have submitted.
The sensitivity and specificity are well above 99 percent,
which is well within the FDA guidelines that have been established already for
rapid tests, and are under consideration today.
Then, the validation of the test system itself, which
includes the labeling and the packaging, for use by a lay consumer, will be
further studied, through other studies that will go on, and that will validate
that.
Then lastly, we propose to demonstrate the effectiveness of
that very important link to counseling and care through post-market
surveillance studies that we want to partner with public health to perform.
So, at this time, I would be glad to answer any questions
you have. I do have other individuals from OraSure here, that can help out with
questions as well.
DR. DI MICHELE:
Thank you very much. Perfect timing. Congratulations. The committee has
questions. We will start with Dr. Nelson.
DR. NELSON: I
wonder if you have done any studies to document the timing of the control spot,
or band.
MS. SUTTON-JONES:
The line?
DR. NELSON:
Yes. In a person who is
positive, does that precede, or is it in parallel with somebody who is positive
for the HIV band?
In other words, if somebody at the home, instead of letting
the device stay in the fluid for 20 minutes, they allowed it to stay 10 minutes
or five minutes or eight-and-a-half minutes, is there any possibility that they
would have a control band showing that it was a valid test, but that the HIV
band had not yet developed?
I wondered if you had done any studies on HIV positives to
look at this sequence. We have had some
experience with injection drug users using bleach to disinfect injection
equipment.
What we find is that, when the drug is there, ready to use,
and it requires one minute to disinfect the syringe, oftentimes they do it for
15 minutes, and we found that this disinfection is not very effective in
practice.
There is a difference between what a lab would do and what
a person would do. I just wondered if this has been studied in any detail.
MS. SUTTON-JONES: It has been looked at, and that is how we
established the window for read. The window actually goes from 20 minutes to no
longer than 40 minutes to read for the test.
There are studies that have been done. I don't know that
any of them have been performed specifically -- unless one of the members of my
team do -- that actually addressed an HIV positive individual, and how fast
that line developed versus the control line.
It all flows together. It is a lateral flow device. So, in
theory, they both come out at the same time and develop.
DR. NELSON: Are any
of your studies on seroconverters, that is, within people who have been known
to be infected, let's say, a month or two months, as opposed to established
infection.
MS. SUTTON-JONES:
Yes, there are seroconversion studies that we have done. This is an antibody test and, as long as
there are antibodies to HIV, I think we have -- our claims are 400 copies are
great. Then, it will most certainly detect it.
We will address the window period in the labeling and following the CDC
guidelines, of course, for re-test.
DR. DOPPELT: You
mentioned that you put the developer in this stand. I assume it has to stay
upright during the full 20 minutes.
What happens if the cat knocks it over and you find it and stick it back
up.
MS. SUTTON-JONES: Actually, it doesn't sit straight up. It
is at a slight angle, once it is in there. What the packaging is intended to be
-- and that is why we propose to build into the package -- is so that, once it
is inserted, it is securely seated there.
So, you would have to turn over the whole test stand to
actually turn over the developer vial. So, it is not going to be set on a flat
surface.
DR. DOPPELT: If it
does fall over, is the test still valid or not valid, and you put it back up.
MS. SUTTON-JONES:
We haven't really considered that.
DR. DOPPELT: Does
it alter the flow. I mean, it falls
over, you put it back up. This is not
done in a laboratory.
MS. SUTTON-JONES:
That would be one of the -- we call it bash testing, but we would do
some consumer testing to actually look at how they perform the test and what
possible mistakes they could make with it, and label for it.
DR. KULKARNI: Even
though I know that this is for oral fluid only, have you tested other body
fluids? I am sure, if I know my
patients, they will probably dip it in every little thing that they can think
about. Would you label it that way? Do
you have data on other body fluids?
MS. SUTTON-JONES:
We have data on blood and plasma, whole blood and plasma.
DR. KULKARNI: I am
talking about breast milk, vaginal fluid, seminal fluid, things like that.
MS. SUTTON-JONES:
We have done testing where it is just common substances, and that is one
of the questions, obviously, that we have to address.
Again, this is an OTC application and previously we were
working, as you said, with a laboratory. So, it is all part of the consumer
testing that we will have to go back and look at, those common substances.
DR. QUINN: On your
slide about the untrained user study validation, I mean you did negative
samples, low positives, high positives and so forth, and you give
sensitivities, how well they did compared, but I wasn't quite sure, what is the
gold standard.
Is that a negative sample on OraSure, compared to a western
blot? In other words, how well did the
untrained people do compared to, say, a trained technology on OraSure? That would be one way of looking at the
data, and your potential studies, I hope, will address it.
The other is, compared to a gold standard of EIA western
blot, how well do these untrained use individuals compare to that golden
standard?
MS. SUTTON-JONES:
That is typically the characterization we do of our specimens. Before we
actually use them, we know, in general -- it depends on the study, but we will
do western blot as well as EIAs.
DR. QUINN: So, for
these, the low positives, high positives, that is like western blot confirmed,
and that is how well they compared to that.
MS. SUTTON-JONES:
Right.
DR. QUINN: Another
study will be, how well does an untrained individual compare to a technician. I
think lots and lots of data on that would be useful.
The follow up question is, although you have addressed many
of the issues that have been raised, the two that I don't know if your future
studies are going to get into, one if these reporting requirements by
state. The other is no follow up, or
partner notification issues. That is a little bit beyond your control. I didn't
know if you had any thoughts about that, for future studies, how you might want
to look at that down the road.
MS. SUTTON-JONES:
Certainly, through post-market surveillance, we would want to look at
it, and you bring up a good point about reporting.
We obviously are not going to distribute or work within an
area where it is not allowed. So, if a state, for instance, has specific
reporting regulations, then we would be precluded from selling over the counter
there.
We are going to work, though, with public health services
to do that, and establish that, and find out what the impact might be, if any,
on them.
DR. SZYMANSKI: I
wonder, to which kind of population you are intending this test. Is your
purpose to meet some need that is not met right now?
MS. SUTTON-JONES:
Right now what we have talked about is just the general population. What
we need to do is a market study, where actually we look at who would be the
most typical consumer of this product.
Right now we are guessing general population, because of
the venue it would be sold in. So, we do need to do further market studies to
actually pinpoint who would do it.
The unmet need is actually -- much of what was up there is
the benefits for an HIV home use test.
That need is not met, because there are individuals that don't get
tested, or won't come back for results to a health clinic.
DR. KUEHNERT: I saw
that the sensitivity and specificity is very high, but you do have some false
positives and false negatives.
I was just wondering if we are going to hear today about
the reasons for those false positives and false negatives, both in terms of
those that are thought to be operator dependent and those operator independent,
along the line of what Dr. Quinn was saying.
That would give us some insight into what the pitfalls
might be. So, I didn't know if you were going to be presenting that data today.
That would be very useful.
MS. SUTTON-JONES:
No, but basically it is just based on the specificity and sensitivity of
the assay. We have a very nice balance where they are very close to each other.
That is the reason, obviously, that they occur.
There are also certain preexisting disease states, for
instance, that would cause a false negative to occur. Certainly, if you are on
any kind of immunosuppressive therapy, for instance, for AIDS, your antibody
level plummets on some of those, and we wouldn't pick that up, but no one
would.
So, it is just that has an antibody based test. So, that
primarily is why you are going to see a false negative.
The other is, it is going to based on obviously also the
predictive positive calculation.
Therefore, we are going to have to identify exactly who might use it or,
if it is general population, what the demographics of the United States are, as
far as prevalence of AIDS infection.
DR. KUEHNERT: So,
for the false positives, that also, you said, was based on some underlying
condition and not based on, as Dr. Doppelt said, something of the cat knocking
over the test.
So, it basically was some underlying condition in the
patient. Is that what was thought to account for false positives?
MS. SUTTON-JONES: That,
and there are just false positives that occur. It picks up something within the
specimen.
I can't say that they are all related to disease states,
no. There are false positives, and that
is in the literature.
DR. KUEHNERT: Just
one more thing. On a false positive or
a false negative, there will also be data on whether, on a repeat test, whether
that happened again? Will there be any
data on that, whether it was associated with the test episode or, again, just
with the patient being repeatedly positive on the test? Will that be sort of looked at?
MR. SUTTON-JONES:
That is part of the clinical studies we do now, yes. We will look at
that.
DR. DI MICHELE:
Just relating to Dr. Kuehnert's question, if you read the brochure and
your untrained individual for the OraSure validation studies you did for CLIA,
it appeared that the errors really did segregate to one or two individuals
performing the test. Is that not correct?
I mean, that is what the brochure says.
MS. SUTTON-JONES:
It does. I am not sure if they were the same individuals in each
instance, though. Do you guys know?
DR. DI MICHELE: We
can come back to that.
DR. MANNO: I have two questions about the package
information. The first is, how likely
do you think it is that people will go to a web site to find a local provider
for care for HIV infection? Do we know
how often that works?
MS. SUTTON-JONES:
Well, there are generalized research studies. We would have to establish
that ourselves.
DR. MANNO: It just
concerns me that some of the people at risk might not be the sort of part of
our population that uses on line resources.
MS. SUTTON-JONES:
No, but there is a toll free number, and there will be 24/7 access for
individuals to call, if they want to call and talk to someone rather than use a
web site.
DR. MANNO: Would
you recommend other local public health recommendations for care?
MS. SUTTON-JONES: Oh, yes. Both will be there. We will have
geographic specific.
DR. MANNO: The
other question I have is about packaging, and I am sure your packaging people
gave you recommendations about how people open packages.
It seems to me that someone would want to see the
information about the requirement for counseling as well as the testing
standards prior to purchasing the product.
It might be a good idea, rather than depending on them
opening these two pieces of cardboard, which I can assure you they would toss,
that some of this information be on the label.
MS. SUTTON-JONES:
Actually, those pieces that flip up would have printing and figures on
them.
DR. MANNO: Once
they get the product, I think they are going to want to use it.
MS. SUTTON-JONES:
Okay, we will do that.
DR. LAAL: I wonder
what the sensitivity of your test is in non-clade B infections, in the other
clades of HIV.
MS. SUTTON-JONES:
Actually, I don't know. Keith, do you know? Keith is from OraSure.
MR. CARDOS: For the
non-clade B, we did run the worldwide panel, and that is reported within the
package insert. So, we did look at the kind of full diversity. I can't quote
that right now without a slide, but it is in the labeling.
The other question that was brought up on the user study,
the reason it was delineated to the two users, when that test was done, it was
a batch mode of randomized samples.
So, in any case where there could be a potential sample
mix, that would count against us, but that was one thing in that study that we
would correct in a following study, is that samples would not be given
together. You would be giving them
together. So, there is no chance of that.
DR. SIEGAL: A
couple of questions. The negative sample is obviously prescreened for HIV
negativity and, therefore, screens out false positives.
What about the characteristics of your low positive
sample? Is the N actually just 200, and
what were the demographic characteristics of that sample?
MS. SUTTON-JONES:
Actually, the negatives are any negative, even if it comes from the high
risk population. So, negatives weren't screened prior to -- we did include
those in specificity. Now, to your next
question, I think Keith is coming back up to actually answer that one.
DR. SIEGAL: I just
wanted to know a little bit more about what you guys considered a low positive
sample. What was the N. Where did they
come from. Where was the geography of that population and so on?
MR. CARDOS: The low
positive -- for the CLIA study, we actually had a panel that was evaluated in a
larger user study, and we picked samples on the low end from really the color
of the line.
You saw in the presentation there was a dark line. There
can be a somewhat fainter line, and we made sure we covered both ends of the
spectrum to make sure we accounted for that in the study. So, the low positive really is the reaction
within the test, is the way we have delineated it.
DR. SIEGAL: My
question really has to do, in part, with whether you are looking at populations
of people from low risk areas, or low prevalence areas for HIV, to find out
what the false positive rate is there.
MR. CARDOS: Within
the population that we have, we did have the low risk population, which was a
substantial set of the clinical data, and also the negatives that came from the
high risk. So, there was a good mix of both of those populations in the study.
DR. SIEGAL: And
what was the N?
MR. CARDOS: The N I
couldn't quote off hand. I would have to look that up in the insert.
DR. SIEGAL: But it
is larger than 200?
MR. CARDOS: It was
larger than 200, yes.
MS. SUTTON-JONES:
It is thousands.
MS. BAKER: I
noticed, in your CLIA waiver studies, you did not include teenagers. The education levels were rather high
compared to what I understand to be the high risk population.
I was curious if you could address primary language,
education level, literacy level, the use of teenagers, and what you would term
as the demographics of expected users in slide 17 and 18, when you are
discussing your studies that will help to validate the efficacy of the
interpretation of untrained users.
MS. SUTTON-JONES:
Now, the CLIA waiver studies, the demographics that included the
educational experience and professional experience, though, are based on that
user. So, it is an untrained individual who is not going to be trained or
prepped prior to reading the instructions and running that test, that we hope
to get CLIA waived.
It really focuses on that intended targeted user group.
What we are proposing to do is repeat those studies, the CLIA studies, in
somewhat the same vein, but do it in our target audience.
We have not established what age, for instance, would be
the lower boundary or cut off yet. In our current package insert it is 12 years
of age and above, but that is something that clearly needs to be looked at and
addressed, that we have not made a determination on yet.
DR. KLEIN: My
question is similar, and perhaps a follow up.
You obviously are looking at English and Spanish and I agree, from what
I saw in your original data, the education level if pretty high.
Do you have data from other manufacturers' home use test on
other non-English, native English speaking populations in the United States, of
which there are many?
Of the high level of illiteracy, actually, whether it is a
native English speaker or a non-native English speaker, how do you deal with
that, or do you have any data at all from other manufacturers?
MS. SUTTON-JONES: Right, now, again, this is part of the
development process that we are going through, and there is one bullet on one
of the slides that actually has multilingual.
So, what we have now within the current product is English
and Spanish and we would propose that, minimum, we would have to do that.
We are going to have to go back, though, and look at the
demographics of our target user and, if it is the general population, then
there will have to be multiple languages, as well as our call center will be
set up with the most prevalent languages as well.
DR. DI BISCEGLIE: I
guess I am still not getting a clear picture of this question of the expected
user. It is not defined, and I also -- you are sort of trying to build a case
that there is a an unmet medical among medically underserved individuals, but
it sounds like you want to sell the kit to the general population with dollars
in their pocket.
So, you kind of need to do your studies, I think, where the
need is, I think, and more clearly define the expected user.
With that in mind, I had a specific question. The
specificity was very good, but the place where the rubber meets the road is in
the low risk individuals, the negative individuals.
You showed data for specificity with everybody all lumped
together. I would like to know the specificity in the low risk group alone.
MS. SUTTON-JONES:
My recollection is it essentially the same, is it not?
MR. CARDOS: That
would be an issue we would want to follow up and actually recalculate the data
with just that in mind and get back to you.
DR. DI BISCEGLIE:
One follow up if I may, Madame Chair. The other kind of research you
might want to consider -- because now you are marketing to the public directly
-- is qualitative research.
You know, we are all used to quantitative research, but
focus groups. Get a group of consumers together of various education levels, give
them packages, and ask them what they think of it, not put in the packet what
you think should be in it.
Then the very final question is, the studies, how do you
intend to do them? Do you intend to
send the individuals home with a test, do it at home and come back and tell you
the result, or put them in a back room somewhere and do it? I suspect this needs to be tested with the
person doing the test at home.
MS. SUTTON-JONES:
Again, it goes back to, we wanted input about the design. You know, obviously we do the focus groups
and generally do them in a room with individuals.
That is something we will have to consider, then, is
actually sending the person home and getting the results back from them.
DR. NAKHASI:
Following on the same line of questioning, one of the criteria that Dr.
Elliott Cowan had elucidated in his presentation, was the supplemental
test. Maybe i missed it in the slides.
Did you mention anything about how that will be done and
how that will be conveyed to the person, and what would be the methodologies by
which they would do the supplemental testing?
MS. SUTTON-JONES:
That will be conveyed to the user through the packaging and labeling.
One of the slides addressed that it is a preliminary positive.
However, the follow up test, the confirmatory test, is
going to be done through referral to care, medical care, and counseling.
So, the follow up, we would hope to reflex them, for
instance, to public health, to their own physician, and that labeling would
convey the importance of doing that to them.
DR. SZYMANSKI: The
pamphlet that we received was intended for a different purpose, I understand.
The new pamphlet that you are going to make for this particular test, is that
going to be similar, and how can you comment on that? I didn't think this was really valid for the home test using the
oral fluids, that we received.
MS. SUTTON-JONES:
When you say package you received, the hand out. Well, what we are
saying is valid is the technical performance of the kit, because we have done
thousands of clinical specimens and samples.
Oh, you actually have a package insert.
DR. SZYMANSKI: Yes,
all the information for the person doing the --
MS. SUTTON-JONES:
It would be completely redone. It would be very different for the one
that we hand out for personal use. That
is part of the development process.
DR. CRYER: I just
wanted to know -- maybe I missed it in your presentation -- but how often is
the test invalid, and what would you propose to do for the customer if it
turned out that way?
MS. SUTTON-JONES:
Actually, it is very seldom the test would be invalid. We don't have to date -- you know, knock on
wood -- complaints that say the test is invalid, or reports of that, from users
that we have, so far.
What we do for the user, I think that is more of a
marketing decision than anything else. They can obviously credit them, replace
the product, help them walk through the testing prior to doing it again, if
they did something mechanically wrong that gave them a funny result. So, that
is something that needs to be decided.
DR. SCHREIBER: In
one of our handouts, on table six, there is some data on the positive
predictive value for HIV-2.
It appeared that there were actually three true positives,
but the test picked up 32. It would
seem that -- this is in a high risk population. The known positives, it was 100 percent, but on the other group
it seemed like you had almost three times as many positives detected as were
true positives.
That led me a little bit to worry about whether, in fact,
the labeling should be as an HIV-1, 2 kit. I know that the 2s were taken from
an African population, and maybe there is a strain difference or something, but
can you comment on that?
MS. SUTTON-JONES:
No, those slides weren't from the ones I presented, were they?
DR. SCHREIBER: No,
but it was in our packet, the company propaganda.
MS. SUTTON-JONES: I
actually don't even have a copy of that. Can someone else address that?
MR. CARDOS: If I
could ask to see the table? [Peruses
document.] Through the labeling for
HIV-2, a lot of samples that get into an area that reported HIV-2 could end up
to be determined to be HIV-1, and we had a lot of that through the insert.
You notice a lot of that labeling, that we had to have a
minimum number of true HIV-2 only positives, and that was part -- as you look
through that labeling -- part of that delineation in the insert.
DR. SCHREIBER: The
way I read the material in here, it said that those that were true HIV-1 versus
2 were eliminated from the table.
MR. CARDOS:
Correct, in what we called the total HIV-2 positives out of that
population versus what we called positive.
DR. SCHREIBER: It
still seems to me, at least when you read this, and maybe it really needs more
detail to go into it, but it really looked to me that you have already culled
out what you called the 2s, so that these are now testing as positive on your
test, but in fact, there are very few of them that were truly positive.
MR. CARDOS: I think
we can work to further clarify the insert.
DR. HOLMBERG: You
mentioned that you would only market to those states that did not require
reporting the HIV results. Do you know
how many states do not require reporting?
MS. SUTTON-JONES:
If I said that, I misspoke. What I meant was, we are going to have to
work through that, and we are going to work with the public health services.
Again, it goes back to that collection and gathering of
information that is a two-way street. We would actually share information back
with public service, so that we can get a better idea of the number of
individuals tested, as well as the options.
So, we would work with each state.
Now, if it came down to, in a certain locality, for
instance, that through our negotiations we just weren't able to work something
out with them, and they did not want it as an OTC, we obviously wouldn't sell
it, and would try to deal with that, but that is something that really has to
be worked out.
We are hoping that that will definitely not be the case,
but there are some states and localities that the reporting of the number is
key and essential. So, we need to get back to those and work with them.
DR. HOLMBERG: I
have another question concerning your language on the package insert. You know,
we do have quite a few African immigrants who speak French, and i would just
bring that to your attention.
MS. SUTTON-JONES:
Thank you.
DR. QUINN: Just in
terms of this state reporting, again, it comes back to how you are going to
position the confirmatory testing, the supplemental testing.
You call it preliminary. It could be probable, you could
use a number of different adjectives to educate the individual that this is not
a definite answer, here, it is done, you don't need to do any more, you are
positive, you are negative.
You are going to need to get them into a referral setting
where they get that confirmatory testing. That place should be licensed to report
to the state, if it is a state, and there are about 29 states -- probably
Bernie Branson knows this -- but about 29 states that are not reportable, or
something like that, and the others it is a reportable mandate. You could
comment on that.
DR. BRANSON: There
have been, up until now, 33 states that require named reporting of HIV, and
AIDS, all the states require reporting of AIDS.
The number of states that require reporting is increasing,
but they require reporting of confirmed positive results, as you point out.
This test, as it is already approved, we don't do any
reporting of preliminary positive results from individuals.
Similarly, many states allow anonymous testing where there
is no possibility of reporting in those circumstances. So, in terms of the
committee's questions with respect to reporting, we are already dealing with
this phenomenon with the preliminary positive, and the reporting occurs after
the confirmatory testing is done.
DR. DI MICHELE: Let
me ask one question, and then I will go to maybe the last question for this
session, because I guess we need to move on or forego lunch, I am not sure
which.
You know, obviously there is going to be a tremendous
amount of anxiety in the false positive. In addressing that, I know that you have
looked at interfering substances and unrelated medical conditions -- some of
which you have documented -- can go on to cause false positivity.
I was just wondering to what extent individuals with
autoimmune disease -- for instance, recently vaccinated, such as influenza
vaccinated individuals, will be looked at with respect to the potential for
false positivity, and whether you will indicate in your patient-related
materials, or consumer related materials, what conditions might give false
positivity, in order to allay anxiety.
MS. SUTTON-JONES:
Well, we would. We are going to have to establish some of that, because
we have not done the testing on an individual that has just been recently
vaccinated, for instance, to see if there is any interference. So, those are the types of studies that we
are going to have to do with our audience.
MS. BAKER: Are you
familiar with the experience of other countries with home use HIV tests, and
how will you use that information to inform your further work, or is this the
first ever?
MS. SUTTON-JONES: I
don't think it is the first ever. If you look on the internet, you can buy
tests right now, and have them shipped to you, where you can do your own test
at home. It is not legal, but it is done.
What we will do, though, is do market research, as well as
liaise with different individuals who oversee different groups with our
notified body, for instance, and get information from them about the
performance of this test over the counter elsewhere.
Again, we are focusing on the domestic market, and there
are very different cultures, and there is different acceptance, even from
European country to European country, for HIV testing in general.
I think the most valuable information is probably here for
us, given that this is going to be our target, initially anyway.
DR. DI MICHELE:
Thank you, Ms. Sutton-Jones. I think you finally earned your right to
sit down. Finally, Dr. Branson, you can come up.
Dr. Branson, from the CDC, will actually speak on changes
in HIV testing practices and counseling recommendations.
Agenda Item:
Changes in HIV Testing Practices and Counseling Recommendations.
DR. BRANSON: My
name is Barnard Branson. I am the associate director for laboratory diagnostics
in the division of HIV/AIDS prevention at the CDC.
The FDA has asked us to address some issues with respect to
our experience, first of all, with rapid HIV tests, in particular the OraQuick
test, and our post-marketing surveillance, as well as some of the other
information that we have from the earlier experiences with home sample
collection.
So, the outline of my presentation is, I will first
describe what CDC sees as the role of rapid HIV tests in the initiative
announced in April 2003, advancing HIV prevention.
Second, to just describe and present data that I think will
answer some of the questions the committee has raised on post-marketing
surveillance for rapid HIV tests and for the home sample collection HIV test
kits.
I will present some information on the revisions in
counseling recommendations since the committee last considered the home sample
collection kit, because I think there have been a number of those, and I will
then discuss some of the CDC's planned revisions of testing practices, and then
a few words on the anticipated value of an OTC differentiated from a CLIA
waived test, and then a comment on validating HIV tests for home use potential studies.
Advancing HIV prevention was a strategy announced in April
2003 that changed somewhat the focus of CDC's prevention activities toward more
of a focus on identifying HIV positive individuals.
There were four key strategies: making voluntary HIV testing a routine part of medical care;
implementing new models for diagnosing HIV outside medical settings to prevent
new infections; working with persons diagnosed with HIV and their partners; and
to further decrease perinatal HIV transmission.
So, in three of the four strategies of the new initiative,
testing -- and in particular rapid testing -- plays a significant role.
The reason for the change in this strategy is that it is
currently estimated, as of a revision this year, that there are between one and
1.2 million people with HIV infection in the United States.
Approximately one quarter of them are unaware that they are
HIV infected, and approximately 65 percent of new infections are attributed to
this quarter of the individuals who are infected, and there continue to be
40,000 new HIV infections annually in the country.
The role for rapid HIV tests in this initiative, and in
CDC's strategy is, first and foremost, to help increase the receipt of test
results.
Elliott Cowan presented some of this data but, in 2000, 31
percent of the people tested in publicly funded sites by CDC, with conventional
tests and who tested positive, did not return to receive their results.
The second role, we feel, is to increase the feasibility of
testing in acute care settings, by providing same day results.
Many acute care settings, such as emergency departments,
number one, have very low rates of return, if they test individuals with
conventional tests and, number two, are often unwilling to test individuals
with conventional tests because of their inability to provide follow up in
order to locate people who don't return who test positive, and therefore incur
liability.
The third is to increase the number of venues where testing
can be offered to high risk persons, and this in particular relates to waived
rapid HIV testing.
Then the fourth role for rapid test is to increase
identification of HIV-infected pregnant women, who have an undocumented HIV
status at the time of labor, so that they can be rapid tested and then be
offered effective prophylaxis if found to be positive.
Some of the results of our experience with rapid HIV
testing, we conducted a number of studies in different acute care settings,
using rapid HIV tests, and others have had similar experiences in the past
several years.
Here you see that the prevalence in most of the emergency
department studies were considerably higher than the prevalence found in the
CDC HIV testing sites with targeted high risk persons.
A large proportion of these individuals, usually about half
in each of these studies, had not been tested before, and usually approximately
half of these individuals do not have identified risk factors, so that risk
based screening would not necessarily help identify these individuals.
CDC initiated a series of demonstration projects looking at
rapid HIV screening in medical care settings, not necessarily emergency
departments.
As you see, in New York City, there were two clinics and an
emergency department with rapid testing that identified prevalence of two
percent among those individuals.
Similarly, in Los Angeles, with clinics and emergency
departments, an emergency department in Alameda County Hospital in Oakland, the
prevalence ranged from .4 to two percent, but we found that facilitating testing
with rapid tests in these care settings, again, found a higher proportion of
individuals who were infected.
Virtually all of them received their HIV test results and,
in most of our studies, 80 percent of the individuals found to be positive
entered into care.
In non-clinical settings, we found that a number of
demonstration projects -- this is the list of the community based organizations
that are providing primarily outreach testing -- this is testing either in
storefront sites or very often in mobile vans.
The overall prevalence is 1.4 percent in these kinds of
settings, ranging from 0.7 to three percent, depending on the site.
Again, all the individuals received their preliminary
positive test results. For many of these individuals, we do not have follow up
information on how many received their confirmatory test results.
CDC also conducted a study of HIV screening specifically
with the OraQuick test, and this was done prior to its approval, under a
treatment IDE from the FDA, and the study was called MIRIAD, the mother infant
rapid intervention at delivery.
It involved testing pregnant women in labor for whom no HIV
test results were available. It was conducted in 12 hospitals in five cities,
and a total of nearly 8,000 women were screened, of whom 54, or 0.7 percent,
were found to be new HIV infections.
In this study, there were six false positive OraQuick tests
and no false negatives. All individuals were compared to EIA and western blot.
There were 15 false positive EIAs in this population, seven
with a P24 band only, and eight of whom were western blot negative.
So, overall, the specificity of the OraQuick in this
population with 0.7 percent prevalence was 99.92 percent specificity of the
EIA, and 99.8 percent. The predictive
value, 90 percent for OraQuick, and 70 percent for the EIA.
We also conducted four studies comparing OraQuick with both
whole blood and oral fluid to EIA and western blot.
One was conducted among known HIV positive persons
recruited from a clinic in Los Angeles, and then prospective studies were done
in an HIV clinic and STD clinics in Los Angeles, which were high prevalence,
high risk individuals, another in Phoenix, which was low prevalence high risk
individuals.
The pregnant women, there was a substudy done in the MIRIAD
sites comparing blood and oral fluid, on an outreach setting study done in
Minneapolis which, again, was high risk individuals in a low prevalence
setting.
These are the data from the performance of the OraQuick in
the known HIV positive persons.
Overall, the sensitivity with whole blood was 99.5 percent, with oral
fluid it was 99.4 percent.
However, stratifying these individuals by their therapy
status, among the people on HAART, all the false negatives occurred on people
who were on highly active antiretroviral therapy.
This finding has been previous reported in 2000 by the
paper by O'Connell et al, in the Journal of Clinical Microbiology.
In that particular study, they had follow up. It was done
in the air force hospital, and they had pre-treatment specimens from
individuals who were found to be false negative on the OraQuick test.
These individuals' pretreatment specimens were
positive. End point dilution titers on
the individuals who were false negative showed substantial reductions in their
GP 41 antibody, and decreases in intensity on their western blot bans. In the know positives not on HAART, 186
individuals, there were no false negatives.
In the prospective testing -- I am presenting data from the
combined study population, of whom 327 were HIV positive by reference test and
12,000 were HIV negative by reference test, and I am sorry that have not stratified this by different study
site, given the information that the committee is seeking from this study with
respect to predictive value, because it would obviously depend on the
prevalence at the different sites.
Overall, the sensitivity of OraQuick with hole blood in
this group was 99.7 percent, and specificity 99.9 percent.
The sensitivity with oral fluid was 99.1 percent, and
specificity 99.6 percent, and in this population the specificity of the serum
EIA, compared to western blot, was 99.7 percent.
We have conducted post-marketing surveillance on the
OraQuick test since it was introduced into HIV testing sites in 2003.
In this first start-up phase, there were 20,585 rapid whole
blood rapid whole blood HIV tests evaluated. This was at the time when the test
only had an indication for finger stick whole blood testing. Of those tests, 392, or 1.9 percent, were
confirmed HIV positive.
We did follow up on all the individuals who had discordant
confirmatory test results. So,in that group of -- it ended up being over 400
individuals who had reactive tests -- there were 21, or 5.4 percent, who had a
reactive OraQuick test, and a negative or indeterminant confirmatory test
result.
In subsequent follow up of these individuals, 10 resolved
to be true positive on follow up, and four resolved to be false positive on
follow up, and seven individuals, one of whom had a positive EIA, and two of
whom had indeterminate western blots, were lost to follow up. So, we don't have
specific information on what resolved.
We continued doing post-marketing surveillance on
individuals with discordant teste results to see if there are any associations
we can identify with false positive test results.
Obviously, because this is post-marketing surveillance, we
aren't doing parallel testing. So, we don't' have information to validate any
false negatives that may occur.
In the more recent post-marketing surveillance, when the
test has been in more widespread use, with both finger stick hole blood and
oral fluid, conducted in 2004 and 2005, we have data from 347 testing sites and
14 project areas.
