DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
MEETING
Thursday, August 16, 2007
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.
This
meeting came to order at 8:00 a.m. in the Doubletree Hotel and
PRESENT:
DONALD W.
MARK BALLOW, MD, MEMBER
HENRY M. CRYER,
ADRIAN DI BISCEGLIE,
MD, MEMBER
WILLARDA V. EDWARDS,
MD, MEMBER
MAUREEN A. FINNEGAN, MD, MEMBER
SIMONE A. GLYNN, MD, MEMBER
KEITH C. QUIROLO, MD, MEMBER
GEORGE B. SCHREIBER, SCD, MEMBER
IRMA SZYMANSKI,
DONNA S. WHITTAKER, PHD, MEMBER
JUDITH R. BAKER, MHSA, CONSUMER REPRESENTATIVE
LOUIS M. KATZ, MD, NON-VOTING INDUSTRY
REPRESENTATIVE
MELVIN BERGER, MD, PHD, TEMPORARY VOTING MEMBER
RICHARD A COLVIN, MD PHD TEMPORARY VOTING MEMBER
JAMES R. ALLEN, MD, MPH, NON-VOTING TEMPORARY
MEMBER
T-A-B-L-E O-F C-O-N-T-E-N-T-S
Page
Statement of Conflict 4
Opening Remarks 10
Committee Updates
Summary
of May 10-11 Meeting of DHHS 11
Advisory
committee on Blood Safety and
Availability
Summary
of April 25-26 Workshop on Immune 20
Globulins
for Primary Immune Deficiency
Diseases
Summary
of August 15 Workshop on 28
Licensure
of Apheresis Blood Products
Informational Presentations: WHO Biological
Standards
Summary
of January 29-30 WHO meeting 34
Potency
and Safety Standards for Plasma 52
Derivatives
Joint
FDA/WHO Minimum Potency Standards 72
for
Certain Blood Grouping Reagents
Topic I Response to the Office of Blood Research
and
Review Office Level Site Visit
Introduction 79
Office
Response 100
Open Committee Discussion 132
Topic II Measles Antibody Levels in
Globulin
Products
Introduction 151
Current
Epidemiology of Measles in
Measles
Infections and Estimated 195
Protective
Titers
T-A-B-L-E O-F
C-O-N-T-E-N-T-S
Page
Topic II cont'd.
Measles Antibody Titers in Plasma Donors 219
Measles Antibody Levels over Time in Licensed 236
Immune
Globulin Products and Patients with
Primary
Immune Deficiency Diseases
(Baxter
Healthcare and CSL Behring)
Open Public Hearing 253
Open Committee Discussion 261
P-R-O-C-E-E-D-I-N-G-S
8:05 a.m.
EXECUTIVE
SECRETARY JEHN: Let's go ahead and get
started. Mr. Chairperson, Members of the
Committee, invited guests, temporary voting members and public participants, I
would like to welcome all of you to this 90th meeting of the Blood
Products Advisory Committee. I'm Donald
Jehn, the Executive Secretary for this meeting.
This
meeting will be completely open to the public.
At this time, I would like introduce the individuals seated at the head
table for today. To my immediate left is
our BPAC Chairperson Dr. Frederick Siegal, Medical Director of
To
my right and going down the table is Dr. James Allen, Medical Advisor, American
Social Health Association; Dr. Mark Ballow, Chief Division of Allergy and
Immunology, SUNY New York and Women's and Children's Hospital of Buffalo; Dr.
Richard Colvin, Clinical Assistant in Medicine, Center for Immunology and
Inflammatory Diseases, Massachusetts General Hospital East; Dr. Henry Cryer,
Chief of Trauma and Clinical Care at UCLA; Dr. Adrian Di Bisceglie, Chief of
Hepatology, St. Louis University School of Medicine; Dr. Willarda Edwards,
President and Chief Operating Officer of Sickle Cell Disease Association of
America; Dr. Maureen Finnegan, Associate Professor, Department of Orthopedic
Surgery, University of Texas Southwestern Medical Center; Dr. Simone Glynn,
Branch Chief Transfusion and Medicine and Therapeutics Branch, NHLBI.
And
then on my left side going down, Dr. Keith Quirolo, Clinical Director,
Apheresis Program, Department of Hematology, Children's Hospital at Oakland;
Dr. George Schreiber, Vice President of Health Studies, Westat; Dr. Irma
Szymanski, Professor of Pathology, Emerita, University of Massachusetts Medical
Center; Dr. Donna Whittaker, Chief Department of Clinical Support Services,
U.S. Army Medical Department Center and School, Fort Sam, Houston; and Ms.
Judith Baker, our Consumer Rep located at UCLA; and, finally, our Industry Rep,
Dr. Louis Katz, Executive Vice President, Medical Affairs, Mississippi Valley
Regional Blood Center.
Committee
members not in attendance are Drs. Cooner, Kulkarni, Manno and Quinn. Dr. Allen is at the table for the discussion
of the response of the Office of Blood, Research and Review Office Level Site
Visit for Research. I would like to
thank all of you for attending this meeting.
Now
if I could have Dr. Goodman. We have
four retiring members after this meeting and we would like to recognize
them. Dr. Szymanski.
(Applause.)
EXECUTIVE
SECRETARY JEHN: Dr. Donna Whittaker.
(Applause.)
EXECUTIVE
SECRETARY JEHN: Dr. Keith Quirolo.
(Applause.)
DR.
WHITTAKER: And Dr. George Schreiber.
(Applause.)
EXECUTIVE
SECRETARY JEHN: We thank them all. Thanks very much.
Okay. Before we start the meeting, I do have a
conflict of interest statement to read.
It's rather lengthy, so please bear with me.
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, FACA, of 1972. With the
exception of the Industry Representative, all participants of the Committee are
special government employees, SGEs, or regular federal employees from other
agencies and are subject to the 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 208 and 21 USC Section 355(n)(4) is being provided to
participants in today's meeting and to the public. FDA has determined that participants of this
advisory committee are in compliance with Federal Ethics and Conflict of Interest
Laws including, but not limited to, 18 USC Section 208 and 21 USC 355
(n)(4). Under 18 USC 208 applicable to
all government agencies and 21 USC 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 essential expertise, Section 355.
Members
of the Committee who are special government employees at today's meeting
including special government employees appointed as 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 employers, spouse or
minor child related to the discussion of (1) FDA's response to the Officer of
Blood Research and Review Office Site Visit held on July 22, 2005 and (2)
measles antibody levels in U.S. immune globulin 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 also includes several updates. In
accordance with 18 USC Section 208(b)(3), waivers were granted to Dr. Mark
Ballow and Dr. Melvin Berger for the discussion of topic two on Measles
Antibody Levels in U.S. Globulin Products.
A copy of the written waiver may be obtained by submitting a written
request to the Agency's Freedom of Information Office, Room 12A-30 of the
With
regard to the FDA's guest speakers for Topic two, the Agency has determined
that the information provided by these speakers is essential. The following information is being made
public to allow the audience to objectively evaluate any presentation and/or
comments made. Dr. Donald Baker is
employed by Baxter Healthcare Corporation.
Dr. Baker has financial interests in his employer. Dr. William
Moss is employed by Johns Hopkins Bloomberg's
In
addition, there may be regulated industry and other outside organizations'
speakers making presentations. These
speakers may have financial interests associated with their employer and with
other regulated firms. The FDA asks in
the interest 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 the
FDA for conflicts of interest.
Dr.
Louis Katz is serving as the Industry Representative acting on behalf of all
related industry and is employed by the
This
conflict of interest statement will be available for review at the registration
table. We would like to remind members
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.
The 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.
Before
I turn the microphone over to the Chair, I would like to request that everybody
take a moment and check to make sure they have their cell phones and pagers set
to silent or turned off. Thank you. Dr. Siegal, I'll turn it over to you.
CHAIRMAN
SIEGAL: Thank you, Don. I would like to welcome you all to this
glorious summer meeting of the Blood Products Advisory Committee. Fortunately,
we don't have a lot of controversial topics, but we have a fair amount to
cover. I particularly want to welcome
back Jim Allen, an old friend from the AIDS wars. Can you not hear me? Well, it's not really important anyway.
(Laughter)
CHAIRMAN
SIEGAL: But Jim was, of course, my
predecessor on this committee and we've known one another since about 1981
maybe.
Our
first set of topics are the Committee updates and we're going to start with
Jerry Holmberg who is going to review and summarize the meeting of the DHHS
Advisory Committee on Blood Safety and Availability. Jerry.
DR.
HOLMBERG: While we are waiting to get
that up on the screen, I'll just give you a little disclosure. I do have financial interests in my company,
the Federal Government, and that financial interest is not only receiving a
salary, but paying taxes.
(Laughter.)
DR.
HOLMBERG: And if anybody would like to
know, I have had my annual financial review with the Ethics Office.
What
I would like to do today is to give you an update on the Advisory Committee on
Blood Safety and Availability and the Office of Blood Safety and Availability
and also primarily give you a summary of the May 10 and 11, 2007 meeting.
First
of all, I would like to note that we have some staff changes. The biggest staff change that I would like to
mention that is not on the slide here is that Dr. Aquinobi, the Assistant
Secretary for Health, has resigned from the Administration and that resignation is as effective as of September 3rd. In my office, we do have Lt. Commander Rich
Henry who has moved up to the Deputy Director position and we have a new Public
Health Officer, LTjg Jennifer Lunney who is our Senior Health Preparedness
Advisor.
At
the May 10th and 11th meeting, Dr. Aquinobi asked the
committee to review several commonalities between transfusion and
transplantation safety. The reason for
that is in October the charter for the Advisory Committee on Blood Safety and
Availability was modified to include interests or concerns of transfusion and
transplantation safety. This sort of
opens up the scope of issues that we can deal with at the committee and Dr.
Aquinobi was looking to see are there areas of commonality.
So
the first question was is there a process, an opportunity, to lay out a process
for transfusion and transplantation safety for the future and the committee
overwhelmingly said that, yes, there is a need to develop a process to enhance
the quality and improvement in transfusion medicine and transplantation
medicine.
Is
there scientific evidence to support a need for a master strategy? In this particular area, the committee really
struggled as far as finding scientific evidence, but based on surveillance
evidence there is a limited reports of infectious disease transmission and
therefore, substantiate the need for a master strategy and you can read on
there as far as the differences in the risk/benefit profiles between
transfusion tissue and transplantation recipients but that all these patients
have the potential for acquiring life-threatening infections if an infectious
disease screening is flawed or emerging or unknown diseases evolve unchecked
over time.
So
another question that was asked was what should be the scope of a master
strategy and the number one issue that came out was a recipient outcome
surveillance or a biovigilance system to identify all donors using common
identification numbers linked to biological products that are uniquely
identified; mandatory adverse event reporting process for tissues, organs and
blood therapy through appropriate mechanisms to designated public health
authorities and to recipients and donors and timely and efficiently trace all
biological products to the clinical user, recipient, and donor and to recognize
transmissible events resulting in adverse outcomes including infectious agents,
malignancies and toxins; also to build communication and education networks to
disseminate data to users; to develop informatics to support surveillance,
process, involvement, improvement and evidence-based research; and to include
other strategic plan elements as needed such as donor recruitment, donor
screening, research coordination and emergency preparedness.
What
are the areas of commonality of blood products, cohort progenitor cells and
bone marrow tissues and organs? Key
elements in common with transfusion required for ensuring high quality include
donor recruitment; donor screening; and, of course, eligibility; collection;
infectious disease testing; transportation; storage; processing; labeling;
traceability; good manufacturing practices; good tissue practices. I would also say probably good
transplantation practices; outcome analysis; adverse event reporting. And in addition, there needs to be a way to
evaluate the differences between the different transfusion and transplantation
products, modalities.
How
best should this be done with the stakeholders and how do we begin? The recommendation was that HHS should
convene a forum of stakeholders to include public health agencies, accrediting
agencies, manufacturers, clinicians, consumers and endusers and HHS should be
responsible for implementing a master strategy with appropriate resources based
on input from stakeholders.
And
what are the resources needed and what are the estimated costs? The committee really do not get to that area
and had a difficult time trying to put a price tag on what this would mean.
Let
me just go back to that slide there. As
an outcome of the recommendations, Dr. Aquinobi has sent a letter to Dr. Bracey
who is the Chairman of the Advisory Committee on Blood Safety and
Availability. In that letter, he does
recognize the recommendations and the answers to the questions and also
reassures Dr. Bracey that the Department has already moved forward in various
aspects on bioviligence and we have already put resources towards those
bioviligence endeavors through not only the recipient side but also through the
donor side of surveillance and also CDC is supporting a collaborative effort
with the TTSN for tissues and transplantation.
Our
next meeting is next week. The two
issues that we're primarily looking at ethical considerations and risk benefits
for ensuring transfusion and transplantation safety during focal periods of
shortages. Those focal periods of
shortages could be seasonal shortages, preparation for pandemic, disasters both
manmade or natural and then also to review and discuss the elasticity of the
blood supply to support transfusion and transplantation safety as well as
strategies and barriers to those strategies.
And
that's all I have. If there are any
questions, I'll be happy to entertain those.
CHAIRMAN
SIEGAL: Questions from the Committee?
DR.
FINNEGAN: One of my questions and I
realize I'm a little bit naive about what the infrastructure for IT is within
this environment, but would you consider having IT infrastructure as one of the
stakeholders? Because it would seem to
me if you had a good IT infrastructure, that the cost long term would be much
less.
DR.
HOLMBERG: Absolutely. We have already initiated some of those
discussions primarily using some of the infrastructure that is already in place
within the Federal Government and outside the Federal Government. Also within the Department of Health and
Human Services is a health information technology office that is personally --
that reports directly to Secretary Leavitt.
They've done case studies analysis for electronic health records and
also for laboratory surveillance.
So
we're moving in that direction, but, yes, definitely in our stakeholder
meetings, we will consider IT so that there are stakeholders, there are
placeholders, I should say, for future systems that are developed that we can
mine the data down into.