This charge presents the median for confirmed HIV
seropositivity, specificity and the positive predictive value.
So, for the rapid test, OraQuick on whole blood, 83,000
tests were done. The positivity median
was 0.9 percent, ranging from 0.1 to 2.8 percent.
The estimated specificity is 99.9 and the predictive value
in this group was 97.3, as a median overall, with a range of 76.5 in the area
with 0.1 percent prevalence to 100 percent in higher prevalence settings.
With oral fluid, we have data so far on 17,000 tests,
approximately, of which 1.2 percent is the median positivity rate.
The estimated specificity of the test in this group with
oral fluid is 99.8, and the positive predictive value is 94.5.
In conventional testing done in these same sites, about
31,000 tests were conducted, and the HIV seropositivity was 1.5 percent.
An additional point of information was whether people
received their confirmatory test results, after being tested with a rapid test.
These data compare rapid and conventional testing from
post-marketing surveillance, again, from the 347 testing sites in 14 project
areas.
With rapid testing, 99.7 percent of people received their
negative test results, compared with 79.9 receiving their conventional results.
. Remember, there is a substantial difference of approximately 90,000 people
were tested with rapid tests and about 30,000 with conventional tests.
All individuals received their preliminary positive rapid
test results. In 90.6 percent -- again, this is a median -- returned for their
confirmed positive test results, compared to a median of 83.3 percent of
individuals tested with conventional tests.
We have also done follow up quality assurance and outcomes
on post-marketing surveillance done in this. >We have data only from 154
sites in seven project areas conducted from January to June of this year.
In those sites, there were 35,188 persons tested. There were reports of four invalid test
results. I think that was a question that was raised earlier by the committee.
There was a total of 1,086 controls run for this testing,
which represented a median of 2.7 percent with a range of 0.5 to nearly 10
percent of all tests conducted and, out of those 1,000, two controls were
reported as invalid.
Two sites each reported testing clients on one day when
temperatures were out of range, and one site reported one day when the test
kits were stored outside the recommended temperature range.
This now is switching gears to the post-marketing
surveillance on home sample collection for HIV testing, which was conducted
between May 1996 and September 1997.
CDC has long been cooperating with FDA in evaluating these
tests in post-marketing surveillance. There were two home sample collection
kits that were approved.
One of the kits, which is no longer no the market, used a
pamphlet in the kit package to provide pre-test counseling information.
The other required users to telephone in and register their
test kit before the test would be performed. Those users were invited to
provide certain demographic information and risk information by touch tone
telephone when they called in to register their test kit.
So, out of 165,000 total users during this time period, we
have data for just about 59 percent or 77,000 people.
This, we hope, will give us some information on who might
be potential users of these kinds of tests. So, as you see, about 62 percent of
the individuals were male, among whom prevalence we higher. Eighty-five percent of the users were white.
Although five percent of the users were African American
and Hispanic, the prevalence among those groups was nearly three percent
compared to a prevalence of about 0.7 percent among white individuals.
Seventy-seven percent of all the purchasers were
heterosexual -- I should say of all those who responded to the survey -- were
heterosexual, representing 23 percent of the HIV positive users, for an overall
prevalence of 0.3 percent.
Eight percent of the purchasers reportedly were bisexual
males, representing 27 percent of HIV positive users, with an HIV prevalence of
about three percent among the bisexuals.
Ten percent of users were men who had sex with men,
representing 38 percent of the positives, and 3.5 percent prevalence or only
one percent of the users were injection drug users, representing six percent of
the HIV positive users and an HIV prevalence of 4.1 percent.
One of the companies provided information in follow up that
was collected in counseling and this is, again, in approximately 76,000 users.
Fifty-eight percent of all the purchases of the kit, and 49
percent of the users who tested HIV positive, had never been tested for HIV
before.
HIV prevalence was similar, 0.8 percent among those who had
no previous tests, and 0.7 percent among those who reported a previous negative
test.
We also did an analysis of the call log that was kept by
counselors, when people were provided with their telephone results.
The individuals had an opportunity to call in for their
test results. If they were negative,
they would receive a prerecorded message with an option to speak to a
counselor. All HIV positive individuals
were directed immediately toward a counselor.
Of these HIV positive users -- and I don't have a total
number up here, there were about 1,600 -- 23 percent had a source of follow up
care already at the time of their call.
Sixty-five percent accepted referrals for care, and 12 percent were
already receiving antiretroviral therapy, and had used the test kit to see
whether it worked.
Among the individuals reporting psychological distress in
the counselor's call log, seven percent of individuals who were positive expressed
shock at the unexpected HIV positive test results. Five percent of the callers hung up immediately without
counseling.
Among the HIV negative users, 82 percent opted to receive
the recorded message only. Twenty-nine percent of people called more than once
to receive the recorded message and post-test counseling, and only 12 percent
of HIV negative people elected to speak with a counselor.
I wanted to just present some data overall on where testing
is at, and testing practices in the United States.
These are two surveys, the National Health Interview
Survey, and the behavioral risk factors surveillance system from 2002.
The National Health Interview Survey is a probability based
household sample, and the BRASS is a state based telephone survey.
Overall, the indication from 2002 is that the estimate of
either 38 or 43 percent of all individuals say they have ever been tested for
HIV. Approximately 10 to 12 percent say
they have been tested in the past year.
Testing among individuals who report one or more risk
factors in the past year is about twice as high, 21 percent of the NHIS and 27
percent in the behavioral risk factor surveillance system, and pregnant women
report testing approximately 50 percent of the time.
Both of these surveys include only non-institutionalized
populations. So, they would not include individuals in corrections.
So, the estimate is that, for diagnostic testing, not
including blood donation, is there are approximately 20 million HIV tests done
annually in the country.
The tests in general, about 43 percent are reported to be
done by private doctors in HMOs, about 23 percent in hospital emergency
departments, 23 percent by public sources, and five percent at home.
Some of these report that they are being done by a health
care provider in the individual's home. So, this does not reflect the use of
home sample collection kits, and 4.8 percent of individuals report using tests
at other locations.
CDC has had a number of changes or evolutions in their
counseling and testing recommendations since 1996 when the home sample
collection kit was approved.
Number one, we recommend routine HIV screening in health
care settings in high prevalence communities or facilities. This we recommended
since 1993.
We recommend opt out consent for pregnant women, where they
would receive written or verbal notification that testing would be done, and
consent is inferred, unless the woman exercises an option to decline testing.
We now recommend that people can be provided written or
verbal information about HIV and, with increasing evidence, in particular, in
health care settings, that prevention counseling discourages providers from
offering the testing that we recommend, and from some surveys that individuals
say that prevention counseling discourages individuals who have been previously
tested but remain at high risk from seeking testing, the prevention counseling,
in conjunction with HIV testing, is not required in health care settings.
We recommend re-testing at least annually for persons at
high risk. Right now this
recommendation is for men who have sex with men, and we are considering
revisions of that. Obviously, we
encourage insurance of linkage of care for persons who test HIV positive.
The rationale for these changes, and some changes that are
being proposed, is that there are high levels of knowledge about HIV, about the
availability of effective treatment, and experience with HIV testing.
The National Health Interview Survey stopped asking
questions on HIV knowledge in 1998 because they were consistently higher than
90 percent.
Many HIV infected persons access the health care system,
but are not tested for HIV until symptomatic. It was estimated in 2002 that 42
percent of the people diagnosed with AIDS reported that they had had their
first HIV test within one year of their AIDS diagnosis, many at the time they
were diagnosed with AIDS.
We have now determined there is inconclusive evidence about
prevention benefits from typical counseling for persons who test negative. This
is based on meta analysis of 17 counseling studies.
There are specific theory-based counseling interventions
that require two 20-minute sessions, and there have been two reports of
randomized controlled trials that do show benefit for persons who test
negative. So, I stress the term typical in terms of these findings with respect
to counseling for HIV negative persons.
On the other hand, we have noted substantial reductions in
high risk sexual behavior among persons when they become aware of their HIV
infection.
From another meta analysis, there was a 68 percent
reduction in unprotected intercourse with partners not known to be HIV
positive, among people who were aware of their HIV infection, compared to
people who were unaware of their HIV infection.
We continue to encourage prevention counseling for high
risk persons, but we believe it does not need to occur entirely in the context
of HIV testing, that there are many other indications for prevention
counseling, such as for STD clinic patients, who may not necessarily be tested
for HIV.
In terms of the potential value that CDC perceives in
over-the-counter versus CLIA waived tests -- and I stress potential because we
don't have any experience with this yet -- but first of all, we have some
qualitative information indicating, from these health care settings, when we
have done focus groups among people who refuse testing, that they indicated
they might be willing to use a home test. So, there is potential value for
persons unwilling to be tested in other settings.
We believe there would be value for these tests among
persons who retest frequently. In the
National Health Interview Survey, among high risk individuals tested in the
past year, the range of tests reported by individuals, the median was 1.2, and
the range was from two to 50.
We think also there is a benefit of the knowledge of the
partner's status as a prevention intervention. We have done an analysis of the
relative reductions in risk comparing condom use, different sexual acts, and
having sex with a partner who had recently tested negative for HIV, and having
knowledge of a partner's status confers an obvious protective benefit for
individuals when they are aware of both their own and their partner's status.
Finally, although Elliott Cowan described the CLIA
requirements, our experience, since rapid test introduction has begun, is that
there are numerous local requirements for laboratories beyond CLIA requirements
that, in some circumstances, impede HIV testing.
For example, CDC has been unable to initiate rapid HIV
testing in the state of Hawaii. In New Jersey, CLIA waiver is not recognized.
They have enacted legislation in order to allow for testing, but we think that
in some circumstances, an over-the-counter test might promote testing in areas
where right now it is inhibited or restricted.
We recently have also been notified by some private
providers that if they feel that their utilization of HIV tests in their
practice was low, they would prefer to have an over-the-counter test in lieu of
applying for a CLIA waiver and maintaining a status as a waive laboratory.
Our opinion on the potential for validation studies is that
we would recommend observation of self testing at high risk venues.
We would select high risk venues in order that we would
have the opportunity to identify reactions of people who test themselves and
find out that they are positive.
So, the design we propose would be to have the counselor
provide the client with an OTC testing device, observe the client, do the
specimen collection and testing, and interpretation of the result, document the
client's reaction to receiving the test result, and then, of course, verify the
client's interpretation of the test result.
We would recommend that we select several settings serving
clients with different characteristics, similar to the studies we did with
rapid HIV testing, and test a minimum of 500 clients in settings with a
prevalence of three percent to five percent, so that we would have enough
opportunity to observe clients who tested themselves and obtained an HIV
positive test result. Thank you very much.
DR. DI MICHELE:
Thank you very much for that presentation. Questions for Dr. Branson?
DR. NELSON: One of
your slides I may have misinterpreted, but where you talked about the testing
of persons aged 18 to 64 in 2002, and you had the national health interview
study, 48 percent. Is that 48 percent
of pregnant women or, of the people who tested, were 48 percent pregnant?
DR. BRANSON: Those
are, of the individuals who tested in the past year.
DR. NELSON: So, the
denominator is not pregnant women.
DR. BRANSON: No,
individuals who tested in the past year so that, of the women who were
pregnant, 48 percent reported that they had tested in the past year. Does that make sense?
DR. BRANSON: Only
48 percent of pregnant women tested?
That is very disturbing.
DR. BRANSON: We thought so, too, but this is survey based
data, and we are obviously attempting to increase those figures. So, we don't have any way of verifying it.
DR. BRANSON: In
Thailand it is over 90 percent. We are not doing very well.
DR. KLEIN: I have
two questions. First, could you tell me how the phase IV studies were performed,
and whether you think that there was some bias in the data that you collected?
DR. BRANSON: The
phase IV studies were performed. I think there is definitely a high likelihood
that there is some bias in the data that we collected on the post-marketing
surveillance.
As I mentioned, there were two kits that were approved and
only one collected information from clients, and not all clients answered all
questions with the same frequency.
The most frequently answered questions, when they
registered on the touch tone phone, was sex. The least frequently answered was
zip code. So, people obviously had some concerns, even through the anonymity of
that system.
DR. KLEIN: The
second question was, do you know how many of the state public health agencies do
contact follow up for HIV, and is that a problem, if more people are not
presenting through the usual channels, so that contact follow up isn't done, or
isn't contact follow up done for HIV?
DR. BRANSON: Many
states do contact follow up. I think all states offer some kind of contact
follow up service but, in most states, the contact follow up is only done for
people who are tested in their publicly funded sites, like STD clinics, or HIV
clinics.
Some states do offer those services to people who are tested
by private providers, or in other circumstances, but it is by no means
universal.
DR. KUEHNERT: I
just had a quick question. On this slide on the performance of OraQuick in
known HIV positive patients, there was a difference in sensitivity and specificity
between those on HAART and those not on HAARt.
Since it is an antibody test, that didn't make sense to
me. So, I just wondered what the
explanation was and what you thought the reason for it was, or whether you
thought it was not statistically significant.
DR. BRANSON: We
documented this earlier and that was what I mentioned. We, in fact, did a case
control study on individuals who were on HAART therapy who proved to be false
negative on the test, and compared them to individuals who were positive.
There was clearly an association with reduction in antibody
titer, in individuals who had started HAART early after their infection and
maintained long term and effective viral suppression.
Some of these people, in fact, bordered on being
indeterminant on the western blot because of the reductions in antibody levels.
DR. KUEHNERT: Would
this also be a concern in, say, health care workers who are put on
post-exposure prophylaxis and had a needle stick, and are trying to find out
what their status is? Would this have
an effect?
DR. BRANSON: Do you
mean -- I am not sure what the question is. If you are testing the source
patient?
DR. KUEHNERT: Yes,
for health care workers using the OraQuick after a needle stick.
DR. BRANSON: I
think that if you tested a source patient who was on HAART who might be false
negative, you would know he is in HAART, most likely. There is the possibility, and that was raised in the paper and we
discussed this, that you could potentially get a needle stick from an individual
who had been on long-term effective HAART and failed to disclose that
information.
On the other hand, if he is on long-term effective HAART
with undetectable viral load, the chances of transmission are also lower, since
the occupational exposure risk is related to the viral load in the
contaminating substance.
For the health care worker themselves, I think we have
shown that there are attenuated antibody responses, if you start the person on
HAART. If you were doing follow up on a
health care worker, I am not sure why you would do it with a rapid test.
DR. KUEHNERT: That
was actually my point, was the second.
They might not follow up. They might want to just do it themselves if
they had an option of an over-the-counter option. I agree with you, that they should be following up, but they
might not, if they had the option.
DR. SZYMANSKI: I
was very interested in your statement that counseling might not be so necessary
any more in hospitals.
Up until now, it is a very important requirement that the
person who is tested for HIV will receive counseling.
Also, of course, you need to have permission of a person to
test that person for HIV, and now if you have over-the-counter testing, you
might have testing -- sort of coerced testing of HIV.
Let's say parents want to have their kids tested and they
don't want to, or if you have your partner, and you will test the partner while
he is asleep. You could use that
without telling anybody or getting any kind of permission. These might possibly be risks.
DR. BRANSON: I am
not sure exactly what part of that question to answer. I certainly suspect that
somebody using an OraQuick test on my gums while I was sleeping, I would
probably wake up.
I would like to address the first part of your question in
terms of CDC's recommendation with respect to consent and counseling in health
care settings.
Since April 2003, CDC has recommended streamlined
procedures for both consent and counseling in health care settings, because
many providers perceived that the old perceived requirement for counseling was
a significant barrier.
They claim to not have time or at times they claimed to not
have skill in order to perform that counseling.
As we continue to document that many HIV infected
individuals who are undiagnosed pass through the health care setting without
getting HIV testing, that has been a recommendation.
I don't wish to -- I don't remember exactly the way you
phrased it, that CDC thinks counseling is not useful, but we are saying that it
is not a requirement in health care settings.
We are doing that similarly, in particular, for pregnant
women. We recommend the opt out approach to testing, which does not require
signing a consent form. It requires -- and this is also recommended by the
Institute of Medicine -- that the individual be notified that they are going to
be HIV tested as part of a routine panel of tests, and it is clear that they
have the option to define, but they do not have to affirmatively sign a
consent.
DR. QUINN: Bernie,
just to follow up on that, the proposed changes for testing and counseling, are
those published now?
DR. BRANSON: No. We
have a set of changes that are in process. We had a community forum. We
recently had a panel of professional consultants review them, and they are in
the process of modification.
The current set of proposed changes apply explicitly to
health care settings, and then there is also a revision of the counseling and
testing guidelines for non-clinical settings, but the revision of those is
probably about 18 months away.
The reason I bring it up is, for the streamlined testing,
it seems to be taking place in some arenas but not all, the emergency room at
Hopkins, as you pointed out, is streamlined.
In the clinic, when patients are referred in, you need to
get detailed informed consent, detailed counseling needs to be provided.
If you want to re-test them six months later, you need to
go through the whole process all over again, and it is inhibitory to getting
the testing done, both from the health care provider who doesn't want to spend
that amount of time, and the individual or the patient doesn't.
It would be really interesting to collect data after CDC
issues these guidelines, to see whether health care centers and other
facilities are actually following through on streamlining the testing
procedures.
DR. BRANSON: I
would like to think that CDC's recommendations could solve your problems. On
the other hand, at the current time, there are actually a substantial number of
states that have statutory requirements for either counseling or consent, that
would probably need to be addressed before the CDC guidelines could actually be
implemented.
DR. QUINN: Labs are
the same way. Labs are actually saying, we won't test that blood unless we get
a copy of the informed consent and the counseling has been provided. So, laboratory settings as well.
DR. KULKARNI: I
just have a question for you. I am
wondering whether, in the different medical settings of prevalence of HIV,
whether you look at HIV in sexually abused patients, whether they be adults or
children, and would that population benefit from rapid HIV testing or, if a
home testing is available, my question is whether they would ever report that
abuse, even.
DR. BRANSON: We
don't have any data on that, and the nature of our post-marketing surveillance
is that we don't collect information that would potentially be that detailed.
DR. DI BISCEGLIE:
You mentioned that individuals with a positive test sort of altered
their behavior in an appropriate fashion.
Any evidence that somebody with a negative test might take
that as a license to participate in high risk activity?
DR. BRANSON: There
has been one study reported in the literature in -- don't quote me on this -- I
think it was 1992, looking at a retrospective analysis of data from a Miami
clinic, showing higher levels of risk behavior among people who tested HIV
negative, after they received their test result, compared to the people who
didn't receive their test result, compared to the people who didn't receive
their test result.
An attempt was made to repeat that study in the same data
set in the same clinic in a subsequent year, and the same finding did not
persist.
So, this is raised very frequently. There was only one
study that suggests the potential for the disinhibition effect that you are
asking about.
MS. BAKER: At the
risk of sounding like a broken record, are you aware of any other governments
who are either in the process of approving over-the-counter HIV home testing,
or who have approved it. If there are,
what of their experience could inform?
DR. BRANSON: The
only other place that I am aware of that has approved a home test for
over-the-counter user, is Hong Kong, and I believe it was six months ago and
we, so far, have no information on what has happened since it has been approved
for over-the-counter use.
DR. DI MICHELE:
Seeing no other questions, I will take the last question, if possible.
When you spoke about the fact, initially, with conventional testing, that 31
percent did not return for positive results, for HIV positive results, how did
that compare with individuals not returning for HIV negative results? I have a follow up question to that, but go
ahead.
DR. BRANSON:
Thirty-one percent of the individuals who don't return for their results
usually averages between 44 and 48 percent. So, that 31 percent figure reflects
the additional efforts that were taken to locate individuals with positive
results, but those efforts were unsuccessful.
DR. DI MICHELE: So,
there isn't, for instance, a prohibitive effect of someone who thinks that they
may have engaged in high risk behavior and doesn't want to really know that
they are positive. It sounds like there
isn't a prohibitive effect in terms of coming back for confirmatory results.
DR. BRANSON: Since
the people don't come back, we don't know why.
DR. DI MICHELE: The
reason I am asking is, one of the things I wondered about it, in terms of the
same thing with the home testing.
I mean, if people were really concerned or very nervous
about a positive test, and knew that it wasn't confirmatory, the question is,
psychologically, what would be the prohibitions of actually going and getting
that confirmatory testing.
You have one follow up study that suggests that 90 percent
did, if I was reading that right, which sounds like it is a whole lot better
than for confirmatory testing. Is that correct? Am I reading those results
right?
DR. BRANSON: Ninety
percent of the people who received a rapid reactive test came back for a
confirmatory test.
We have actually looked at that more closely in several
studies, and we find that some individuals -- for example, when they are tested
at a testing site that doesn't offer medical services, and they receive a
positive rapid test -- elect to not get confirmatory testing at that site and
choose to go to a source of medical care, so they can get their confirmation
and have it in the record.
In several instances of people that showed up with a
discordant test result, by the time we reached them for follow up, they had
already had a viral load done.
I think there are many alternatives that people do, but one
issue with respect to the return rates for after reactive test results in these
settings is that, since many of these only offer testing services, we have some
evidence that people, when they get a positive or a reactive rapid test, go to
a care site for follow up testing, rather than return to the testing site and
then go to the care site afterward, especially because, in these sites, the
number and rate of false positives have been extremely low.
DR. DI MICHELE: Am
I reading this right? Do your
post-marketing surveillance studies suggest that there is better compliance
with confirmatory follow up with the rapid test than with the standard confirmatory
testing?
DR. BRANSON: Yes,
and that has been a very consistent finding.
DR. DI MICHELE:
Thank you. We are going to be under the constraints of lunch. The
restaurant will only be open until 2:00, which means that we have to stop at
1:00, or shortly after 1:00.
What I think we will do is actually take one more
presentation, and then we will break for lunch and come back for the remaining
presentations.
So, I would like to ask Dr. Devery Howerton from the CDC to
speak on the role of quality systems for diagnostic tests. By the way, thank you, Dr. Branson.
Agenda Item:
Role of Quality Systems for Diagnostic Tests.
DR. HOWERTON: Good
afternoon. I would like to focus your attention now on a little bit different
topic. We are going to switch gears now.
I was asked to address the considerations of quality
systems as they apply to, or potentially apply to, over-the-counter testing.
I know you are all anxious to get out of here and go to
lunch, so I will try to speak quickly. The outline of my talk, just briefly, I
will touch on what are termed quality system essentials, and then focus briefly
on what we might think of as the basic components for testing.
Then, a brief discussion of CLIA waived testing in general,
and then some issues to consider in test evaluation.
So, what do I mean by quality systems? This is a definition from a COSI document.
That is the Clinical and Laboratory Standards Institute, that a quality system
provides a basic framework for laboratories and other health care units to
direct and control activities and functions along the path of work flow, with a
focus on managing quality.
What is meant by the path of work flow here is,
essentially, the sequence of steps or processes that are required to transform
the decision to perform a test into the actual test result information.
So, if we can think of a path of work flow, typically we
think of it, in a laboratory setting, as involving processes throughout the
total testing process, that we describe as pre-analytic, analytic and post-analytic.
If you wanted to imagine this as a home testing process, we
could also think of this path of work flow to involve the same processes or the
same phases of testing.
In the pre-analytic phase, the individual would need to
obtain the test, whether that be going out to their local pharmacy and
purchasing it, for example, be able and willing to read the instructions, set
up a testing area according to those instructions, collect a specimen and then,
in the analytic phase, actually perform the test.
So, in the case of the test under consideration here,
whether they would put the device in the developer and read it at appropriate
periods of time, and be able to read the results, and then post-analytically
interpret that result in light of their own personal health history
information. Then, obtain the
appropriate follow up testing or counseling as needed.
The quality system essentials, as described in a COSI
document, cited at the bottom of this slide, describe 12 of what we call QSEs.
What I have done here is gone through these 12 QSEs and
highlighted what I think would actually apply to over-the-counter testing.
That would be personnel, obviously, the individual who is
performing the test. The purchasing and
inventory control would basically be performed by both the retail outlet, if
you would, and the individual purchaser, to ensure that the product is used and
stored appropriately, that it is not purchased or used beyond its expiration
date, for example.
Then, process control refers to actually performing the
procedure, following the steps as prescribed in the package insert, or
documentation that comes with the product, whether they adhere to the timing
requirements, et cetera.
Information management is something that we typically think
of in the laboratory as being done through electronic data reporting systems,
for example, where the patient information and test result information are
managed.
In the case of over-the-counter testing, this would be
actually done by the individual, obviously, and that would require the
individual to be able to manage the information obtained from the test results,
in light of their own risk behaviors and history.
Facilities and safety, I think has been touched on briefly.
Facilities obviously are the environment where the test is stored.
That would be the retail outlet, for example, as well as
where the test is performed. The requirements for safety with an oral fluid
test would basically be precluded as typically, in a laboratory setting where
you have to abide by OSHA standards, for example, for biosafety, which wouldn't
really apply in this particular case.
Just distilling this down even further to what I would
think of as the three basic components to performing a test, no matter where it
is done, this would depend on the individual, the person doing the test, the
test environment, and the test materials.
So, if we look at the characteristics of the tester, or the
self tester, in this case, one would need to consider the ability of that
individual, as well as the willingness of that individual to read the
instructions, to follow those instructions, and then to evaluate results and
take appropriate action.
Also, the need for that individual to be aware of the need
to follow the instructions explicitly without deviation.
Looking at characteristics of the testing environment, I
think these are fairly obvious. The
controls for temperature, humidity, the need for adequate lighting, for
example, in reading the lines on the device, and the level, stable work service
without a cat around to knock things over.
The characteristics of test materials, the robustness of
the test device at the temperature extremes. What would happen, for example, if
it was frozen inadvertently, the shelf life, the impact of using tests after
their expiration date.
The complexity of test instructions, I think that has
already been touched on a fair amount, and how those instructions -- how
readable they are, and how the user has the ability to follow them.
Then some human factor considerations that may come up in
the next presentation as far as how the packaging and the device are
configured, and how the specimen collection device is used.
Now, just briefly, touching on CLIA waive testing, I think
this may be somewhat informative for the discussion today.
Elliott, in his presentation, did describe CLIA waiver.
These are the criteria in the CLIA amendment for waiver, the considerations
done by the FDA as to whether the test is FDA cleared for home use, employs
methodologies that are so simple and accurate as to render the likelihood of
erroneous result negligible, or pose no reasonable risk to harm to the patient
if performed incorrectly.
Essentially, the limited requirement for a site performing
only waive testing is that they obtain a certificate of waiver, follow
manufacturers instructions, and permit inspections by HHS under certain
conditions.
What I wanted to focus on here briefly is the requirement
to follow manufacturer's instructions, which is the only quality system, if you
will, requirement for waive testing.
The CLIA regulations, in general, for laboratories
performing higher complexity testing, does follow a quality system approach.
These are some data from some surveys conducted by CMS
during 2003, 2004. This represents, this is a little over 3,000 testing sites.
Currently, there are approximately 100,000 testing sites
with a certificate of waiver. I am just showing this to give you an idea of
what the most frequently performed waive tests are in these settings that were
surveyed.
This represents a fairly cross sectional survey of the
types of sites performing waive testing, and throughout the country.
As you can see, glucose is the test performed most often,
about 45 percent of the sites all the way through prothrombin time, which is
done in about five percent of the sites.
Interestingly, on this slide, of these top 10 tests, all of
them are available over the counter except for the group A strep antigen, the
only infectious disease type test here.
Prothrombin time test is available over the counter by
prescription, I believe, although these tests performed in waive sites are not
relegated only to over the counter testing. There are many, many other tests
that are available for these particular analites that are not available over
the counter.
Looking at the information that was collected during these
surveys by CMS, just to focus in on whether or not the sites were following the
manufacturers instructions.
During these surveys, this represents data from 2002 to
2004, where there were about 4,200 sites surveyed. During these surveys, these
were on site surveys in which the surveyors had questionnaires that they filled
out.
The purpose was primarily not just to collect information
on the procedures and the processes being done in these sites, but as well to
provide some educational benefit.
During the surveys, they found that 12 percent of these
sites did not have current instructions. They weren't even available for all of
the tests that they were performing.
Twenty-one percent did not routinely check for changes in
the instructions. Just looking at whether they followed manufacturer
instructions, about 21 percent did not perform the quality control as
recommended in those instructions, and two percent respectively, did not adhere
to expiration dates or use the appropriate waive test estimates.
Also, from CDC studies, through the laboratory medicine
sentinel network, during a slightly earlier period of time in three different
states -- Washington, Arkansas and New York -- just looking at whether these
waive testing sites followed instructions for quality control, as you can see
here, approximately 60 to 70 percent of the sites did follow instructions,
which translates into the finding that 30 to 40 percent did not.
So, given what we know about waive testing, and these gaps
that were discovered during these and some other surveys, a number of different
approaches have been used to try to give some educational outreach to waive
testing sites.
One, of course, is the first one that Elliott mentioned
earlier, the FDA sales restriction for rapid HIV testing.
Let me back up just briefly. What I was presenting to you
on waive testing really is not focused on rapid HIV. That is waive testing in
general.
In fact, I think out of those 4,000 surveys, only about
four of them, as I remember, were performing rapid HIV testing. So, I am just looking at this in a broad
sense.
Although the rapid HIV waive tests are the only waive tests
that do have sales restrictions, and those were basically by a CDC work group
that met early, I think it was in 2002, to address quality assurance for rapid
HIV, especially with the Oraquick rapid HIV test that had just been approved.
At that time, the CDC developed guidelines for quality
assurance, to provide some educational information to sites who might want to
perform the Oraquick test on basic quality assurance practices like training
and documentation and record keeping, the essentials of quality control, and
that kind of information.
These were published on the CDC web site in the summer of
2003. Currently, on the basis of the
CMS data and other data collected by CMS, during those surveys, CLIAC, which is
the Clinical Laboratory Improvement Advisory Committee, in reviewing those
data, recommended that a document be prepared that would provide basic good
laboratory practice information for waive testing sites.
This is actually in press currently. We anticipate it will
be coming out some time later this month.
It goes through the CMS survey data, as well as other data that we have
on waive testing performance, and provides a fairly comprehensive set of
guidelines for sites performing waive testing.
The intention here is to provide this as an educational
outreach. In addition to the MMWR, we are looking at other kinds of products
that can be provided as educational components or materials that some of these
sites may be able to use.
As I mentioned, the CMS, during these surveys, also
provided some educational documents. They have a one-page good laboratory
practice document that is provided at these sites at the time of survey. Professional organizations, in addition,
provide quality guidance for waive testing, such as COLA.
Now, switching gears briefly just to touch on some issues
that might be considered in a test evaluation of a product like this, I have
gone through a couple of CLSI guidance documents, again cited here at the
bottom of the slide.
The first one is for users, basically for end users, on how
to evaluate qualitative test performance.
The other. on specifications for immunological testing for infectious
diseases, is focused on the manufacturers, to the most extent.
This just lists some of the criteria that you can find in
these documents that might be considered during the discussion today.
The obvious one has come up a number of times, the
instructions, and the familiarization period with the device.
The evaluation materials, what are the appropriate
materials, to evaluate a test in a home use environment, whether they would be
actual test specimens or simulated, the process of specimen collection,
reproducibility of results, and how the test performs at antibody
concentrations near the cut off. That
would be where the line would form in a positive test.