The
other thing that I want to emphasize there is that we are really looking at
this as a quality system in such a way that this will be a system to develop or
to get data that we can analysis in hopes of being able to share it throughout
the entire community and not to be punitive against a stakeholder. So it's trying to be very open in the way we
collect the data and for that reason, we have already involved many of the
stakeholders such as the AABB and the UNIS and the various -- the American
Association of Tissue Banks. Yes. Dr. Ballow.
DR.
BALLOW: So is this to include all
fractionated blood banks as well?
DR.
HOLMBERG: Well, we do have them --
DR.
BALLOW: Coagulation products, IV, IG,
etc.?
DR.
HOLMBERG: We do have them as one of the
stakeholders and we have not had the meeting yet, but they are on the list to
participate.
The
other thing I want to draw the attention to is that we do have a federal
registry notice out that came out on July 30th seeking nominations
to the Advisory Committee on Blood Safety and Availability. I would like to take this opportunity to draw
your attention to that and to remind people that nominations are due by August
31st.
Thank you.
DR.
SZYMANSKI: I had one more question. I notice an interesting word
"malignancy" and how are you going to screen for that? In donors or in the recipients? Is that something new that is not being done
now when you screen donors?
DR.
HOLMBERG: I didn't understand the word
that you were referring to.
DR.
SZYMANSKI: You said you are going to not
only worry about infectious diseases, but transmission or something with
malignancy and I was wondering. Do you
have any other approaches than what are used right now when you screen donors
for blood donation?
DR.
HOLMBERG: As far as blood donations, we
do not have a mechanism to be able to track that. However, in the organ community they do have
the adverse event reporting and that does get passed back to UNIS. But it's open. We're the point right now of just developing
this and, of course, as we move forward in bioviligence, I'm sure there will be
other avenues that we want to investigate.
I think that what he want to do is to not only look at what we know
today but also to look towards the future and to be able to look beyond the horizon
for anything that may potentially affect the blood organ or tissue products.
CHAIRMAN
SIEGAL: Are there any other questions
for Dr. Holmberg? Okay. If not, Jerry, thank you. The next speaker will be Jennifer Scharpf who
is going to review the FDA workshop from last April on immune globulins for
primary immune deficiency disease referencing antibody specificity, potency and
testing. Dr. Scharpf.
DR.
SCHARPF: Thank you, Dr. Siegal, and good
morning. This morning I will provide the
Committee on the FDA's workshop on immune globulins for primary immune
deficiency diseases and the workshop was officially titled "Immune
Globulins for Primary Immune Deficiency Diseases; Antibody Specificity, Potency
and Testing." And the workshop was
held on April 25 through 26 of this year at the National Institutes of
Health. FDA is grateful to The Immune
Deficiency Foundation, The Plasma Protein Therapeutic Association and Dr.
Holmberg and the Office of the Secretary, Office of Public Health and Science
at HHS for their sponsorship of the workshop.
And we thank the sponsors not only for their financial support but also
their scientific contributions to the program.
Additionally, I would like to recognize Dr. Dorothy Scott for her role
as organizer and chair of the program.
The
goals of the workshop were fourfold: (1)
to assess the current potency testing of immune globulins. The potency tests currently required are for
antibodies to measles, polio and diphtheria and at the workshop, we wished to
examine the potential for potency tests for antibodies against pathogens most
commonly associated with infection in PIDD patients; (2) to list antibodies
needed to protect primary immune deficient patients from infections; (3) to
identify candidate antibody specificities for potency testing of immune
globulins for treatment of PIDD; and, finally, on the second day, our goal was
to address approaches to diminishing measles antibody levels in currently
licensed products.
So
on the first day of the workshop, our goal was to identify the most clinically
relevant antibody specificities for PIDD patients. Epidemiology and surveillance data was
reviewed and there was a description of patient registries in Europe and the
The
first question we addressed to the panel of experts and the workshop audience
was which pathogens are of greatest concern in immune globulin treated and
untreated patients. And to address this
question, data on infectious diseases and PIDD, both patients with humeral and
cellular immunodeficiencies was presented by clinicians.
The
workshop participants identified Strep pneumococcus and Haemophiles influenzae
as the most important bacterial infections for this patient population. Several viral infections were also mentioned
as pathogens of concern including Epstein-Barr Virus, Cytomegalovirus,
echoviruses, Varicella Zoster, adenovirus and Coxsackie.
Representatives
from the FDA, the Paul-Ehrlich-Institut in
So
at the end of the first day of the workshop, it was proposed that pilot testing
of immune globulins for Strep pneumonia and H. influenza should be conducted
and we believe this type of study is feasible since assays have been validated
for the specificities in serum and who reference labs already exist to which
samples could be sent for testing.
In
the proposed studies, manufacturers would voluntarily send blinded samples to
their reference lab for testing antibody levels to determine the feasibility,
antibody levels and function, and several manufacturers have expressed their
willingness to send samples. And
finally, we would like to measure the trough titer level antibodies to these
bacterial pathogens in patients receiving the product to determine the
relationship between in vitro potency and in vivo levels. And we anticipate that by working with
manufacturers, samples from clinical studies would be available for this type
of testing.
On
the second day of the workshop, we discussed the current lot release tests for
measles antibodies and measles antibody levels are a standard lot release
measure of potency in the
The
regulatory impact of declining measles titers is that the product could fail
the lot release specification and the specific lots must be rejected and
rejection of lots could lead to an obvious negative impact on the availability
of the product for the primary immune deficient patients.
Presentations
at the workshop revealed data on the measles epidemiology in the
Following
those presentations, we asked the following questions to the expert panel and
the audience: is measles infection of
current clinical concern for primary immune deficient patients, how much
measles antibody is needed to attenuate or prevent measles in this patient
population; what is the potential clinical impact of diminishing anti-measles
titers in immune globulin products; and finally, what are the possible
approaches to address the decline of anti-measles antibodies in immune
globulins with respect to clinical efficacy in prevention of measles infection
as well as with respect to utility of a test for lot-to-lot consistency.
So
the possible approaches identified by the discussants at the workshop included:
(1) gathering relevant data relating product titers to patient trough levels
and estimated protective levels and (2) the option that CBER can potentially
change the recommendation on antibody potency, however, this change in level
must be scientifically and clinically justifiable and this is the issue that
will be before the Committee today.
So
in summary, the next steps identified at the workshop are to (1) design and
implement testing protocols to assess levels of antibodies in immune globulins
to H. Influenza and Strep pneumonia pathogens commonly associated with infection
in primary immunodeficient patients and the study will evaluate the feasibility
of using these specificities as potency tests; (2) implement a study to measure
measles antibody trough levels by neutralization assays in patients to better
ascertain the relationship between product dose and trough level; and finally,
CBER will deliberate on solutions to address the diminishing measles antibodies
titers and immune globulins weighing, of course, the scientific, clinical and
supply considerations.
And
finally, information is available on the CBER website including the transcript
and all of the workshop presentations.
Thank you for your attention.
CHAIRMAN
SIEGAL: Thank you, Dr. Scharpf. Are there questions from the Committee? I actually do have a question which is that
since we will discuss this later but is it feasible to change the licensure
requirements entirely so that measles antibody which may not really be relevant
is simply not part of the criteria for approval of the product.
DR.
SCHARPF: I think we can look at
examining changing the titer and that's what we will present later this
afternoon to the Committee.
CHAIRMAN
SIEGAL: Because it certainly would be
more relevant to look at representative pneumococcal antibody titers for the
PIDD population.
DR.
SCHARPF: And that was some of the
conclusions of the workshop.
CHAIRMAN
SIEGAL: Anybody else?
DR.
GOLDING: Yes, I'll just help to answer
that question. I mean we are looking
very actively at changing this, the relevant titers, and what Jennifer
mentioned is that we're looking at H. influenzae and also at Strep pneumoniae
as being much more important and relevant pathogens. But I don't think we have any plans in the
near future to drop measles because as you will hear later, we still think this
is a pathogen we need to worry about even though it's much rarer these
days. But also in terms of consistency
of lot-to-lot testing, it's important to have tests in place that have the
history and the ability to show differences between batches.
CHAIRMAN
SIEGAL: Okay. Let's move on. Finally, Lore Fields from FDA is going to
summarize the FDA workshop just yesterday on licensure of apheresis blood
products.
MS.
FIELDS: Good morning. Yesterday we had a workshop on the licensure
of aphersis blood products at Lister Hill Auditorium at NIH.
In
keeping with the vision of CBER to protect and improve public health and to
approve safe and effective blood products, we planned a workshop to help
educate industry on how we approve apheresis submissions at the Blood and
Plasma branch. We estimate that
currently appropriately 40 percent of the submissions coming into the Blood and
Plasma branch are on apheresis products.
We did have 175 places available yesterday for the workshop and we did
fill the entire auditorium.
The
goals and objectives for the workshop were to educate industry on the licensure
process for apheresis platelets, red blood cells and plasma for
transfusion. We wanted to discuss the
managed review process as it applies to the Blood and Plasma branch, discuss
and review the required documents needed for submission, review the
comparability protocol and what is required to obtain one and review the
requirements for an apheresis instrument.
Additionally, we asked speakers from industry to give examples on how
they successfully submit their FDA's licensure submissions. We also asked Dr.
Katz from the
The
workshop was developed and cosponsored by CBER, the Department of Health and
Human Services, AABB and
During
the workshop, we had several presentations.
I'm going to go over just very brief overviews of what was
discussed. Dr. Goodman did open the
workshop for us.
Dr.
Williams provided an informative presentation on the statutes and regulations
that we use to do licensure submissions.
Dr. Williams also covered licensing, changes to an approved application,
alternative procedures and how managed review is applied to the Blood and Plasma
branch.
Ms.
Ciaraldi did a comprehensive presentation that described how we perform
reviews. This presentation included the
documents, regulations, guidance and operators' manuals references that we
frequently use when we are doing our reviews.
Ms.
Nesbitt did a top ten pitfalls with submissions presentation and what we did
with this was he got together in the Blood and Plasma branch and we came up
with the top ten reasons that we find errors in submissions and she went
through them. Hopefully, the blood
centers will then be able to apply this to their submissions before they send
them in and it will facilitate the process of getting licensure done in a timely manner.
The
next two presentations were given by representatives of the American Red Cross
and Blood Systems. We are always being
asked for examples of acceptable submissions.
So we asked these two blood centers to provide the attendees with an
overview of their processes.
Steve
Kassapian who is the Director of Regulatory Affairs at American Red Cross
reviewed his processes and included some of the examples and forms that his
group has put together over the last couple of years that they use to
facilitate their process.
Ms.
Kathleen Hopping from BSI reviewed how they have standardized their platelet
Apheresis licensure process. She also
provided the attendees with timetables on how the process improvement has
reduced the time of the licensure or the approval for licensure at their blood
centers.
I
went over a brief review of the current guidance for platelet Apheresis and the
2005 draft guidance.
We
did have an unexpected presentation yesterday that is unfortunately not on your
slides. A direct final rule was actually
displayed yesterday as well. So we had a
surprise presentation by Ms. Elizabeth Callahan who is the Acting Director of
the Division of Blood Applications and in this is the changes that will allow a
storage period of seven days for platelet Apheresis and also the increase for
the minimum pH from 6.0 to 6.2 for platelet Apheresis quality control.
Dr.
Katz put on a presentation based on the comments to the 2005 draft
guidance. His group did a study to
determine what the impact is on platelet counts and donation intervals. This is the data that was previously
presented to you in March of 2006. The
paper was recently published and so we asked him to present the data to the
attendees.
The
failure investigation presentations covered the regulations behind the
investigations by Ms. Hoi-may Wong and also one example of how a structured
investigation process is working at a major blood center.
Ms.
Faye Kugele described how the ARC has standardized their failure investigation
processes and how the standardized procedures have improved their investigation
of failed products.
We
did something a little different at our workshop and one of the things is we
spent a lot of time talking to the regulatory people at the blood centers, but
they never actually see our faces. So we
spent about 30 minutes at our afternoon break kind of introducing ourselves to
them so they had a face to go with the person that they talked to.
The
Device Manufacturers Forum was an opportunity for the manufacturers to provide
the attendees with pertinent information from their operators' manuals, package
inserts and other documents that should be included with their submission. They also provided updates on recent changes
on their cleared devices and this was done by Merilyn Wiler from Gambro, Dr.
Orton from Fenwal and Sue Finneran from Haemonetics.
The
final session was a question and answer sessions. Questions were actually provided to a docket
in advance and we discussed the answers as our final session. There were 17 questions submitted and
discussed.
Overall,
we received excellent feedback on the workshop.
The Regulatory Affairs staff from the blood centers who attended said
they learned a lot and they were provided an excellent resource to help them
with their next submission to CBER.
The
workshop planning committees contains six people from industry: Celso Bianco,
Sue Finneran from Haemonetics, Joe Giglio from AABB, Steve Kassapian from
American Red Cross, Dr. Orton from Fenwal and Merilyn Wiler from Gambro
BCT. In addition, there were seven
people from FDA on the planning workshop.
Thank you.
CHAIRMAN
SIEGAL: Thank you. Are there questions from the Committee or
anybody else?
(No
response.)
CHAIRMAN
SIEGAL: All right. Thank you very much. In view of that, let's go onto the
Informational Presentations on WHO Biological Standards. The first presentation will be by Paul Mied
from FDA talking about the WHO meeting and Collaborating Centers for Biological
Standards and Standardization to Support the Development of WHO Biological
Reference Preparations for Blood Safety-related in vitro Diagnostic Tests. Dr. Mied.
DR.
MIED: Thank you, Dr. Siegal.
This
morning I would like to present a summary of the January 29th and 30th
WHO meeting with the WHO Collaborating Centers for Biological Standards and
Standardization. Now this two day
meeting was held at CBER in
The
meeting was convened by WHO, specifically the Quality Assurance and Safety
Blood Products and Related Biologicals Team and the Department of Medicines,
Policies and Standards of the World Health Organization. The objective of the meeting was to foster
cooperation among the WHO Collaborating Centers in the development of WHO
international biological reference preparations for the control of in vitro
diagnostic tests related to blood safety.