Comparison with existing methods or gold standards, and the
clinical diagnosis, which would translate into the clinical sensitivity.
Continuing on, looking at test kit stability, as I
mentioned earlier, the impact of the shelf life of the test devices, and the
use of the test beyond the expiration date, and the variability and reagent
lots and source materials, how that would impact the test.
The adequacy of specimen collection, obviously whether
there is enough specimen on the device to adequately perform the test.
Test performance, as I mentioned earlier, the analytic
sensitivity specificity which was touched on, I believe, in OraSure's
presentation with interfering substances, or the limits of detection.
One consideration is the method for assuring quality in the
absence of external controls. As these
kits are packaged now, there is a stipulation that external liquid controls
will be run periodically to evaluate the test performance and, in the
over-the-counter packaging, these controls would not be required.
Then, continuing on to considerations by the tester, again,
some of this has already been addressed, but whether the tester, when they
obtain a reactive results, would seek confirmatory testing, or know how to go
about doing that, obtain post-test counseling, and accessing care as needed.
For a non-reactive result, considerations that the
individual would need to know as to whether they would need to be retested, and
for how long a period of time they would need to wait to have a re-test.
The manufacturers oversight, adverse event reporting. I think I skipped over this in one of the
earlier slides. I was looking at the QSEs that addresses the occurrence
management.
When we talk about occurrence management, we are talking
about the ability to document and report problems. So, one issue would be how
would an individual tester or purchaser of this test, or even the pharmacies
that might stock them report adverse events, or non-conformities or have
questions or comments, how would those be addressed. Also, how the manufacturer would control for changes in
production and lot to lot variability.
Just in summary, the basic quality system approach can be
applied to home testing. Quality recommendations and guidance were developed,
and are continuing to be developed to address gaps in CLIA waive testing, which
may be something that might be considered for over the counter testing, some
kind of educational outreach.
Lastly, recommendations for test evaluation, include an
evaluation of the total testing process.
Any questions?
DR. DI MICHELE:
Thank you very much. Questions from the committee? Everybody wants to go to lunch. Actually, I
have one quick question.
The performance statistics that you gave for CLIA waived
facilities, were they meant to show us that, even in the hands of sort of
professional users, so to speak, there isn't always good adherence to quality
control and to using the test correctly.
Is the implication that in the home you would expect it to
be even worse than this in terms of the compliance or better?
MS. HOWERTON: My
purpose in showing that was, as you said, demonstrate that -- these are health
care settings, primarily. It is a smattering of different types of settings.
About half of these sites are physician office
laboratories. Many of them are clinic
settings or nursing home settings, outpatient surgery centers, and those kinds
of places.
They are typically staffed by health care professionals,
although the individuals performing these tests are not laboratory trained.
So, the purpose was just to show you what we know about
waive testing, and that in that testing environment the control requirements or
just having the manufacturer's instructions available are followed.
How you can translate that into over-the-counter testing, I
am not sure, but that is just sort of a measurement, I think, that you might
want to have considered in the context of home testing.
DR. DI MICHELE:
Okay, thank you very much. If there are no further questions, in closing
this particular session, I would like to first of all thank all the speakers
for adhering to time so extremely well.
It really allowed the committee to be able to ask a lot of
questions and have a lot of their questions answered. So, I want to thank
everybody.
We will break for lunch. I have been asked to make sure
that everyone is still back here at 2:00, so that we can begin again at 2:00,
and to notify the public that it is anticipated, given that we are running
behind schedule, that the public hearing will begin closer to 3:00 p.m. Okay,
thank you very much. Have a good lunch, everyone.
[Whereupon, at 1:15 p.m., the meeting was recessed, to
reconvene at 2:00 p.m., that same day.]
A F T E R N O O N S E S S I O N (2:00 p.m.)
DR. DI MICHELE:
Good afternoon, everyone. We are going to begin the afternoon session. I
am pleased to invite Dr. Joseph Inungo from Central Michigan University to
speak to us now about the psychological and social issues associated with HIV
testing, and OTC home use HIV tests.
Dr. Inungu, welcome.
Agenda Item:
Psychological/Social Issues Associated with HIV Testing and OTC
Home-Based HIV Tests.
DR. INUNGU: Thank
you very much. The diagnosis of HIV is
associated with ongoing deterioration of the quality of life, and a significant
curtailment of life expectancy.
It is, therefore, not surprising for the general public to
assume that an HIV test will lead to an increase in anxiety, depression and
suicide. This concern has been
supported by several studies that have been published in respectable journals.
After 25 years of HIV epidemic, there are 40,000 new cases
reported every single year in the United States. The fact that the infection in
these cases is being driven by people who are not aware of their HVI serostatus
underscores the need for us to increase the number of people who know their HIV
serostatus.
The question is, how can we meet this objective without
causing undue pain. In the next few minutes, really, the objective of this
presentation will be to answer the following questions.
The first one will be, what are the reasons people seek HIV
testing. The second one, does
notification of a positive HIV test result in adverse emotional consequences.
The last question is, does notification of a positive HIV
test lead to a sudden and substantial rise in suicide deaths or adverse social
consequences.
We will start with the first question, what are the reasons
people seek HIV testing. Many studies
have been conducted and addressed this specific question, but I will try to
summarize the one that I published in the May 2005 issue of the Drug Benefit
Trend and AIDS Reader.
We reviewed data from the 1998 and 2002 national health
interview survey, to determine the percentage of adults in the United States
who ever tested for HIV and the reason why they did so.
In 1998, about 31,000 adults tested were interviewed, and
31 percent of them reported to have been tested for HIV.
In 2002, about 31,000 adults were also interviewed, and 35
percent reported to have been tested for HIV.
Those who reported to have ever been tested for HIV were
quite similar between 1998 and 2002, with regard to selected social demographic
characteristics.
The main reasons recorded in 1998 were, in 1998, about 34
percent of adults reported to have been tested to find out whether they were
infected or not, followed by 16 percent of adults reporting to have been tested
because somebody suggested it.
The third most commonly reported reason in 1998 was because
of pregnancy or delivery. In 11 percent of cases, it was because the test was
part of a routine medical check up.
Then, in 10 percent of the cases it was because of health
or life insurance, and then the remaining were less than five percent.
If we consider what happened in 2002, the most commonly
reported reason for testing for HIV was because it was because it was part of a
routine medical check up that was reported by 24 percent of the people,
followed by pregnancy or delivery, and then they wanted to find out if they were
infected or not.
So, if we were to compare the two years, what we can see
here is people who tested because it was part of a routine check up, the number
has gone up from 1998 to 2002.
We can see a similar trend for pregnancy or delivery, but
people who seek HIV testing because they wanted to find out whether or not they
were infected has decreased from 1998 to 2002.
In this group, that we can consider as mandatory HIV testing, things
remain about stable.
Although we know that adolescents or young adults represent
about 50 percent of the newly diagnosed cases in the United States, they happen
to be reluctant compared to adults to seek HIV testing.
When they do test, the return rate is quite low. So, we
wanted also to understand the reasons why youth seek HIV testing.
We rely on a study by Murphy that was conducted in 2000,
where they studied 246 HIV infected adolescents compared to 141 high risk, unaffected,
in 15 cities in the United States.
In 73 percent of the cases, adolescents sought HIV testing
out of fear, following high risk behavior. The second most common reason
reported among adolescents was because it was recommended by somebody
else. Then there was a small percentage
that seek HIV testing because they were feeling sick.
These findings seem to support others that were reported by
Bogart in 2001, were a recent high risk exposure was mainly the reason that
brought youth to seek HIV testing.
When asked why they did not seek HIV testing, again, the
most commonly reported reasons had to do with trying to avoid having to deal
with distress following a positive HIV test.
The second question that we are going to examine is, does
notification of a positive HIV test result in adverse emotional consequences.
Here, the majority of the studies that we reviewed agreed
on one thing, that people do experience a high level of distress following at
the time of HIV testing.
Once the test result is made available, those who tested
negative experienced a significant relief of distress.
When they got a positive test, we found some discrepancies.
There was a group of studies that reported an increase in the level of distress
following a positive HIV stress, and there was a second group of studies that
found a more stable or non-significant change in the level of distress.
Interestingly enough, there was even a third group that
reported a decrease in the level of distress following a positive HIV test.
Among people who experienced a significant level of
distress, they were further analyzed, and it came out that people who
experienced averse emotional reactions were likely to have advanced HIV disease
or AIDS.
They were also more likely to have a previous history of
psychiatric disorders. They were more likely to be female, low income, to be an
injection drug user or a heterosexual, compared to men who have sex with men.
Significantly, they were also more likely to have lack of
social support and family. They were likely to be African American or people
who were of young age.
Now, we wanted to see what is happening among young adults.
Unfortunately, here, I would like to acknowledge that there are limited
longitudinal studies on changes of psychological symptoms among adolescents.
All we know so far is really based on cross sectional
studies, studies that showed a high prevalence of psychiatric disorders among
adolescents.
These will range from anxiety, depression, substance abuse,
homelessness, runaway, and all sorts of abuses.
We also know, from cross sectional studies, that
adolescents do not handle stressful life events very well. In fact, the younger
they are, the more poorly they react to stressful life events.
Further studies were done to review all the studies that
reported an increase in the level of emotional reactions following a positive
HIV test.
Chesney and associates reviewed all the studies, and what
they noticed is that the majority of studies that reported an increase in the
level of emotional reactions were conducted in the 1980s, early in the
infection, and the numbers of that type of study decreased over time.
That change in the perception really has been attributed to
good counseling but also to all the improvement in the HIV management that has
taken place in the last 10 years.
I would like to skip the next six slides for the sake of
time. These were just a review of specific studies, and they will not affect
anything in this presentation.
We will now move to the third question which is, does
notification of a positive HIV test lead to a sudden and substantial rise in
suicide death.
Here, we need to recognize that there are about 30,000
cases of suicide reported in this country every year, and that number has not
changed a lot in the last 10 years.
We also recognize that people who suffer from cancer are
maybe four times more likely to commit suicide compared to the general
population, whereas people who suffer from AIDS are 66 times more likely than
the general community or the general population to commit suicide.
What is interesting to remember is, even if they commit
suicide, 90 percent of the people who do commit suicide do have a history of
psychiatric disorders.
The question now is, does notification of a positive HIV
test lead to increased suicide death. To answer that question, we will review a
study by Perry and associates conducted in 1990, where they compared 244 men to
56 females.
They compared the level of suicide ideation two weeks
before notification of a positive HIV test, one week after, and then two months
later.
What they found is, two weeks before notification, there
were 28 percent and 27 percent among HIV positive and among HIV negative who
had some suicide ideas. Here, it is again two weeks before notification.
Following notification, the percentage of people who had
suicide ideas went down, to the extent that, by the time we reached two months,
both of them went down to about 15 percent.
If I were to go back, four percent of people had what we
called a suicide which, which is a strong feeling for committing suicide. Interestingly, among this four percent, all
of them had clinical symptoms of depression as well.
These findings were also reported by Grassi and associate
in 2001, where they compared suicide ideas among HIV positive, HIV negative,
and people who had hepatitis C also.
Again, in this group of injection drug users, they did not
find a significant difference in the proportion of suicide ideas between HIV
positive and HIV negative before and after notification of an HIV test.
The third study that we will review is an interesting one,
and here I would like to mention that this study was done in the Netherlands.
So, taking into consideration the difference of the country
and culture, I would like you to factor that into the interpretation of what we
are going to find.
This study was conducted on injection drug users who were
followed for four years. After four years, there were 17 cases of death. Seven were
suicide, 10 were due to overdose.
Comparing the two groups, what they found was there was a
higher risk of committing suicide among HIV positive than among HIV negative.
However, the difference was not statistically significant, as you can see by
the 95 confidence interval shown here.
The other finding is, they did not report any single case
in this study. They did not find a single case of suicide immediately after
notification.
As a matter of fact, the first case that they reported here
occurred after six months. So, that in itself is probably suggesting that
notification is not directly associated with a behavior that was explained
here.
So, based on studies that we reviewed, notification of an
HIV positive serostatus does not appear to lead to a sudden and substantial
rise in suicide death.
However, the development of HIV symptoms, and the presence
of depression are probably the two major factors that lead to depression in all
the cases that we review from the literature.
This will lead us to our last question. Does notification
of a positive HIV test lead to adverse social reactions.
We also here need to recognize that increased violence
after HIV infection is a reality.
Considering a study conducted by Zieler on about 3,000 HIV positive people,
21 percent are women, 12 percent were men who have sex with men, and eight
percent of heterosexual men did report some type of physical harm.
In half of all these cases, notification of HIV positive
results was considered as the major cause of abuse that they sustained.
In the United States, violence is quite common among women.
About one third to one fifth of women in the United States will experience some
sort of violence during their life time.
It is now established that gender oriented violence is, in
many cases, the cause of HIV infection, that sometimes, as in these cases, it
can be the consequence of HIV infection.
Another study conducted by Sewell in 2002, based on 275 HIV
positive women, showed that 33 percent of all these women reported physical
abuse following an HIV positive result.
There was a study by Koenig that reviewed all the studies
that reported violence among women, but this time they took into consideration
the demographics and the behavior.
When they stratified by these groups, they realized that
really, in the final analysis, there was no significant difference between
women who were HIV positive versus those who were HIV negative.
Here, the author did recognize that violence in women does
exist, and this occurs mainly following disclosure, or around condom
negotiation. Those would be the two incidents where violence occurred in HIV
positive women.
I wanted also to mention another study, and this one by
Klimax that was conducted in 1998, that showed, in that group, that four
percent of people did lose their job following HIV testing.
One percent were asked to move out of the house by the
landlord, and then one percent did report a case of physical abuse.
So, now we come to our summary. People seek HIV testing for various reasons. What caught my attention here is what is
happening among adolescents who happen to be seeking HIV tests out of fear
after high risk exposure.
You saw the study by Pollack that showed a recent high risk
exposure. That, in itself, is a matter of concern that needs to be addressed
because, as previous speakers mentioned, the importance of the window period
that will affect the results, and may be misleading for some of the teenagers.
Another concern here is, I would like to point out here
that the majority of the studies on psychosocial effect were conducted in the
1980s and the 1990s.
There are very limited studies conducted during the highly
active retroviral era. So, there is a
need for us to conduct the studies during this time to see how people really
react.
The majority of studies that we reviewed are unanimous
about the fact that, as soon as somebody gets a negative HIV test, that will
lead to a significant decrease in the level of anxiety.
As we mentioned, the result is not that clear for a
positive HIV test, and there will be many reasons that will explain the
discrepancies that we found here.
The first one would just be based on the way the studies
are designed, or the type of instrument that was used to measure the anxiety,
depression and other disorders.
Also, one may think that notification of an HIV test may
probably not, in itself, be a strong predictor of suicide in this specific
case, that other factors, like psychiatric disorders, lack of social support,
the fact that somebody has symptoms may play a more major role than
notification itself. Again, we need
studies, more studies, to confirm what we are just mentioning now.
Although death from suicide is common among people with
notification of a positive, it does not appear to lead to a sudden substantial
rise in suicide death.
To conclude, social adverse reactions do occur following
HIV diagnosis, and it has been shown that these reactions most of the time are
associated with lack of knowledge and fear.
This is the end, and I will be pleased to take a few questions.
DR. DI MICHELE:
Thank you, Dr. Inungu. That was excellent. Committee questions?
DR. KLEIN: I may
have missed this, but I am presuming that most of these, if not all of the
people in the studies, were actually notified by a medical person and had
relatively immediate access to some kind of explanation or counseling, rather
than self testing, where there might be no knowledgeable person available, or
were there some studies where this is not true.
DR. INUNGU: That is
correct.
DR. SCHREIBER: I
was wondering if you could comment on the length of follow up for suicide. It seems to me, from my reading, that
suicide is contemplated, and is usually a planned event, and perhaps the follow
up period is not long enough to see the true effect of being notified that you
have HIV.
I don't think I would expect to see it within the first
couple of months, but I might expect to see some impact further down along the
line.
DR. INUNGU: What
you said is correct. In that case, it becomes even more difficult for you to
link notification with the occurrence of suicide, and that is a difficulty that
we are now facing.
DR. SCHREIBER: I
think the other comment that I would make is that a lot of these studies seem
to be very small and, while there appear to be perhaps some trends, they are
probably underpowered to be able to detect any differences between the two test
groups, when you have 100 or so, and you have a rate of occurrence of less than
five percent.
DR. INUNGU: That is
what we know. For every single study, the sample size is really key to
determining the power of the test.
At the same time, things have changed with the management
of HIV. So, there is really a need for us to see what is happening now that we
have effective antiretroviral therapy in place.
DR. NELSON: You
mentioned one, I think,key issue, and that is that people who were symptomatic
or had more advanced HIV were more likely to commit suicide than those who were
asymptomatic and were early in the infection.
In fact, since we know that nearly everyone will eventually
become symptomatic, I think the real issue is perhaps less the testing and, in
fact, early testing and perhaps management might actually prevent some suicides
that might occur if people were untested until they became symptomatic.
That is a complex situation to evaluate, in a research
protocol, but I think it makes some sense that that might be the case. Could
you comment on it?
DR. INUNGU: In
fact, the literature supports exactly your statement. Many researchers even
pointed out that physicians or health care providers will start playing a major
role now to prevent suicide from occurring.
It is not just something that happens. It happens in a
specific group of people, those who have symptoms, and people who have a
history of depression.
With these characteristics,if somebody were to come and see
you, you can at least probe whether or not there are suicide ideas, and take
action to prevent suicide from occurring.
DR. SZYMANSKI: I
think that suicide is one of the extreme emotions that could happen after being
informed about HIV status.
There are other very adverse feelings and anxieties that
would be created when you learn whether you are HIV positive or negative. Those things, I think, are important as
well, in addition to suicide.
DR. INUNGU: Yes,
while preparing this, I was specifically asked or tasked to look for anxiety,
depression, suicide, and those were the three that I looked at.
I definitely could have expanded that and come up with
different conclusions, but we wanted just to start, for this one, and show what
is happening really, because suicide and depression were the most -- those are
what people refer to when they fear adverse emotional reactions in HIV positive
people.
DR. DI MICHELE: I
have one question. I don't think you have the data to answer this, but I am
going to ask it anyway.
Is there anything, from what you have gleaned in the
literature, that would allow you to have some conjecture as to how the
availability of over-the-counter home testing might impact on the emotional
climate that you just conveyed to us today, and the potential emotional
ramifications of HIV testing, particularly in the high risk groups such as the
adolescents and young adults.
DR. INUNGU: I would
probably say that my answer probably will be just pure speculation, and I would
rather keep quiet than go on the record with something that has not been
proven.
DR. BRANSON: In
response to your most recent question, I think the only thing we are familiar
with in the literature that has bearing is based on now three published studies
looking at increasing numbers of places that perform HIV testing but provide
results by telephone, because that has been shown to increase people's receipt
of results.
Many people have expressed that they prefer to receive
positive test result in their home situation where they are comfortable, or
where they may be someone around, rather than in a clinic situation with a
stranger.
So, I think that
potentially we should look at the telephone notification of results while
people are at home to give us some advice or parallels to what might happen
with over-the-counter tests.
DR. SIEGAL: Just a
comment, that it is all well and good to show that this very crude measure of
distress, which is suicide, doesn't change much, but we shouldn't lose sight of
the fact that notification of HIV seropositivity is a life changing event.
If you actually talk to human beings who have HIV
infection, you certainly know that. It is hard for me to believe that people's
anxiety levels, over all, go down. That
is just a personal guess.
DR. DUFFELL: To ut
that in context, I think you would have to agree that there are a lot of things
in medicine that patients are informed of, find out about, that create stress
as well.
DR. SIEGAL: I agree
completely, but you have to keep it in perspective.
DR. DI MICHELE: Any other comments for Dr. Inungu? Hearing none, I want to thank you very much.
We will go on to our last formal presentation by Arleen Pinkos, on human
factors in OTC testing.
Agenda Item:
Human Factors in OTC Testing.
MS. PINKOS: Thank
you, Madame Chair, and good afternoon to everybody. I want to start off by just
giving you a frame of reference.
In vitro diagnostic devices are reviewed within the office
of in vitro diagnostic devices, and that is in CDRH, and I am a member of that
group.
Today, I will start you off with a little background
information, and then cover the three major elements of our review practice,
and end up with a few conclusions.
I think we have talked about this already today, but there
are about 817 over-the-counter devices that we have cleared, and they are
presented before you. Most are on this list.
Of note is the absence of any infectious disease products.
Although IVD has reviewed three types of infectious disease
products -- self diagnosis for strep A, influenza A and B, and the performance
of these devices in professional hands were sensitivity around 55 to 80
percent, and specificity averaging 80 to 90 percent, this type of performance.
In combination with the high risks associated with false
positives and negatives, it led the center to determine they were not suitable
for home use.
Before CDRH can start their review, they really have to
know the who, what, where, when and why about a test, because that is so
important.
That not only drives the protocol that needs to be done,
but the questions that are going to come up and the data that is likely to be
needed.
There are three primary review elements, and I am going to
cover each of these in detail. Can the
device be accurate and reliable in the hands of lay users? Is it adequately labeled, and do the risks
outweigh -- hopefully not the risks outweighing the benefit.
So, the first element is whether the device is accurate and
reliable in the hands of the user. As we talk about this element, we are going
to talk about five different topics, whether the test can provide the right
answer, whether the lay user can get the right answer, a little bit about human
factors and risk mitigation, and then end up with some information about stress
studies.
Okay, can the test provide the right answer. This question
is answered by evaluating the analytical and clinical performance parameters of
that test.
Almost all of the over-the-counter devices that we receive
have previous clearance for prescription use. So, that information typically
comes from that earlier submission.
So, I am not going to spend a lot of time on that, but you
can see that generally the analytical and clinical sensitivity and specificity
of the device, or predictive values, cross reactivity and interferences, both
of which can cause false positives or false negatives, the precision.
We also look at some environmental factors, both of the
storage requirements and the requirements for when the test is actually done,
and stability of both the reagents and the sample.
Also, as these unitized disposable devices become more and
more popular, the actual manufacturing or lot to lot variability in those
devices becomes much more critical.
Now we know how it works under optimal conditions in the
hands of professionals. The next step is to perform consumer studies.
The goal of a consumer study is to demonstrate that the
device has comparable performance when it is used as intended.
So, here we are looking at not only is the stud enrolling
representative lay users, but also is it in a representative home environment.
A home is not always a home. As we said earlier, it could
be in a mall, in the back room at a doctor's office or a clinic.
One very, very important thing is that you want to capture
the entire testing process, from collecting it to running it, to interpreting
it, and maybe sending a sample back to the lab for confirmation testing.
It is important that that testing take place unassisted,
because that is how it is going to happen in real life.
The studies should be using representative labeling, and
that is usually just a single package insert, but the most important thing is
that the study is developed and packed just like it is going to happen in real
world.
So, if there are educational materials or training, like a
video, or an 800 hot line available or something like that, that should also be
part of the study, but nothing more.
There are a few things that we need to consider about the
sample in the consumer study. It might be a clinical sample or it might be
something that is prepared but, if it is prepared, it obviously has to have a
matrix, and whatever you are adding to it, such that it is going to act like a
clinical sample.
The concentrations of the analite in that whatever it is
has to be challenging to the medical decision points of the test.
If you are only testing negative or sky high, everybody is
going to look good, and you are not going to know who is good and who is bad.
Sometimes getting clinical samples challenging to the cut
off is difficult. What we always have to remember, whether we are using banked
samples or selected samples or prepared samples, is that when we review those
results, we are not looking at clinical performance. We are really looking at
analytical performance. We also want to
see that the sample concentrations span the range of expected concentrations.
Okay, prospective sample collection does not always have to
occur, but there are certain conditions that would dictate that, like if you
needed to re-establish sensitivity and specificity in a different target
population, or to determine whether they can actually collect the right sample,
or if the sample is not stable.
We also want to avoid exposing participants to biohazardous
materials whenever we can, but that is not always possible.
Also, the sample has to be well characterized, whether it
is clinically characterized by a diagnostic criteria like WHO, or if it is
compared to another credible test.
When we look at the protocol, the protocol should be
comprehensive. It should certainly enroll enough participants or samples.
They should be using the correct statistical tools, like
when they estimate the sample size, or how they are analyzing the data.
They should be employing masking and randomization
techniques to avoid bias. Last but not least -- which you would be surprised
about -- but that the protocol was actually written before the study was done,
because often that happens, and that certainly biases the test results.
When we consider all devices, but particularly those that
are going to be used over the counter, it is important to think about human
factors.
Human factors is a discipline that is involved in how
people interact or interface with the device. It is why we do the little things
we do, and that we don't do.
They are so very important, because we know that users have
varying ability, both mentally and physically, and they have a variety of
behaviors.
It might be an individual trait, like being color blind, or
it might be a group tendency, like not wanting to read the directions.
There are also -- these factors are all very important.
They impact the safety and effectiveness of the device.
Human factor-related errors occur when users fail to
perform a necessary step or they add something extra, they choose something
wrong, make the wrong decision, or if they perform an action poorly, like if it
requires a certain technique.
Who is responsible for these user errors, if you want to
call them user errors. This
illustration, the instructions are telling people to read the directions or
read the result from right to left, and the sponsor is wondering, well, how was
I to know they were going to do that.
That might be an exaggerated example, but it really
stresses that manufacturers need to anticipate all the potential errors. I always like to think of that as applying
both common sense and Murphy's law in your thinking.
All user errors cannot be prevented. We found that out when
diabetics were cutting their glucose strips in half. I don't think anybody
could have estimated or anticipated that.
Certainly some, like this example, can be avoided with thinking ahead.
Okay, what do we expect from sponsors regarding
errors? We are not talking about just
human factors errors, but a mechanical failure, an electrical failure.
We are really hoping, and we try to stress to
manufacturers, to have an effective and systematic approach to identifying and
dealing with those errors.
The first step is usually identifying potential errors, and
then identifying the risk, and then eliminating or reducing those risks to what
is seen by most people as an acceptable level.
Then finally, to verify the effectiveness of those mitigations.
Okay, here are some examples of the common types of
safeguards that manufacturers might built into their device.
They might have a built in mechanism or control mechanism
to look for short samples, whether it is the wrong sample, reagent integrity,
or maybe they have a temperature strip that is sensitive in the box, to know
whether the product ever got outside the required temperature range.
Internal QC is often limited in scope. The best example of
this is the little immunochromatographic test strip for pregnancy and things
like that.
Those built in controls are really not doing anything more
than monitoring the volume of the sample, and nothing else.
People often think that they are monitoring the integrity
of the reagent, and they are not doing that at all.
A device might have a shut off mechanism. Manufacturers
love using labeling to mitigate errors. There are some labeling techniques,
like bolding or putting a box around something.
That can be very effective, but sometimes it is sort of
iffy whether that is an adequate mitigation, and we often find out about that
after the product gets on the market.
The goal in all of those mitigations is to head it off at
the pass before it starts identifying the wrong results.
A sample detection system that allows a result to drop to
half the real value before it kicks in, is not really very good, but there are
some like that on the market, unfortunately.
Although external QC is very beneficial in professional
settings, it is not always a good fit for over the counter products.
It is ont always available or practical. IT is not always
adequate. It doesn't necessarily always monitor the entire analytical process,
and unfortunately there is no external control that I know of that monitors the
sample collection procedures.
Is external QC actually needed? There are a lot of people that, because of the developing technologies
and the advent of these little idiot proof devices, so to speak, that a lot of
people argue that there is not a lot of value in it.
Lastly, will consumers even do it. Even if you built the
best mousetrap in town, there is no guarantee anybody is going to do it. We see
that with glucose meters a lot.
After manufacturers develop safeguards, we need to see if
they are effective, if they are working.
This is often achieved by running stress studies.
What are stress studies?
They are basically challenges to the system in order to characterize
performance under various conditions of use.
As an example, if the instructions say, read it in 10
minutes, well, you might be anxious and read it in eight, or the phone might
ring and you don't read it for 15 minutes.
How are stress studies performed? You artificially simulate a potential error or deviation in some
condition, and you are concentrating on the areas that are most prone to errors
or failures.
For instance, if there is a certain technique needed, they
might shake it instead of inverting it. If the directions are complicated or
too long, they may not be able to follow it.
We are always interested in looking at deviations in the
temperature, because it is not uncommon for somebody to stop at the mall on the
way home from the drug store and leave the product in the hot car for three
hours.
Then, after we do the studies, we look at the effect of
those deviations on the test result.
Okay, here are some stress study examples.
If the procedure were to say to store the kit at 60 to 80
degrees, you might store it that way, but also store it with intermittent
freezing, or a little lower or a little higher.
If the procedure says to add three drops of sample, you
might add two, three, four, five and see what the effect is.
The key to interpreting studies is, if a deviation that you
can reasonably expect to occur is having a result that is clinically
significant, then it might not be suitable for use. I saw you crinkle your head. Did that not make sense?
Okay, now let's move on to the second element of review, is
the device adequately labeled. Are the steps and instructions simple, concise.
If they are too long, too complicated, you are going to
lose your readers. .There have also been a lot of studies that indicate that
the level of the writing should be at a seventh grade reading level to be most
effective for over-the-counter use.
Do the consumers know who and how they should use the
device and when, and are there clear instructions for interpretation.
Sometimes reading result is counter-intuitive. I don't know
-- in many pregnancy tests, for instance, the absence of a line is actually a
positive result, and the presence of a line is a negative result. That can be
confusing.
Do consumers know the limitations of a test? Do they know that no device is ever
manufactured perfectly each time or that there are biological variations that
could affect the results.
Do they know when to call the doctor? Do they know what to do if the device didn't
work. Do they know when and if they should repeat the test.
How do you know when it is good enough? This generally verified in the consumer
study. If you get good results, you can assume everything went well.
Consumer studies are limited in their value. There are not
usually a large number of individuals, and we observe a trial effect.
For instance, if somebody knows that they are being watched,
or the results they get are going to be scrutinized, they are not necessarily
acting like themselves. Again, will
they read it.
Another tool that we use is a questionnaire. What that is,
after the consumer does the testing, you give them a series of questions to
ask.
Those questions should be very challenging. They shouldn't
be open ended questions like, do you like my device or something like that. It
should really hit them and really give you an idea of whether they got it.
The third and final element is where we balance risk versus
benefit. As we do this, it is important to remember that lay users are very
unique.
They are operating in an unregulated environment, and they
may lack medical and technical training. They do not have the access to other
medical information like other lab tests or physical examination.
They may not be able to collect sample or follow the
directions. They may or may not follow up. They may not do what they are
supposed to do.
One thing for sure, there is a high amount of variability
in lay users, both in terms of their skills, abilities and knowledge.
We have internet junkies out there, but then we also have
people who are very limited in their motor skills. Obviously, a good
over-the-counter device is one that is suitable for use by everybody.
When we think about risk and benefit, we need to consider
medical benefits and risks to both the user and the public.
Here are two questions that might best capture how we think
about risk. What is the impact of a false positive or a false negative, such as
in no following up or adverse medical conditions or unnecessary treatment.
What are the medical risks if there is a delay in obtaining
professional examination or treatment, or if the device gives an equivocal
result.
Here are also two questions that capture the benefit. What
is the clinical benefit in terms of screening or diagnosing or doing whatever
it is doing. What is the benefit, and what is the medical benefit to having the
test available for use at home as opposed to having to go in to a
professional's office.