Now
the WHO is establishing a five year strategic plan to prioritize development of
these reagents. These biological
reference preparations are used for the validation, quality control, assessment
of comparability and regulation on a global basis of blood safety related in
vitro diagnostic tests. This contributes
to a harmonized regulation of blood and blood products. Specifically, these reagents are used to
provide an indication of the analytical sensitivity of in vitro diagnostic test
kits.
Now
the meeting, the two day meeting, covered the following agents which have an
impact on blood safety: HAV, HBV, HCV,
Parvo B19, HTLV 1 and 2, CMV, West Nile Virus, Dengue Virus, HHVA, prion
agents, bacteria and the causative agents of syphilis, malaria, Chagas and
Leishmaniasis. The existing established
WHO biological reference preparations were discussed at length along with
several new proposals for development of international standards and reference
panels and the priority projects identified were, first of all, the replacement
of four existing WHO biological reference preparations and I'll briefly
describe for you some of these highest priorities.
One
of the highest priorities identified was a proposed second international
reference preparation for anti HBS immunoglobulin to replace the first
international reference preparation that was established back in 1977 and it's
now close to exhaustion. NIBSC will be
the coordinator of the WHO collaboration study to demonstrate the usefulness of
candidate materials for use with a wide range of assay kits and the report of
the WHO collaborative study is expected to be submitted to the Expert Committee
on Biological Standardization or ECBS in October 2008.
For
HCV RNA, there is an ongoing collaborative study that NIBSC is coordinating
that was begun in 2006 to replace the second international standard of HCV RNA
with the proposed third international standard.
Two lyophilized candidate materials generate from anti HCV-negative
window period genotype 1A donations have been distributed to 32 laboratories
covering the main commercially-available NAT tests for HCV RNA. It's expected that the proposal for the establishment
of this standard will be submitted at the meeting of the ECBS in October 2007.
The
first international standard for Parvo B19 DNA which was established in 2000
will be nearly exhausted by 2009. A
small collaborative study was proposed by NIBSC to demonstrate the comparable
potency of a freeze-dried candidate replacement material to this standard. NIBSC will present an update of discussions
from the SoGAT meetings to the ECBS in 2007 and the Collaborative Centers
agreed to submit the report of the WHO collaborative study to the ECBS in 2008
for establishment of the second international standard.
Now
there was some discussion at the meeting that what was really needed is a
genotype reference panel for Parvo B19 DNA and a consensus was reached to
identify source plasma materials of genotypes 2 and 3 and to present an update
to the ECBS about that in 2007.
Regulators want to be sure that all three genotypes 1, 2 and 3 with two
subgroups are detected by various NAT assays worldwide for the testing of
plasma pools and that appropriate plasma standards are available to validate
those NAT tests. There will be future
discussion about the establishment of a Parvo B19 genotype reference panel.
The
current anti syphilitic reference here and the first international standard was
established way back in 1957 and it has assigned unitage and it's used by
reference laboratories, diagnostic labs and manufacturers of diagnostic
immunoassays. NIBSC is the coordinator of
an WHO international collaborative study that is already underway to evaluate
two freeze-dried plasma pool preparations, one representing active syphilis IGG
and IGM and the other latent syphilis for IGG that had been selected as
replaced candidates for this first international standard for T. palladum
particle agglutination tests and cardiolipin assays and various
immunoassays. The data are currently
being analyzed and the study report will be submitted to the ECBS meeting in
October.
Now
a second set, as a second set, of priority projects, there was agreement among
the collaborating centers that several new WHO biological reference
preparations are needed. First of all,
an HIV-1 genotype panel is needed to assess the impact of new HIV variants on
test sensitivity.
The
first international reference panel for HIV-1 RNA genotypes was established by
the ECBS in 2003. Now this was a set of
ten HIV-1 genotypes A, B, C and D, CRF 01AE, F and G, AGGH and Group N and
Group O. But CBER and NIBSC will be
collaborating to identify representatives of the less common subtypes such as
G, H, J and K and a range of circulating recombinant forms such as CRF 01AE and
CRF 02AG to be used in a panel that's an extension of this reference panel and
CBER and NIBSC will develop a plan and hold a discussion at a WHO workshop and
report on the WHO collaborative study to ECBS in 2009.
For
an HIV-2 RNA standard, CBER and NIBSC are collaborating to exchange information
on available candidate HIV-2 strains.
These are cultured subtypes A and B and there will be a discussion of a
plan at a WHO workshop and a report of the WHO collaborative study to ECBS in
2009.
The
proposed second anti HIV international reference panel will be an extension of
the established first panel for anti HIV-1/2 antibodies. This first panel was a six member panel
established by the ECBS in 2006 and it consists of subtypes A, B, C, CRF 01AE,
Group O and HIV-2. This panel is needed
for the control of the HIV EIA tests, rapid tests and combo antigen antibody
tests. Samples from CBER comprised of
different HIV-1 and HIV-2 subtypes from different geographical regions will be
provided as candidate materials. The
project proposal is to be submitted to ECBS for endorsement by 2008.
Eight
different genotypes are known for HBV, A to H, representing different subtypes
related to A determinant of HBsAG. The current WHO biological reference
preparations for HBsAG and HBV DNA both generated from genotype A2, subtype
ADW2 represent only one percent of worldwide HBV infected population. So there is a need for the development of HBV
genotype reference panels to evaluate surface antigen tests and HBV DNA NAT
tests in terms of their ability to detect those other genotypes or subtypes
prevalent in the regions where the tests are on the market.
The
aim here is to develop two genotype panels, one for HBsAG tests and one for NAT
assays and PEI is coordinating efforts to collect plasma units worldwide that
represent these different genotypes and is conducting a feasibility study to
characterize and assess candidate panel members and by September 2007, PEI will
develop protocol for the collaborative study to investigate the impact of the
different genotypes on the sensitivity of surface antigen and NAT tests. The report of the collaborative study will be
submitted to ECBS in 2008.
The
standardization of anti Hepatis-B core testing using WHO international standard
and the assessment of the sensitivity of anti-core assays is important to
ensure the detection of true low level reactive samples.
After
the international collaboration study the statistical analysis will be done at
An
anti HCV reference panel containing antibodies directed against single HCV
antigens is needed for the quality control of anti-HCV tests. This would be a reference panel for each of
the four major antibodies detectable by
commercial anti-HCV test kits, anti-core and antibodies to the nonstructural
proteins NS3, NS4, NS5. Now Chiron
offered to help by preparing mono-specific anti-HCV antibodies and these are
from pooled HCV Genotype 1A positive plasma units with high titers against each
of the four Reba-3 antigens. A
feasibility was conducted by the WHO collaborating centers using these
candidate materials. But because of the
limited quantity of these materials that was available, this panel was
considered useful for regulatory authorities to determine the potencies of the
tests rather than to be used for the control of batch consistency by
manufacturers.
As
you know, there is now mandatory screening for antibodies to HTLV-1 and -2 in
many countries around the world. These
agents pose significant risks to the blood supply in specific areas such as
Africa, South America, the Caribbean and
The
collaborating centers felt that for the development of a reference panel the
candidate material should include samples from HTLV infected individuals, from
areas where HTLV-1 and -2 are endemic including special samples that represent
the HTLV-2 subtypes and CBER will coordinate the feasibility study by collecting
and testing samples from these diverse geographical areas.
For
Plasmodium, there is a need for an antibody reference panel to define the
sensitivity and specificity of serology assays to detect malaria
infection. The panel would be useful for
the validation of EIA test kits and to compare the efficacy of commercial test
kits by regulatory agencies and by the user.
Additionally, these antibody standard preparations would be a useful
tool for assays to measure safety and efficacy in the development of malaria
vaccines.
It
was decided that the panel should include sera from individuals who were
exposed to only one species of Plasmodium and should cover the recognition of
all species of Plasmodium. NIBSC will
send samples from positive donors to CBER to determine their reactivity to
different mono-specific recombinant antigens and CBER and NIBSC will select a
pilot panel of sera and develop a protocol for the collaborative study that
would be reported to the ECBS.
Several
countries in Latin America representing the highest endemic region for Chagas
disease, the
CBER
proposed the development of an international reference panel for anti T. cruzi
antibodies and WHO will form a working group that will discuss issues related
to the development of this WHO anti T. cruzi panel including the need for the
establishment for the panel of reactive sera representing multiple geographical
areas. Now at the WHO Chagas meeting in
July, it was agreed that the panel would include antibody-positive plasma units
from
Now
in addition to these priorities, there were several other biological reference
preparations that were proposed that need further discussion by the
collaborating centers, an HIV-2 RNA genotype panel, an HCV genotype panel, as I
mentioned earlier, a Parvo virus B19 genotype panel, an anti CMV standard, a
West Nile Virus RNA preparation or a Pan panel for arthropod born flavivirus
RNA, an HCV core antigen preparation, anti-HHV8 and HHV8 DNA preparations, TSE
blood preparations, a blood-borne bacteria panel and anti Leishmania
panel. So there will be additional
discussion among the WHO collaborating centers in future meetings about those
various panels.
Now
there were some additional agreements among the WHO collaborating centers such
as a need for collection and exchange of epidemiological information which has
an impact on blood safety. It was agreed
that the established WHO biological reference preparations and those to be
developed in the future are suitable to cover new technologies such as
microarray and nano particle assays for the detection of infectious agents.
They
recognized a need for improved collaboration among WHO collaborating centers
and with the WHO. Annual face-to-face
meetings and teleconferences are necessary to monitor progress on all of these
priority projects I talked about and there is a need to establish a network of
WHO collaborating centers for IVD-related biological standardization
representing all WHO regions to ensure complimentary and focused expertise at
the global level.
So
what's the plan of action? Well, the
priority projects to establish WHO biological reference preparations, to
support international regulations for blood and blood products safety. We'll form a five year in vitro diagnostic
strategic plan and this plan will be submitted to the ECBS for endorsement in
October 2007.
Thank
you for your attention.
CHAIRMAN
SIEGAL: Thank you, Dr. Mied. Are there questions?
DR.
DI BISCEGLIE: I have a question
please. With regard to the standard for
HCR RNA, you said that the standard that was being reworked was for genotype
1. Are there other existing standards
for other genotypes and, if not, why not, I guess?
DR.
MIED: I think they're very hard to
get. I know that what they have has been
generated from a genotype 1A donation or several genotype 1A donations.
DR.
DI BISCEGLIE: The issue being this that
I think it's well known that the genotype may affect the sensitivity of assays
to detect HCV RNA.
DR.
MIED: Yes.
DR.
DI BISCEGLIE: And, for example,
genotypes 3 and 4 are emerging in
DR.
MIED: Yes. That's one thing we really -- Mei-ying, go
ahead.
DR.
YU: I would like to comment about
this. Usually, the primers and the
approach should be situated in the very conserved region. So whatever you are detecting you should detect
all genotypes at least for HCV. I mean,
yes, I understand there are mutants and there are some nearly evolved isolates,
but in essence for HCV NAT, they are selected.
But I understand your issue.
DR.
DI BISCEGLIE: No, I understand that and
I think those of us with longer memories will recall that the very first assay
that was developed for measurement of HCR RNA was found within a few months to
have very discrepant ability to detect various genotypes despite the primer
selection. So I am somewhat concerned
about this.
DR.
MIED: Yes, it is a concern. But I think that the assays that are licensed
for use in the
DR. DI
BISCEGLIE: Sorry to be persistent. I
accept that. I did see, for example,
there was a plan to develop an HBV genotype panel for similar reasons. I would have thought the reasons to develop
an HCV RNA standard of different genotypes would be more compelling than that
for HBV DNA and at this stage, I'll just -- I won't comment anymore.
DR.
YU: May I just add one more thing? Actually, NIBAC has HCV genotype panels that
there is a panel that contained all six genotypes of HCV and you can obtain
that from NIBAC and again, during that collaborative studies, there were using
the primers and, of course, those all six genotypes were calibrated against the
first international standard of HCV and again, in that study, yes, there are
some. They are less sensitive, one of
the genotypes and so forth. But again,
primers and probes should be situated in the conserved regions in order to get
the maximum sensitivity.
CHAIRMAN
SIEGAL: Dr. Katz.
DR. KATZ: Yes. Paul, on your next to the last slide, you had the
very tantalizing category, blood-borne bacteria. Would you enlighten me?
DR.
MIED: The blood-borne bacteria were
discussed. I think that
DR.
KATZ: So this is some, I presume,
relatively arbitrary clinical samples from blood or platelet contamination
spiked into something?
DR.
MIED: I'm not sure what they actually
are. I don't know. I'll have to check on that.
CHAIRMAN
SIEGAL: Dr. Epstein.
DR.
EPSTEIN: I could just comment on
that. The Paul-Erhlich-Institut, Miesha
Kneubbling, has actually published on this.
They have developed a candidate panel.
The source of the isolates, of course, is from clinical cases, but the
isolates are selected for very reproducible growth conditions and resistance to
serum killing so that they can then be spiked into samples that others wish to
study and then the presumption is then you have a level playing field for assessing
the capability of detect assays and obviously they are designed to span a range
of bacterial groups and types. So that's
the underlying concept because right now, if a manufacturer wants to validate a
bacterial detection assay you simply have to engage in a conversation on where
they get their isolates and which ones they choose instead of having any kind
of standard array.
DR.
MIED: Yes. The
MS.
BAKER: Thank you for the
presentation. I know that the World
Federation of Hemophilia has held near annual meetings about blood safety, the
next being in September, I believe, in
DR.
MIED: No, I'm not aware of those
efforts.
MS.
BAKER: Okay.
DR.
MIED: There may be some on the part of
WHO. I don't know what the plans are
there.
MS.
BAKER: Thank you.
DR.
COLVIN: I just want to go back to the
hepatis C issue again in that from a infectious disease point of view it seems
to me that we could almost treat the different HVC genotypes as almost
different infectious agents because they act so differently and, yes, there are
obviously conserved sequences.
But
I agree with Dr. Di Bisceglie that we may not be looking at the same
thing. Yes, in some panels, they may
work. But especially if we're setting an international standard, it seems
that we should look at each one individually.
DR.
EPSTEIN: Let me just say that this is an
issue that has been recognized by the WHO and there have been consultations and
certainly it's open for additional discussion and we go to this meeting. We're members of the panel. We hear you.
We can pursue this further. But
the bottom line here is whether the reagents that are available do or don't
work as generalizable standards and that can be determined at the laboratory
level.
And
as it's been said, each of these reagents is evaluated in a large collaboration
of multiple laboratories. So we will get
the right answers through the studies and the question is how do we approach
the problem up front. But, yes, we can
bring this discussion to
DR.
MIED: The plasma samples that NIBSC has,
they've procured HCV genotypes 2 through 6 specifically, 2B, 3A, 4A, 5 and
6A. These were calibrated against the
first international standard for HCV RNA in a collaborative study and they have
been set at 1,000 International Units per mil for each genotype. The problem is that the expression of these
genotypes 2 through 6 in International Units should be taken with caution due
to the genetic variability of the virus and the fact that the calibration had
been made against the International Standard representing the genotype 1A.
So
it was agreed that this panel didn't have the status of the WHO international
reference panel, but it is suitable for use in NAT assay validation. So we'll just have to see. We need scientific studies to assess the
global variation of HCV and evaluate the impact of these variants on the
sensitivity of various NAT tests around the world.
CHAIRMAN
SIEGAL: Thank you, Dr. Mied. Next we'll hear from Dr. Mei-ying Yu from FDA
on the potency and safety standards for plasma derivatives.
DR.
YU: My talk will be potency and safety
standards for plasma derivatives. The
outline of my talk, first I will briefly give the introduction and then I will
describe the available potency standards for clotting factors, potency and
safety standards for immune globulin and albumin products, safety standards for
in process control and finally standards under development.
The
Division of Hematology in CBER FDA has the primary responsibility for the
scientific evaluation of manufactured biological products derived from blood or
plasma and their analogs from recombinant DNA technology. To ensure their safety and effectiveness, DH
personnel have actively participated in developing and establishing CBER
FDA/WHO global potency and safety standards through close collaboration with
WHO collaborative centers, EDQM and industry.
Now
the global potency standard means that it's not only a WHO standard but also is
European Pharmacopeia standard as well as CBER standard. So CBER FDA standards are available to
So
the next few slides will be the potency standards for clotting factors. The first one is Factor 9 potency
standards. These are for Factor 9
products like Factor 9 Complex, Coagulation Factor 9, Coagulation Factor 9
that's recombinant. Now this standard is
called WHO 3rd International Standard for Factor 8 Concentrates, but
it's also European Pharmacopeia standard and as well a CBER standard. So this standard is a global standard.
It
has an assigned unitage, 10.7 IU/vial.
This is based on the international collaborative studies. It was formulated from a Coagulation Factor 9
product that is manufactured by using monoclonal antibody chromatography. It was available since 1996. Now there is a need to develop a new replacing
standard because of the low inventory.
This
one is a potency standard for Factor 8 products. The Factor 8 product assays are
antihemophilic factor and the recombinant antihemophilic factor. The standard is CBER Mega 2 from European
Pharmacopeia Biological Reference Preparation Batch 3 for Factor 8.
Again,
based on the international studies, the assigned unitage is 11.4 per vial. This is based on a one stage clotting
assay. If it's based on the chromogenic
assay the unitage has been assigned as 8.6 IU/vial. It was formulated from a plasma-derived high
purity Factor 8 preparation provided by CBER and CBER/FDA.
This
standard was available since 2001 and this is after the potency calibration
against four Factor 8 concentration standards.
That's there were Mega 1 from European Pharmacopeia BRP Batch 2, WHO
Fifth International Standard and Sixth International Standard in a
collaborative study.
This
is a potency standard for von Willebrand Factor. The product assays, antihemophilic factor,
von Willebrand Factor Complex (Human).
This standard is the first international standard for von Willebrand
Factor Concentrate and the unitage has been assigned as 9.4 IU von Willebrand
Factor. This is based on the Ristocetin
co-factor assay. It contains 9.4 von
Willebrand Factor per ampoule.
It
was formulated from a von Willebrand concentrate product by NIBAC, and it has
been available since November 2001 after potency calibration against the WHO
Fourth International Standard for Factor 8 von Willebrand plasma in a
collaborative study.
This
one is a potency standard for Thrombin-containing products. The product assays are Fibrogen sealant and bovine thrombin. This standard is WHO Second International
Standard for Thrombin and also it's called CBER Lot K. The unitage is 110 IU Human Thrombin per
ampoule. It was formulated from a human
plasma derived thrombin by NIBSC. It has
been available since 2003 after potency calibration against a First
International Standard for Alpha Thrombin and the U.S. Standard Thrombin Lot J
in a collaborative study.
The
next few slides I will show you this potency and safety standards for immune
globulins and albumin. CBER referenced
immune globulin for measles and poliomyelitis antibody levels. This standard is to be used for setting the
minimum requirement for measles and polio antibodies and the product assays are
all the immune globulin products. Here I
listed immune globulin, immune globulin intravenous, immune globulin
subcutaneous and so that this standard is called CBER Lot 176. It was 2 mL fill per vial and stored liquid
frozen.
It
was formulated from one immune globulin lot as 16.5 percent IGG solution in
1991 and made available since 1992 after a collaborative study with IG and IGIV
manufacturers. It was calibrated against
Now
this standard will be discussed further.
It will be mentioned in this afternoon's session.
And
now this standard,
It
was calibrated --
Now
there is a need to develop a replacement standard,
CBER
Reference Hepatitis B Immune Globulin for Anti-HBs Potency Assay is used to
assay products such as hepatitis B immune globulin or hepatitis B immune
globulin intravenous. The current lot is
And
there is a need to develop the second international standard for anti-HBs
immune globulin and also that will serve as a CBER Lot 3 as well in
collaboration with NIBSC and Paul-Ehrlich-Institut because of depleted supplies
of the First International Standard and CBER Lot 2. Now a candidate HBIG preparation is available
and it is kindly provided by Nabi.
CBER
Reference Prekallikrein Activator, this is a safety standard and the product's
assays are albumin product IGIV, IGSC and some specific IGIVs. This standard is
called, current standard is CBER Lot 3.
It contains 100 IU PKA per mL and it's a liquid frozen preparation. It was formulated from a highly purified
PKA. It actually contained 26 nanogram
per mL Beta Factor 12A in a 5 percent albumin solution. It was calibrated against
Now
we have a maximum PKA level in plasma protein fraction. So the upper limit is no more than 35.7
percent of
Again,
since this reference material was prepared, was made available very early, now
the inventory is very low. So we need to
replace CBER Lot 3 and we have recommended to use Second International standard
for PKA, and that is 29 IU per ampoule.
Global
potency standard for anti-D immune globulin, this standard is used to assay
Rhi(d),
And
this standard was calibrated against the WHO first international reference
preparation for anti-D immune globulin and along with two other reserve
candidate preparations that is by European Pharmacopeia and also CBER Lot 3 in
a collaborative study co-sponsored by NIBSC, EDQM and CBER FDA. It was established and available since 2003.
Now
the standard dose for use in preventing hemolytic disease of the new bone, this
is by the FDA, should be not less than 15 IU per dose or equivalent to 300
microgram per dose. Now the detail of
the study please reference to Susan Foab's paper in Vox Sanguinis 2003 or in
Pharmacopeia -- I mean Pharmeuropa Bio 2003.
International
reference reagents for anti-D to standardize hemagglutination testing, now this
is a safety standard obviously and the product to be assay is IGIV, IGSC, and
some specific IGIV. It was after the
collaborative study the WHO recognized this as international reference reagents
and it's to standard hemagglutination testing.
This
standard was formulated by NIBSC by spiking an anti-D free 5 percent IGIV
kindly provided by Bio Products Laboratory with the WHO Second International
Standard for anti-D immunoglobulin and the spike, the total amount that had
been spiked, was 0.475 IU anti-D per mL and the negative, it's just 5 percent
IGIV and we call this the positive -- there is a positive international
reference reagent as well as the negative international reference reagent. The positive international reagent is also
called CBER Lot 1A and so forth. So
anyway, these international reference reagents are kindly shared with CBER by
NIBSC. Again, all papers are published
in Vox Sanguinis 2005. This is by Susan
Thorpe, et al.
Briefly
in that international collaborative study, the sample assay were those positive
and negative international -- those are positive and negative reference
reagents along with four IGIV samples with varying levels of anti-D by a
proposed reference method which is a so-called direct hemagglutination
test. So the direct hemagglutination
test was carried out by 19 of the 20 laboratories.
But
then six of the 20 labs also assay these materials with an in-house indirect
anti-globulin test that's called IAGTs.
And based on the collaborative study by the direct method, the positive
reference reagents has a nominal titer of 8.
However, with those indirect methods in the collaborative study, it
shows that it has in fact about six of the laboratories, only one of them show
up that has the same titer as the direct method. Some of them could not even detect any titer
at all. So anyway, indirect method shows
why inter-laboratory variability and less sensitivity.
So
there is a need for using positive international reference reagents to define
the maximum level of anti-D in immunoglobulin products and to ensure sufficient
sensitivity of hemagglutination testing.
Now
the results were presented to the European at the Group 6B meeting and it was
recommended by the Group 6B to revise the appropriate monograph and to include
the specification and to use the direct test.
CBER also adopted the same limit and the direct test after CBER's
preliminary findings that only one of nearly 140 lots of the all-licensed
immunoglobulin products failed the proposed specification.
Now
since the international reference reagents, the stocks are limited. So larger fills were carried out by NIBSC and
this larger fill is called reference preparation and this is for anti-D
immunoglobulin. And because it's larger
fill, more vials were available. So it's
going to be -- it's being used to control the level of anti-D in Europe as well
as in the
Now
the reference, so it's this reference.
These reference preparations are called European Pharmacopeia BRP Batch
1 or CBER Lot 1B. That's for positive
reference standard and the negative, there`s also a negative standard. Now the positive standard, as I say, is very
similar to the previous one. It also was
spiked with 0.0475 IU of the anti-D per mL and based on the collaborative study
in which all
So
the standards were shared with EDQM and CBER and, as I mentioned already, that
it was calibrated against international reference reagents with the proposed
direct method and found to be nondistinguishable, at least, this is for the
positive reference reagents. So now, the
maximum anti-D titer for five percent IGG for lot release is not more than the
level in positive reference preparation by a direct method.
The
next few slides will be the safety standards for in-process control. First is CBER Papovirus B19 DNA standard. Now this standard later on was sequenced and
found to be genotype 1 of B19. This
standard is to be used, it's used for validating in-process powers B19, not
methods, for plasma for further manufacturing as analytical procedures which
are viewed and approved under biologic licensing applications called BLAs and
all their supplements for plasma derivatives and this is based on the September
1999 BPAC recommendation.
This
B19 standard is to use for screening plasma minipool to exclude B19 DNA positive
donation is used as a standard and it's
to monitor the level of B19 DNA in manufacturing pools destined for plasma
derivatives to ensure that the level does not exceed 104 IU/mL which
is the FDA's proposed limit.
Now
this standard has a unitage of 106 IU or genome equivalent of B19
DNA per mL and it's 1 mL per vial. And
it was formulated from a window period plasma unit and diluted with a
cryo-poor-anti-B19 negative plasma pool and it was provided as one of the candidate
preparation for the WHO collaborative study to establish an international
standard for B19 DNA. And the results of
that collaborative study is shown in this slide and it's freeze-dried
preparation by NIBSC and CC is the CBER reference preparation, and since AA was
recognized as a WHO First International Standard for B19 DNA in October 2000
and the unitage was assigned as actually it's 5 X 105 IU per
vial. But when reconstituted, it's 106
IU per mL and based on because from the
collaborative study AA, BB, CC are indistinguishable statistically. So CC has international units of 106
IU/mL.
And
now because AA soon will be depleted, the proposed Second International
Standard will be BB preparation and it will be NIBSC who will soon carry out
the collaborative study to make sure that BB can used as a second international
standard for B19 NAT.
Another
in-process control is CBER hepatitis A virus RNA standard. This is used for validating in-process HAV
nucleic acid testing method for plasma for further manufacturing and it's for
minipools and meant to screen minipools and for manufacturing pools. And these are since -- HAV NAT is considered
as -- is validated as an analytical procedure which are reviewed and approved
under BLAs or supplements for plasma
derivatives. Now this is based on the
recommendation of the June 2000 BPAC.
The
standards contain 6 X 103 IU or 104 genome equivalent of
HAV RNA and again it's a 1 mL fill. It
was formulated from a window period plasma unit and diluted with with a
cryo-poor, anti-HAV negative plasma pool and again this standard was provided
as one of the candidate preparation for the WHO collaborative study to
establish the international standard for HAV RNA.
And
the data is shown in this slide. There
are quite few preparations, candidate preparations, and EE is the CBER
preparation and so forth and then AA that is a freeze-dried preparation was
then later on based on the collaborative study it was recognized as the WHO
First International Standard that contained 5 X 104 IU/mL or 105
IU/mL when reconstituted and it was established in the -- recognized as the WHO
First International Standard in February of 2003. So AA was 105 IU/mL. So EE when calibrated against AA it was 3.79
which means 6,000 IU/mL. Now again, all
these studies are being published for B19 as well as HAV NAT is referred to J.
Saldanha's paper in Vox Sanguinis.
Now
the next few slides will describe the potency and safety standards under
development. First is the WHO Second
International Standard for anti-HBs immunoglobulin CBER Lot 3 in collaboration
with Dr. Morag Ferguson of NIBSC. Dr.
Paul Mied already mentioned about this.
Now I already mentioned that a candidate five percent HBIG preparation
is available and kindly provided by Nabi Biopharmaceuticals.
And
the second is CBER Reference Immune Globulin Lot 177. Again, a candidate 10 percent IGIB
preparation is available and is kindly provided by Baxter Bioscience.
The
third standard under development is Global Reference Preparations for Anti-A
and Anti-B Hemagglutinins to control the levels in immune globulin products and
to standardize hemagglutination testing in collaboration with Dr. Susan Thorpe
of NIBSC and Dr. Marie-Emmanuelle Behr-Gross of EDQM. Now again, a candidate negative five percent
IGIV preparation derived from type AB plasma donation is available kindly
provided by Baxter BioScience. And Dr.