In the end, we end up with the same three questions. Is it
accurate and reliable in the hands of the lay user.
Is the labeling good enough, and do the benefits outweigh
the risks. If the answers to these three questions are yes, we are generally
going to find the device suitable for home use, and I thank you for your
attention.
DR. DI MICHELE:
Thank you, Ms. Pinkos. Questions for the speaker from the committee?
MS. PINKOS: Oh, I
did want to answer about that pregnancy test question. Pregnancy tests were
actually pre-amendment.
They snuck in right before 1976. So, they were
grandfathered in and we didn't have to worry about it. So, we lucked out on
that one.
DR. KUEHNERT: I
just had a quick question about you had group A strep and flu in there. Were
those discussed in any public meetings, or were those discussed internally
only?
MR. GUTMAN: This is
Steve Gutman from Arleen's work group, and the strep went to a public panel
twice, the influenza never made it to a public panel.
DR. KUEHNERT: It
might be useful, if there is a public record for that, to have that, if this
comes before the committee again, or when it does, to have those available.
DR. MICHELE: Good
comment.
MS. BAKER: You
mentioned that over 800 OTC products have been cleared for home use. Do you
have any sense of how many have not been cleared for home use and what the
general trends were as to why they were not.
MS. PINKOS: Gosh, I
don't know if I could even venture a guess. Steve, do you have any good idea?
DR. GUTMAN: I don't
actually think we have that tracking information.
MS. PINKOS:
Obviously, the newer types of devices are the ones which may not
necessarily get a stamp. If it has been around for a long time, it is going to
have an easier path.
DR. QUINN: I Just
wanted to again get a sense for how this would proceed. The test seems to be fairly accurate. How
the benefits might outweigh the risks is the big issue, and how well the
individual will actually do the test.
Will a company, such as OraSure, work closely with the
FDA? In other words, there was a
discussion of some studies that might need to be performed. Is there an
interaction with the FDA saying, here are the studies we are going to
perform. If these come in and they look
good, positive --
MS. PINKOS: Oh,
yes, absolutely.
DR. QUINN: So, it
comes to your work group?
MS. PINKOS: I am
not sure exactly where it is going to go to be reviewed, but it is going to be
right here.
DR. COWAN: To
clarify that, there was an inter-center agreement which was written, which said
that most in vitro diagnostics would be reviewed and handled by CDRH.
However, all blood donor screening tests and any HIV
diagnostics would be handled by CBER. So, CBER would be the one to actually do
the review.
Of course, we would be consulting with our colleagues in
CDRH to get input based on their experience, and that is a critical part of
this.
At the same time, the question you ask is a very good one,
because the questions you are asking are the questions we are asking of
you. We want you to tell us. I didn't want you to get away without -- so,
we will be coming back to that in a little while, but I just did want to remind
you that, yes, we are going to be working very closely with a company to
determine suitability but, at the same time, we need to know what sort of
information we would need, or a company would need, to validate for
over-the-counter use.
DR. KULKARNI: I was
just wondering if there were any requirements for disposal of OTC products. For
instance, this OraSure, as somebody said, you can throw it in the trash. I wonder if a roommate looks at the trash
and finds out this test, what is the implication of that.
MS. PINKOS: I think
OraSure would probably have to answer that, because I am not positive. I don't
know what chemicals or reagents are included in their test.
DR. KULKARNI: Or
would it be like Mission Impossible and it just disintegrates.
MS. PINKOS: Do you
all want to take that question?
MR. CARDOS: From
everything we have looked at, a device like this would just fall under standard
municipal waste and be disposed of that way.
MS. PINKOS: So, I
guess the user just has to use his or her discretion.
DR. SCHREIBER: Does
the FDA have performance guidelines for devices? In other words, do you have set, or in the back of your mind,
sensitivity, specificity and other measures that you use to evaluate against so
that something with an 80 percent is not accepted, but something with a 99 is?
MS. PINKOS: I wish
we did.
DR. GUTMAN:
Obviously, Elliott pointed out in biologics there are. In the center for
devices, there is a handful.
There are well established standards, for example, for
cholesterol testing as an international standard for glucose testing.
If any of you have spent much time pursuing the general
laboratory literature, you will be astounded by the paucity of information
there is on performance of devices, and how good is good enough.
Our work group takes a somewhat contingent approach, as
Arleen pointed out. Where it is going
to be used and why it is going to be used might determine what kind of performance
we would expect, but there isn't a rule of thumb, and there isn't anything cast
on gold tablets.
DR. COWAN; If I
could just add on to that, question one, I am going to be asking of the
committee, the BPAC did concur with the standards for performance that we had
recommended back in 2000, and that is 98 percent as the lower bound of the 95
percent confidence interval for sensitivity and specificity.
That was based on state of the art for tests such as that
up to that point. The first question that we are asking, of course, is, is the
standard which we are currently applying to rapid HIV tests appropriate for use
with an over-the-counter test as well.
The two centers do differ, depending on what the analite
is, depending on the public health significance, for what the minimal
acceptable level of performance actually is, that we chose to have as a
criterion.
DR. DI MICHELE:
Okay, thank you very much. The bad news is we are behind time. The good
news is that, on the revised schedule, we are on time. I will hand this over to you, Don, to
initiate the public hearing.
Agenda Item:
Open Public Hearing.
MR. JEHN: As part
of the FDA advisory committee meeting procedure, we hear open public hearings
to give members of the public an opportunity to make statements concerning
matters pending before the committee.
Madame Chairperson, at this time, we have 12 written
submissions. These statements, when they are cleared, they will be posted on
our web site.
We also have received 19 requests in advance for oral
presentations, and we are asking that they be held to five minutes each, and do
you want to go ahead and read your statement?
DR. DI MICHELE: I
need to read, verbatim, a statement prior to opening the public hearing
session, and it is the open public hearing announcement for a particular
matters meeting. It goes as follows:
Both the Food and Drug Administration -- the FDA -- and the
public believe in a transparent process for information gathering and decision
making.
To ensure such transparency at the open public hearing
session of the advisory committee meeting, FDA believes it important to
understand the context of an individual's presentation.
For this reason, FDA encourages you, the open public
hearing speaker, at the beginning of your written or oral statements, to advise
the committee of any financial relationship that you may have with the sponsor,
its product and, if known, its direct competitors.
For example, this financial information may include the
sponsor's payment of your travel, lodging or other expenses in connection with
your attendance at this meeting.
Likewise, FDA encourages you, at the beginning or your
statement, to advise the committee if you do not have any such financial
relationships.
If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude you from
speaking. With that, we will open the public hearing.
MR. JEHN: There are
three microphones behind the committee, and we ask -- I am going to call off
several names to begin with, so we can sort of queue so we can sort of speed
things up. Again, everybody is entitled to their time. Mr. Elliott Millenson, Dr. Wendy Strong, and
Mr. Wesley Rodriguez.
Agenda Item:
Remarks of Elliott Millenson.
MR. MILLENSON: Hi,
I am Elliott Millenson. I was founder and chief executive officer of Direct
Access Diagnostics, which was a Johnson and Johnson company which developed Confide,
the first home AIDS test approved by the FDA.
I no longer have any financial interest in AIDS testing,
but I do have an interest in public health. I am here to offer some history on
home AIDS testing, a perspective on how FDA's actions have been perceived by
industry, the folks who must commit the resources to bring a home test to
market, and some thoughts, as an armchair quarterback, on where we go from
here.
I am a businessperson, but I worked with the U.S. Public
Health Service in the 1970s, helping educate Americans of the health
consequences of smoking.
I have seen first hand what those in public health face.
Strong science sometimes needs stronger politics. When I had the idea for a
home AIDS test, I thought of developing a rapid test, since the technology was
available.
It was clear FDA would not approve such a test. So, we
developed a blood collection kit instead, and sought FDA approval.
We expected, after approval, we would quickly transition to
a rapid home AIDS test, which we always knew had much broader appeal.
Even getting Confide approved turned into a nine year
battle. It started with our 1987 application, to which FDA responded by placing
a ban on all home AIDS tests.
FDA announced, in March 1988, by letter to our company,
which they copied other companies on, as I gather from their history, but we
were the only company which had actually submitted data, based on clinical
trials at Johns Hopkins.
FDA responded that they would only consider AIDS test
applications -- quote -- for professional use only in a health care
environment.
Industry believed FDA's ban was politically motivated. FDA
was pressured by AIDS activists, who feared the social consequences of making
AIDS tests too easily acceptable, and clinics who feared the financial
consequences, reduced government funding, if home AIDS testing caught on.
Opponents have lobbied aggressively against home AIDS
testing at all levels of government, with particular focus on FDA.
Opponents conjured up the scare tactic that face-to-face
counseling was essential to prevent suicides, a claim that, as you heard
earlier, had absolutely no scientific basis.
In fact, for well over a decade, studies have revealed the
overwhelming majority of people getting testing for AIDS haven't received
counseling anyway.
For perspective, in 1992, CDC conducted a survey and, as
part of that survey, at my company's request, they asked about counseling.
That survey showed, in public clinics, 79 percent of people
received no counseling, no pre-test counseling or no post-test counseling, 79
percent.
If counseling was so important to avoid this grave social
consequence, to avoid suicides, why didn't CDC threaten to cut off funding to
those public clinics who didn't provide counseling?
That same survey showed 89 percent of people getting tested
in private settings -- at their doctor -- 89 percent received no pre-test or
post-test counseling.
The same question for you to ponder. If counseling was so
important, why didn't FDA put a boxed warning label on HIV test kits, warning
doctors of the grave consequences if counseling weren't provided. Why haven't either of those agencies done
anything to this day?
It took two lawsuits from my company just to get FDA to
consider our application. Finally, in
1994, FDA brought Confide, our company's product, before this advisory
committee, the predecessor committee, which expressed support.
In a subsequent private meeting, documented in a smoking
gun memo aired by CBS news, CDC opposed Confide which, I should mention, they
had publicly supported.
In private, they opposed it, arguing that approval could
lead to -- quote -- a sudden increase in referrals to already over-burdened
health clinics.
Two more years passed. About 80,000 more Americans became
infected before FDA finally approved Confide in 1996, nine years after FDA
refused even to consider our applications.
That is all history now, but past actions affect future
actions. AIDS is an incurable sexually transmitted disease that has already
killed half a million Americans.
Every day, over 100 more men and women in America become
infected with HIV, most from sex with an infected person.
That is a wake up call. Some people don't abstain, aren't
faithful, and won't use condoms. Actual
use data represent a 10 percent failure rate for condoms, and that is a
conservative estimate.
You have been talking about labeling today. If you look at
the labeling for condoms, you won't see that mentioned, but it is a
reality. Any number of studies have
shown it.
That is particularly worrisome, since an alarming number of
people who know they are infected with HIV don't tell their partners.
Encouraging people to know not just their HIV status, but
that of their partner as well could save many lives and reduce much suffering.
Let me give you some perspective, because we were talking
earlier, the question about people testing their partner while they are
sleeping in bed.
I am worried about what people do in bed when they are
wake. Forty-two percent of gay men self
report that they haven't informed their partners of their HIV status, 21
percent of heterosexual men and 19 percent of women.
The only true safe sex is sex between two uninfected
partners. We teach our children to put condoms on cucumbers. We need to teach
our children the importance of AIDS testing.
In our sexually active society, testing must be accessible
in many places, especially the home. The majority of people don't want to go to
a doctor's office of clinic for an AIDS test.
Let me go back to some CDC data. CDC -- and you haven't hard this here this morning -- they have
known it for well over a decade.
They know a rapid test could quadruple the number of
Americans getting tested for AIDS. It is a good sign that a company presented
here today. I can prove I have no financial relationship. I haven't mentioned
their name.
FDA needs to encourage many companies to develop and market
home AIDS tests. Competition means less
expensive, faster, more reliable, and more user friendly home AIDS tests will
be developed quickly.
Companies skilled in reaching consumers will educate
Americans about the benefits of AIDS testing, and responsibly market their
tests through a broad range of distribution channels including, no doubt,
public clinics, who can give the test away to those with limited resources.
Senior executives at major health care companies believe
that FDA has had a strong bias against home AIDS testing. How could they
not? For two decades.
America's most innovative companies will be slow to commit
their research and development dollars to home testing, unless it is clear that
FDA's long-standing opposition has truly softened.
For perspective, I don't know if those of you on the
committee know this, but 15 years ago, when the FDA held its advisor's meeting,
it was held as part of a settlement agreement.
I sued them. They proposed settlement and said, Elliott, we
will hold an advisor's meeting to consider your product.
You know what they said before that meeting? They said, in The New York Times, we are
holding the meeting because new treatments mean people are less likely to have
adverse reactions to an AIDS test result.
I think the politics have really changed this time. It is
too late for a lot of people, but I urge you, the advisors in this room,
recommend FDA send a clear, credible, decisive message to industry that FDA is
not just accepting applications. It is strongly encouraging them. Thank you
very much for your time.
DR. DI MICHELE:
Thank you, Mr. Millenson. I appreciate your comments. By the way, I just
wanted to indicate to the committee, because there are so many statements being
read at the public hearing, that we won't specifically ask questions of any of
the speakers, if that is okay with everyone, but if there are any questions, we
can ask them at the time of our committee discussions. Is that all right with
everyone? Okay, thank you again. We will move on.
Agenda Item:
Remarks by Wesley Rodriguez.
MR. RODRIGUEZ: My
name is Wesley Rodriguez, and I am from the Latino Commission on AIDS in New
York. Thank you for this opportunity to
testify today.
As the Blood Products Advisory Committee hears a proposal
from OraSure for its oral fluid OraQuick advanced rapid HIV antibody test, the
Latino Commission on AIDS is a national and regional organization dedicated to
addressing HIV and AIDS in the many Latino communities throughout the country.
We have never testified before this or any other panel
convened before the FDA. We are here
because almost one half of Latinos who are positive do not know their status.
An over-the-counter home test that provides rapid results,
that is available in any drug store or on line, would have direct and indirect
benefits that would result in more Latinos knowing their status and getting
connected to care.
In addition, the mere fact that the test would be available
just as simple as glucose tolerance and pregnancy tests would help to
de-stigmatize this HIV test.
The stigma associated now with testing is that only bad
people get HIV and AIDS, men and women who use drugs, homosexuals, and/or seen
as promiscuous, are viewed by many Latinos as persons who become HIV infected.
So, just taking the test is seen, in many parts of the
Latino community, as admission of engagement in this bad behavior.
Making a test that produces rapid results over the counter
would help to routinize HIV testing, but we all share the responsibility for
fostering and even encouraging the stigma associated with HIV testing in the
past.
First, many state laboratories make it very difficult to
obtain the limited waiver necessary for rapid testing currently.
Some jurisdictions require that a nurse or a medical
technician administer the oral rapid test. Others charge exorbitant fees for
these community based organizations that want to offer the rapid test.
Still others make the application process needlessly
complex. This contributes to the inaccessibility of the rapid test for those
organizations that truly know the communities they serve best.
This patchwork of regulatory requirements only serves to
collect revenue for state governments and protect jobs.
The requirements have little to do with public health,
especially with the enormous investment that they have made in training
community organizations to offer the testing.
Second, many HIV and AIDS organizations and clinics have
made a sizeable real estate and personnel investment in the testing process.
The possibility of a home, over-the-counter quick test
threatens their revenues and grants of these organizations.
Many of them will try to block the approval of this
over-the-counter rapid test for reasons that may be public health oriented,
such as proper counseling or coercive testing, but in reality, they turn on
financial concerns for their organization.
Third, the FDA and CMS have contributed to this mythology
that only certain people can perform the rapid test, with the licensing
requirement and the requirement of control tests.
Hundreds of thousands of dollars have been spent on control
kits that many in government and industry will tell you are completely
unnecessary.
All of these very powerful forces have combined to make
testing as something other than routine. They have helped to perpetuate this
hysteria that surrounds HIV to this day, surrounds the HIV positive test
result, and helps to reinforce fear that many Latinos feel when they get a
positive result.
Still, there are legitimate issues that must and can be
addressed in any over-the-counter rapid test. First, the package inserts need
to be written in a very simple language that explains the necessity of a
confirmatory test, also follow up medical care, the time lag between infection
and the production of an HIV antibody.
While our concern is that the inserts be easily available
in Spanish, other languages are also as important for the African and Asian
communities.
Second, the telephone service that comes with the home test
needs to be comprehensive and in several languages.
We conducted an informal survey at the commission of the
home access telephone service, and found it to be excellent in providing needed
referrals, access to medical and mental health care, the importance of partner
notification, and the need for a confirmatory test. So, we know it can work.
We would only recommend that some way be found for the
company offering the service to obtain a HIPAA waiver from the purchaser, that
would enable them to contact a person testing positive in some manner that
respects privacy, but ensures that there is follow up. We need to think outside the box to make
sure that persons testing positive are connected to care.
Third, state and local health departments need to collect
information on persons testing positive in their jurisdictions.
This can be done through emphasizing that the
over-the-counter test is only a screening device that requires a confirmatory
test.
Through the confirmatory testing, or subsequent medical
visits, the government can collect the necessary information it needs.
The confirmatory test and follow up medical visit is a
challenge to the current system and will be probably a continuing challenge for
the rapid over-the-counter test.
The advancing HIV prevention initiative of the CDC is an
important step in reducing the number of HIV infections in the Latino
community.
Testing, condom use, monogamy and abstinence are all
critical to lowering the number of new infections, but any testing, whether
over the counter or in person, needs to be culturally and linguistically
responsive.
It also needs to be responsive to the rigid gender roles
that impact on men and gay women, and contribute to accessing care and testing.
It also needs to be responsive to the Latino family
realities that often fail, the man or woman testing positive for HIV, because
of the stigma surrounding an HIV test that is positive.
It also needs to be responsive to the immigration realities
confronting many Latinos, making their accessing medical service, housing,
employment, and stabilizing their immigrant status more problematic.
It also needs to be responsive to the religious context of
many Latinos that fosters the stigmatizing of so many behaviors associated with
HIV infection.
Finally, it needs to be responsive to the sexual silent
imposed on so many Latinos, which make it so difficult for Latino parents to
discuss HIV with their children, or openly confront homophobia and sexism.
All these challenges can and must be met by any counseling
offered by the company offering OTC rapid HIV testing, in partnership with
medical and community based social service providers.
Ultimately, only a relatively small number of Latinos may
take advantage of this over-the-counter rapid test but, for those persons, we
need to respect their choices for home testing, and the fact that HIV infection
is no longer a death sentence.
By providing a rapid test over the counter, we are one step
closer to making it clear that HIV and AIDS is just one more chronic disease.
It is manageable with education and care, and preventible with education. Thank you.
DR. DI MICHELE:
Thank you, Mr. Rodriguez.
Agenda Item:
Remarks by Patrick Keenan.
DR. KEENAN: Good
afternoon. I am Dr. Patrick Keenan with the University of Minnesota, Department
of Family Practice. Thank you for
allowing me to make a statement at this meeting. It is exciting to be here
discussing even the possibility of an over-the-counter rapid HIV test.
Financial disclosure, OraSure Technologies paid for my
flight and hotel so that I could attend this meeting. Otherwise, I have no
disclosures.
My background, in Minneapolis, we have done operational
research on the use of OraQuick in the outreach setting, using both whole blood
and oral fluid.
We did a CDC funded project from July 2002 through August
2004. When we started the project, OraQuick was still an investigational test.
We have had ongoing rapid HIV testing projects with the
Minnesota Department of Health. In the past three years, our outreach workers
have done over 5,000 OraQuick tests in diverse settings, such as homeless
shelters, chemical dependency programs, patient home visits, et cetera. So, I feel we know this test well, and I
would like to tell you about some of our in-the-field experience with OraQuick.
I would like to comment on the technical simplicity of the
test. We found that, with a minimum of training, basically the time it takes to
demonstrate one run through of the test, about 30 to 60 minutes, people from
diverse backgrounds, such as being a printer, a bus driver, chef or bartender,
were able to do the test well. We
trained 14 workers with the test.
Of course, to train a good outreach worker, we had to cover
a lot of other topics, such as universal precautions, HIPAA, pre and post test
counseling.
In fact, we felt that the teaching of the OraQuick testing
procedure itself was the easiest part of the outreach worker training.
Certainly even this brief amount of training is a lot
different from the anticipated over-the-counter use we are talking about today.
How people would do with no previous training certainly
needs to be studied extensively, but it is a fact that you don't have to be a
laboratorian to perform this test.
Second, I would like to say that OraQuick is a robust test.
Our team demonstrated, sometimes inadvertently, that this test held up to
temperature extremes in Minnesota weather without loss of accuracy. I don't want to go into that further.
We had very few problems with invalid tests or controls. We
did external controls with each worker every day for two years, and we never
had an invalid control.
In the 5,000 tests we have done in the outreach setting, we
have had only seven invalid tests. Five were blank with no lines at control or
test line areas. The other two had been
dropped on the floor. I haven't heard whether there was a cat involved or not.
Sometimes, for training purposes, we made use of test
devices that had expired dates. We found that the control and test lines became
gradually fainter after several months. So, use of expired test devices is a
real concern with OTC use of this test, because it could lead to false negative
tests.
Post-test counseling, the information that accompanies the
OTC test must emphasize the possibility of a false positive test.
In Minnesota, we tested the highest risk persons we could
find. We had about a one in 200 to 300 rate of true positives.
Our rate of false positives was just about the same, about
one in 200 or 300. So, our positive predictive value was roughly 50 percent.
I think that, in a lot of populations with OTC testing,
this is the kind of positive predictive value that would be expected.
I would also like to talk about what I call a knowledge
gap. >From personal experience, I think there is a knowledge gap between the
public health community that knows a lot about rapid HIV testing, and the rest
of the medical community which does not.
I speak of this coming from a primary care department in an
academic center. My concern is that a person with a reactive rapid HIV test
might see their doctor and receive inappropriate confirmatory testing or
counseling.
The post-test element of the packaging should specify that
a western blot is needed for confirmation, and the person with a reactive test
should be encouraged to impart this information to his or her physician.
If over-the-counter testing becomes a reality, I would
recommend an effort to educate primary care physicians about rapid HIV testing,
for example, talks at state and regional meetings, and perhaps a mailing from
their professional organizations.
Conclusion, the United States would benefit, I feel, from
having an over-the-counter, technically simple, rapid HIV test.
There remain many questions to be answered and much work to
be done before implementation of such a test, but I think the time is right to
start addressing those issues. Thank you.
DR. DI MICHELE:
Thank you, Dr. Keenan.
Agenda Item:
Remarks by Freya Spielberg.
I am pleased to be here today, to be a part of this
discussion. I would first like to say that I don't believe that I have a
conflict of interest with OraSure technologies. I am not a consultant and,
sadly, I do not have any stock in the company.
I did, however, accept travel expenses, so that I could be
part of this today, and I appreciate this.
I am an assistant professor of family medicine at the University
of Washington, and a researcher in the Center for AIDS Prevention Research
there, and have spent 15 years, actually, studying rapid testing and
alternative HIV counseling and testing strategies, both in developing the test
and in looking at use in the field, and acceptability of different strategies.
I have done a small study recently that looked at
acceptability and feasibility of self testing for HIV that I want to share a
little bit of data with you from today.
I don't need to go over the need, because we have heard it
over na dover again today, but I think that certainly there is clear reason to
believe that the epidemic is being fueled by these 250,000 people who are
unaware of their status, and that an over-the-counter test could actually have an
impact in changing that steady rate of 40,000 new infections each year.
When people find out they are HIV positive, it actually is
the most powerful prevention intervention we have to use, even in all the
behavioral interventions that are being promoted, many of which have been
proven effective in good studies. Still, finding out that you are positive is
more positive than any of those.
So, why an over-the-counter rapid test? Studies have shown that self testing is
actually preferable to people at risk, who have never tested.
I have done survey studies among over 400 high risk people.
Also, a study in UCSF found the same thing. People who have never tested are
more likely to prefer an over-the-counter test.
Also, I think it is important to realize that self testing
or an over-the-counter test is more preferable than a home specimen collection
test.
I did qualitative studies to find out why people preferred
different strategies, and learned that people with the home specimen collection
test didn't like a few things about it.
They had to collect it themselves. So, they could make
mistakes, but also, of course, they had to wait for results, and they had to
put it in the mail, and no one really trusts the mail. So, you could wait for a
really long time, and that caused a lot of anxiety.
Then, getting the results over the telephone, even though
it is anonymous, people can figure out where you are calling from. So, it is
not actually so anonymous.
People were actually 25 times more likely to prefer a self
test than a home specimen collection kit, and I think we can expect the market
for this test will be much greater.
I think it is also important to think about
over-the-counter testing in the context of stigma, and that in areas and
communities where there is high stigma around HIV testing, that may be keeping
people out of the clinics. This is an option.
Also, the safety. I think you have already heard the data,
so I won't go into that, but there are a lot of fears that haven't really been
confirmed by evidence.
We need to do the right studies to make sure that getting
the test results doesn't cause increased risk, but we don't have any reason to
believe that it would.
So, the questions that have to be answered are: Can people perform the test accurately? Will they understand the meaning of the test
results? Will they follow up for
counseling?
I am really interested in finding out what type of
education and counseling will be necessary to ensure accuracy, safety and
follow up.
One of the other research projects that I am involved in
is, we have created an interactive computer counseling tool that we are using
in an urgent care, where the staff couldn't do HIV testing, because they didn't
have counseling.
We have found that, with that counseling with the computer,
people have good levels of understanding about the test and we are hopeful that
it will also result in risk reduction.
So, something like that could also be used in the context
of an over-the-counter test, either through the internet or in a kiosk in a
pharmacy. Clearly, for post-test
counseling, 24 hour telephone counseling will need to be available.
I think it is also important to think about how much people
will be willing to pay. In the home
specimen collection kit that was priced $35 to $50, that is clearly high above
what the people who really need the test are willing to pay.
So, we are not going to have much public health benefit if
the test is priced so high that no one is willing to use it.
I conducted a preliminary study of self testing to see just
what people thought of it, whether they would be able to take a kit without any
instructions except for written materials, and perform it, what the
difficulties were in performing the test and interpreting the test.
Initially, what we did was, we performed this in the
Madison Clinic, which is an HIV clinic in Seattle. It is an urban, kind of
underserved setting. So, very diverse, low socioeconomic status, low education
level.
I wanted to find out, among people who already were HIV
positive -- so they knew what it was like to get a positive test result -- what
they thought about an over-the-counter test.
We did seven waves of 20 people. We did observations to see
what the difficulties were. We adjusted the instructions to try to address some
of the difficulties, and then we held the instructions fixed and performed
another 100 tests. We asked about
preferences, and about willingness to pay.
What is important to think about with this data is that
this is probably the most difficult population, and with the most difficult
climate for the test, I suppose, in that 70 percent of these people were on
antiretrovirals.
You have already heard data today about how that decreased
the signal level. So, I think that this is a very low estimate of the
sensitivity.
So, we saw, for finger stick and oral fluid, there were
five to six false negatives out of 100.
All of those people were on antiretrovirals.
We also saw almost 10 percent invalids. What the invalids
were due to -- and this is something that will need to be addressed by the
instructions.
We did make some dent, but there were people that would
actually take the device, and they would put it in the fluid, then put it in
their mouth, then lie it down, or they would put blood right on the device and
then lay it down, and they wouldn't interact with the fluid in the right
way. So, that led to invalid results.
The invalids, however, I think we can tolerate a certain
level of invalids, because those people realized, oh, the test didn't work. I
need to do it again, or I need to go somewhere else for testing.
Preferences, this was really interesting, I thought. As far as location, where would you prefer
to test.
If you didn't know your HIV status, where would you prefer
to get your test results, and find out you are positive.
Sixty-one percent said they would prefer to get it at home.
These are people who knew what it was like. Privacy was considered much better
with the home kit, convenience obviously much better. They were more comfortable doing the home kit, it felt safer to
them.
The only thing that wasn't as good with the home kit was
accuracy, but clearly, a lot of the people who felt that it wasn't as accurate
still preferred to do it, because their other priorities were more important.
Willingness to pay.
There was a clear cut off in what people are willing to pay. If the test
cost about $15 around 70 percent of the people would be willing to buy it and
use it.
When you go above that, you see a marked drop off. So, I
think that is something that will have to be considered, and I think we also
need to be creative about how this test is gotten out there, and that there may
be a place for public health to subsidize use of these kits, if it makes it
possible for people to afford them and to use them.
Clinical trial considerations, as others have said, I think
it is really important to do the clinical trials among the populations where
the marketing is planned over the internet and the drug stores, et cetera, and
in high risk outreach venues, so we get some data on what the effectiveness
would be if we did use it in public health settings.
This question of how sensitive does an over-the-counter
test have to be is, I think, a really important one. If the main goal is to
increase the number of people in this country who are aware that they have HIV,
then we can actually tolerate a lower sensitivity in this test than in a test
that we might use in a clinical setting.
I say that because there are a substantial number of people
out there who won't access testing in other places.
So, those are people who are only going to be identified if
you have a home test. The risk, of course, is if there is a lower sensitivity,
then there is going to be a certain population who would have tested in the
clinic and gotten accurate results, but switch over, use the over-the-counter
test, and may be one of the people who are false negatives.
I think that is the balance that really has to be weighed
out. Looking at just sort of modeling some of the considerations -- this is
just a rough estimate -- but say that the sensitivity is greater than 80
percent even.
The benefits of a test would outweigh the risks if, for
every one first time tester who tested positive using an OTC, there were less
than five people that switched over, that would have gone to a clinic but,
instead, used an over-the-counter test.
If you assume that over 25 percent of the testers will be
first time testers -- which is conservative, because with home specimen
collection, it was 49 percent that were first time testers -- then there may be
a ratio of one new tester to less than four to five that switch over.
I think, in the least favorable circumstances, from the
study that we did, the sensitivity was round 93, 94 percent.
I think that -- well, I think two things. I think that it
is very likely that they will be able to design a test that has much higher
sensitivity than what I saw here, given the limitations that we discussed.
I also think that, even at lower sensitivities, it is
pretty clear that the benefits will likely outweigh the risks.
Post-marketing studies we have already talked about. We
need to see what happens to these people. Do they follow up for care, is there
increased risk of adverse events.
There will be good mechanisms, I think, to do some of this
follow up by integrating into some of the existing behavioral surveillance that
is going on, but also I think a longitudinal follow up should be requested
among the subset of the people that test using the product.
So, in summary, I think the main concerns, especially of
suicide, the risk of self testing remain unproven.
I think actually the concerns about increased anxiety with
positive test results, I think that is rather beside the point.
I mean, we wouldn't say don't do a home self breast exam,
because if you find something it might make you anxious, and we don't want that
to happen.
The ultimate goal is to get people so that they are aware
of their status. .There may be some anxiety associated with that, but if they
find out they are positive, they can access life saving treatments, and stop
infecting others.
So, I think that the FDA should move forward quickly to
encourage clinical trials for an over-the-counter rapid test.
I think that it really is one of the few tools that we have
to change the course of the epidemic right now, anyway. I am hoping that it is fast tracked. Thank you.
DR. DI MICHELE:
Thank you, Dr. Spielberg. Dr. Waheed Khan?