Susan Thorpe is formulating a candidate positive IGIV preparation.
Last
one. The Papovirus B19 Genotype Panel
containing all three B19 genotypes in collaboration with Dr. Sally Baylis of
NIBSC. There is a need to detect all B19
strains which are recently classified into three genotypes because of genetic
diversity by B19 NAT and the higher titer window period donation of both
genotypes 2 and 3 are available kindly provided by Baxter BioScience and
Talecris Biotherapeutics to NIBSC and CBER.
Negative plasma donations totaling 20 liters not detectable by all kinds
of NAT procedures is kindly provided by NGI and so we will have to formulate a
negative plasma pool and then that would be used as a negative member as well
and also as a diluent for high viral stocks.
The
last one that I would like to mention is the WHO Fourth International Standard
for Factor IX Concentrate. This is in
collaboration with Dr. Elaine Gray of NIBSC.
Now
the very last slide, this is the conclusion.
So DH personnel in CBER/FDA will continue active collaborations and
participation in developing biological standards when needed and in testing
candidate material in collaboration with WHO collaborative centers, EDQM, and
industry to ensure the safety and effectiveness of plasma-derived products and
their analogs.
Thank
you for your attention.
CHAIRMAN
SIEGAL: Okay. Thank you, Dr. Yu. Are there any questions? If not, anybody? Yes.
DR.
SZYMANSKI: I'm asking for
clarification. Your slide which says
"Reference Preparation to Control the Level of Anti-D in Immune Globulin
Products" you say you are titering the anti-D by direct method.
DR.
YU: Yes.
DR.
SZYMANSKI: What do you mean with
that? Do you mean that there is IGM
anti-D there?
DR.
YU: No.
This is an IGG anti-D.
DR.
SZYMANSKI: Okay. So what is the direct method?
DR.
YU: Yes, it's by preparing treated red
blood cells. So you don't really need a
second --
DR.
SZYMANSKI: Thank you.
DR.
SCHREIBER: I have one naive
question. I was noticing in your slides
that
DR.
YU: Actually, it's very common. IGIV is prepared as 10 percent IGIV, as a ten
percent formulation. In fact, many of
the five percent IGIV I know when it was infused that you usually like to
reconstitute two ten percent IGIV and then use clinically.
Now
again, why back in 1991, that's the only product available. It's intramuscular immunoglobulin which is a
16.5 percent IGG concentration and you are right. Nowadays it's five percent or ten percent
IGIV. There are more such preparations
and we can dilute the ten percent to five percent if needed. But it's ten percent. Actually, I would like to say the assays,
when you compare it, you have to assay under the same IGG concentration anyway
and it's available, donated by the manufacturer.
DR.
SCHREIBER: Well, I had just noticed that
on your slides some of your standards that you are proposing are five percent,
in five percent and some are ten.
DR.
YU: Yes, you are correct.
DR.
GOLDING: Can I just -- I think for
clarification when the assays are done, they dilute it down to one percent so
that the standard and the product are both at one percent. So when the assay is done, they have the same
concentration in terms of immunoglobulins.
So I think there's a way of taking that into account.
DR.
YU: Besides 16.5 percent IGG really
cannot freeze well. We were surprised
that it lasts for so long since the 1991 until now.
CHAIRMAN
SIEGAL: All right. Well, we should probably move along because
we are way over time unfortunately.
Dr.
Kochman, please, is going to talk about minimum potency standards for certain
blood grouping reagents.
DR.
KOCHMAN: This is just a brief summary to
clarify what minimum potency standards are available for some of the blood
grouping reagents that CBER regulates.
The list that has been available up until very recently includes Anti-A,
Anti-B. There are two Anti-Ds listed
here. The second one should actually say
Anti-CD although it is intended as a standard for Anti-D. Two standards for Anti-C, one for Anti-c, two
standards for Anti-E, one for Anti-e, one standard for the Anti-IgG portion of
any anti-human globulin reagent and one standard for the Anti-C3d portion of
any anti-human globulin reagent and interestingly, you can sort of get a sense
for what order these were prepared in by their lot numbers because the lot
numbers were pretty much assigned sequentially.
These
were all manufactured in the early 1970s.
So they're getting quite old.
They are all polyclonal material, and we've always recognized that they
were all potentially biohazardous.
Why
would we want new standards? There has
been a lot of question as to whether or not they're actually relevant to
current reagents since most of these reagents in particular are available in
monoclonal form. We also recognized
diminishing stocks both here at FDA and in WHO.
The
European Union's In Vitro Diagnostics Medical Device Directive No. 98/79/EC was
recently implemented, and you may ask if it's European Union directive why
should FDA care. There are two reasons
we care. One is that many of our
licensed manufacturers wish to be able to manufacture a product for
distribution in Europe, and they would like to not have to worry about juggling
different sets of standards, and we also have a number of foreign manufacturers
who are expressing interest in becoming licensed so that they can distribute
product here in the United States. So
it's best for both worlds if we can come to some sort of agreement on these
things.
And,
lastly, and most unfortunately, some of the CBER standards have been found to
be reactive for some of the tests for hepatitis. This isn't totally unexpected because at the
time the tests for HCV were implemented, they found that a number of source
plasma donors with blood grouping reagent antibodies or even other entities of
interest in use for controls in the reagent industry were found to be reactive in some of the tests for HCV. So while we weren't surprised, we weren't real
happy about it either.
Why
did you choose to collaborate? As I
mentioned just before, to encourage international harmonization. Maybe more importantly, to elicit input from
a larger pool of experts in the area.
The collaborating centers included NIBSC, the International Blood Group
Reference Laboratory in
For
materials and methods, I should preface this by saying a method, a very
specific method, was developed, put down on paper, and provided to all centers
who chose to participate, and there were standardized worksheets for them to
report their instructions on. We
recognize that hemagglutination testing is extremely variable. So we wanted to standardize as much of the
process as we could.
Part
of that standardization was to include only potency testing. We didn't want to know specificity or avidity
or anything like that. We just wanted to
focus on potency testing. This was done
with serial two-fold dilution titrations again in a hemagglutination test and
most importantly in manual tube tests.
We recognize that reagents can be used in various other forms these
days, but the manual tube test needed to be the baseline on which we
standardized things.
The
participants were asked to test as many commercial reagents and/or reference
standards as were available to them and the result was that there were 45 low
protein anti-D reagents in the study.
There were only ten high protein anti-D reagents in the study, 22
anti-As and 23 anti-Bs, and we did not ask them to distinguish whether these
reagents were monoclonal or polyclonal.
We normally were able to figure that out though.
The
anti-D study was done first. There were
20 laboratories in 13 countries that participated.
The
anti-A and -B studies were done later.
The participants were fewer. We
had only 17 in nine countries, perhaps because they found out it was so much
work. Again, the same licensed
manufacturers participated in these studies.
So the good thing is that all of the currently licensed manufacturers at
the time of the study were participating in it.
As we expected the results were very widespread in variability. Endpoint titer results varied by between four
and eight tubes and the endpoint titer across the laboratories for both the
standards and the reagents. There were
only few outliers, predominantly a few that were extremely low titers and a few
that were extremely high titers. So very
few datapoints were believed to be incorrect.
But
because of the extreme variability and the huge number of tests involved, it
was an extremely complex analysis of the data that would have been far too
complicated to go into here. So if you
really, really care, the results of the analyses are published in these two articles
in Vox Sanguinis. I believe the
Committee received copies of both of these.
The
conclusions from the studies were that for Anti-D reagents, the Anti-D standard
which is now designated as 99/836 for manufacturers who are making a low
protein Anti-D reagent, they are to reconstitute the standard because it's
provided freeze dried. They are to
reconstitute it as described in the insert that comes with it and then prepare
a 1:3 dilution. This standard replaces FDA's
standard Anti-CD and as I said before, this is actually a standard for Anti-D. It just happens to also contain Anti-C,
number 9.
For
high protein Anti-D reagents, the manufacturers are to again reconstitute it
according to the directions provided and then make a 1:8 dilution, and this
replaces FDA standard Anti-D 4A1. The difference
in dilution is not anticipated to be a significant problem. The high protein reagents are rapidly
disappearing from the market in favor of the low protein monoclonal antibodies
and so in reality, most of the products will be at that higher potency level.
The
Anti-A standard 03/188 results in a 1:8 dilution after reconstitution and this
replaces the FDA's Anti-A Standard 6A.
The Anti-B Standard 03/164 is used at a 1:4 dilution after
reconstitution and replaces FDA Anti-B 7A1.
I would like to point out that these are minimum potency standards and
that is the only thing they're good for.
Manufacturers can make their products a little bit stronger,
significantly stronger, if they choose to, but they have to balance that
increased potency with the other written standards for specificity, avidity,
and other characteristics.
The
reason that we go with a minimum potency standard rather than sort of a what
the market would love to see standard is that we want to make sure that
reagents are not going to waste or that they aren't so strong that they start
causing difficulty in differentiating some of the blood groups from each other
as frequently happens with the monoclonals.
It was less common with polyclonal antisera that you were confused as to
the true status of a donor or patient.
But with the monoclonal antibodies, they can be so potent that they
appear to be nonspecific or they're picking up extremely small amounts of the
opposite antigen.
And
anyone who wishes to request any of these standards including the new ones, I
included the address to send the request, and I wanted to mention also that
this address is stated in the CFR.
That's it.
CHAIRMAN
SIEGAL: Any questions from the audience?
(No
response.)
CHAIRMAN
SIEGAL: Okay. At this point, we will take a break. Let's take only a ten minute break so we can
try to get back on track. Thank you
all.
(Whereupon,
at 10:10 a.m., the above-entitled matter recessed and reconvened at 10:26 a.m.
the same day.)
CHAIRMAN
SIEGAL: Could we please reassemble,
ladies and gentlemen? Okay, our first
topic for the later morning session is the response of the Office of Blood
Research and Review Office Level Site Visit for Research, July 22, 2005. Kathy Carbone will introduce this. Dr. Carbone.
DR.
CARBONE: Thank you. Today I would like to start with sort of an
overview of CBER research, CBER's research mission, and some of the research
management initiatives that have been initiated in the past few years as an
overview and then I'll turn it over to the Office to respond directly to the
site visit comments.
But
let me start by thanking everyone for their efforts in doing the first, at
least, in my history at CBER, the first office level research site visit. The site visit was valuable, provided
wonderful information in the report and gave us a lot of good things to respond
to.
Basically,
I'll start with a little introduction about CBER in managing the research to
program goals. The important part about
the research, it has to cover like many of the regulatory bases we have to
cover, it has to cover the gamut. We
have to provide and maintain a long-term programmatic, scientific expertise
base to be able to respond to the variety of challenges that reach us. But similarly, we have to be prepared to
respond to crisis and I should say actually try to be prepared to respond in
advance and prepare for the crisis because as you all know, research is the
Titanic. You can't turn on a dime. So you have to be very forward thinking and
get out of the old crystal ball.
Clearly,
in our job, the FDA has a clear job to do and, therefore, we are driving
research management to continue to be outcomes driven. In other words, there are specific high
priority challenges that are holding up product evaluation that are making
product prediction of risk and benefit difficult and these are the scientific
challenges that have to rise to the top to be resolved.
We
focus on the critical gaps and scientific tools and knowledge for product
evaluation. There's been a tremendous
investment in product discovery, biomedical discovery, and unfortunately, the
same investment in the ability to develop the evaluation tools and knowledge to
regulate those discoveries has not been forthcoming. That's changing with the Critical Path
Initiative through the Office of the Commissioner, but we really need to
recognize that evaluation science is a special needs science and has been under
supported and not given enough attention along with the biomedical discovery
boom.
So
basically, our goal is to support product development for critical unmet public
health needs. CBER's products in
general, the vaccines, the bloods, the cell tissue gene therapy, all have major
public health impacts.
CBER
research solutions. We've approached
this and I think in many ways I'm very proud of the staff at the Center because
we've achieved something which given our disease orientation and public health
orientation is critical and that is multidisciplinary type research. We use coordinated teams for regulatory
challenges. Everybody has a piece of the
elephant to grab onto but we all are talking about our piece and keep in
communication and must support that and facilitate that in the Center. In addition, the external communication piece
is very important and part of this discussion is -- and this discussion is part
of that initiative.
CBER
research quality initiative is important because obviously, the work that's
done in the Center needs to be communicated to the outside, evaluated by the
outside scientific community, confirmed or refuted in the scientific process
because the science that we use to do product evaluation must be the soundest
science possible. And, therefore, peer
review journals, external arbitrary site visits and this kind of input is
critical and we appreciate your time.
It's
also important to increase CBER research impact by providing more visibility
because what we do to help promote and facilitate product evaluation should
benefit all products and all classes of products and that's one of the benefits
of being a nonconflicted government group but doing research is that what we do
can provide benefit for every product and every sponsor.
Funding
these efforts is always a challenge.
It's a challenge for everybody and working with the Office of the
Commissioner for Intramural Funding as well as partnerships for leverage
funding is a critical part of our goal.
And providing core research support, it's not always possible to give a
complete and thorough introduction of every scientific issue at CBER, but I do
want you to know that, having been an extramural scientist for many years, we
do internally at CBER have a very good support system for the staff including
animal facilities, core facilities. We
have a flow cytometry core. We have
proteomics core. So all these and sort
of cooperatively across the offices facilitate the research at CBER.
The
research management initiative, this is one slide in a nutshell and I'm going
to walk you through it in a little more detail and that is the first thing to
do when you're trying to figure out what to do is you have to figure out what
the job is. And so we initiated a
regulatory and public health portfolio analysis which is done on a yearly basis
and updated and the bottom line is by taking a quantitative look at the
applications, for example, that come into the Center as well as the pre IND
meetings, we actually get a quantitative view of the scientific base of the
issues that are coming to the Center.
One
can track documents, of course, and they must be tracked through PDUFA, etc. in
terms of where they go, which office, whose doing the review, is the review
done in a timely fashion. This is a
different kind of tracking. This is
tracking based on the scientific challenges within those particular
applications. In addition as the public
health center, if you will, we also must scan the horizon, look outside, deal
with the Department and other organizations, CDC and NIH, to get a good feel for
the public health issues that are coming down the pike as well as the ones that
are here. And that analysis basically
gives us the universe of needs which is tremendous obviously.