Agenda Item:
Remarks by Waheed Khan.
DR. KHAN: Good
afternoon, and the honorable committee members. My name is Waheed Khan. I am a retired physician and scientist from
Children's National Medical Center here in Washington, D.C., and now presently
I am president of ASCO, Inc., who is involved in research and education for
HIV/AIDS.
Before I start saying anything, let me mention that I have
no interest in any of the companies dealing with this product.
So, my comments will be not as highly educational as the
colleagues and previous speakers have presented here, but I am also a world
traveler, and I have traveled practically all over the world, and I have seen
the devastation of AIDS, especially in Africa and in India.
I know all the extent of tests which are available to
people over there and here. Last year, I was in South Africa, and I saw every
test available in this country and also abroad. They were available in the pharmacy for people to use it, buy it.
I went to the pharmacy and they offered me -- I inquired,
and they wanted to sell me. So, what I am saying is that all the technologies
which are developed here, they are not available to the benefit of the people,
average people here, whereas the rest of the world is taking advantage for
themselves, and for their children and also for their spouses, making good use
of whatever is developed here.
So, if I can put in a similar example, that all the
medications which are available for AIDS -- ARVs, which are available in other
countries at a very small fraction of the cost that it costs here, we have a
situation where many of the states here are trying to get all medications,
including the ARVs, from Canada with a 30 or 40 percent discount, and there are
people in the government who are not in favor of that.
Anyway, I am very much in favor of these home tests. Last
April, I submitted a paper in a conference which was going to happen, arranged
by CDC and, unfortunately, it was not accepted.
By the way, I have circulated an abstract of that thing
here, but what I would like to emphasize is, to give you an example, I am a
diabetic for the past 20 years, and I have used the home glucose test.
I quoted my numbers as 16 million people in the United
States doing this home use glucose test, and I am not aware of any single -- I
am an infectious disease person. So, I am not aware of any single case where,
by finger pricking everybody, that anybody has gotten an infection or gotten
into trouble.
Similarly, now that this new company, OraSure, have come up
with an oral test, which is far simpler than doing even glucose tests, so again
I would say, it is highly recommended that this should be followed and, if
possible, I would recommend to FDA to speed up this process.
I did learn that, even for a simple pregnancy test, FDA
took 12 years to approve it. Now, today, I learned that it was a grandfather
clause that brought it in rather than -- so, as a practical advantage, if I may
make one suggestion.
Recently, I read in the papers that circumcision gives 60
to 70 percent protection against HIV. I would recommend to my non-Muslim or
non-Jewish people, to get ready for that protection.
I must also tell you today, today is our end of Ramadan,
which makes it even fitter. This is a very big family affair, and the
equivalent of Christmas, that kind of celebration.
I knew this committee was holding this session, and I had
presented my little thoughts on the subject. So, I forego the family get
together, but I would recommend very highly that, for the human family, let's
get together on this thing, and approve all of this home testing as soon as
possible.
DR. DI MICHELE:
Thank you for being here, and thank you for comments, Dr. Khan.
Agenda Item:
Remarks by Patricia Charache.
DR. CHARACHE: I am
Patricia Charache, and I represent the American Society for Microbiology. My formal title at Johns Hopkins is program
director, quality assurance and outcomes research.
The position of the American Society for Microbiology is
that the home use of HIV antibody testing removes all responsibility for result
interpretation and counseling from trained professionals, and that erroneous
test performance represents a significant risk, not only to subjects, but to
society at large.
Such consequences, we felt, could not be justified in the
name of increased susceptibility at this time.
The requirements for the waive test is where we have
started, and that is that there are essentially two, to employ methodologies
that are so simple and accurate that erroneous test results are negligible, an
they pose no reasonable risk of harm to the patient if the test if performed
inaccurately, and I am going to just address each of those very briefly.
I am going to go quickly, because I will try not to repeat
those points that have been made by others this afternoon and this morning.
The risk of error varies with the nature of the population
being tested. I think important there
is the fact that, with the home test kits, the purchasing population cannot be
accurately controlled.
Now, all submissions -- this I haven't heard before here --
of waive tests perform studies. They perform studies to show that the untrained
can give accurate results.
I think we should emphasize that the results from such
studies need not reflect the accuracy when the test is put out on the market.
The experience is that frequently it does not. In part,
that may be because, in the test setting, you have people who know they are
supposed to read the instruction and follow them closely, and in the market
that doesn't happen.
For the ASM, I think the best example of this is the other
infectious disease test that was licensed for influenza.
In trials, it had a very high sensitivity, which is
important for that particular assay. In the market place, its sensitivity fell
to about 50 percent, meaning that patients would be returned to a nursing home
who, in fact, had the disease and perhaps should have even had an antiviral
agent.
So, the tests that show the comparisons of the ability of
an untrained person to do the test may not parallel out on the market.
Now, in this case, with the OraQuick, we saw that only 12
percent of the patients tested in the untrained studies had 11th or 12th grade
educations. Four percent had a GED. Everybody else had advanced learning beyond
high school.
That is not likely to be the only population that purchases
the test. So, even in the study groups, there may be disparity.
Now, I am not going to go over many of these because Dr.
Howerton reported on many of these, but it certainly is the ability of the
purchaser to read the directions, ability to follow the directions they have
read, ability to monitor time and other test requirements, and we are
particularly worried about the time test, because 20 minutes is a long time,
and they will get false negatives if they don't follow it. We are worried about whether or not they
have cats.
Now here, also, I would emphasize that compliance with confirmatory
testing cannot predict compliance with confirmatory tests that are done by
looking at the results of the current OraQuick waive test, and trying to
predict what we are going to see with an over-the-counter test.
I think we have to remember that, with the waive test, the
patients are not simply deciding whether it is a yes or no. Somebody is telling
them the results, advising them on how to interpret the test.
They may not see a particular counselor, but somebody is
answering their questions and usually making sure that they know where to go to
get a confirmatory test, and in some settings, particularly the hospital
settings, they may get appointments to clinics or, in other places like our own
institution, they will get the blood drawn for the confirmatory test.
So, you can't predict from current confirmatory studies
what would happen when there is no consultative support from anyone.
This is just taken from the study that was already quoted
here by CMS, showing the compliance and the ability of waive test laboratories
to do a waive test correctly.
This happens to be a very minor modification of Judy Yost's
slide, that summarized these studies for CLIAC. What they did was look at about five percent of all the waived
laboratories in each of eight states, and they found the important factor here
would be that 48 percent of the waived laboratories had quality testing
problems. We can anticipate that an
over-the-counter -- a home sale product would not be any better than that.
Now, we have talked about some of the very simple things
with methodology that are challenges, if it is an over-the-counter test, but I
would like to comment now on just a few of the second aspect, the no
unreasonable harm.
I think what we have to emphasize here is that the risk of
harm will vary with the likelihood of a purchase from a high risk population
versus a member of the worried well, and that will have to do with the
predictive value of the test, as has been discussed.
I can certainly speak from personal experience with working
with patients who had a false diagnosis of HIV when they didn't have the
disease.
I will just give you one example, a woman and her spouse
both sold their private businesses, bought a Winnebago, and decided to drive
around the United States until they found she was too sick to travel. It was a false test, and it actually
destroyed their lives and their marriage.
The demographics of the purchaser, we said, cannot be
predicted, but a subject from a low risk population has a high likelihood of a
false positive, such as the worried well, and it can lead to substantial harm,
just as a false negative would lead to delay, or less likely to get the test
done elsewhere, and delay in appropriate management strategies.
Of highest concern to the ASM is the fact that HIV is a
contagious disease, and that the error can harm not only the subject but also
partners and others who have someone who is unknowledgeable about his status,
but thinks that he knows it. It isn't
that he doesn't know if he knows or not. He thinks that he is safe.
Now, we do believe that the way to control such an epidemic
is access to quality testing, but we think access to testing which has major
questions of accuracy is a greater risk than developing strategies for making
controlled tests available, and tests in which there can be some type of a
professional, whether it is someone in a group that is interested in HIV, or
whether it is a physician or nurse, who can help guide the patient. Thank you very much.
DR. DI MICHELE:
Thank you, Dr. Charache.
Agenda Item:
Remarks by Tracy Powell.
MR. POWELL: Good
afternoon. My name is Tracy Powell. I am the chairman of Home Access Health
Corporation. We are the company that is being referred to as collection
technology in the market place.
Let me first have a disclosure, that I am not financially
involved with OraSure, although if they are looking forward to reimbursing my
expenses, it would be appreciated.
I have the challenge to convey everything I have learned in
the last 10 years in the next five minutes.
Because I am not a scientist, regulatory person, what have you, my brain
is a lot smaller than all of you sitting around the table, so I think I can
handle it.
We are honored to have received FDA approval from both CBER
for HIV at home testing, as well as CDRH for hepatitis C at home testing, and
we are privileged to service hundreds and hundreds of thousands of Americans,
who have placed their trust in us for education, testing, counseling, referrals,
confirmation testing, et cetera, under a world class medically directed system.
It is important for me to point out that what we do is not
a kit, a test. It is a subset. Testing
is a subset of what we do.
Our system works in a way that there is a collection device
that allows an individual to take a micro sample of blood very simply, and I
say simply because 96 percent of people who take our test do, in fact, get
their results.
A small sample is submitted into a return mailer, to a
laboratory, and there is a code number that is attached to that testing system.
That code number gives access to a medically directed
system, not a test, but a system. When
we tell someone that they are positive for HIV, they are positive for HIV. I think that is extremely important and
germane to this discussion.
Now, with respect to my opinion, or Home Access' opinion of
rapid testing, at home testing, I am all for it. I think it is a great, great
thing, but done so in a systematic way.
There is no reason why standards should be lowered. The
system that is in place today is bullet proof. It allows people to get tested
in a very highly, highly, standard environment.
I would like to clear up what I think are a couple of
misconceptions about rapid testing, over the counter. First of all, it is going
to open the flood gates, and we are going to find 300,000 people, like that,
that are infected with HIV.
I don't buy it. Two reasons. This is an OTC approval. It is
a low risk population. Secondly, when we are out in high risk settings, and we
work with public health departments and community based organizations, and when
we identify many, many high risk individuals, and we ask them to go ahead and
take this test free, sometimes they will literally back up, like we are
projecting, magnetizing them.
That is not about time for results. That is about stigma.
If there were a cure, I would be altogether different about my opinion about
rapid testing and lowering standards that exist.
There is another misconception. A rapid test for HIV is
just like rapid testing for pregnancy. Well, I think a pregnancy test, a
positive result, is a happy thing and something that is life beginning.
A positive test for HIV is earth shattering. It is life
threatening. In the words that our counselors tell me, from many, many
individuals, it represents social death.
In terms of efficacy, my view, strongly, is that the
general population that we encounter, there is no difference today than there
was 10 years ago that we see, with respect to the confusion about HIV/AIDS. In
particular, what do you mean, window period. If I am negative, do you mean I am
not really negative?
By the way, learning that one is positive or, even worse,
indeterminant for HIV is the same catastrophe today as it was 10 years ago.
So, in summary, I truly believe that rapid testing is a
good, good thing, but I believe that it is a good thing if it is done in the
context of a system.
I agree, it should be approved if, systematically, all of
the elements that are such gold standard, high standard, that exist today, will
be demonstrated tomorrow by a rapid test that could theoretically be a subset
of an existing system.
There are a couple of things that concern me, about
lowering standards. When you deal with
negative test results, I can't even imagine -- in our case, under FDA guidance,
we made sure that every single negative test encounter goes along with an
educational interaction that says, you may not be negative, even though your
test says negative.
Why? Because there
is a window period. This is critical, to provide people, as opposed to having
them feel like, time to party.
Next, when someone gets a negative reaction, I can tell you
that our counselors say that the most traumatic thing that they deal with is an
indeterminant result, because people don't know. They are in never never land.
They are actually better to get finality around a positive result.
An indeterminant result, it is not good. We went to the IFA
method of testing as opposed to western blot for one reason. We wanted to avoid as many indeterminant
results as we could. I, as I did 10
years ago, believe that confirmation testing is a critical and needed test.
Lastly, people who are told that they are positive, or may
be positive, for HIV, they need immediate, one on one, professional assistance
right then and there.
I am not suggesting that they are going to commit suicide
if they don't get it, but there is a system that is well proven, that it
delivers information very professionally, and it allows people to get guided
into care.
The system that is in place today absolutely works and,
again, in my opinion, the rapid test as a subset to a system like that, by all
means, should be expedited for approval. Thank you, on behalf of Home Access
Health, for your attention.
DR. DI MICHELE:
Thank you, Mr. Powell, and for sticking to the time limits.
Agenda Item:
Remarks by Ernest Hopkins.
MR. HOPKINS: My
name is Ernest Hopkins, and I am the director of federal affairs out at the San
Francisco AIDS Foundation, and I would like to thank the Blood Products Safety
Advisory Committee for the opportunity to provide some remarks today.
First, let me state that the San Francisco AIDS foundation
generally supports the availability of at home HIV rapid test kits.
We believe the availability of such a product could play a
key role in increasing access to HIV testing, and in helping many Americans
more rapidly determine their HIV status.
With the CDC estimating that fully 25 to 30 percent of the
estimated 1.1 million Americans living with HIV are still not aware that they
are infected, clearly, we must continue to develop innovative and creative
approaches that will significantly reduce the number of people in our country
who are unaware that they are HIV positive.
At home rapid HIV test kits should be a part of a larger
effort, however. In particular, home HIV tests could be especially helpful and
useful for individuals who are uncomfortable seeking an HIV test at a
physician's office of HIV testing clinic, but who desire speedy test results,
and prefer the privacy and anonymity of testing at home.
They could also be used by those who feel they do not have
the time to spend waiting at a physician's office, or HIV testing clinic, and
would far more likely get tested if they could get speedy HIV test results at
home.
We recognize the potential misuses of this product, as
described by members of the panel and some of the presentations that have been
provide earlier today, such as a person somehow coercing or forcing a spouse or
sexual partner to take such a test, or an individual attempting to gather a
sample from someone else to be tested without his or her consent, and we
understand that those concerns pose significant issues that must be addressed
in the approval process.
We believe, however, that the benefits of such a product
outweigh these risks. Now, having said that, we also believe that the FDA needs
to apply rigorous criteria in reviewing such products, to ensure that they are
as effective as possible, and do not produce negative health outcomes for those
who purchase and use the products.
So, specifically, we recommend that the committee support
the following criteria:
Number one, the kits must ensure that those who purchase
and use the products are able to easily and correctly interpret the results.
It is critical that the person taking the test is able to
easily understand the results, and has ample and easily accessible information
that helps him or her understand what the results mean.
The fact that a negative test result could still mean that
the person is actually infected because of the window period, for example, must
be clearly explained in language that is easily understood.
Similarly, the remote chance that the test results could be
inaccurate needs to be explained in clear terms that will be understood by all
who use the product.
Two, the companies who sell these products must ensure that
the individuals who test positive have immediate access to emotional support
and counseling.
For many individuals, testing positive for HIV can create
significant emotional distress, and the individuals who find out that they are
HIV infected should have 24 hour phone access to trained emotional support
counselors, who can assist them with dealing with the array of reactions that
they may have.
Three, individuals who use the products must have an easy
and reliable mechanism to obtain referrals to HIV treatment and prevention
services in their local communities.
We believe it is critical that people who opt to use these
home use tests be able to quickly link to HIV programs in their area.
Those who test positive should be able to quickly identify
resources in their area that will assist them in getting confirmatory tests,
and to obtain HIV care, treatment and support.
Certainly, those who test negative or who have inconclusive
results should be able to easily get information about organizations that they
can turn to for additional information about HIV/AIDS.
Now, the product should also include information about the
risks posed by other sexually transmitted diseases, and how to prevent the
spread of both HIV and other STDs.
If a consumer is concerned enough to buy an at home HIV
test, because they believe they may be at risk for HIV, they may also be at
risk for other STDs.
We believe the manufacturer has a responsibility to help
educate consumers about this, and potential risks, to provide clear and
comprehensive information about how individuals can best protect themselves
from getting HIV and other STDs.
This information and these resources should be made
available in a variety of languages, also. In order to be effective in our
populations, as many individuals as possible must be able to understand what
their results mean, and where they can receive additional support and
referrals. So, at a minimum, materials,
emotional support, and referrals should be made available in Spanish.
Finally, these test kits must be priced appropriately to
ensure maximum utilization and benefit. If at home test kits are expensive,
they will be used by a much smaller segment of the population and our goal of
helping more Americans identify their HIV status will be undermined.
Especially given the disproportionate impact of HIV on
those with lower incomes, it is critical that these products be priced to
ensure that as many people at risk for HIV have access to them as possible.
We sincerely appreciate the time that we had to provide
those remarks, and we look forward to the results of your deliberations.
DR. DI MICHELE:
Thank you, Mr. Hopkins.
Agenda Item:
Remarks by Tom Donahue.
MR. DONAHUE: My mom
and my dad are grateful, grateful that I know, grateful that I have the
knowledge I need to keep myself healthy, grateful because I now know that I
need tools to keep me healthy and vibrant for years to come.
Good afternoon. My name is Tom Donahue. I am a 26-year-old
from State College, Pennsylvania. I am the executive director and founder of
anon-profit organization called Who's Positive.
Who's Positive is committed to raising the awareness of HIV
and AIDS and its consequences. Our organization foregrounds the reality of
living with HIV through first-hand accounts of young adults coping with the
disease.
Who's Positive strives to remind the public that this is a
virus that has no cure. Through the
stories of those living with HIV, Who's Positive hopes to reduce the
transmission of HIV among teens and young adults, a population with one of the
fastest growing infection rates.
I, too, am grateful that I know. Two years ago, I was
diagnosed with HIV. It was one moment of passion, of intimacy, of
irresponsibility, that was responsible for my infection.
I live in a rural town where my one local AIDS service
organization services two counties with four employees.
Young people are afraid to get tested in fear someone may
recognize one's destination might be the AIDS project.
I live in a community surrounded by students and stigma,
one main barrier which prevents young people from getting tested for HIV.
America has the tools for fighting and ending this
epidemic. I come before you today in support of the over-the-counter rapid HIV
test, and urge your immediate attention and approval to moving forward with
this proposal.
As over-the-counter tests will break down the barriers for
so many young people, it will allow smaller rural communities, who do not have
access to quick, reliable testing, to go out to their local drug store and get
tested in the convenience of their own home, while getting results back in 20
minutes.
I believe that this will significantly reduce the amount of
young people who are unaware that they are HIV positive, ultimately resulting
in prevention of more infections.
This committee must recognize the responsibility it has to
my friends and my peers, to your friends, to your family, and especially your
children, of giving an extra tool for them to empower themselves to get tested.
Young people continue to bear the brunt of the global
HIV/AIDS epidemic, with youth under the age of 25 accounting for more than half
of all HIV infections each year.
Through my work with Who's Positive, I go to different
schools and universities throughout the United States to share my personal
story about being HIV positive.
We use a peer-to-peer approach as a prevention tool, which
has been very successful. Since finding out about OTC tests, I have used this
opportunity as a forum to open dialogue with the young people on the issue.
The majority of young folks see this as an additional
resource, an alternative to facing one's actions and behaviors to a stranger
face to face.
They see it as a true confidential and anonymous test. They
see it as a way to help remove the social stigma surrounding HIV/AIDS, as a way
to reduce the amount of young people who don't know their status, and a way to
reduce the number of infections among young people.
Some have shared concerns. Many were uneducated. They were
unfamiliar with the rapid test and its accuracy. Some expressed concerns with
being alone if they were to find a positive result. Who would they turn to.
What resource would be available for them.
While raising these concerns, most still supported this concept.
As I end my comments, I don't end my fight, my journey
through this tough world of the unknown. Knowing your status is important to
you, your family, your friends and your partners.
I am very lucky. I am a very lucky uncle of three and a
brother of one. My parents and my family are saddened and challenged by the
actions which put me in the situation I am in, but they are relieved that I
know my status.
I now know I have the tools to keep me healthy. I have the
knowledge and responsibility for not infecting others. Most important to me, I
may live a bit longer to enjoy those moments with the ones I love, simply
because I empowered myself to know my status early enough in my journey to fight
HIV/AIDS.
At my request, due to our limited available funding, I
thank OraSure Technologies for providing transportation and accommodations, to
allow this opportunity to give you this perspective.
In the fight, with all these folks together, until cure is
found, I thank you for your time, and I request these remarks be submitted for
the record.
I am going to take one more second and go off my written
statements and say, I am HIV positive. When you need a perspective of somebody
who is HIV positive, come ask me. I am certainly open for questions.
Sometimes it is difficult for me to sit back and listen to
somebody say, this is the way it is, or this is what people tell me. I know. I
know what it is like to be HIV positive. I know what it is like to find out. I
am certainly willing to discuss it. So,
if you want a perspective of somebody who is HIV positive, ask me. Thank you.
DR. DI MICHELE:
Thank you very much, Mr. Donahue.
Agenda Item:
Remarks by Duralba Munoz.
MS. MUNOZ: Good
afternoon. I hope I am facing east,
because I always try to face east when I am talking about things like
this. I have no idea which direction I
am facing right now.
I am going to request -- I know I have probably less than
five minutes because some of us have spoken a lot already, but I always, in
memory of my friends, my colleagues, my family, when I am in a setting where we
are talking about HIV and AIDS, I always request from the public, again my
colleagues and my people, in this case because of restriction of time, I am
requesting from you half a minute of silence for all the millions of people who
have died of AIDS because they didn't have the resources, they didn't know
their status, and they died without the support and help that could have been
available, because this epidemic has been going on, has taken place since 25
years ago.
Again, my name is Duralba Munoz. I have been in the field
of public health now for 25 years. It makes me feel very old now when I look
back, and I hope that some of the people who are sitting in this room are some
of the people that were with me 20 years ago, when we were marching in front of
the White House, the Supreme Court, and places like that near by, demanding,
requesting, pleading, praying for resources for the people who were dying and
had no help.
Today, something very interesting happened to me in terms
of memories, when the doctor was talking about the incidence of suicides in
relation to people and their HIV status.
You reminded me, not of the people who I knew who were dear
friends and colleagues to me, of them committing suicide because they found out
they were HIV positive, but they committed suicide, many of them, because they
had no hope, back then, in terms of there was no AZT, and those who were taking
it, it was not working. The medications were not working.
The medications were not coming through in time enough to
save their lives. They lost hope, they wasted, and they have been gone for a
long, long time.
These were people that, if you were now with all these new
regulations from, for example, the CDC in terms of high risk categories, these
people were not high risk categories.
Back then, I lived in Boston. I lived in Boston for 22
years as a public health officer, as a senior executive in government, as a
Latina, as an activist.
We really had no choices. We had no resources. We had no
hope, and all we did as friends and colleagues was just meet at funerals.
It got to a point that we stopped going to funerals,
because the only way we would see each other was in funerals for our friends
and colleagues.
Now I no longer live in Boston. I moved to Miami Dade
County. So, now I am going to speak to
you as a Latina woman living in Miami Dade County, dealing with my people, the
Latino community, and feeling sometimes guilty of having spent 22 years of my
life up north, and now being down south and seeing that, in Miami Dade County,
and in most of the state of Florida, people are still talking about things that
could be done, that should be done, that were already done in places like the
state of Maryland, in Massachusetts, in New York, et cetera.
So, when I heard about -- first, when I heard about rapid
testing, that was an incredible relief to me. I am the executive director for a
community based organization that provides HIV services in terms of prevention,
Ryan White, prevention case management support groups.
We have a CDC grant. We are very honored to have received a
CDC grant, where we are trying to implement three of the famous daily
interventions that have been tested for the last 10 years, I believe, none of
which -- and I think there are either 15 or 25, and I am taking a risk here,
because I know there is somebody sitting here from CDC -- none of them apply to
the Latino community.
They are all in English. They are all for the Anglo
population or the African American population and the only one of the daily
interventions that is being funded has been funded for the last 15 years or 10
years, is one called Voces, in which, when you hear that, it is offensive to
the Latino population because it is half English and half Spanish. It was done
some time in the 1990s and it just doesn't fit.
So, the only recourse that we have in Miami Dade County,
and in my position as executive director, and the person that runs this agency,
targeting Latinos in Miami Dade County, is to find as quickly as possible the
funding sources to get Latinos tested, so that they can get care and treatment
before they die, so they don't get reinfected with other strains of the virus,
and that they don't infect others without knowing it.
The resources that I have, in terms of the testing
supplies, are provided to me through the Florida Department of Health and now
through the CDC.
I had an experience with the Florida Department of Health
in terms of CLIA where I said to them, we need to apply. I need to be able to
provide these kind of services to the Latino community. They told me, you
can't. Why can't I? Well, because we
have four other agencies. I said, okay, I will look into it.
I have a colleague sitting here that actually I told him
back then -- back then he was working at the Florida Department of Health.
I said to him, I am going to find a way, I am going to look
at ways to get the CLIA, because I know I don't need authorization.
So, when I got the licenses to do rapid testing, I called
him and I called the chief of the bureau and I said, out of courtesy, I am
telling you that I have the license, I have the certification to do it. So, we
are going to do it. I would like to think that we can do it together.
So, I am here today in terms of the rapid testing being
available over the counter with certain hesitations and concerns and, at the
same time, with hope.
This is something that I have expressed to a number of
people at the CDC, also to a number of people at the OraSure company, and that
is that I am going to just basically, at this moment, because other people have
talked about the general population, et cetera, I am going to talk about the
Latino community.
I am going to talk about the people who do not speak
English. I am going to talk about people who are poor, undocumented, and have
no insurance.
I am excited about the possibility of being able to access
rapid testing over the counter for populations that otherwise would not be
available to have an HIV test or would choose not to have an HIV test.
When I was asked from the FDA if I was representing, if I
was coming to represent the Latino community in Miami Dade County, I said, that
is a big load. I am representing the Latino community, I am representing the
people that I see every day in my agency, and in terms of the experience that I
have in seeing what is happening with them.
I am in support of having as many resources as possible for
the Latino community and other non-English speaking communities, available to
them, regardless of where they come from.
Again, it has been 25 years of this epidemic and we still
don't have enough resources. We don't have enough medications, we don't have
the funding. We don't have the
resources for testing. We don't even have the capacity to send people to places
to receive their proper counseling or their proper care and treatment, or the
appropriate amount of services because there is no funding available, and we
are seeing day by day that they are being conned.
My concern with this new idea of having the
over-the-counter rapid testing has to do with the quality in which it is
provided.
I don't trust the system, and I will start by saying that,
when it comes to non-English speaking people, when it comes to services to
non-English speaking people.
I have seen posters and I have seen flyers that have been
paid and printed and so on and so on, by government institutions that, when you
read them, they are misspelled, they have grammar errors, and sometimes they
just simply make no sense, in terms of the way the information is represented.
So, what I am here for is to challenge both the OraSure
company and also the CDC in terms of -- and I am very happy to see Bernie here
from the CDC when he talked about the routine testing -- that whatever comes
out of this is independent of what I think, what I feel, or what I suggest.
Please, whatever you do in terms of making this available,
that it is made available with high quality, with some thinking, some
conscience into what you are putting out, because that has not been the case,
again, when it comes to services for non-English speaking people.
I am terrified -- and I am using two pairs of glasses, by
the way, because I am one of those people who went to -- I had some procedure
done in my eyes about a month ago that works for everybody, but it didn't work
for me.
So, things can fail. So, I am literally working with four
pair of glasses. I see now less than when I had my procedure done. So, I
apologize. It is not that I am crazy.
It is just that I can't see.
Again, in terms of Julian Positiva(?), Julian Positiva is
an organization in Miami Dade that has been in place for about six years.
We are now seeing an average of 2,500, we are testing 2,500
Latinos every year at our agency, and we are only an agency that has 14 staff
members where we are. So, you can
imagine the amount of work that we are doing.
It is interesting for me to hear some of the scientists and
some of the physicians and some of the researchers that have spoken here, and
it is also interesting for me to feel the reactions that I am having when I
hear about referring people, if they are positive, to an 800 number or a web
site, or if they get a routine test done at a hospital or a clinic or a primary
care physician.
My experience has been that I trust better a high school
graduate who is committed to the HIV cause, in terms of their sensitivity,
their knowledge, their commitment and their compassion, and their interest to
help someone who comes to them and is HIV positive, then having that person go
through an emergency room or talk to a pharmacist about being positive, and who
knows what they are going to tell them.
I am very serious about that.
What I am requesting from here is that, regardless of what
happens in terms of you making available this rapid testing or not, through
over-the-counter or whichever way, is that you build a safety net around the
provision of these services, a safety net from the beginning to the end,
meaning, in terms of marketing, the way you are going to market this product,
that it will make sense to people who do not speak English, who are uninsured,
who are undocumented, who have low education.
A safety net for the people who take the test, and then
where do they go from there. The Latino
community will not go to a public health clinic.
You go to a public health clinic when something dirty has
happened to you. Either you have TB or you have an STD or, if you are HIV
positive, that means you are a prostitute or a drug user, or you are an idiot
that got infected by somebody else.
So, what I am requesting, what I am truly seriously
requesting here, just to limit my comment is, whatever you do, whatever is
approved, please do this with a very, very, very strong safety net where, from
the beginning to the end, no one gets lost in the process.
I want to actually think -- it is my first time in front of
the FDA committee. I want to thank you
for this, because in this experience today you kind of broke a stereotype that
I had about the FDA, and some of the comments that you have said, some of the
questions that you have formulated have indicated to me that you really care
about human beings.
I mean, you have asked questions about people, about human
beings. So, I am leaving this meeting with a new experience and a new kind of
respect.
Please don't wait nine years, like with the pregnancy test,
because that is a long time and it has been already 25 years. Thank you.
DR. DI MICHELE:
Thank you very much.
Agenda Item:
Remarks by Reverend Richard Cizik.
REVEREND CIZIK:
Thank you and good afternoon. Ladies and gentlemen, members of the Blood
Products Advisory Committee, my name is Reverend Richard Cizik. I am vice
president of governmental affairs for the National Association of Evangelicals.
I would like to thank the advisory committee and the FDA
for offering all the parties here concerned an opportunity to participate in
this dialogue on this critical national issue.
I have 20 years of experience on this issue, including
counseling, ministry counseling, including on issues such as suicide, on
HIV/AIDS, as well as governmental advocacy.
I think I was here when the first meeting was held by a
predecessor committee on this topic. I am sure it was one of the very first
meetings.
For the record, I have no financial interest in this
company or any other company, do not own stock, and have never received any
financial remuneration for travel or other expenses.
I would like to say this. I represent the network of
churches and ministries that belong to the NAE, with 54 denominations, a
service constituency of 30 million people, and over 100 agencies that are
involved in compassionate work here in the United States and around the world,
compassionate ministries that work as well with HIV/AIDS and are named by such
organizations as the Salvation Army, World Relief, Samaritan's Purse, and many,
many others. These are the organizations that belong to the NAE.
Let me be quick and absolutely clear. The position of our
association is straightforward on the matter of rapid HIV testing.
The need for such testing to be approved by you for
over-the-counter use empowering individuals to take more control over their
health care by knowing their HIV status is absolutely critical and essential.
To do this, additional testing options, such as the
availability of FDA approved over-the-counter oral fluid HIV tests, such as
OraQuick, is, in my estimation, a must in our fight against the spread of this
disease.
We believe that HIV/AIDS -- as evangelicals, we believe --
that it represents one of the most pressing public health issues of our time,
of our generation, of the world today.
Our position is consistent starting in 1988, when we
challenged public health officials to recognize HIV/AIDS as, first and
foremost, a public health concern.
Early on, evangelicals participated in the national debate
and favored legislation that would, among other things, require testing and
reporting of those with the disease to local health officials, on the same
basis as other sexually transmitted diseases.
Equally important, our public comments are backed up by our
action and practice. For example, we
encourage pastors to request couples, coming to them for marriage, to be
empowered to know their HIV status, and to share the results with each other
before marriage.
Member churches have embraced initiatives at the community
level which provide ministry to HIV patients and their families.
We act in practice with compassion, with Christian
compassion, because we offer the hope of Christ's redemption and grace to
victims of HIV/AIDS.
We cannot permit fear or apathy to prevent us from bringing
these life changing resources to those who do not know their HIV status, or
suffer from the disease.
We believe that there are limits to legislation, of course,
and this is why our faith compels us to offer hope to victims.
Thus, we bring to this whole issue that hope and compassion,
as well as a call for chastity before marriage and fidelity in marriage.
Yet, let me say in conclusion, very straightforward to you,
you have incredible power in your hands.
I have watched this, lo, many, many years, and I say that
it is unconscionable that our nation permits the number of HIV infections to
continue to grow. It is time to move
the HIV prevention debate from well intentioned talking points to clear and
present action steps.
In our mind, action steps include an FDA approved over-the-counter
HIV test, which is simple to use and delivers rapid results, empowering people
to know their status.
We join all those other groups who came here today to say
the same thing. Let us learn from our past, embrace the opportunities available
to us today with this new technology of OraQuick over-the-counter testing, and
help change tomorrow for the betterment of millions and millions of people.
I would say, lastly, as a society, we need not, cannot,
must not, wait any longer for your action, and I would say in closing, thank
you, and may God give you wisdom in these and all matters. Thank you very much.
DR. DI MICHELE:
Thank you, Reverend Cizik.
Agenda Item:
Remarks by Tom Myers.
MR. MYERS: Good
afternoon. My name is Tom Myers. I am general counsel for AIDS Health Care
Foundation and, on behalf of AHF, I thank you for this opportunity to address
you and voice AHF's strong support for the approval of in-home HIV tests. I
have no financial relationship or dealings with OraSure.
AHF is a non-profit that provides medical care and advocacy
to people with HIV/AIDS regardless of ability to pay.
It provides medical services to over 25,000 people in the
United States, Africa, India, Central America, and Asia.
AHF also operates the largest HIV testing program in the
state of California, and provides more HIV tests per year than the governments
of Los Angeles and Alameda counties combined.
We have pioneered the use of new and innovative testing
programs and sites, including the use of mobile testing facilities, placing
testing sites within retail thrift stores, and instituting testing and
counseling services in bath houses. We,
thus, have a great deal of experience in providing tests outside a normal
clinical setting.
The primary lesson that HAS has taken from its long
involvement in HIV testing is that knowledge is power. The single largest
reason for the continuing spread of HIV in the United States today is
ignorance, ignorance of HIV status.
In the United States today, some three out of 10 people
infected with HIV do not know their status. That means 30 percent of all people
with HIV are acting out of ignorance, infecting out of ignorance. This must
change.
Without this knowledge, people cannot care for themselves
and cannot protect themselves and their families. Everyone who wants to know
their HIV status must have every available means of finding out their status at
their disposal.
The introduction of a simple, safe and effective home test
will make great strides in reaching those people who are unable or unwilling to
be tested by already existing means.
AHF is aware of the concerns raised regarding home testing.
While, of course, due care should be taken in these matters, AHF believes these
concerns to be largely hypothetical, and are completely outweighed by the
benefits that home testing represents.
Today, HIV positive status is not a death status. HIV is a
chronic but manageable condition. Having HIV today simply does not mean what it
did only a few years ago.
Properly treated, people with HIV do not face the same
serious ailments and opportunistic infections as they did previously.
The medications available today are far more effective, are
far easier to take, and have fewer side effects than before.
However, people cannot access this care if they do not know
their status. Moreover, people cannot act rationally when they do not have
proper information.
Numerous studies show that people who know their HIV status
are more likely to take steps to reduce the risk of infecting their partners.
Once again, however, they cannot take these steps if they
do not know their status. This
technology has the potential to educate and empower hundreds of thousands of
people.
It has the potential to significantly reduce rates of
infection. To keep this technology and knowledge out of the hands of hundreds
of thousands of people, which consigns them to further ignorance, and
infection, is not acceptable.
The concerns put forward, no matter how noble or well
intentioned, do not justify this outcome. The AHF strongly supports approval of
this test, and looks forward to the day when this testing option will be
available. Thank you very much.
DR. DI MICHELE:
Thank you, Mr. Myers.
Agenda Item:
Remarks by Shawn Fay.
DR. FAY: I am Dr.
Shawn Fay. I have had past collaborative and advisory relationships with the
FDA, CDC and NIST, and I have numerous publications in the area of quality
control, standardization and quantitation as applied to blood drive systems.
I am also one of the inventors of one of the first full
process controls for immunophenotyping that was globally commercialized and
marketed by Johnson and Johnson under the name of Absolute Control. I have no financial relationships or
conflicts to report.
As I listened to the proceedings today, I started thinking
of a perspective that might have been a little bit different than everyone else
was talking about.
When the question was initially posed about adding
questions to the committee besides addressing the needs for sensitivity and
specificity and the design of clinical studies, I thought it might be useful to
add also for the maintenance and investigation of the proper scientific rigors
in the basic performance of it.
This was also brought out, to some degree, in testimony in
the area of quality control, particularly evaluation of the test sets, and the
evaluation of the collection, the adequacy or, I might add, appropriateness or
non-infectiousness of the sample, and also the test performance.
Although OraSure has called its product today an oral
fluids based test, I would say what differentiates it from other orally based
tests that are available is in terms of its performance and specificity and
sensitivity.
It is not just that it is an orally based test, but it is
specifically based on mucosal transudate, as has been presented in different
publications that have been written about the product.
Because of that, I feel that this quality control issue, in
terms of sample collection, is most important. I don't think that, based on the
information presented, that it has been thoroughly addressed.
If you might think about the biomechanics of self
administering this test in a non-coached, non-monitored way, the collection
process is explained as a simple two step test, and drawing the applicator
across the correct tissue in the top of the mouth, and the same with the
bottom.
I would say, though, that this might be more difficult to
actually perform than a simple two step test. One of the things, one might just
think, for example, of the difficulty many people have in obtaining accurate
oral thermometer readings, and also even doing the process of brushing your
teeth. One typically rests the device,
changes the grip before proceeding.
In previous information that has been presented by OraSure,
they mentioned, for instances, in the PMA summaries, that the placement of the
device is more specific than just across the top and bottom areas, specifically
that it is in the gingival crevice of the mouth.
It is also mentioned in these previous documents to
specifically avoid placement of the device against the roof of the mouth and
the tongue.
In a non-monitored situation, I would ask myself, certainly
this has to be tested. I think the question should at least be raised that the
test taker would at least position the device temporarily in one place of the
mouth that might put it in contact with saliva prior to getting it in the right
position, if it is ever gotten into the right position, since it is not
monitored.
I would also like to site that today, during the
presentation, the directions that were given or proposed were just basically a
picture with the device placed upward and downward, again, no information about
the specific placement.
In terms of what was written for instructions, there didn't
seem to be any specific detail. I would say, even if there were, would this be
really reducible to the second grade level, explaining how to get into the
gingival crevice area.
I think in the data that were presented, even though they
are very compelling and interesting, the question must be raised, as has been
brought up by other speakers today, do the studies parallel what would happen
in actual marketing situations.
Now, even if the problem that I am saying were to take
place, one could ask, how would that affect the results. Wouldn't they be
reflected in the data.
I would say probably not, because there are also available
tests that show very high specificity and sensitivity under the right
conditions, based on saliva rather than the mucosal transudate.
Another problem is based on the quality control. If this
were performed incorrectly, the collection of the sample, does the internal
quality control provision within the device have the ability to catch this. My
argument would be no.
If one looks at the form or the history of the PMA
summaries from OraSure, it seems like the same anti-human IGG controls have
been used the whole time.
I would say it probably is appropriate for blood sample,
serum samples, and even if it were saliva samples, but because this is a very
specific -- if we do agree that the performance is based on very specific
sampling, then I would say that the control is not appropriate and is
insufficient to really control in this situation, because there is no part of
the test that shows actually the site of derivation of the sample.
Even though this is kind of a technically based point, I
would say many people would probably ask, what is the impact this would have in
terms of real life performance.
Well, one would suggest that, under negative situations, it
would have none. Under positive situations where a person is already well into
progression of the infection, it would have none.
As the concentration of antibodies, both specific and
non-specific for HIV are elevated in the saliva, it may have none.
During the window period, I would say that this problem
would serve to elongate the period that false negatives or indeterminant
results would be found.
I think this has to be taken into consideration when
assessing how many people are going to be getting false negatives.
The implications of false positive tests have been really
stressed by many different speakers. However, if one looks at the proceedings
of different government agencies -- for instance, in Canada, Australia and
Great Britain -- the implications of false negatives is also very much
stressed, and also very much cited as a determining factor of whether to
commercialize these types of OTC products, based on the impedance it would have
to getting people, for instance, the knowledge of their infection, and also
getting into the right treatment programs, and the possibility for the
progression of disease spread from a public health perspective.
Another thing I would say, on another but related issue, in
terms of the tests that OraSure presented, in terms of the untrained
individual, it was unclear to me - the results, of course, looked very good,
but it was unclear to me if the tests were really taken from themselves or
another patient or from a test panel, in which case, the actual test taking
would not have been controlled.
Another thing is that, based on the need for correct
instructions and directions -- the performance looked very good in these tests,
but I would say, if one were really testing the ability for a person taking the
test to follow them carefully, one would have to actually put engineered
samples into the design that would give questionable failed or other kinds of
spurious results, to see the rate of detection that one was able to find with
the different participants in the test.
Did they catch them or didn't they.
Were the instructions good enough or not.
Finally, I would just like to add that, before considering
the different types of clinical testing that should be done before approval is
considered for this, shouldn't one also take into consideration these basic
scientific needs.
I would point out, too, that if this lack of control is
really a problem in this, then the same control scenario that is used in the
currently marketed version of the advance test, when used with saliva or oral
fluid samples, so shouldn't one also go back retrospectively and consider the
appropriateness for using these kinds of tests before really total control was
in place.
MR. JEHN: Is Mary
Allen here, please? If not, Damen
Dozier.
Agenda Item:
Remarks by Damen Dozier.
MR. DOZIER: Good
afternoon. Members of the council, ladies and gentlemen, my name is Damen
Dozier, and I serve as the congressional liaison at the National Minority AIDS
Council, of NMAC.
I am here today to share with you our view regarding the
availability of rapid HIV testing over the counter.
For perspective, let me briefly outline for you what the
National Minority AIDS Council is, and from what perspective we speak to you
all this afternoon.
Established in 1987, NMAC is the premier national
organization dedicated to developing leadership within communities of color to
address the challenges of HIV and AIDS.
NMAC advocates for increasing federal resources to address
the HIV/AIDS epidemic among people of color, and sponsor regional policy and
advocacy skills training and technical assistance sessions for minority
communities.
We also are the sponsors of an HIV prevention leadership
summit, and the United States Conference on HIV and AIDS.
To effectively advocate these issues, NMAC holds policy
briefings on Capitol Hill, produces policy briefs and newsletters, and works in
coalition with other national AIDS groups to promote the interests of all
people of color.
The overall goal of the government relations and public
policy of NMAC is to ensure that the voices and perspectives of people of color
affected by, infected by, HIV and AIDS are heard and listened to when important
legislation and policies are being considered.
We carry out our work by sponsoring many different programs
and initiatives, providing the resources and activities, and I will just
describe a couple of those activities for you.
First of all, we have partnerships and initiatives. To
fulfill our mission, we institute initiatives and trainings to develop
leadership in communities of color to address the challenges of HIV and AIDS.
We work with many different social justice groups across
the nation, including the National Council of LORASA, the National Association
for the Advancement of Colored People, and also the National Urban League.
We also have many different advocacy vehicles through which
we communicate to people of color suffering from HIV and AIDS, and that is
called our NMAC in action system.
That briefly touches on our area of work. I realize the
committee has heard many different perspectives about the OTC rapid testing
today, and I am not going to go over point by point, because I think many other
folks in our community have kind of touched on some of the concerns.
We would like to say that we believe that over the counter
availability of HIV testing is a good idea.
This is why:
According to the CDC -- and we have heard this -- although
African Americans are only 12 percent of the United States population, they
account for 40 percent of all AIDS cases since the start of the epidemic and,
in 2003, the latest data we have available, represented fully half of all new
HIV diagnoses.
Almost two thirds of new HIV infections in teens occur
among African Americans aged 13 to 19. HIV was the leading cause of death for
African American women age 25 to 34 in 2001.
In the United States, HIV rates among African American
women are 19 times higher than those of white women, and five times higher than
those of Hispanic women believed to be susceptible to this disease.
Now, these statistics are unacceptable, certainly in our
nation which has a lot of resources. Think of your children, think of your
nieces, think of your nephews, think of your brothers, think of your sisters,
think of people in the community. When
you think of those people, you see people who are suffering from HIV and AIDS.
In Washington, D.C., it is estimated that one out of 20
people living in the city are suffering from this disease. Not only that, a
full 25 percent of them -- which mirrors the nationwide statistics -- are fully
unaware of their status.
However, your consideration of this issue is not just about
data, statistics and sound bytes. It is about lives that are affected every
day, simply because people do not know their status, and do not have access to
knowing their status, do not have access to primary care, do not have access to
secondary care, and do not have access to support networks.
I think the FDA issues document, which you all provided to
us, says it best. I will just touch on
three points.
One, the test is simple to use compared to other types of
HIV tests, and earlier versions of rapid HIV tests, suggesting that untrained
persons will be able to perform the test properly.
Two, home use tests are used at home by untrained persons
without the help of a health care professional. Most home use tests, such as
tests for blood glucose, cholesterol and others, are available over the counter
without a prescription.
Three, and perhaps more important, the test provides highly
accurate results for the detection of antibody to HIV within 20 minutes.
On the matter before you, NMAC strongly encourages your
action to call for the FDA to approve and make available this powerful new
option in the fight against the continuing spread of this disease.
Before I close my comments, I would just like to say that
we heard from many people today, and especially from people in the community
who are on the front lines fighting against HIV and AIDS.
I think that they have been unanimous in their comments to
this body, that we have to think outside the box, that we have to take new
methods to make sure that people know their status.
Once people know their status, then they can empower
themselves not only to change their behavior and hopefully to notify their
partners, but also seek the care, resources and other connections that they so
desperately need. I thank you for your
time.
DR. DI MICHELE:
Thank you, Mr. Dozier.
Agenda Item:
Remarks by James Sykes.
MR. SYKES: Good
afternoon. Distinguished committee members, my name is James Sykes. I am
representing the AIDS Institute, a national public policy organization.
Thank you for your consideration of my public comments
regarding over-the-counter home use HIV tests.
I do not have any conflicts of interest nor disclosures to make for
myself or the agency I work for.
The AIDS Institute supports efforts by the Centers for
Disease Control and Prevention to increase access to, and availability of, HIV
testing.
The goal of HIV testing is two-fold. First, that an individual becomes informed
of his or her HIV status, so that appropriate medical evaluation and treatment
can be sought.
Unlike the early domestic HIV epidemic, today, improved
treatment options are available to people living with HIV. In many instances, HIV has become a chronic
disease.
Secondly, people who are aware of their HIV status may be
less likely to transmit the virus to others. This is an important public health
consideration.
The introduction of HIV rapid testing in recent years has
expanded HIV testing and increases testing access and availability.
One of the advantages of the rapid test is the relative
immediacy of receiving the test results.
More conventional testing is handled by a relatively poor client return
rate, often resulting in clients not receiving test results at all.
The AIDS Institute supports the concept of over the counter
home use HIV testing kits. The testing
approach will further increase access to, and availability of, HIV testing.
This approach can play a role in the overall HIV domestic
testing system. In particular, the
approach may be appealing to individuals who are resistant to HIV testing in
public health setting and private medical practice.
So, these individuals' use of an over-the-counter home HIV
test kit may be the only approach by which they become aware of their HIV status.
There are a number of issues the AIDS Institute believes
must be addressed prior to the implementation of this approach.
First, the absence of direct counseling in the
over-the-counter home HIV test kit setting will require the provision of clear
information with the kit, including appropriate use of the kit, HIV prevention,
and a statement that HIV infection is a treatable disease.
Secondly and likewise, the absence of direct counseling
with this method will need to be addressed by provision of a toll free,
24-hour, seven-day-a-week telephone number staffed by qualified counselors.
The counselors would need to be prepared to answer
questions about the test kit and its use, HIV prevention, and local referral
options for medical and psychosocial evaluation and assistance.
Lastly, the CDC will need to address how to approach the
impact on HIV reporting and HIV surveillance status.
I thank you for the opportunity to put these public
comments before you, and I wish you all a very good evening.
DR. DI MICHELE:
Thank you, Mr. Sykes.
Agenda Item:
Remarks by Bill Parra.
MR. PARRA: Good
afternoon. My name is William Parra, and I am senior vice president and chief
operating officer for the American Social Health Association, better known as
ASHA.
I would like to advise the committee that ASHA has no
financial relationship to OraSure Technologies, although we have met with them to
discuss possible algorithms for telephone based test results counseling.
ASHA has been informing the public about, and advocating
for, the prevention of sexually transmitted diseases since 1914.
Since our inception 91 years ago, we have encouraged early
diagnosis and treatment as the way to reduce transmission in the community.
The CDC currently estimates that about 250,000 to 300,000
people in the United States are infected, yet unaware, of their HIV status.
Since HIV infection often takes a decade to develop into
AIDS, people living with HIV, who remain undiagnosed, risk spreading HIV
without their knowledge for many years.
For decades, ASHA has been an advocate of broader
availability and use of HIV tests, to facilitate more rapid diagnosis and treatment
for those infected, and to prevent further transmission in the community.
Unfortunately, many people avoid, or are unable to get
tested in clinics or in a physician's office for a variety of reasons,
including lack of access to health care services, distrust of the health care
system, and the stigma of discovery.
We support the goals to implement new models for diagnosing
HIV infection outside medical settings, and to prevent new infections by
working with people, diagnosed with HIV, and their partners.
A greater set of options, including over-the-counter, home
use, rapid HIV tests, may increase the number of people who are willing to be
tested.
Clearly, it would be preferable to all individuals seeking
HIV testing to receive pre and post-test counseling in a supportive
environment.
However, the availability of these home tests could be a
very powerful strategy to reduce barriers to testing and increase early
detection of HIV infection.
It is imperative that those who test negative fully understand
the implications of their test results, and those who test positive should have
immediate access to counseling service, and referral to quality medical care.
In closing, we ask that the Blood Products Advisory
Committee recommend the approval of the over-the-counter home use rapid HIV
tests.
DR. DI MICHELE:
Thank you, Mr. Parra.
Agenda Item:
Remarks by Neeraj Vats.
DR. VATS: Good
afternoon. My name is Dr. Vats. I work for Medmire Laboratories, the
manufacturer of the FDA approved Reveal rapid HIV-1 antibody test. Thank you for this opportunity to speak here
today.
Medmire has launched our OTC test for rapid detection of
HIV in Hong Kong and Macao. Drawing on
our experience in Hong Kong and Macao, I would like to express a few thoughts
based on experience gained in the field, that may contribute to implementation
and monitoring of an OTC rapid test for HIV in the United States.
First of all, when considering a test for OTC use, we must
ensure an easy to use product that has an appropriate internal procedural
reagent control and uses a proven analite, that is put forward for approval.
It is also vital that the regulatory practices developed by
the FDA for rapid HIV testing in professional settings be carried through to
consumer home tests.
Following this, there must also be trials carried out among
the intended users in the intended settings. Even if it is the case that a
fully validated test is used, it is important to consider that no test is
accurate 100 percent of the time, and that the product inserts must address
this and other test limitations.
Once an appropriate test is identified, we must also ensure
the user has the required support. This would include access routes for
counseling, confirmation and treatment, and ensuring that the user is fully
aware of them.
Finally, we need to consider the impact an OTC rapid test
would hava on the ability to identify adverse events and the investigation of
them.
Such procedures would have to be diligently followed to
ensure a continuous supply of a safe and effective test.
Presently, rapid HIV tests are regulated by systems that
work hand in hand with a laboratory or a testing center.
With an OTC test, it may be necessary to implement a
consumer advocate system in order to maintain standards of quality and
counseling associated with current HIV testing practices.
A model for such a system may include the following: Following approval, a consumer would be able
to buy an OTC test, which would have an excellent label.
That label would also have to contain information to direct
the user to access the web based or phone in support prior to testing.
Following that, the consumer could utilize the test output
instructions, again, with access to similar support via the world wide web or
phone in, in case they encounter any difficulties.
Third, with the interpretation of the test, again,
counseling would be available, by similar means of web or by phone.
An additional component of a test may be something to
address confirmation. If a reactive result was observed, there could be a
sample collection device in the package that could be used for confirmation.
We believe that such a consumer advocate program would be
very useful in supporting or be an actual component of an OTC rapid test.
In conclusion, we believe that, with appropriate guidance,
government approval and use, OTC tests for HIV would be an excellent tool in
combatting this epidemic. Thank you.
DR. DI MICHELE:
Thank you, Mr. Vats. That
actually is the end of the prepared public comments, and I must ask if there is
anyone in the audience who would like to make an additional comment at this
time?
Agenda Item:
Remarks by Terry Anderson.
MR. ANDERSON: Good
evening. I will be very brief. My name is Terry Anderson. I work as executive
director of the National Association of People With AIDS.
I am a person living with AIDS and HIV. I have been working
in the field for about 20 years. First in the way of disclosure, OraSure has
not supported me coming here, although they do annually give some small
financial support to our national annual HIV testing day campaign, which seeks
to have people learn their HIV status.
We are here today to offer support to the idea of making
over-the-counter testing available, but I want to touch on just three very
quick points about that.
The first one is, I want us to understand that this is
unlikely to revolutionize testing in the way many people think it will.
I strongly believe the people most likely to use this test
are the people who are already most aware of their HIV risk, most likely to be
repeat testers, and that we will not see the hundreds of thousands of millions
of people getting tested in this country as a result of this availability, for
many of the reasons that people have touched on -- stigma, lack of
self-awareness of HIV risk, price points. All of those things will be there.
I do want to argue that, for a small number of people, that
having the choice about where and when to get tested does, in fact, increase
the likelihood that they will get tested, and that small audience, rather than
believing that we will make massive changes in the testing environment, is an
important reason.
We need to stop being paternalistic to people and telling
them that we understand solely how they should get tested, and give them the
choice to do client centered decisions on their own about how they want to
learn their HIV status.
I am somebody who actually learned that I was HIV positive
using the home collection kit. I can tell you that, if that hadn't been
available, I may have waited several more years before I actually presented to
a public health clinic or talked to my physician about this, and I am somebody
who has been working in this field for an awfully long time.
The second thing is, obviously -- and many people said it
today -- it is absolutely essential that the information that is included in
the package be available in multiple languages, be appropriate to a wide
variety of educational levels.
If this product is going to be marketed, people need to
know who to use it right, they need to know what the test is about, from all
the materials they have gotten.
Clearly, the need for 24/7, 365 days quality counseling and
referrals is essential. Learning your HIV status in the absence of quality
referrals mitigates against all the advantages.
The reality is, we want people to know their HIV status so
they can take advantage of the advances in care and treatment.
The referral networks that are set up through this or any
other testing system will determine whether people really do enter into care
and treatment and take advantage of that.
Just having people test positive, and not having the resources
in place that will help them successfully negotiate their way through a very
complex, underfunded public health care system, I think, is an invitation to
failure.
As you think about where we go with this, I encourage you
to make that kind of a system a strong requirement, if this test is ultimately
to move into the market.
With that, I just would end by saying, we believe that
people have the right to make choices about learning their HIV status, that the
more options we give people, the more chance there is that people will learn
their status, and learning their HIV status is a life-saving decision.
For hundreds of thousands of people in this country who
don't know their status, we have to give them additional options and additional
tools. Thank you.
DR. DI MICHELE:
Thank you, Mr. Anderson. Are there any other statements in the public
hearing session? Okay, with that, we
will take an 11th inning stretch for five minutes for essential functions, and
return for committee deliberations. Five minutes. Thank you.
[Whereupon, at 5:15 p.m., the meeting was recessed, to
reconvene at 5:35 p.m., that same day.]
E V E N I N G S E S S I O N (5:30 p.m.)
Agenda Item: Questions to the Committee and Committee Discussion.
DR. DI MICHELE: It is now time for the committee discussion and advice we have
been asked to give to the FDA. As you
recall, this is advice that would allow -- basically what we are doing is
advising the FDA on the information that would be needed to get such products
licensed.
There is not a vote being taken at these
committee deliberations. It is purely advisory. To initiate the discussion, I
would like Dr. Cowan to remind us of the questions before us today.
DR. COWAN:
Yes, thank you very much. I just want to let you know how absolutely
important this discussion is to us, because we are asking you to advise us on
what criteria FDA should use to validate an HIV test kit for home use. So, please give us any and all of your
comments. We will take them all to heart.
Question number one. Are FDA's previously established criteria
for sensitivity and specificity for rapid HIV tests also appropriate to support
over-the-counter use for home use HIV test kits.
I should remind you that this is 98 percent
for both sensitivity and specificity, as the lower bound of the 95 percent
confidence interval, those criteria that we are currently using for rapid HIV
tests.
Number two, please comment on the design of
clinical studies necessary to validate the safety and effectiveness of an
over-the-counter home use HIV test kit.
Number three, please comment on the
proposed content of the informational materials, and the steps that should be
taken to validate the adequacy of the informational materials to communicate or
provide pathways to adequately address issues, including the following: accuracy of testing; correct test
interpretation; the importance of supplemental testing for confirmation of
positive results; management of psychological and social issues; availability
of counseling; and medical referral. I should add that E is something that is
not on your list that you have now. That was added at a later time, that is,
availability of counseling. Thank you.
DR. DI MICHELE: Thank you. With that, what I would like to do, if you don't mind,
we will initiate some general discussion, because a lot of the issues actually
impact on one question or another, and a lot of our discussion on one question
will impact on the other. So, let's go
ahead and have some general discussion, and then we can take the questions one
by one.
DR. DUFFELL: The currently established sensitivity and specificity, could you
clarify for me, that is for a definitive test, is it not?
DR. COWAN:
No, that is for a rapid HIV test, which would be a screening test
essentially, which would give you a preliminary positive result if reactive,
and would have to be confirmed. So, this is not a definitive test result.
DR. DUFFELL: My general thought from the discussion is that, if a home test is
to be seen as preliminary or as a screening test, which you say this criteria
is for, I guess in that case it sounds like it should be at least that,
possibly lower, since you are going to require that it be repeat testing
anyway.
DR. SZYMANSKI: Since I have seen the data of the test as it is now, and it is
very good -- it is 99 percent -- hopefully so in unexperienced hands as well, I
think we should not lower the standards.
DR. NELSON: I agree, and I was going to say the same thing. The data have
been presented. The one thing that hasn't been presented is, in what stage of
HIV.
In other words, are these people with
established infection, with AIDS, or seroconverters? You know, I don't know if we need to comment on that. I am happy
with the results that were presented, but I think most of the data that were
presented were the sensitivity in people with established HIV.
I am told, in Africa where the rapid tests
are used -- not oral tests but blood tests -- that two tests are used and, if
there is a discrepancy, that is often a marker for a seroconverter, that if one
test is positive -- Tom can talk about that more -- if one is positive and the
other is negative, or if there is an indeterminant result, and you test the
person a month later, most of them are HIV positive.
Now, that is in a setting of a high
incidence and prevalence population, but I think it is unlikely that we could
ever do better than this.
Therefore, I think this test is very impressive,
for the data we are given, but the stage of the person, in addition to the
sensitivity, might vary by at what stage they are tested.
DR. QUINN:
I also concur. I think you are using the 98 percent confidence interval
bound as the sensitivity and the specificity. It should at least be that for a
test that is going into the home.
The second part of the home is, how do you
define that. Now, the assay, you know, in a standard laboratory with well
trained technicians, compared to another gold standard, derived those results
when they submitted for approval.
So, now, when we are talking sensitivity
and specificity, that is of the test and its value. Now, what about when we
talk about it is in use in the home by an untrained person.
You know, again it is how you define the
sensitivity and specificity. The assay itself, in the well trained hand of a
well user, should have that 98 percent lower bound.
In the home is where -- and I think that
comes to number two. What are the kind of studies you are going to do and what
is going to be considered acceptable if, in the home, as compared to in a
laboratory with the same assay, you are finding 96 percent sensitivity, 96
specificity. Is that going to be acceptable or not.
It is the same assay that is 98 percent in
the lab but 96 in the home, something like that. It is going to change your
predictive value. So, your first
question almost has to be refined for sensitivity and specificity in the home?
DR. COWAN:
That is our intent.
DR. QUINN:
That is your intention, okay.
DR. COWAN:
That the performance as intended meet the same criteria that we have in
place now.
DR. QUINN:
It is a stringent criteria, and I think for this first go around with
this, I would agree, that that is probably required.
DR. DI MICHELE: I just wanted to make one clarification comment. Are we really
talking about test sensitivity and specificity that includes the user? So, it is not only the test itself, but
obviously includes the user, and that all elements of the test -- user and the
test itself -- really do need to maybe be taken into account with respect to
the sensitivity and specificity and over a wide range of potential consumers
who would be tested.
DR. DI BISCEGLIE: I wanted to expand no what Dr. Quinn is saying. I would turn
it around the other way and ask, what is the gold standard.
Is the gold standard a blood test done with
a confirmatory test in a certified laboratory?
Is the gold standard this same test done in a laboratory setting?
That is kind of what you are getting at,
and I would turn it around the other way and say, what is the gold standard.
Then 98 percent sounds fine to me, but I
think you have to decide what the gold standard is that you are using to
measure that 98 percent.
DR. DI MICHELE: Is there anything that you would suggest?
DR. DI BISCEGLIE: I think it needs to be probably not compared against a laboratory
test with a confirmation, but simply a screening test, but I think it needs to
be done against a blood test, not just how does this test perform in the hands
-- the way it is currently done in an office setting.
It is a screening test. So, you need to compare it to the best kind
of screening test, which is an ELISA and an EIA done in a laboratory, I think.
DR. DI MICHELE: If I could just ask one question, isn't the point of it to
minimize false positives and false negatives and, therefore, doesn't it have to
be compared against the gold standard, which is the truly positive and the
truly negative?
DR. DI BISCEGLIE: No, I don't think so. One
of the things that I was going to bring up as we came to the first question is,
we haven't discussed very much positive predictive value.
I heard a disturbing number, which is 50
percent, and it sounds right, 50 percent. So, we are not going to make that
number smaller without using a confirmatory test. I think we are going to have
to deal with that number.