From
that universe of needs, we set the specific CBER research priorities. This is a cross-office effort including the
Office of Compliance and Biologics Quality which has been very, although they
do not actively do research at CBER, they've been very contributory to this
process and this research priority setting includes the regulatory scientists,
the regulatory scientists leaders, the research regulator scientist and the
research regulatory scientist leaders.
This is a common effort across CBER.
And
what this does and I'll show you in a little more detail how we set this, this
basically tells us what specifically we're going to be working on because
clearly we can't work on the universe.
From that, each office then derives its specific plans for the
year. They propose that over the year
they will be working on these issues and they will be listing their deliverables
as well as in this office research plan reporting on their achievements. But
the main purpose of the office research plan is to talk about in the coming
year what is the research plan for that office.
Those are all, again, shared across the Center. It's a combined sort of CBER research plan
and then off we go.
At
the end of the fiscal year after the research has been done, there's a careful
scientific program review, both of the individual scientists as well as the
offices, and a report is prepared. In
fact, we've just completed the individual research program reporting on our
web-based system this week.
Then
this become the effort we are doing right now that at least one year we commit
to coming to the advisory committee, talking about the research priorities,
talking about some of the achievements, talking about the research plans coming
up for the future, and getting the advisory committee and the public input in
these plans. We, of course, seek input
throughout the year and, in fact, as one of our deliverables we're encouraging
staff to provide with every research program or research proposal the
communication deliverable that goes along with that. How are they going to communicate the results
and get feedback as well as communicate the design and get feedback.
So
in terms of the portfolio analysis, as I was saying, we talked to the policy
leadership about key policy activities.
There are prioritization lists of guidances that need to be put out and
the scientific dilemmas and challenges that come with those guidances that we
can sometimes help resolve through our intramural and collaborative research
program, the regulatory workload analysis as I mentioned, what kinds of
scientific challenges are coming in and what's coming in in the future with the
early as well as current issues and, of course, the public health.
The
research priorities are a complicated activity done jointly across the
Center. But basically, we take into
account the regulatory workload which may or may not come with scientific
challenges. Sometimes there's an area of
large regulatory activity but it's fairly standard, fairly historically
accurate, a comfortable level of workload.
Then there might be even a small area, relatively speaking, where the
challenges are enormous and the science is simply not there to do the
regulation which we would like to do it science-lead.
We
look at product quality issues that are either anticipated to come down the
pike or are there. Safety and efficacy
issues, the public impact of what needs to be done, the unique expertise we
have available to do it. Obviously, we
want to be able to set priorities that are achievable with our given resources
and given staff and also in seeking out the right collaborators to have and
then the impact on product success.
Sometimes the high priority research items are not what you would call
major impact, new discovery type.
They're often sometimes very standard, assays as you've heard, the
standards. These are sometimes critical
elements that get the products through.
So we obviously look for things that will be high impact and things that
aren't being done in the outside world.
This
is just a massive list of the `07 research priorities, and keep in mind these
are sort of the areas that we think are important to work on. Each office will then take these priorities
and then work down and say "And
this specifically is what we're going to do within these priorities." And now since this is a blood review, I won't
take up a lot of time. You have this in
your book. But the Office of Blood will
be talking specifically about their priorities in detail in the next talk.
So
the research plan as I mentioned is misspelled.
I apologize. My spell checker
missed that. But the research plan is
actually a combined plan for all the offices, and as you notice, the leverage
research projects which we have several working with NIH and Cell Substrates,
etc., are incorporated within this research program plan. It's not done
separately. In addition, it's incorporated
as a separate element in the research program reporting. So we track that as well.
Not
to get into too much detail, but we have an administrative process, for
example, that before a grant or a partnership is made in the outside world, it
has to be circulated and approved for issues of relevance, etc., within the
office leadership before the application is even permitted to go outside the
Center.
Communication
piece. Since in the last four years,
five years, since I've been the Associate for Research, we've managed to get up
on the website, the research program summaries for all our research
programs. They include a, if you will,
sort of public, plain language summary of the research efforts within that
program, the issue of relevance, the public health issue, the outcomes and how
research is solving these problems followed by a list of publications for the
more scientifically inclined, and through this mechanism we're able when we go
out to talk to other agencies and partners and stakeholders and people want to
know who to talk to about what issue, we direct them at the website and
similarly with collaborations. We direct
them at the website.
But
in addition to the office by office because our researchers are also direct
regulators, they have product expertise, they are sorted by administrative
lines within the product, we also recognize though that there's scientific
expertise across the Center. The
greatest example I like to use is retrovirology in blood. It's retroviral contamination of blood. In vaccines, it's HIV vaccines and in cell
tissue and gene therapy, it's retroviral vectors. So we have product experts in each of those
areas who all happen to be retrovirologists, and to facilitate communication
within the Center and in speaking with the regulatory scientists leaders who
all were delighted to hear about this to be able to have a resource to go
within the Center to find out who your compatriots are, these individual teams
are -- currently we call them the Virtual Teams because they're outside the
administrative lines. But, in fact, the
plan is to bring these people together as teams for communication efforts and
appoint team leaders who won't be responsible necessarily for the administration
of budget issues, but for bringing the scientists together in critical mass and
keeping everybody communicating.
So
research program evaluation, it's critical when you make changes. When you're doing these sort of management,
do a follow-up to see how well you're doing.
And we try and do that on several levels. One level is as I mentioned, we have a
web-based extensive research program reporting which includes research
achievements from the past year.
Research achievements include publications, guidances, policies, etc.,
workshops held. They also list future
plans. So they're rated on an individual
basis, what somebody achieved and how, what their future plans are for that
coming year. We also use this web base
to do sort of laboratory management, freezer database, staffing models, etc. So it's quite a utilitarian web-based
reporting.
But,
in addition, at the next level up from the view, maybe the 15,000 foot view,
every four years, each laboratory program consisting of several PIs undergoes
an external site visit, and this is through the advisory committee and chaired
by a member of the advisory committee, actually two members, along with
bringing in the expert scientists based on each of the individual lab's
expertise, and that report is generated.
It's sort of, if you will, a small version of the office site visit, and
every staff member gets reviewed every four years.
This
also feeds into our Promotions, Conversions and Evaluations Committee,
internally the peer review which is composed of research regulators/scientists
and regulatory scientists who will be doing cyclical reviews. FDA has just established these cyclical
reviews every four years of all staff members, so even if a promotion or a
conversion issue is not at hand. These
are very helpful and, in fact, just like this site visit where we're responding
back to the site visit -- the advisory committee, the four year research
program laboratory site visits will also be generating a written response back
to the advisory committee based on the suggestions given, and from this, every
year we formulate as part of the annual program report the successes and future
plans for research.
The
web based reporting is reviewed internally by leadership and by
achievements. Let me give you a little
more detail, with achievements, a return on research resources expanded, the
direct impact of the research on the regulatory challenges, the quality of the
research which is critical obviously, the contribution to guidances, policies
and workshops. So we're not talking
simply counting papers here. We're
talking about the whole ball of wax for the regulatory impact.
Future
research plans. We do short-term, yearly
basis. The long-term are proposed in
every four year research assessment research site visit, and it's similar sort
of criteria.
This
slide is in your book, and I won't go into this in great detail. But the bottom line is this describes how we
do the site visits for each of the laboratories.
And
then the four year cycle internal review and I was talking about the cyclical
assessments. We have formal operating
procedures for all of these because when staff come in on day one we want them
to know what's expected of them as they come in. So all of this is formalized and done with as
much communication. We have a website
internally to communicate to the staff.
So
stakeholder input, that's what we're doing today. This is part of our external input. We ask for input into all levels, all, the
entire circle of research management at CBER, and today Blood will be
responding to the office site visit that was kindly provided by many of these
Committee members.
So
I just want to quickly review some of the things that were said in site visits
which these are a compilation of all the office site visits that we had, all
the three major laboratory research offices and the Office of Biostatistics and
Epidemiology were planning their first office site visit soon.
Basically,
we had actually an individual on one of the office site visits who also sat on
the 1998 CBER Scientific Review, and this was a quote from that individual who
felt "there's been a striking improvement since that time and focus in
relevance and quality." That was
very kind to hear. The site visits as a
rule, the Site Visit Committee, strongly supported the FDA's research on -- the
emphasis on the importance of research and also gave suggestions for the
importance of maintaining support.
The
strengths and summary from the multiple site visits, productivity, scientific
merit, mission relevance. They well
recognized the staff for the outreach efforts that they do, the complimentary
cross office expertise, success of recruitment and retention, core facilities,
and then leveraging and collaboration.
However,
the concerns were numerous. Some of the
concerns were increasing regulatory workload and decreasing support. This may not be in toto. It may mean sometimes in specific areas where
the resources decrease and yet the workload is increasing.
Best
mechanism, trying to understand how to manage research to make sure that we get
the end result without it being a process of micro-management. To allowing sort of the creative juices to
flow, if you will, but just trying to direct those juices in the right
direction.
Covering
research bases versus focus on quality in fewer areas. As you know, our portfolio is tremendous and
yet we can't cover every base. So how to
approach that successfully.
And
then developing an explicit and strategic plan for research with regulatory and
stakeholder input and as you can see that we're on the road to doing.
The
issue of mentoring came up in some of the site visits. One of the research regulatory staff actually
initiated through one of our internal research committees, coordinating
committees, mentoring efforts that they sort of started. They got a manual together and started to
promote this and thanks to our Office of Communications and Training they have
picked this up and there's now a formal mentoring program at CBER that's been
piloted this last year and next year, there's a plan for expansion.
Recruitment
and retention. Sometimes we do well and
sometimes we haven't done so well and we need to continue to attend to
that. They suggested we needed increased
research program visibility, continuing education support, making sure the
scientists are given the opportunity to stay up-to-date, increased
collaboration within and outside the FDA, increased FDA base funding,
continuing leveraging support, public relations campaign, and a system for
reward for successful research.
And
I want to thank you very much for your attention and overview and rush through
it at the 50,000 foot level, and I would be happy to take any questions if
there are any.
DR.
FINNEGAN: You talked about your
website. Do you know how many hits you
have, and how many of those are unique visitors, and how many of those are
people outside of the government?
DR.
CARBONE: You know, that's an excellent
question, and I haven't tracked that. I
will ask.
DR.
FINNEGAN: Because you can very
definitely -- there's auditing. So you
can very definitely --
DR.
CARBONE: Yes.
DR.
FINNEGAN: My reason for asking this is
because my bigger question and I don't know how to help you answer it is do you
know where you fall into Google. In
other words, if I were to Google Chagas disease in transfusion medicine, would
you show up in the first 50 or 75 because I'm pretty such most people don't go
much past those numbers, and I do know that there's an art to how you put your
titles in order to come up first in Google.
DR.
CARBONE: That's an excellent
suggestion. We have a staff member in my
office, Tom Madrew, who has done a marvelous job with the web with the support
of the Communications group and we will look into that. Jesse would like to say something.
DR.
GOODMAN: Just to recognize the
importance of what you're saying in how we communicate, the FDA as a whole is
taking a very -- is devoting some resources now to taking a systematic look at
how we make our web-based communications have the maximum impact and we're very
-- the Center is very gauged in those efforts.
But
I think you highlight that we tend to focus in those efforts on our direct
public health and product related communication and there's also a lot of other
layers including the scientific communication, and we need to be attentive to
that. It's one of these areas that when
you're resource constrained you tend to have less time and expertise to
devote. But it's very, very important,
and we're also trying to bring into the center an expert on strategic
scientific communication and again, that's mostly focused around our complex
risk messages and our interactions with the public sector and the media
sector. But I think the point you raise
is an opportunity there also. Thank you.
DR.
FINNEGAN: The two groups I'm sort of
interested in are college and senior high school level and also public health
people because I think that this is information that would be useful for them,
and they actually can be your allies if they can figure out how to get to you.
DR.
CARBONE: Thank you very much. In fact, I was very appreciative of the
Office of Communication that moved the scientific research expertise
information from a little nine point sentence in the middle of a paragraph and
we moved it to the side in a big bar of the same size there. But I think it's important to see how we're
doing and thank you for that suggestion.
We will look into that.
DR.
ELGIN: I had a question regarding the
four year cycle for individual, I think, this is individual reviews. I'm just a little old city doc with internal
medicine in a small nonprofit organization where we do our reviews biyearly or
twice a year and I just want to understand better if you're saying that you
only review individuals every four years for promotion.
DR.
CARBONE: This is external scientific
experts. Internal reviews are
yearly. So you'll see --
DR.
ELGIN: Okay.
DR.
CARBONE: -- under this, the annual
internal review occurs yearly by supervisors and by my office. That's the -- the four year cycle is with
external scientists. For example, it
would be really tough to review Dr. Nakhasi's Chagas program because we don't
have any other Chagas Disease experts or Leishmania experts. So we actually go out every four years and
bring people in, and a research program as you know may take three or four
years to become productive when new directions are taken. So that -- In fact, the rest of the Agency
went to five years, and I got on my knees and begged and said "I don't
want -- any more than four years because our staff trainees, the staff fellows,
senior staff fellows, they are on a seven year cycle and this four years gives
us right around the middle of their tenure.
They get an assessment from the outside world and that gives them time
to fix it.
So,
yes, we do internal evaluations every single year and four years --
DR.
ELGIN: The next slide I think says four
years.
DR.
CARBONE: This is the promotions and
conversion. That's a third level
review. So there's the internal yearly,
the external every four years and then once the external is done, that goes
back to a separate committee which is across the Center. So every year the internal supervisory chain
reviews it as well as my office, and then every four years a committee that's
composed of regulatory and research scientists from across the Center does a
formal assessment. This, if you will, is
sort of a counterbalance as the internal supervisory with an external/internal
review. So that's really three levels of
review.
CHAIRMAN
SIEGAL: All right. Next we're going to hear from Dr. CD Atreya
from FDA.
DR.