Either it has to be mitigated in some way
by a sponsor in terms of education, how do you minimize the badness of that
number, or we are going to have to require the sponsor to include some sort of
confirmation in the assay that is being sold.
So, the positive predictive value, I would
suggest, somehow be added to be equation. Maybe we don't have to set a number,
but I think we have to discuss it, because that is really going to be where we
are going to have the false positives.
One of every two positives is going to be a false positive.
DR. NELSON: You can't have that, because it varies dramatically in the
different populations. So, for one population it will be 50 percent, for the
other it will be 99.9, and we are targeting really the high risk population.
That is the one we want to reach.
DR. DI BISCEGLIE: I am not sure that is the case. I raised earlier the question of
what exactly is the expected population. Is it the high risk or is it not? I don't think it is.
I don't think you can set a number for the
positive predictive value because it will vary according to the population that
you use it in, but I think we need to discuss that and think about that as part
of an analysis.
DR. DOPPELT: I think related to this, you are sort of treading on new ground
because you are going to have a test that is going to be done at home by
inexperienced people. This test seems
to be pretty straightforward. It is pretty hard to screw it up, but anything is
possible.
My question is, if you are shooting for 98
percent, and this test has that, and then you do an ongoing study and you find
out it is something less than that, what do you do with the test then?
You said that the standard is 98 percent or
better, and for argument purposes, you find that it is 96 percent or 95
percent. Then what?
DR. DI MICHELE: I assume you weren't looking to me for the answer.
DR. COWAN:
I can address that, if you like.
If I could, when we set a criterion, it is an approval criterion, and
that would be our standard for evaluating safety and effectiveness of the
device.
If, in a clinical trial, the test does not
perform up to that standard, we have the option not to approve it, because it
didn't meet our requirements for safety and effectiveness.
DR. SCHREIBER: Given that this is a screening test and that there is no
requirement that the person go to be confirmed, I personally feel a lot more
comfortable with a higher level of sensitivity and specificity, because I think
you want to avoid false positives and not picking up true positives, because
this is the opportunity that these individuals are going to have.
I am also concerned, just as you are, with
the positive predictive value. I am really concerned that you might have a lot
of false positives, and then you have quite an impact on people who are called
positive but truly aren't.
I think you don't want to have a test that
has a very low positive predictive value. In some of these tables that we saw,
the positive predictive value is very good and, in others, it is considerably
less.
That also, as we mentioned, is a function
of the population. So, I think when you look at the sensitivity and
specificity, I think you have to look at it in a variety of populations, and
when you present your numbers, you have to watch the mix of the positives and
the negatives that are selected to test that on, because if I am running a
clinical trial, I can derive my specificity and sensitivity by selecting the
right people.
I am sure that FDA has a lot of experience
in that, but I think that you really need to be careful that at least there is
some mimicking of what we suspect the population is going to be.
I don't agree that the population is
necessarily going to be high risk people. I suspect it will be young binge
drinkers.
DR. CRYER:
I will just take the opposite tack, almost, and that is that if it is a
screening test, I am really not that concerned with false positives, because
you are going to get a confirmatory test.
You just need to make sure that you are
going to pick it up. The false negative
is what I am worried about. I think that is the area that we really need to be
concerned about.
In any design of a trial on this, then as I
recall hearing the various speakers, all of the false negatives were in
patients who were being treated with antiviral therapy and already had a known
diagnosis.
So, those patients clearly ought to be
excluded from any further trial. What we really need to know is, in patients
who don't know whether they have the disease or not, are there going to be
false negatives.
DR. SCHREIBER: I would agree with you if, in fact, you could force people to get
confirmatory tests. I would doubt that a significant number of these people
might get confirmatory tests. I would
be really afraid that the confirmatory test rate would be low.
Just one other point, I think that when we
compare the sensitivity and the specificity, we need to compare against the
most accurate test for true positivity.
I think that is what we want, because there
is no guarantee that people will do anything but get screened, and their
conclusion is going to be that I am positive.
I think what we want to do is have the best
test and comparison for the sensitivity and specificity, so we know that they
are true positives and true negatives.
DR. KUEHNERT: I think, as you have the question posed here, I think what you
have is fine for established criteria.
As I mentioned before, having some more
information for the reasons behind the false positives and false negatives, I
think will be critical in designing some of the other things that we are going
to be talking about, concerning what goes into the package insert, and how the
test can be optimized, as far as its function.
We talked about separating out operator
dependent procedural issues concerning false positive and false negative versus
those that are reproducible but are due to patient factors. That sort of thing needs to be, I think,
ferreted out.
The other thing concerning the positive
predictive value and, for that matter, negative predictive value, it is true
that depends on the population that is studied.
I think that is important, not as making it
a criteria but rather having it explained. I think we all could use an
explanation on sensitivity and specificity and PPV and NPV.
So, considering that, I think that to try
to explain that in a package insert is going to be very challenging, but I
think it is very important for a user to understand that, in their risk group,
what the likelihood of what a positive result means.
Trying to describe that in a word like
preliminary positive, or possible positive or whatever is used, is really going
to be a challenge, but it is something that has to be considered in this
process.
DR. SIEGAL: We heard from Dr. Spielberg, who actually did a clinical trial in
a presumably real world setting, perhaps in a population that we would like to
reach, but probably won't reach with this kind of testing, but she argues for a
much lower sensitivity than we are talking about, 80 percent. I would like to understand that, because I
didn't really understand her rationale.
DR. SPIELBERG: I think the point is that if you set the bar for sensitivity high
-- although I would love to see an OTC test that was 98, 99 percent sensitive
and specific, I think that it is going to be a bit lower, given the reality of
what happens when people take the kits home, and their ability to interpret the
test.
I would really hate to see the standard set
so high that it is unattainable. The 80 percent cut off was a point that I was
trying to make.
When we decide on what the bar for
sensitivity should be, I think the decision should be based on where is the cut
off point where the benefits still outweigh the risks.
That is where that 80 percent came from. If
you are identifying a lot more new positives by having this OTC test out there,
then you are missing people who switch from clinic testing, move over to OTC
testing, and are one of the false negatives. You still have greater benefit.
I think I would be happy to see the
sensitivity at 95 percent, 96 percent, because I think still there would be a
great benefit to risk. Can I just say
one thing about the positive predictive value?
Would that be okay?
DR. DI MICHELE: I am going to ask you to actually hold on that so we can
continue. We can go back in here, but if there are any further questions, we
will have you come back up to the mike.
DR. NELSON: I just had a quick question about the technical. One of the
speakers talked about misplacing the applicator in the tongue or whatever. Does this depend on crevicular fluid? What if somebody is dentureless, has no
teeth, and puts it in the side. Will the test still be positive under those
conditions as long as it is wet, or does it actually depend on crevicular
fluid.
MR. CARDOS: Actually, for the execution of the test, when we went through the
CLIA waiver studies, we did take a look at other types of collection, if
somebody missed collected wiping the gum line, and showed that we had a fairly
robust collection method, even if they weren't in close contact, or had touched
the tongue with the collection.
So, there is an enriched antibody near the
gum line, but it wasn't supercritical, when we did the flex studies, that it
was a perfect collection for an accurate result.
DR. DI MICHELE: Do they have to have teeth?
MR. CARDOS: No, it is actually around the gum line.
DR. BRANSON: I wanted to respond to Dr. Siegal's question. If the committee is
interested, there is a peer review publication that deals with this exact
concept, which is looking at the lower sensitivity of a test used for
screening, but it being advantageous, because of the large number of people who
received their test results. So, the
effective sensitivity in the home use is what I think Freya was referring to.
This has actually been now analyzed in
other screening settings for sexually transmissible diseases, showing that,
despite the actual analytic sensitivity being lower, the effective sensitivity
in terms of people getting their test result is higher in that situation, and I
think that is what Freya is referring to with respect to a different threshold
in practice.
DR. QUINN:
In Africa, what we do is, we take the test with the highest sensitivity
and use the second test that has the highest specificity to do the
confirmation, because you want to be picking up as many of your positives on
your screening test, and you will even sacrifice a few false positives, because
you will have a secondary confirmatory test. That has been published from the
African studies that I am aware of.
It does get, I will just mention, from
Ken's perspective, when we do dual testing like that -- and you have done this
-- we have done reflex testing with two rapids.
When you get a discrepant, it is usually
because they are in the acute. We did that in Malawi with Mike Cowan's group
and others, and we actually could pick up 20 acute seroconverters with this
reflex discrepant thing.
That is off the site of OTC, but just
getting at that sensitivity, I actually think the higher the sensitivity, the
better. You don't want to be missing some of those positives, even with the
sacrifice of some false positives, because you have got confirmatory testing
going. It is which way you want the screening test to lean toward.
I will come back to my earlier comment. I
agree, it should be done to the gold standard. The gold standard should be the
infection status, and that can be worked out by EIA, western blot and, if there
is still a discrepancy, you can do RNA and see if there is virus present.
DR. SIEGAL: Tom, you do those testings in tandem at the same sitting; right?
DR. QUINN:
We do.
DR. SIEGAL: That is not going to happen over the counter.
DR. QUINN:
That is not going to happen here. I am sorry we got on that, but in
terms of weighing sensitivity and specificity, it depends on the setting.
The setting over there was, since we are
doing reflexing and are doing the sort of confirmation rate in the same
setting, we want the first test to have the highest sensitivity, the second
test the highest specificity. That is
sort of what we do with the EIA and western blot or IFA. It is the same kind of
format.
DR. SZYMANSKI: We mentioned here about the
population for which this testing is intended. According to all the testimony
we heard today, it seems to me that it is intended, hopefully, for the
population that is highly seroconverted.
If you release it into the market, it will
go also to the worried well. Because of
that, I think the instructions there should contain information about this
window period, and that those worried well can be diagnosed in this window period
by using another test, PCR or NAT test.
This should be just mentioned there.
DR. WHITTAKER: I agree. I think that this test, although it may be intended for
people at high risk, I think it is going to be the college student who went out
and had a wild night, and I think exposure -- they are going to use this as a
morning after, you know, I had an exposure, and I think that needs to be well
documented, that this is not for exposure the next day, that you need to wait
for a period of time.
DR. DI MICHELE: That will relate to the educational materials you are talking
about.
DR. DUFFELL: I want to bring our thinking back to what FDA just said a few
moments ago, and that is, if any company doesn't meet that criteria, the
likelihood that that test would ever come to market, and that there would be a
public health benefit of that test coming to market, is very, very remote.
They very typically don't go against a
standard of that sort. Bearing in mind that, if it is 98, and the test comes in
at 97, are we saying there is no public health benefit for this test out there
on the market?
I am not sure that I would think that. I
think there probably is. I think labeling and all should probably carry with it
some very good language to inform them of what that means, and what additional
testing needs to be done, but having worked with the agency for a long time, I
can tell you that is very likely the way this thing would go.
So, we need to keep in mind what the public
health impact of that type of a decision or recommendation that the committee makes
will be to FDA.
Then the other thing -- I may be shooting
myself in the foot with this -- but Dr. Cowan, do you know, like for home
pregnancy testing and that sort of thing, what was done in that case, when
those products came to market, or maybe they weren't approved, they were
grandfathered, I think you said, but what is the standard by which we hold
those companies to in that case. Must
they meet the same type of sensitivity and specificity as is done in a clinical
setting?
DR. COWAN:
I am going to defer to Dr. Gutman, because those are the products that
his office deals with.
DR. GUTMAN: The risk profile is substantially different, and the review
history is substantially different. I
actually don't think it is a good comparison, but the truth is that pregnancy
tests are --
DR. DUFFELL: When I found out my wife was pregnant, I will tell you, it was a
traumatic event. It really was. The risk was high.
DR. GUTMAN: Well, there is risk. I can't argue that there is no risk. I think
the profile and the sensibilities are different.
Pregnancy tests are credentialed
analytically. So, when Arleen showed her slide, she was talking, we are very
hung up about having them credentialed against WHO standards.
There are arguments in that community what
the appropriate cut off is. Should it be 25 units, should it be 50 units,
should they bring it down to -- some people say 12.5 units. There is no
agreement on what the appropriate actual characterizations are, and how much to
pay for false positives.
Pregnancies have been found for 20 years --
I was talking to the speaker who was talking about the social issues, and there
has been no evidence based studies on pregnancy tests.
You know, we have a general sense that we
have done some good by having it out there. Maybe we haven't, I don't know, but
it is all analytically credentialed.
It works probably because most people run
the test far enough along that -- you know, when HCG starts to go up, wow, we
are not talking about some equivocal signal.
Most people, when they get a funny result
that doesn't match they say, oh, I screwed up, and then they repeat it or go
see their doctor, or there is the period test.
I am just not sure it is 100 percent
equivocal, and it is a very different standard, but it actually graphically
illustrates that there is no truth when you look for truth.
DR. DUFFELL: In follow up, I would say that that is probably what is likely to
happen in this case, too, that they would go to specialized care to try to get
that diagnosis made.
DR. DI MICHELE: You know, in some ways, maybe if I could just direct the
committee for a second, in some ways we are kind of in uncharted waters, and I
am not sure we want to make a specific recommendation, if it is not going to
lead to the right outcome.
Maybe what I can ask the committee is to
maybe prioritize what the biggest issues would be with respect to
over-the-counter home testing.
In other words, is out biggest concern that
there would never be a kit approved? I
mean, I think we have heard from the community that there appears to be almost
unanimous support for this kind of testing to enter into the community.
So, is the worst thing that could happen
the fact that we never get a test because of stringent criteria? Is the worst thing that we miss some true
positives? Is the worst thing that we actually test a lot of people who are
provisionally positive, who may not get to confirmatory testing right away, and
the psychological impact of that.
I am wondering if maybe if the FDA would
accept some sort of prioritization in terms of what we think the biggest
problems would be facing the FDA with respect to getting something like this to
market, and maybe the sensitivity and the specificity have to be a slightly
moving target.
I was just wondering if anybody on the
committee wants to just entertain that discussion a little bit in terms of what
they think the priorities should be, and then maybe we can make some
recommendations that way.
DR. NELSON: Maybe it doesn't exactly answer your question, but I thought of
an interaction that could be adverse.
That is, there has been a growing use of
post-exposure prophylaxis, of sexual exposures, drug use, et cetera.
If people incorporated this test after they
had had an exposure, let's say the night before, a day or two, and then didn't
do post-exposure prophylaxis, it probably works.
I mean, the studies in perinatal and
hospital exposures suggest that it does, and it is certainly widely used.
So, I wouldn't say that there shouldn't be
over-the-counter testing because of this, but I would say that the insert
should definitely say that you shouldn't use the results of this test to not
get post-exposure prophylaxis, if the person was convinced that they had a true
exposure to an HIV positive source, whether it be a health care worker or
somebody with a sexual or drug use exposure.
We don't have the product insert, but that is something that I think
should be considered.
DR. DI BISCEGLIE: To respond to your question, I am not sure we have heard enough
today to really address this, what is the broad sensitivity and specificity.
I have heard sort of this field sensitivity
question. It is kind of a novel concept to me. So, to answer your question of
what is most important, I would hate to see us not approve a test.
It seems to me there is a compelling community need. I think there is
a medical need. An analogy I might site to the committee is, in 1999 when we
first got a test for hepatitis C, the first test approved had a sensitivity
that was not much better than 95 percent and a specificity that was pretty
awful.
We needed something, and we screened blood
and we saved lines then, and I suspect we need to think along those lines here,
too.
DR. CRYER:
I think the goal here, if we are trying -- of being here all day -- is
to find people who are positive and don't know it. That is the goal. If this kit is going to help do that, then
we ought to be putting that out there and making it work.
Then the next job is to figure out what the
limitations of it are and try to minimize those, or communicate those to the
people that use the test. That would be how I would put it together.
DR. DI MICHELE: And we can actually counsel on some of those limitations when we
get to the educational materials.
DR. QUINN:
Just for the discussion, just to address that, so we already know the
sensitivity and specificity of the assay. You have got all the data, and it
performs extremely well in the standardized laboratory.
It is now going to move into the home. It
will be studied. It is not going to be better than what it is in that lab. It
is going to drop some.
I would agree that we probably could lower
the bar a little bit, for the public health good. Where I would put the
emphasis is try to maintain as much sensitivity as possible, because if you
drop sensitivity to 80 percent, like we were talking about, you are going to
have lots of false negatives. You are missing the positives.
You really want to get the positives into
care, and a test that is only 80 percent is going to be missing a lot. So, I
would just, for the discussion purposes, I think we should be flexible on what
the numbers are going to be.
They are not going to be better than what
you already have. They are going to be lower. We know that right up front.
Let's see how good the sensitivity is. I
think it is a screening test. We can be
more flexible on the specificity, I think.
When the numbers come in, I think the FDA
should not be held to that absolute bar that is in the laboratory, but have
some flexibility. The area where I
would want the highest regard would be in the sensitivity area.
DR. KULKARNI: I agree. I think setting the bar too high might be a deterrent
for a lot of people, and I think the benefits of getting this testing done,
somebody who takes this kit home obviously has a reason for taking the kit
home.
The only thing that I was kind of unclear
about was the window period. How long is that window period. Do we recommend a
repeat testing if the first one is negative?
Should that be a part of the packaging?
If so, when is the repeat testing?
So, these are things I wasn't sure.
DR. DI MICHELE: I think we will have the opportunity to address those in some of
the subsequent questions. Dr. Branson,
did you want to address this particular question?
DR. BRANSON: For the purposes of the committee grappling with this issue --
and we deal with this at CDC all the time -- it seems to me that analytic
sensitivity ought to be in your criterion one because, for this or any other
test that comes in, you want to have the same standard.
Then the way that it performs in the
community ought to be in question two, which is the effectiveness, because we
have an efficacy standard, and then how it performs in these populations is
really an effectiveness issue.
We definitely don't want to say that it
should have a lower analytic sensitivity. So, if we change that threshold for
question one, and then just talk about effectiveness in question two, in order
to address the issue of what it is going to do out in the community.
DR. DI MICHELE: Good idea. Is that acceptable to you, to reframe the question one
in terms of analytic sensitivity and specificity?
DR. COWAN:
I am speechless. Dr. Epstein is
going to have a comment Traditionally
we have dealt with the clinical sensitivity and specificity of those numbers.
DR. EPSTEIN: This simply defers the debate to question two, or the question
that we provoked in question one becomes question two.
I think it can be assumed that FDA will not
entertain consideration of tests that don't have high analytical sensitivity
and specificity.
Really, the core issue is how well must it
perform in field use, because that will be its intended use, and it should be
validated in a target population.
I think we could just agree that we want a
test certainly to be no less accurate than the rapid tests that have been
approved for professional use or are under CLIA waiver.
I did hear at least one comment -- I think
it was Dr. Szymanski -- that we ought not to reduce it beyond the analytic
performance of the OraQuick tests, which actually was at the higher end.
Certainly, I think there is general
agreement that, at the analytical level, it ought to be as sensitive and
specific as we know how to make a state-of-the-art test.
DR. DI MICHELE: I was just wondering, based on the discussion we have had, does
the FDA need more information from us, or have we addressed issue one with
respect to the information that you need, and is the prioritization of what the
goal should be with respect to sensitivity and specificity, is that helpful in
your being able to make a decision about this?
DR. EPSTEIN: Yes. I think, to paraphrase, what we have heard is a general
agreement that tests should have very high analytical sensitivity and
specificity.
What we have heard is that there is room
for debate on how sensitive and specific it has to be in the target population.
The general sense -- it is not a question
for voting -- was that those who spoke would rather see us approve a reasonably
good test than reject one because it didn't meet a very high standard. We heard that discussion and we have to
think about it.
DR. DI MICHELE: Right, and relative to the goals of testing, which you heard are
getting a test into the community and what the goals of that test are, in terms
of finding as many positive patients as we can, to get them into the care
system.
DR. COWAN:
Question two, I think, is something that still has to be grappled with
here. At the heart of question two is the types of clinical studies that would
be needed to show how well this test performs in its intended use setting.
DR. DI MICHELE: Very good. Again, question three will address a lot of the
educational materials, and everybody's concern about what needs to be addressed
in the educational materials and referral materials. Thoughts on clinical studies and design of clinical studies
necessary to validate safety and efficacy?
MS. BAKER:
I would think with the clinical studies we have a terrific opportunity
to learn about home use, and we shouldn't waste that opportunity.
I would recommend that there be
collaboration with a variety of community based organizations that serve the
most at risk populations, such as the African American community, Latino
community.
The presentation that Arleen Pinkos
provided in terms of the stress studies, those sound really compelling, that
studies involve all kinds of potential errors that could occur.
Some that come to my mind is, when you are
going to put something in your mouth, you wonder what it is going to taste
like. So, what is the effect of licking
the wand prior to application?
What if somebody who was really concerned
that they might be HIV positive thought that it would be better, instead of
doing just one swipe each on the upper and lower gums, did two swipes each. Has
that been tested?
Sharing the test. I could see groups of young people, you have enough money only to
buy one test. So, you share the test.
You are laughing.
DR. DI MICHELE: That is called mini-pool testing.
MS. BAKER:
Also, the time period. What is 20 minutes? Has it been tested, and are the test results the same if it is 10
minutes, 15 minutes. I didn't see any data to answer those questions.
Then the confirmatory, some of my comments
also I should perhaps wait until the educational material, but I also have
questions about Spanish language. Spanish in Miami is not the same as Spanish
in Southern California, Puerto Rican Spanish versus Mexican Spanish.
There are a variety of issues that need to
be considered, but it is a phenomenal opportunity to involve the communities in
the design of these studies.
DR. SZYMANSKI: I just wonder where these subjects are going to be gotten. How do
you get the subjects for the study.
DR. DI BISCEGLIE: If I might, I think that is very important. We have talked
several times about the expected users, who should really be represented in the
test population.
It is not a case of going and finding 500
people in an HIV clinic and 500 healthy blood donors. It is not that. I think a more thoughtful approach to
identifying the expected users would be needed.
Then you need some of those at each end to
sort of test the test, you know, to stress the test. I think we need to define
the expected user.
If I might, so in addition to the target
population, this is a home test, and the sponsor seemed kind of shocked when I
suggested that the test be tested at home.
I think at least some of it, we need to
allow the participants to take the test home and do it at home, I think.
Then we heard about the need for the window
period. We didn't see any data. Maybe there are data as to when this test
becomes positive, so that information can be provided.
What about low level positives, you know,
dilute out a positive sample with normal human plasma, those kinds of tests.
Maybe those data exist, but we haven't seen them yet.
DR. NELSON: I think the suggestion that it would be very useful to look at --
you know, somebody may not have a watch or something to know 20 minutes.
If the control strip turns positive before
the test strip and the person reads it at that time, that is when they might
get a false negative. So, it would be
interesting to get a lot more data on that, and perhaps the company has done
that already.
One of the methods -- in Baltimore there
were -- we have studied injection drug users, and handed our written materials
with diagrams, about how to disinfect a syringe using bleach.
They had been passed out for several years,
and the rates didn't go down at all, despite the fact that everybody said they
were using bleach, and we were handing out little bottles of bleach and stuff.
So, we brought in some drug users and asked
them to just show us how they did it. It turns out that the instructions say
that we are supposed to have several -- five, I think -- fillings and emptying
of a syringe, and it was supposed to have contact with the bleach for one
minute.
The median contact time was actually 20
seconds when we studied a group of drug users.
In fact, with clotted blood and so in there, that is not enough.
So, I would say some really in-depth
studies of how people actually use the test, and not only the college educated,
but adolescents or drug users, et cetera, the target population, despite the
fact that it would be available to everybody.
Still, the target population is to identify those who are infected.
DR. DI MICHELE: Just to summarize what I think I have heard around the committee
table so far is that, with respect to clinical trial design, that we really
need to incorporate subjects that represent the at risk population.
I think from what we have heard, that
includes a wide representation throughout most community groups. We have heard
from the Latino and African American communities.
We have certainly heard that women are
disproportionately affected, and also adolescents, which have not been
incorporated into the first line of testing and data.
I think we have heard that -- it sounds
like to me what we are hearing is that every phase of the test needs to undergo
rigorous assessment, both in an ideal situation and, as someone mentioned,
certainly as Judith mentioned, certainly under stress conditions, in terms of
really getting a brat understand of what can go wrong, and that part of the
field study needs to be done in the home. That is what I have heard so far.
Other comments?
DR. DUFFELL: I would say also there should be some sort of objective evidence
of the adequacy of the labeling material that we try to measure, with the
instructions for use, obviously.
DR. DI MICHELE: In other words, the clinical trials really need to look at the
instructions for use.
DR. NELSON: There should be specific queries relative to its effectiveness.
It shouldn't just be assumed that, based on what you observed in a stress
situation, that they got that from -- we shouldn't assume that it came from the
labeling. We should know that it came
from the labeling, that it did provide adequate instructions for use.
DR. DI MICHELE: So, separate clinical efficacy testing of instructions and the
interpretation of instructions, and obviously that has to be multilingual.
DR. NELSON: Not a separate trial, mind you, just that as part of any trial
that there are specific assessment tools laid out to make sure that the
instructions for use were understandable by that broad population that we have
talked about.
DR. KUEHNERT: This may be a minor issue -- I touched on it before -- but just
the issue about the attenuation of antibody levels with use of antiretrovirals,
as pertains to post-exposure prophylaxis.
If there is a big impact on antibody levels
with post-exposure prophylaxis, even in situations where maybe it is
incompletely used, because they are not sure if it is an exposure or not, they
fall out of health care follow up, then that should be made clear that the
false negative rate is much higher in that sort of a situation. So, maybe that
should be looked at in some way in these studies.
MS. BAKER:
I think that the clinical studies also need to include some follow up
studies, particularly looking at confirmatory testing.
If the confirmatory testing is required to
validate the accuracy of the test, then there needs to be some follow up
testing of who does confirmatory testing, how long does it take, you know, the
context with referral services.
Several of the speakers talked very
eloquently about a system that needs to be put into place. So, we should also
think system-wide, when we think about these clinical trials.
DR. SZYMANSKI: I still need to know where these subjects come from. Does anybody have any suggestions? Also, if this is a study, you have to know
who these subjects are, and you have to know the other side of the test to
which it is compared. So, you need to
have those samples. How do you get
this? What is the design?
DR. DI MICHELE: I think that is a very important question, because when we are
talking about some of the follow up testing in terms of confirmatory testing,
psychosocial issues, we may be talking about a different phase trial, as
opposed to the initial preclinical trials.
DR. QUINN:
You almost can envision this as phase II and III trials. So, the phase
II is very intensive observation while the people are there doing the testing.
You just hand them the kits after they
agree to participate and undergo testing, and you observe how it is being done,
the types of things that Dr. Spielberg had presented in the HIV clinic where
they did it, so you can gather a lot.
That will refine your instructions and the
informational material, because you are learning from those individuals.
As far as the settings, Ken and I are
involved in a lot of different network settings. This could be done very
rapidly in a number of different settings, of youth, of people of color, different
age groups, different educational levels and so forth. It would not be that
difficult to implement that pretty quickly in a number of settings.
I was also thinking of your other question,
when we are comparing this to. I would
say, in that phase II, I would want the test to be done by the individual who
has agreed to consent to do this, and then the second saliva is taken and a
technician does it, who is highly trained, knows exactly how to do this.
You can actually then see, how does this
one test -- we will take OraSure for example -- how does the performance work
with the subject as opposed to that laboratory technician.
Then, of course, it is going to have to get
confirmed anyway. I would like to know, is performance really dropping precipitously
in people who are untrained.
Then you could go to the phase III. So, the
phase III is the home testing that we all talked about. That is where it is
going to be done.
It could be done like the mailing system
right now. The subjects are approached, they are given the kits, but they go
home and they do it at home.
They send their result in, but an extra
swab is again taken in another laboratory and they can test it there. The phase
III is where you get the large numbers.
DR. DOPPELT: I just wanted to comment, I think it is a good idea to have it
tested both by the individual and by a technician, because there are all sorts
of ways of messing things up, unimaginable.
You asked the question, what are potential
pitfalls. I think one is that the users may not understand the limitations of
the test. They may understand the value, but not the limitations.
So, part of the design, I think, should
include some assessment of their understanding of the limitations. This is not
designed to be a morning after. They may or may not understand the window
period and the importance of maybe a follow up test in three months.
So, you are going to have some educational
materials in there, but you have to also assess their understanding of the
limitations.
DR. MANNO:
For the phase II you were describing, I think it makes sense to do the
confirmatory testing at the same time.
You want to confirm what you are finding on
that swab, rather than a few weeks later, when you may, in fact, get a positive
test, but it won't confirm what you saw on the swab, or refute what you saw on
the swab.
DR. DI MICHELE: That is, unless you are using known positives and negatives in
that first phase of the trial, but a very important point.
DR. KULKARNI: As a physician, I would like to know, once these people get the
tests -- because this is in their homes -- who do they report back to? Is it a physician? Is it an AIDS group?
I think we need to study that response, I
mean, who do they feel most comfortable with, and I think that will give us an
idea of how effective this thing is.
DR. DI MICHELE: One of the things that we are going to get to, I think, in
question three, is a lot of those, and maybe we can bring that back into
aspects of the clinical trial that we haven't discussed just yet.
DR. KULKARNI: One more thing. How do people who do get these questions respond
to them? What does a physician do?
DR. DI MICHELE: Where are we still sort of lacking in terms of comments on
clinical studies necessary for validation?
Are there aspects of the clinical studies that we haven't commented on?
FDA STAFF:
I think we have received a number of good comments at this point. In
terms of the size of the trial, we would assume we would be going to our
statisticians to receive input on that information.
What has been particularly valuable, I
think, is just hearing the types of people that should be tested, various ways
that testing could be considered.
Whatever way we strike this, I think we are
dealing with a contrived situation. If one of the concerns is that people who
would be using this test are those who would feel uncomfortable going to a live
person for counseling or to have the test administered, you are still sort of
involved in that situation.
There is going to be -- as someone just
said, the result is still going to be reported out to someone. So, there is a
bit of a twist in terms of it being exactly as it is going to be used, and the
question is, will that ever be approached.
DR. DI MICHELE: I think you also heard that there might need to be a contrived
situation initially and then, further studies in non-contrived situations. I think you heard that as well. Does anybody want to make more comments on
clinical trial design?
DR. LAAL:
Just one minor question. What happens to the swab if it just keeps
sitting around in your garbage after 40 minutes?
You know, somebody gets paranoid, you do
your test, you have your control line coming up positive, your test is
negative. You know, 45 minutes later
you wonder if you saw this properly and you just go and pull this out. Does the
reaction continue to develop, or does it stop?
MR. CARDOS: For the test, after the 20 to 40 minutes, we are going to be
fairly strong in the language that you do not keep it after 40 minutes.
At that point, once you take the device out
of the developer vial and thrown it in the trash, we haven't gone off and taken
a look at that, but we want to be strong with our read window.
[Comment off microphone.]
MR. CARDOS: Not once you take it out and lay it flat in the trash.
DR. WHITTAKER: Earlier it was asked about different fluids in your test, and
there was not an answer whether you get a control line for fluids such as
breast milk or semen or vaginal -- I can see people using this test maybe in
other fluids.
MR. CARDOS: Right now, I can say we have generated no data with the
alternative fluids.