ATREYA: Good morning, everybody. I have a little cough. So bear with me if I have coughing in
between.
I
will briefly comment on the OBRR which is Office of Blood Research and Review
response to the BPAC and the recommendations that the Office has received for
the research program and the Office site visit actually happened on July 22,
2005 and then the BPAC recommendations came back to us on February 10, 2006,
and now we are reporting back to you as of a response as August 16th.
The
OBRR response, what we would like to say is that the CBER and OBRR office
management actually thank the Blood Products Advisory Committee for its
in-depth review and general support for the OBRR research programs, and the
recommendations of the committee have received very closely attention at the
FDA resulting in some programmatic changes to establish a structured and a
transplant management system for OBRR research and also to improve research
focus and prioritization as Kathy was mentioning before.
So
I'll come to the actual issues raised by the committee right away, and there
are like four items, issues. One is the
sufficient time and qualified personnel available to perform mission related
research with respect to enrollment and the retention aspects of it and then to
the support for mission critical research.
The
concerns are that since the funding is really low are you able to find any
alternate funding paths and how are you doing the outside funding and
leveraging the resources. Those items
came up in that review and also the adequate laboratory space which is a
problem for everybody on NIH campus and research prioritization process. What it is is that there seems to be a need
for a transplant process because there was a process but it was not transmitted
to the public. So I think that was a
concern. So we are going to address
that. And then there is a need for broad
expertise or to have a tightly controlled focused research programs so that the
funding will be sufficient for those programs and then, at the end, also as
Kathy mentioned, the visibility of the OBRR research programs.
Let
me take up the first one which is the sufficient time and qualified personnel
to perform mission-related research. I
assure you that the OBRR is committed to resolving regulatory scientific
challenges by providing adequate time for its research and review staff to
engage in relevant laboratory work and also to ensure that research and review
staff are up to date with current scientific and technological advances by
encouraging attendance at scientific meetings and supporting other training
opportunities, also conducting periodic workload assessment within the Office
to address any imbalances in a timely fashion.
And
then comes the support for mission critical research, how we are addressing
this issue. Within CBER, OBRR provides
actually seed moneys wherever possible.
There is no guarantees, but always we try hard to get these funds as
seed moneys and also the non-FTE that is the -- not -- the soft money
post-doctoral positions to support research for the young investigators
embarking on new priority research projects.
We
also try to participate in cross office partnerships for co-research support
specialties as Kathy was mentioning like for major equipment purchases, service
contracts for flow cytometry, TaqMan or sequencing facilities, etc. and we also
evaluate laboratory space needs as a part of an interoffice effort rather than
just an office effort. This is a new
improvement over the years and also CBER expected to relocate to a White Oak
facility somewhere around 2012, and we expect that this move will probably
facilitate and provide additional laboratory space for not only just to the OBRR
research staff but in general to the CBER research staff. That's one expectation we have.
And
then how we are doing the support for the mission critical research in the
other part is that the Office, OBRR, actively seeks external support like many
other offices within the CBER. It's not
unique to OBRR, but we have our own set list of how we do that. When appropriate, OBRR leverages out set
collaborations and partnerships. The
Office participates in developing CBER SOPs and memorandum of understandings,
the templates to facilitate management of the application process for external
grants, and we took recently a leadership role in bringing George Washington
University under Center Scientific Training Program to allow student
participation in CBER labs, and this is very successful and so far we have like
around six or seven students came up from their MPH programs to do their
practicum in CBER labs especially right now in OBRR labs, and that's a trend
that actually has some implications. In
the future, probably these students can engage in having jobs in FDA because
they may be interested. They know that
CBER does research, that helps as a PR, and also the successful OBRR
collaborations have been established with many other government agencies like
NIAID, NHLBI, NCI, DOD and others. So
these are the efforts we are doing.
And
also at the office level, a senior leadership team has been established in
OBRR, and this SLT team what it does is it identifies and monitors progress in
critical areas of regulation and Critical Path research within the Office. And the SLT also collects input from both
research reviewers and full-time regulatory scientists on regulatory science
needs and then develops a comprehensive prioritized office's portfolio
consistent with CBER's overall plan as Kathy was mentioning about, and then we
also do review the applications for external grants both at the division and
office levels to ensure that they are within the context of mission relevance.
So
how are we doing about the visibility of OBRR research programs? We use research to address scientific issues
that are critical to regulation. So that
means the visibility of OBRR research is important to us to ensure that all the
information is publicly available, the science that we do, and external
measures of quality and significance are there and to promote these objects
what we do is, of course, we do publish in scientific work and peer review
journals, present these, our data, at local and national and international
meetings, organize scientific workshops as appropriate of regulatory interest,
present scientific information to advisory committees as we do now and provide
information at major scientific conferences and regulatory meetings and also
provide opportunities for our scientific staff to interact with external
scientists at seminars within CBER and FDA.
Now
I'll come to the point of how OBRR is managing the research. What is its research plan? How we identify key scientific needs? The way we do that is that we anticipate
actually the regulatory scientific needs that are identified by analyzing
recent, like one to two year product application submissions and public health
needs and policy portfolio.
What
we do is that we regularly review workload by product class. We analyze that. We look into all the guidance documents,
recent ones that we develop and then we
analyze the product failures and safety reports. We also do observations at the
inspections. We get information from the
inspectors, field inspectors, and then input from scientific workshops and
interactions with the regulatory industry, other HHS agencies and international
partners like WHO. And then what we do
also is that research is targeted to identify the scientific needs where the
output could lower regulatory barriers, product development or improve product
safety, efficacy and consistency as well as availability.
So
with that, we have some scientific needs identified over the years, in the last
year or so. Those are the list of things
here, practical and effective control of an expanding number of known and
emerging transfusion/transmission of infectious diseases that request new
technology for donor testing and product processing. That means actually these technologies
include adaptable platforms for rapid response to EID and bioterrorism agents;
novel methods to detect malaria and other parasites as well as TSEs;
nanotechnology based donor screens; new pathogen reduction methods for blood
components and derivatives.
Then
we come to the point of efficacy and safety of immune globulin products
enhanced by improved characterization for effectiveness that is useful for the
treatment of primary immune deficiency disorders as well as for passive
immunization against pandemic influenza, anthrax, etc.
The
second tier of scientific needs that we identified are all improvements in the
storage enhancing blood component safety, quality and availability; tests for
sterility to improve safety and permit extended shelf life; biomarkers of
quality and efficacy to reduce needs for clinical trials; advancements in the
development of better predictive
preclinical tests of safety and efficacy for blood substitutes such as
hemoglobulin-based oxygen carriers; and biochemical characterization of HBOCs
linking its structure to the clinical risk outcome as well as better
preclinical models to predict HBOC safety and efficacy.
And
the third slide that shows these, the pharmacogenomic and proteomic studies to
improve safe use of blood products.
Under that, genetic determinants to predict risk for development of
clotting factor inhibitors comes under that category and genomic based blood
grouping and typing to improve blood compatibility determinations. And then lastly, the radio-frequency ID
technology for blood product labeling and tracking which is a promising
approach to reduce errors in blood transfusion management. So these are the key issues we found out.
So
out of that, how do we deal with that and as a plan we cannot do everything on
that as Kathy was mentioning. So what we
do is based on the identified scientific needs and available resources and
expertise within the office and the feasibility of success and public health
significance of the expected outcomes as well as the expertise of the Office
that we have.
What
we have done so far is we've identified using all these criteria around six
high priority areas for the current research program. They are -- number one, a priority. They are not prioritized as they are listed,
but all the six programs are all important.
Number
one is the novel methods of pathogen reduction and inactivation in blood and
blood products. What we expect out of
this research is that as a development impact probably more rapid assessment of
candidate commercial methods can be happening with this knowledge and then open
new avenues to achieve safe and effective pathogen reduction for cellular blood
components and we also probably expect that this research area will provide
insight into the mechanism of cellular damage by pathogen reduction methods.
The
second one is multiplex platforms and high sensitivity methods for pathogen
detection including genetic variant and imaging infectious diseases and
bioterrorism agents. What we expect out
of this is that as usual the more rapid assessment of the candidate commercial
methods, but also it could probably provide insight into the practical
limitations associated with the new technologies.
Then
the third priority area is to develop infectious agent panels for assay
standardization and standards and reagents for product lot release testing
which you already heard a couple of talks on that before and what we expect out
of that is that probably strategy preparations through development of lot
release panels for new infectious agents will be available and replenishment or
replacement of existing control panels is a possibility and also international
standards for hematological products to ensure product potency.
And
the fourth one is the development and evaluation of proteomics and genomics
based biomarkers for efficacy, quality, toxicity and consistency of blood
components, blood-derived products and their analogs including blood
substitutes. Out of this what we expect
as a regulatory impact is provide probably surrogate biomarkers for product
efficacy and safety for more efficient clinical trials.
Priority
area five, development of predictive models for preclinical evaluation of blood
components, blood derivatives and their analogs including blood substitutes and
to study pathogenesis of blood-borne EID agents. The regulatory impact that is expected out of
this is an appropriate animal model to improve HBOC safety and the in vitro
infectivity studies of blood components that could support changes to current
policies on donor deferral and reentry.
So
the area, the last one, is development of methods to evaluate efficacy of
immune globulins of pandemic and BT importance.
The expected outcomes for the regulatory impact are to provide a
scientific basis for dose labeling of immune globulin products to prevent known
and emerging infectious diseases and establish protective levels of specific
antibodies in immune globulins to treat immune deficient patients.
So
in conclusion, what I can say is that
OBRR and CBER have carefully considered all of the recommendations of
the BPAC review of OBRR research. In
particular, program changes have been made in response to the major
recommendation of the BPAC for more structured and transparent management of
research. OBRR and CBER have developed
and are implementing a managed research program as you heard from Kathy based
on prospective evaluation of regulatory science needs, our available resources
and the expected impact of the research.
So
therefore, we look forward to ongoing and frequent discussions with the managed
research program to assist OBRR and prioritize, focus and streamline our
research to best address the scientific needs of the day. Thank you.
CHAIRMAN
SIEGAL: Thank you very much. Are there any questions?
DR.
DI BISCEGLIE: I had a couple questions
at this time. The one was I was pleased
to hear about the commitment of the Office to provide protected time for
research for staff. I wanted to ask a
little bit about how that is done. How
much research, how much time is protected for a particular person? How is that measured? How is that assessed? How is that enforced? In other words, how real is it?
DR.
ATREYA: I mean, there is some reality to
it, but do you want to comment on that or you don't want to comment on that?
DR.
NAKHASI: That's a very excellent
question because I think what we do is at least in the divisions we look at the
portfolio of a particular researcher, PI, and based on the workload of
regulatory workload. Because in the
past, if it was not looked at, one person would be overwhelmed with so many
regulatory applications and time goes down for research. So now we have definite parameters where we
protect, at least let's say, if it is a first time, an initial person. When the new investigator comes into the
division, we protect at least 70 percent of his time or her time to
research. As the time goes on, as the
experience goes on, it can increase to 50 or 60 percent of the regulatory work
and 40 to 50 percent research work. It
again depends. It varies.
Sometimes
in the month, in a year, a person is busy with -- for example, last year there
was a Chagas application for -- we approved the Chagas test. A person who was involved in it had a 70
percent of time in the regulatory. But
the demand of the application, now his time has been brought into the research
area where he can focus on the research.
So it has to be an adjustment but made by the managers, but at the same
time, looking that you have a protected time.
And
Jay reminded me that we have an RRS system that is the time reporting system,
how much we spend on the regulatory as well as on the research and so that
gives an idea.
DR.
DI BISCEGLIE: But is this coordinated
across the laboratory level, the division level or the office level? At what levels is this sort of scrutinized
and coordinated?
DR.
NAKHASI: The RRS is at the Center level
and so it looked at the Center level because every three months it is done.
DR.
GOODMAN: You know, I just want to add
one comment. We do have -- we do think,
and this is from the commissioner to me and everybody, we want to have a strong
scientific infrastructure. We feel that
in our area of products that's particularly important. We think our decisions should be both science
based and science led.
That
said though, we're an agency that has a pretty vast portfolio work under
constrained resources and I just want to say that whenever a public health
problem or a review issue that pertains to a product's quality or safety or
availability comes along we all, whether we're the Center director or a junior
researcher, we have to have the right people flexible enough to move to be able
to do that. So an important long-term
challenge for the FDA is to attract scientists who can work in that kind of way
and many of us who are in academic medicine are -- I know there are people who
can work in that kind of way, but that's exceptional. And also people who are interested in these
unique opportunities who look on the importance of developing a new assay, let's
say, to replace antiquated assays for influenza vaccines as a major public
health contribution but sort of can approach these things flexibly and move to
new problems.
But
I did want to emphasize that often every day we make tough calls about what we're
going to devote our time and energy to and it's very important I think as we
recruit and develop people, both laboratory people and other people, that they
understand the environment that they're working in and that to the extent we
can though we pay attention to their personal development as well. So it's a tricky balance and it's made
especially challenging in a resource constrained environment.
The
other way we try to build and develop people is through these collaborations
with colleagues at NIH, academia, etc., and one of the things we've done, for
example, in starting to evaluate research projects and I think I heard Kathy
say this is to explicitly say do we have the right collaborators, do we have
the right communication plan and that's not just communicating results but
getting input about what we do and that's part of being here. So I think for an extraordinary small amount
of resources and for people who are often busy with a number of other things we
can be proud of some of the impacts that people have had on public health and I
think when you hear, you know, just hearing the list of active standards
development and these are things that somebody else just, they're not going to
get done if we don't participate and they improve patient safety and they
improve industry's ability to get these products which often don't have huge
financial incentives out there. Thanks.
DR.
CARBONE: There's one more level I'd like
to mention and that is proactive rather than reactive, you know, having a staff
member and trying to protect their time and that is that the analysis of the
regulatory workload actually gives us a prediction of where the workload is
going and using that mechanism you can then balance staffing models.
For
example, in another office, they identified a hugely increased workload in two
areas that they don't have anybody working in.
So to avoid having to sort of task everybody or overtask, they then look
at those areas and say, "Well, when resources become available, those are
the areas we're going to staff up."