DR. DI BISCEGLIE: I was just going to offer the suggestions, we have mentioned many
possible things that could go wrong, but it would be nice to measure that as
the proportion of invalid tests. That
is a parameter that should be considered.
When Dr. Spielberg presented, in her study
20 percent were invalid. That seems like a high number, and it seems like a
parameter that we need to pay attention to.
DR. DI MICHELE: Thanks for bringing us back to that term. That is a good one.
DR. QUINN:
Just to answer that question, actually, we have done that. .Actually,
there are antibodies in vaginal fluids, urine, semen. Some of that can disrupt the assay a little bit, but we have
actually done it with vaginal fluids. There is a publication on it. It actually
does work.
It is not licensed for that. It is not supposed to be used for that
purpose, but if someone goes and does it for that, you know, it is off label,
and I don't know what the sensitivity and specificity would be in their assay,
but the antibodies are there, as they are in breast milk. You usually have to wait about a week after
delivery. Then antibodies actually are much higher.
DR. DI MICHELE: Amazing. Aren't you glad
you asked the question? Any other
comments on the clinical trials? Any
other suggestions?
We can come back to that, I think, when we
discuss question three, because there might be some ideas that might come into
clinical trial design. Do you want to
go through question three again?
DR. COWAN:
Sure. Please comment -- it is the fourth time I have read it. So, maybe you will get it by now. Please
comment on the proposed content of the informational materials, and the steps
that should be taken to validate the adequacy of the informational materials to
communicate or provide pathways to adequately address issues including accuracy
of testing, correct test interpretation, the importance of supplemental testing
for confirmation of positive results, management of psychological and social
issues, ability of counseling, and medical referral.
DR. DI MICHELE: I know we have touched on some of these subjects already. Let's
go through them one at a time. If anybody has comments on accuracy of
testing? What are the informational
materials. We are talking now about informational materials and steps that can
be taken to validate the adequacy of these informational materials, which is
what has been brought up already. So, let's talk about accuracy of testing.
DR. NELSON: One method that has been used by people entering into HIV vaccine
trials, is that you give people the information but then you give them a
questionnaire.
The questionnaire sort of tries to figure
out, tries to understand -- now you wouldn't do that after the thing was
licensed, but prior to licensure you could see whether the information was
presented in such a way that the people understood it.
What we found with populations of IV drug
users was that 10 percent of the people who entered the clinical trial or who
were candidates for the clinical trial, thought that, after we gave them the
vaccine, we were going to challenge them with HIV to see whether or not they
were immune.
Obviously, that was a red flag, and those
people weren't enrolled in the clinical trial. If you found something like that
-- I mean, it wouldn't be that dramatic, but if you found something, some
misinformation, you would then go back and change the project insert, so that
it became more clear. I think that
would be one method that you could do to evaluate whether or not the insert was
understood.
DR. DI MICHELE: My understanding of the question of accuracy of testing, in other
words, what we are trying to convey -- I am assuming what you are asking there
is conveying the meaning of a positive and the meaning of a negative.
I think that the group has begun to touch
on som eof that. Does anybody want to bring up those points in terms of the
value of what needs to go into those informational materials with respect to
accuracy of testing? Does anybody want to make a comment on that?
DR. DOPPELT: I just wanted to ask a question in general. You are going to have
this information. For example, you suggested that it be done -- that the test
be done in an observed fashion.
So, you have kind of changed the
environment from what its real intended use is, which is at home by
yourself. In an observed environment,
people are more likely to sit there, they are going to read it, but in the real
world, how do you know they actually read it.
So, I don't have the answer to that. That is what concerns me.
DR. QUINN:
That is why you do the phase III, though, just to respond to that. You
have got to do the follow up.
The only thing about the phase II, the
observational thing, is to just learn, you know -- I mean, I learned a lot from
what Freya Spielberg presented.
I mean, things weren't being done right.
They dipped it in the fluid first and then they swabbed it. You will be able to
see that through the observational part, and you will learn where are the
mistakes being made, to try to adjust your instructional materials.
Then you have got to do what you are
saying. You have got to go to the home, and they take the test there and they
mail in the result, or there has got to be a way that you can then confirm that
right on the spot.
DR. DI MICHELE: I think a lot of what is being brought up now in the committee is
certainly the validation of the understanding of the informational materials.
At this point, though, we want to also
discuss what needs to go in -- I think some of the guidance that the FDA is
looking for is what needs to go into those informational materials, what are
the points that really should be made with respect to accuracy of testing.
DR. CRYER:
I will just comment that I think it ought to be spelled out in plain
English. If this test is positive, you have a nine out of ten chance of having
HIV, and that you need a confirmatory test that will you for sure, one way or
the other.
Then, if this test is negative, whatever it
is, if it is one out of thousand or zero, you know, it depends on the numbers I
saw on the tests there, explain exactly what the odds are that you are really
negative.
DR. DI MICHELE: People brought up issues of window periods and issues of it being
used in an acute exposure condition. This sounds like this might be the ideal
place to bring in some of those issues, that a negative after an immediate
event or an acute exposure doesn't mean that you maybe are negative, and this
is some of the materials that might go into this section.
DR. SZYMANSKI: I mentioned this before, and I do think that there should be
instructions telling that if your possible exposure was at a certain time, what
you do.
If it was within a week ago or two weeks
ago, you can't get that test, but you could maybe get an other kind of
test. I think that would be very
valuable with people.
DR. DI MICHELE: Which goes hand in hand with B, which is the correct test
interpretation, some of what we are discussing.
DR. KULKARNI: I think one of the things I find very useful for informed consent
for a cancer trial is sometimes we have an algorithm, and perhaps an inclusion
of such an algorithm saying, if you are positive, you need to do this, if you
are negative, it needs to do this, makes it probably more readable by the
public.
DR. KUEHNERT: This might be more on B.
DR. DI MICHELE: That is okay, we are discussing A and B.
DR. KUEHNERT: What I was going to say, we would love it all to be simple and
say, if it is possible, there is a nine out of 10 chance that you have HIV, but
it gets back to positive predictive value.
It depends what the pretest probability is.
So, then what do you do? Do you
stratify by population and say, in a general population this, in a high risk
population this, and it gets complicated.
It seems like that is necessary to define
what that pretest probability is, at least have a few suggestions, but maybe
Dr. Branson has some suggestions on how best to do this.
DR. BRANSON: That is why I am shaking my head. CDC has been through this with
rapid tests for a while, and we started out with attempting to do some kind of
an algorithm analysis based on risk, and it was called a qualitative expression
of quantitative probabilistic expressions, and it didn't work.
Our recommendation for counseling with
respect to these tests is to not attempt to communicate what the predictive
value is, but to communicate to people that you have a rapid test that is
positive and you can't tell for sure until you get a confirmatory test, which
combines two of those issues.
So, I think that has to do with
communicating that and the accuracy of testing, but we at CDC would strongly
recommend against having any kind of one from column A, one from column B, your
chances are nine out of ten and your chances are one out of ten, because there
is no way to make that accurate.
DR. QUINN:
Just a question to Dr. Branson. I actually like the algorithm that, test
positive, need confirmatory test, go see doctor or physician or health care,
something like that. Negative, re-test in three months if an exposure has
occurred, because of that window.
While I have got the mike, as far as the
window, actually Dr. Nelson and I were talking about, with the pregnancy test,
just about every woman knows that after intercourse the pregnancy test isn't
positive the next day. She must wait a certain amount of period after that
particular exposure.
The concept, to say that after a high risk
exposure you must wait so many weeks before testing, isn't that problematic. I
think actually it could be conveyed in very simple language.
DR. NELSON: HIV positives don't have a menstrual period that they miss.
DR. DI MICHELE: There is a seroconversion period.
DR. BRANSON: I wanted to respond, I think that is an excellent idea. It is
exactly what we recommend. The difficulty, again, with this issue of saying
what your risk is, is that it decreases the likelihood of people returning for
confirmatory testing if they say we fit into this category, which is what we
would like to avoid.
We have done some considerable, actually,
qualitative research with respect to potential home use for this kind of thing.
One big message that we got back from the
qualitative research was people already understand the window period, and they
are saying, using it at home, one of the problems with it is that there is a
window period. So, that concept actually is out there for a lot of people
already, that it is not useful soon after an exposure.
I am not saying it clearly will be out
there with all populations, but in these groups it was something that was
frequently brought up as a draw back for a home use test.
DR. DI MICHELE: Then, depending on the cost of the test, I don't know how many
people are going to be able to test repeatedly, but that might be a limitation.
DR. SIEGAL: One of the compelling public health issues is identifying true
early seroconversion or pre-seroconversion and acute HIV infection, because
those people are highly infectious.
FDA might well take the position that, on
the outside of the package it says, if you are coming to get this test kit
because you want to find out whether you are just infected, don't buy this test
kit, but go to an appropriate place where you can actually get the appropriate
testing. In other words, it is a way of
alerting people who aren't really aware and it might, in fact, benefit us all.
MS. BAKER: I was glad to hear about the
good qualitative data that you have. That was something I was going to mention,
that perhaps some of these more complex issues, or complex concepts -- the
window period, confirmatory testing, need for referral for medical care -- that
I would recommend that that be tested using some robust qualitative studies in
a variety of racial and ethnic populations, including people who are very savvy
about low literacy, thinking about the homeless, the substance abusing teens.
All of these groups should have some good robust qualitative studies, focus
groups, to see what language, how do they understand these issues. What
language best describes it. Also, not
just the low literacy, but visual, pictorial graphics as well.
DR. CRYER:
I guess I will just take a little -- I guess I just disagree with the
notion that you would not tell the truth about the accuracy of the test in the
instructions.
I mean, I am going to buy a test because I
am worried. Then I would like to know what that means when it is positive.
Just to say, well, if it is positive, you
may have a problem, you need to go contact your doctor, that isn't really very
helpful to me. I wouldn't buy that test and I don't think anybody else would
either.
It is going to be all over the internet
what it means anyway. Why don't we right up front say, this is what the data
says, and this is what we recommend that you do.
DR. DI MICHELE: I think the question only came up in terms of, depending on the
risk, whether the population is at high risk or low risk, that that number
might be a little bit different, and I think people were trying to understand
how to make that clear, what is very, very complicated epidemiology, how to
make that clear in a way that people would understand it. I think that was the
question.
DR. CRYER:
That is not what I heard. I heard that the FDA would not want to, in any
way, put a number on there as to what chances -- or CDC, I am sorry -- wouldn't
want to put a number on there as to what the chances are that you actually had
HIV, which I just disagree with. My opinion.
DR. DI MICHELE: Dr. Branson, did you want to qualify or clarify your statement?
DR. BRANSON: I can just say that that is our current recommendation for the
use of rapid tests in the hands of people -- in other words, from counselors as
opposed to home use.
Having first used that method of attempting
to qualify highly likely, somewhat likely, unlikely, as opposed to just going
in the direction -- CDC's current counseling message is to not attempt to give
an indication of the likelihood of a false positive, because we just found that
it had very, very low predictive value.
DR. INUNGU: From what I am hearing here, it seems like we are just referring
to written material. I am asking if any
consideration has been given to oral or verbal communication, sort of playing a
tape or anything.
Dealing with even college students, I have
realized that they just do not read. If that is at the college level, I am
wondering, what does that mean on the street.
DR. DI MICHELE: I think that people have mentioned issues of pictorial
representation in terms of the instructional materials to address issues of
literacy and the ability to understand complex instructions.
I don't believe that we have addressed the
issue of how much of this the consumer will be looking at themselves, or how
much pre-use counseling they might get.
I think at this point there has been a lot
of assumption that there is no pre-use counseling for this test kit, but maybe
we are incorrect, in terms of maybe some oral communication.
DR. INUNGU: What I was trying to get to is that some of the instructions, if
it is written, some teenagers just do not read it, and how do we get around it.
That is my question.
DR. DI MICHELE: And do pictorial representations, do they get around it, in your
opinion?
DR. INUNGU: It is difficult to say. I will say that in certain communities,
especially having dealt with teenagers in Detroit, they would rather listen to
something or be told a story than having to read it themselves, and that is
something that probably you need to consider and see how that can be done in
this case.
DR. NELSON: Does over the counter mean pharmacy, or does it also mean the
grocery store? In other words, if it is
over the counter, you don't need a prescription or people do it at home, but I
just wonder what FDA's concept is of the concept of how these kits would be
distributed.
If there is a pharmacist in the chain, then
there could be some oral communication. If it is in a grocery store or
sidewalk, whatever, cafe, bar, it is unlikely.
DR. DI MICHELE: Certainly it has been brought up that people want this system
integrated, this test kit, integrated into a system of public health.
I think certainly in some discussions it
was not precluded that, although these tests would be performed at home, they
might still be handed out in public health clinics or in teen clinics or
adolescent clinics.
So, it sounds like the distribution network
could be -- again, that is part of probably integrating it into the system, but
that is a good point.
DR. DI BISCEGLIE: It might just be sold on the internet as well, and then there is
no opportunity. Just very briefly, I suppose it is possible to make a DVD to
put in the box. The actual cost of reproduction of the DVD is just pennies.
There would be a cost, presumably, to produce it.
What I was going to say is, there would need
to be a balance in the written instructions between simplicity and ease of use
and trying to be complete.
During the day we have had people say again
and again, you need to tell them this, you need to tell them this, you need to
tell them this.
So, when I take my new computer out of the
box, there are the instructions which tell me everything, and then there is the
foldout sheet that says how to get started, and that is what I read. Maybe an equivalent of that might be useful.
DR. DI MICHELE: Dr. Cowan, how are we doing?
DR. COWAN:
Actually, there have been some excellent comments here. We really do
appreciate all of your comments. There have been some wonderful suggestions.
There is one piece that is missing, though.
Once these ideas are used, for example, by a company that wants to submit to us
for an over-the-counter claim, how do they demonstrate to FDA that they are
effective?
That is where the validation comes in. So,
we need input on that as well. If we go with any one of a number of suggestions
-- a DVD, if we use pictures, any one of the other suggestions that was raised
-- it is incumbent upon the company to show us that that method is effective at
getting the message across and doing what it is supposed to do.
So, if it is possible to get some input on
what sorts of information the company should provide to us, or the studies the
company should do to demonstrate the effectiveness of their material, and that
is trick.
DR. DI MICHELE: One question I have is, in this committee, at other times, we
have discussed validation of some of the questions used for blood donors and
blood donor questionnaires, et cetera.
I know that there has been lots of
consultation tha that the FDA has had with validating information, transmitting
materials, et cetera.
Do you think that there is a possibility
that some of that same validation process might be usable here without having
to reinvent the wheel?
DR. COWAN:
I think that is actually a good idea. It is certainly something we
should look into. I didn't know if the committee had other suggestions. That is
certainly an excellent start.
DR. DI MICHELE: And we can explore that. Other ideas about validation?
DR. MANNO:
It seems to me just a simple pre and post test of the materials
presented. So, you give them a test and then they read the materials, and then
they take the same test again, to see if they picked up any information. That
is how we validate informational materials.
DR. BISCEGLIE: So, in other words, questioning them afterwards?
DR. MANNO:
Yes.
DR. DI BISCEGLIE: Simply questioning them as to their understanding of the
instructions that they received.
Another aspect of that, that I think would be important is, did they
actually open the instructions.
If a pre-test post-test kind of presumes
that you are going to tell them to open the instructions, it would be nice to
know what proportion of individuals actually read any instructions.
DR. SZYMANSKI: This might be a crazy suggestion, but I was thinking of a
telephone, if you had this question, press number one, and if you have this
question regarding it, press number two, three, four.
So, you don't have to have a live person
there, but you would have a voice. As you said, people don't like to read, but
they like to hear the voice. Just a suggestion.
DR. DI MICHELE: So, you were addressing how some of the information can be
transmitting use telephone, using a 1-800 number, for instance.
Maybe we can also come back to that
question. Do we have to go through C? I
think we still have to go through C,D, E and F.
What kind of comment would you like on the
importance of supplemental testing for confirmation of positive results? Dr. Whittaker would like to comment on that.
DR. WHITTAKER: Since this is the blood product advisory committee, my concern is
that somebody would get a presumptive false positive and go to their local
donor center, because it is still anonymous now, and get their blood collected.
So, is there any thought about that?
DR. KUEHNERT: So, not only saying where to go, but where not to go. Blood
donation should not be used as a method for confirmation.
DR. DI MICHELE: Good point.
DR. SCHREIBER: Except that once you tell them where not to go, that is where
they will go. I mean, I think it is
very important, that we would all agree, that you have to have a very strong
statement about the importance of the supplemental testing.
Depending on what they call this -- I would
prefer to call this a screening test, and that makes it very clear that has to
be confirmed by an additional test.
As Dr. Cryer said, I do think you need
something about what the probability is that you will be false positive.
I think you could do that with just saying
that, in clinical tests, the probability is somewhere between 90 and 50 percent
or whatever it is, that you might have a false positive test result.
I mean, we do that when we read the
instructions in the packet inserts about our adverse reactions to drug effects,
and we have 50 or 60 or 70 or 100 of them at one percent each. So, I think it
is easy to do.
Just a comment on the validation, I think
you are right. It is very easy to do
validation in terms of comprehension.
I would think that using my blood glucose
monitor as a guide, periodically I get a post card from the company asking me
if I have had any problems with it, or if I have had any difficulties in
testing or test strips and things like that.
I think this company could do exactly the
same, or you could even put a post card in the package and have some basic
questions about what they understand are some of the parameters that we want to
evaluate, and you could have them mail it back, and then they could get a
coupon back for X percent off on their next test kit.
DR. DI MICHELE: I think that, looking at C, the importance of supplemental
testing, I think ties in with I think E and F, in terms of the availability of
counseling and medical referrals.
I think we have heard a lot from the
community about the need to integrate back into the system.
This sounds like, you know, we have talked
about a potential integration point being the handing out of test kits, but
certainly this sounds like this is going to need to be the place where you
integrate back into the existing systems, and re-refer them back into the
community.
I think that, with respect to clinical
trials, one of the questions that can be addressed is, what is the best way to
reintegrate now the potentially positive individual back into the community,
and the support systems both medically and the psychological, the social, the
medical support systems that exist within the community.
I think there might need to be -- I am not
sure how much of this would be pre-licensure, but certainly in terms of phase
IV trials, a lot of the effectiveness of these kinds of referral patterns and
what is working best, I think, is probably going to need to be studied as part
of a phase IV clinical trial. Does anybody else have any comments?
DR. CRYER:
Just thinking about C, E and F together, it seems like a little pamphlet
could be put in the kit, that probably ought not to come from the company but
would be some standardized manual on what you need to know about HIV and AIDS,
given the fact that you were worried enough to buy this kit. That could be standardized, scientifically
rigorous, and designed to get people to do C, E and F.
DR. SCHREIBER: On the OraQuick advance subject matter information sheet that we
got, right on the front they list the AIDS hot line.
I think that would be very useful, and then
once a home kit like this gets out, I think it would be very critical to inform
the hot line people, because they are going to answer these questions that we
are raising right now.
Given that that is a confidential hot line,
I think they will be able to address very many of the issues, and also act as a
potential contact point for referral.
DR. DI MICHELE: Good point, and my question is, do you think that the hot line is
-- and we have gotten input from, I think, the community about the fact that
this needs to be a 24/7 hot line, and obviously would be able to answer a
myriad of questions.
Is the hot line the only way to refer back,
or are there other methods that we should be counseling on referring back to
the community? You can either answer
that question or ask your own.
DR. DI BISCEGLIE: Just the first part of it, just to clarify, I think the -- I
would guess that the sponsor would make a separate arrangement for a 24/7, just
as the Home Access health kit has their own operators and so on.
They have talked to ASHA, I think, I
presume, to set up a system for these phone calls. I would guess that would be
part of what we would hear about at some time in the future, maybe not some
preexisting line which might supplement, but this would be sort of part of this
process, I would imagine.
DR. SCHREIBER: I was thinking of ASHA, too.
DR. MANNO: In looking at the questions over
here, the areas to be considered, D, which is management of psychological and
social issues, really should be down with F, it seems to me, because over the
telephone, a referral can be made, but quickly people need to get to resources
in their community.
DR. DI MICHELE: Any other comments on D, in particular? I think that is the one we sort of haven't discussed as much.
DR. DI BISCEGLIE: I would say it is a challenge. To take the example of hepatitis C
again, over and over again I see blood donors who were told 10 years ago that
they had hepatitis C. They got a note from the Red Cross, go see your doctor.
It takes them 10 years to show up in my
office, or they go to their family doctor who says, it is not so important, or
does the wrong kinds of tests. I don't
have a solution, but I am saying it is a problem.
Perhaps one solution that occurred to me
was a card in the box that says, if you are positive, this is what you take to
your doctor, because the doctor may not know anything about the test.
This is the test that was done, it was
positive, and this is the kind of test that needs to be done to confirm
it. It may not go to a doctor. It might
go to a nurse in the county clinic or whatever, perhaps.
MS. BAKER:
Under the management of social issues, one of the issues that comes to
my mind is employment, insurance, people having questions about, does this mean
I am going to lose my job, how can I keep my insurance if I have it, how can I
get insurance if I don't have it, and how will we be able to hook people up
with resources, local resources.
I mean, who is going to determine who is
eligible to be on a resource list and how is that going to be screened.
DR. DI MICHELE: Those are all good questions.
DR. KUEHNERT: I just wondered if Dr. Branson had a comment.
DR. BRANSON: If I may, first with respect to the hot line, as the agency that
funds the current hot line, I want to clarify that we would not consider it
acceptable for any commercial company to refer all their people just to our hot
line. So, whatever service we are
talking about here, we are not talking about doing it for the CDC hot line.
The second, in terms of many of the follow
up issues that we have talked about -- medical referral, confirmatory testing
-- I haven't heard anyone say, compared to what, the adequacy compared to what?
We have large studies underway, for
example, looking at how many people in our current testing system, or medical
testing systems, get into medical care, or get confirmatory testing.
So, when we talked about sending coupons
back or assessing what happens with a home test kit, I am not sure what we are
going to use as the comparison group.
DR. DI MICHELE: The first thing that comes to my mind with respect to that is the
fact that you have some information on people who come in for standard testing
or conventional testing, and how they get integrated into the system, whether
they come back or they don't come back.
It sounds to me like that would almost be the ideal comparison group.
DR. BRANSON: My problem is that the results don't look so good.
DR. DI MICHELE: With the conventional testing?
DR. BRANSON: Right. People don't come back for the results. I understand that
is reality, but just as an understanding, when we talk about having people send
coupons back or assessing or putting a standard on this over-the-counter kit,
recognize that the comparison is a very imperfect one.
DR. DI MICHELE: It is, but it is the
historical control. I think oftentimes, when we are creating an intervention --
and this is an intervention -- another testing intervention, it would seem that
you would want to compare it to the existing situation with all its warts and
everything else.
What you are trying to do, I think, it
sounds like all we have been talking about today is really improving access to
care to the community. I think, against
what? Against the current standard.
DR. BRANSON: But we don't have really good data on issues like medical
referral or getting into care. I mean, confirmatory testing is something that
we will have some data on, but some of these other issues, there isn't
anything.
DR. DI MICHELE: It sounds like, from everything that we are asking the company to
do, it sounds like you have time to get it, by the time this is going to be
assessed.
DR. BRANSON: It is a charge to FDA and to CDC.
DR. SCHREIBER: I guess I took that as more literal. I thought what we were talking about and what it is reasonable to
expect a sponsor to do is validate the adequacy of the informational materials
to communicate.
I wasn't necessarily even contemplating
having to have a standard against which to measure it. I think that, in my
mind, is an unrealistic expectation for the company.
I think that, as long as you can prove that
the information you are telling the user is adequate and gets the information
across to them that they need to know, in my mind, that is adequate.
DR. DI MICHELE: I think you bring up a good point I am just thinking, again, this
is an intervention. It is a testing intervention, and I think at some point we
would like to know.
Whether this is the company's
responsibility or the public health agency's responsibility or whatever, I
think we would want to know the impact
of this intervention on the state of affairs, which we have heard right now has
bene pretty dismal with respect to the number of people who are probably
infected, who don't know they are infected, and this is where I think we are
trying to make an impact.
At some point, an impact study is going to
have to be done, relative to, I think, where we are now. That is what I was
thinking.
Obviously, I think that you are right. We
may need to clarify what is industry's responsibility versus what is the public
health responsibility.
MS. BAKER:
Another thought on the content of the informational materials with
regard to managing social issues.
We have heard, of course, about violence
against women and I think about sexual assault and battering, and while I fear
this is becoming a laundry list of hot lines, I think it might be useful to
consider other hot lines, such as battered women's shelters, children who need
protection against sexual violence, safe houses.
I don't have all of this clearly thought
through, but it seems to me this is a serious social issue, if HIV is the
result of interfamilial sexual abuse or who knows what.
DR. DI MICHELE: So, what you are saying is that, when you are integrating back
into the system, the system may have to go beyond just the system of HIV care
as it is, and maybe take advantage of other social systems. It is becoming very complicated, it sounds
like, but this is a complicated issue.
DR. SZYMANSKI: I understand that this is going to be a study. So, who is
responsible for the study. The company?
FDA? The company, and we are
trying to give the standards now to the company and then they come back with
what they decided, and then it is approved here, or FDA is approving?
DR. DI MICHELE: The FDA.
DR. KULKARNI: I was just wondering, under D, that maybe something should be
addressed to women who are breast feeding and pregnancy women.
I looked at the previous one and it just
said, can be transmitted to breast milk. I think that, in that algorithm, maybe
one can include saying, if you are breast feeding, stop it right now, because
you may transmit it, some way to address women's issues.
DR. DI MICHELE: That is some of what Judith Baker just said.
DR. CRYER:
This is just ignorance on my part, but I was a little concerned about
some of the things I heard today, that many of the things that we are talking
about ought to be available, or we ought to tell people how to do aren't, in
fact, available.
In other words, how robust is the system in
terms of being able to counsel people or get the confirmatory test, or get a
medical referral, for instance.
If you don't have insurance, for instance,
and you are in a bad part of town, maybe you are not going to be able to do any
of that.
I am just asking, is it pretty much
available that, if you put in a pamphlet that this is what you have to do, if
this comes back positive, is it realistic to assume that everybody is going to
be able to do it.
DR. QUINN:
The thought, you go to a blood bank and donate some blood, and you will
get some test. I don't know. I am teasing.
There are public testing sites, and I think
that would need to be available, as to where those public testing sites are.
I mean, CDC, I don't know where Dr. Branson
went, but they are supported by CDC and public funds. So, for getting the
confirmatory test, they could go to that, and they are free and anonymous in
some settings.
Other than that, there are the STD clinics,
and we do free testing there as well, the public free clinics. So, for the indigent and the poor, there is
a little bit of a safety net. It is not great, but there is something there to
get the confirmation done.
DR. DI MICHELE: Dr. Spielberg, did you want to address that?
DR. SPIELBERG: I just wanted to bring up one other possibility that hasn't been
mentioned, which is there could be the option of sending people who call up or
enter in the computer that they have positive rapid test results, you could
send them a home specimen collection kit, where you could do western blot or
PCR.
I mean, that is not FDA approved yet, but
the technology has been tested. So, people who don't have access to a clinic,
or have high stigma and would like to find out their confirmed status before,
that would be an option.
DR. DI MICHELE: Isn't that just one extra steps? Eventually you have to get to
medical care and psychosocial support.
DR. SPIELBERG: Absolutely, but there may be
people who need to take it in steps. Once they find out that, yes, they are
absolutely positive, they may be more comfortable going in and finding a care
provider that they are comfortable seeing.
DR. QUINN:
Again, for the very poor, that layers an additional cost on for them.
DR. SPIELBERG: I would say make it free and amortize it across the cost of all
the kits.
DR. NELSON: I think getting a supplemental test shouldn't cost anything, but
there is a problem with medical referrals.
There are clinics and there is Ryan White, et cetera, but that varies by
where you are.
I have seen patients out of state that I
recommended they move to Maryland if they wanted long term care, from a couple
of neighboring states.
DR. DUFFELL: I would just like to comment, I guess, just on the general
concern. It is pretty sure OraSure is going to have to redesign their package,
because they are going to have a DVD in there, a postcard, they are going to
have a list of battered women's shelter places.
One thing that is clear, though, is we will
not have the CDC's hot line number in there. I would add that I really think we
are going to have to add some magnifying glasses like I was using earlier,
because the labeling is quite small.
Anyway, here is the point. The point is, I
think all this stuff that we talked about may make us feel better at night,
that we put a lot of information in there, but I think you need to come back to
the hard core realities.
That is, as you were speaking before, a lot
of people aren't going to read information. Visuals, pictorials, I think are
important.
I think simplification of the information
is what is really, really important here, and possibly having some sort of a
telephone system to get all this other detailed information that we are talking
about.
Like I said, it sounds great, but I will
tell you, it is just going to drive up the cost of this product. In the end,
somebody has got to pay for all this stuff, and I don't know that we are
achieving what we are after.
I think there have been plenty of studies
that have been published in some of the great medical journals about patients
getting information on prescription drugs and what is happening with that.
I would like for us to really, if in the
closure of today, if we can kind of come back to what is the core essence of
what should really be in that labeling.
I think it is not practical, possibly, to
put all this stuff in there, even if we redesign the packaging. I just don't know that it is accomplishing
what we are after.
DR. DI MICHELE: Are you suggesting that we continue the discussion in that vein?
DR. DUFFELL: Yes, because we have talked about it so much. Is it possible for
the committee to say there are three essential elements here that really need
to be covered.
To me, thinking about it, the most
important thing is what the test does and what it doesn't do, and where to go
with a positive result. To me, that is
the core essence of what it is all about.
Then that resource that they are referred
to takes it from there, provides the outsourcing that is needed. Obviously, the
other thing that has got to be in there is clear instructions on how to take
that test. That is really pivotal.
DR. DI MICHELE: That is a very good point in terms of bringing us back to reality
here. Dr. Cowan, how are we going with
the information that you need?
DR. COWAN:
I think we have covered most of the ground except for the last point.
DR. DI MICHELE: I think you got the essence
of it, which I think the committee agreed with.
DR. COWAN:
If that is the case, then I think we are --
DR. DUFFELL: The only thing I didn't cover was about the cat, though.
DR. DI MICHELE: I think as a cat lover, and as the chair of this committee, there
is going to be no maligning of cats at this point.
DR. COWAN:
Actually, Madame Chair, I quite agree with you. I thought it was quite
prejudicial against dogs and other issues.
DR. DI MICHELE: Would the FDA like us to continue discussion in any way, or have
we pretty much answered most of the questions?
DR. EPSTEIN: I think we tried to make clear that this is an initial step, and
there is going to be some learning process as we go along.
I personally would like to thank the
committee for going the distance and giving us a large amount of extremely
useful feedback and insight.
We will go back and think about everything that
we have heard, and of course we will be engaging in a dialogue with candidate
product sponsors. So, you may hear from
us again. It is possible we will bring the issue back at a future meeting.
DR. DI MICHELE: I guess, with that, I would also like to add my thanks to the
committee members and to the general public, and to OraSure for bringing this
issue up. I think we have all earned
our dinner. Thank you very much, everyone.
[Whereupon, at 7:20 p.m., the meeting was
recessed, to reconvene the following day, Friday, November 4, 2005.]