So this sort of proactive way of the analysis of the workload gives us
the opportunity on a big picture to staff areas that need more, the time for
research or staff areas that are bigger regulatory demands so that the staff
members aren't so overwhelmed individually.
So there is also that planning level too.
DR.
SCHREIBER: We did the site visit a
little over two years ago now and I was just wondering if there's been any
change in the ability to recruit and the retention of staff because that was a
major consideration or discussion and even Dr. Goodman mentioned it again in
his point. So I just wondered if in the
two years you've had any differences or seen any changes.
DR.
EPSTEIN: Well, there are always changes
because we live in a dynamic environment.
We're always in the process of recruiting and hiring people and also we
always lose people to attrition. I would
have to tell you that the last year was a difficult year because we had a
difficult situation with funding and we did have a temporary freeze on hiring
and we did continue to attrit staff during that period and that for the last
several months we've been rebuilding.
So
I think the honest answer is that we have some critical unfilled positions and
that we're working very aggressively to fill them. I think that the positive side of the
equation is that we do get applicants and our programs are seen as a good place
to come work. So I would say right now
the situation is that we're in transition.
Some of the groups did suffer significant losses of persons who had been
at the FDA a long time, were holding major responsibilities, were very active
at the bench and so forth and we have had to do a little bit of restructuring
and some aggressive recruitment.
DR.
GOODMAN: I could just comment again a
little from the Center and the Agency point of view. I think I agree with what Jay said. The Federal budget process is complex, but I
think the good news is I think some of the potential opportunities to
strengthen the Agency, etc., are being recognized and we're hopefully entering
into a period of more budget stability.
I
would say that there have been some very fine recruitments within CBER of
scientists, of new people. So I think it
can be done and I think making the process for how we will manage the research
transparent to people who come in can help in that and also showing as we have
what are some of the unique opportunities.
But
it's a continuing challenge. I mean it's
very -- as everybody who has worked closely with us knows it's a very
challenging situation. I was in academia
for a long time and I can say that the five or six major issues I deal with
every day at FDA are more complex and more challenging and that's another
reason why we really want the best people and to make it a good place for those
people to be.
So
one thing I would mention, for example, we're about to be doing very high level
recruitment and this is relevant to your question for a new office director for
the Office of Biostatistics and Epidemiology and we see that as a very
important scientific not just service that does our safety activities and our
statistical activities, but a research and scientific area of incredible
importance to the Center. I'm saying
that publicly and to you because we welcome and we really try to go outside,
both develop our people inside, but also bring outside people in and we welcome
the committee supporting us to do that.
Thank you.
DR.
EPSTEIN: I just want to add another
dimension to this discussion from your question and Dr. Di Bisceglie's
question. We have had a change which was
noted both by Drs. Carbone and Atreya which is the ability to seek outside
funding support through grants. We can't
compete for R01s. It was noted that
there's been an assessment that we're at the same standard of people compete
for R01s. We can collaborate with
holders of R01s. We can compete for
interagency grants and we can apply for foundation grants. We can also collaborate under cooperative
research and development agreements with industry, although the persons who are
in those collaborations cannot also be the reviewers of products from that
industry. Obviously, we have to be
careful of that issue.
But
the fact that we're able to bring in outside grants does mean that we have
another mechanism to support the laboratory program and I can tell you that
where we're most short even though we're constrained in terms of number of
people, full-time equivalents, that we can support with tax dollars, we have a
worst situation with operating dollars because the operating dollars per capita
for a principal investigator are nowhere near the standards that major research
institutions whether they be government, NIH or academic. But the ability to bring in ability to bring
in grant funding we have somewhat improved the situation and that does have an
effect both in terms of protecting the research because you can fund support
persons. In other words, you can fund
contract hires and of course, you can leverage effort through collaborations
and at the same time it has an effect in improving retention because our
scientists are able to remain more productive.
So they're happier staying within the organization rather than feeling,
"I can't do the work I'm interested in unless I move on." So I think that that becomes a very important
matter.
There's
a flip side to it, of course, which is when people apply for and obtain
grants. They are also making commitments
to the work under the grant. So within
this program of management of research, we have to pay a lot of attention to
what people are allowed to apply for because we have to ensure that looking
over a multi-year time horizon which is, of course, typical for grant funding
that the work is highly mission relevant and it does meet our sense of on-going
priorities, future-looking for product development. So I think that again grant funding is
another mechanism by which we are both protecting the program and also keeping
people in the organization.
DR.
KATZ: I'm going to change focus a little
bit with this question, but certainly in our community, in the voluntary blood
community, biovigilance is the latest jargon and while FDA may find it
difficult to actually do research in biovigilance, there's going to be a body
of data developed over the next three to five or eight years that's going to
have regulatory implications and I don't see in the research program anything
that explicitly begins to prepare the Agency for dealing with the kind of data
that we're going to see.
DR.
EPSTEIN: Okay. Well, let me just give a brief answer and
then if Dr. Goodman wants to comment.
But we're actually very heavily invested in the whole issue of
safety. We're very mindful of the
Within
CBER, the lead entity is Office of Biostatistics and Epidemiology which is very
involved with the whole issue of databases, use of data mining tools and
strategies for monitoring safety. We
also have increased the focus on Phase IV monitoring of products post
approval. We have safety teams that Dr.
Goodman has requested be created across CBER and we do have a safety team for
blood. We do have a safety team for
tissues and we do participate very principally in the interagency
activities. The PHS has established a
task force on biovigilance. I know
you're aware of that and FDA and in particular, the staff in my office are
leading participants in that cross-agency initiative and within the blood
safety team, the leads are cooperatively with Biostatistics and Epidemiology
and with my Office of Blood Research and Review.
So
there's a lot of activity in that domain and I would say in terms of the
research focus at our level it's principally about the databases. It's about how to orchestrate data so that we
can extract useful information, report it back out publicly. We've built bridges, for example, with CMS
where there's a tremendous amount of hospital data which was not historically
available to the FDA and we're also, of course, interested in building bridges
with the initiative of AABB and other components of the private sector.
So
we are very active in that area, but within the research program, I would say
the lead is in the Office of Biostatistics and Epidemiology. But we're certainly big time players. Did you want to add? Do you think I covered the base? Yes.
Okay.
CHAIRMAN
SIEGAL: Okay. Any other comments? Mark, I'm sorry.
DR.
BALLOW: I was on a site visit not too
long ago. Maybe it was in the spring if
I remember right and one of the issues came up about the White Oak site or
location and whether that's going to have all the core laboratory facilities,
particularly animal.
Whether
the White Oak facility is going to have all the core facilities including
animal facilities and of course, it takes them away from the NIH campus where a
lot of collaborations take place and the travel distance between the new
facility and NIH is a potential barrier particularly with the traffic in
So
I don't know. How are you going to
address some of the barriers or some of the concerns of moving your facility
outside the NIH campus?
DR.
CARBONE: I'll take that on because I'm
part of the, well, lead for the White Oak Subcommittee for Laboratories within
CBER and also part of the OC's effort.
Just sort of as background, White Oak is located sort of northeast of
the D.C. area just outside the Beltway and currently CDRH and much of CDER is
located there and the plans are to move everybody but Foods to that campus and
there are a couple of issues.
I
mean the one issue about leaving the NIH community is what it is. But the bottom line is we actually will be
joining up for the first time with our FDA colleagues which is a wonderful
scientific base that we have not had previously. For example, the CDRH group developed a
wonderful new engineering building that's just state-of-the-art and has
facilities there that don't exist elsewhere.
We are given the opportunity for building our research buildings and the
animal facilities will be ditto. We
currently do not have primate facilities.
Right now, for example, we don't have BSL-3 small animal
facilities. We've had to work them into
our BSL-3 laboratories which is less than ideal conditions. So the new animal facilities actually have
been designed with CBER input, with CBER numbers and we'll be addressing things
like putting in BSL-3 small animal facilities which we currently don't have.
The
campus is actually quite nice and the opportunities to design buildings, the
Building 29 currently is an ancient building and is actually very difficult to
do research in. We had a pipe burst and
it flooded our 200 freezers and put them all at risk in 29A and in 29B we had
to decommission a BSL-3 laboratory because the ventilation was not up to the
new standards. We had to build new
laboratories on the top floor because of ventilation issues. So the opportunity to actually construct
novel facilities is really tremendous, the ones we can design for ourselves.
The
issues such as adjoining with NIH have been discussed. We've been talking with the Agency, for
example, on our access to NIH library system and they are currently in
discussions with NIH to try and see to actually maintain that.
The
other options we've discussed are shuttle buses to the NIH campus to give staff
an opportunity to come down for seminars, etc., and for example, I for most of
my academic career collaborated extensively at
So
we will do everything we can. In fact,
we've already surveyed the staff to say tell us exactly what you will be losing
when you leave the NIH campus and about two-thirds of their concerns are
actually covered, things like who will take care of radiation, who will do
safety and other things that we can address directly with White Oak.
And
the remainder, such as travel. We're
looking at innovative ways to address it.
We actually established tours with the help of the Office of Management
to get our CBER staff over to tour the facilities because a lot of people were
expressing concerns without ever having visited the site and about an 80
percent response rate of people who visited was actually tremendously positive
when they saw the opportunities at that site.
The
rest in terms of distancing from our NIH colleagues, we will be doing our best
to address and resolve those. But the
opportunities for joining at White Oak are actually many.
DR.
GOODMAN: We actually just had a meeting
of our leadership within the Center yesterday to discuss this and learn from
some of the experience of some of the people who are already there. These are real concerns that you've
identified, I think.
One
thing I would say is I think that what we're trying to do since this is a
planning decision that's been made is say what is our vision of how we want our
science to be and how do we maximally enable that. For example, we have the opportunity to think
about how does the architecture of our offices and laboratories, how can that
instead of be an impediment to how we work, fit with how we work and fit with
the mission. So there are various models
we're going to consider internally and with the architect of bringing
laboratory, sort of like many people have gone through in academia with
translational research. You know, how do
you bring the Ph.D. scientists together with the M.D. scientists and in our
case, how do you bring the people who are full-time reviewers together with the
scientists. So actually, there are a lot
of opportunities.
I
think a critical, critical thing is going to be we do have many life science
relationships and projects that are leveraged with NIH and many personal
relationships and also as you said that is an attractive thing in recruiting,
etc. And I think we want to look at
those and try to be sure we can continue to support those or build other
opportunities. I think it's going to
make on-going, explicit support for science at FDA very, very important and
we're starting to see recognition by the outside and Congress and industry that
there should be support for science at FDA because of its value and I think
there's going to be this need for our scientists and again, I don't view this
as just the laboratory science. I think
this is everyone to feel that there is support for building knowledge,
improving knowledge, etc. What we're
trying to do overall with the research program should strengthen that.
I'm
not sure exactly how it will play out, but in legislation that Congress is
considering, for example, there's a provision for some kind of potential
foundation that can support certain scientific activities and things like that
again may enhance our abilities. But I
know many, many people are concerned about this.
The
other thing I wanted to mention, I think you guys may have heard this before,
but there's a review of science at FDA in toto, the whole Agency, that's being
done by a group called The Science Board.
It's -- I can't remember the whole board, but it has been chaired this
visit at least, the board I think is chaired by Ken Shine who is the former
president of the Institute of Medicine and many of us know Ken and then this
Review of Research which is on-going is being chaired by, I think, him and Gail
Cassell who is the Vice President of Eli Lilly and a former president of the
American Society for Microbiology. So
they're looking at for FDA to be a 21st century effective
science-led organization, what is needed, and I think that report hopefully
will help articulate the future going forward.
So we've been an active participant in that.
And
as much as this is a challenge for CBER, there's much of the scientific
tradition at CBER and the interactions with NIH that has really helped support
us and keep us going and some of the other centers have had even more
challenges than we've had. Thanks a lot.
MR.
ALLEN: Mr. Chairman, I beg your
indulgence. We seem to have sort of
gotten in the open committee discussion here.
So let me just make a couple of comments as the chair of the Review
Committee.
Dr.
Goodman, Dr. Carbone, Dr. Epstein, Dr. Nakshi and Dr. Golding, I would very
much like to thank you and your staff for your response to the report. I think it goes far beyond what I had hoped
might come out of this and I feel very gratified that we've been able to be
part of a process. I'm extremely
impressed that this has been responded to not only by OBRR but by the entire
CBER structure.
I
like the Research Management Initiative concept that has been put forward. I like the Research Leadership Council, the
Senior Leadership Team and the development of priority research areas as well
as the rest of the responses. I think
this clearly -- the report that the Committee put forward was looked at very,
very carefully and appropriate responses have been developed. They are in the process of being
implemented. I don't at all get the
sense that this was a one time, it's done, we don't have to respond to it
anymore. This is an on-going process and
I'm very encouraged between the 1998 CBER report and our 2005-2006 OBRR report
clearly there was an improvement in the quality and the focus of the
research. I'm encouraged that this is
going to continue despite one of our major concerns which was the paucity of
resources and I hope that this issue will continue to be addressed. I think it is from what Dr. Goodman has said,
because clearly it's important to have the appropriate resources, both
financial, personnel and the facilities and the equipment issues are being
addressed also.
So
I want to thank the Office for their response and to the entire CBER staff for
the way in which they've responded to this report instead of just putting it up
on a shelf somewhere to gather dust. I
think it's been useful.
CHAIRMAN
SIEGAL: Thank you for your comments, Dr.
Allen. We now ostensibly have an open
public hearing, but I understand that no one has signed up to speak. Is there anyone from the audience or anyone
who wishes to contribute at this time?
(No
response.)
CHAIRMAN
SIEGAL: And that point we can dispense
with the conflict of interest statements.
Then we might as well open our committee discussion at this point unless
people want to take a break. Let's
proceed. Is there any further open
committee discussion?
DR.
FINNEGAN: Mr. Chairman, you're allowing
me one rude question per topic. Right?
(Laughter.)
DR.
FINNEGAN: My question has to do with
considering managing your regulatory loads the same way you are managing your
research protocols. As we were sitting
here this morning and I will tell you in advance I have no expertise in potency
and standards and after this morning's presentation, that's just fine.
But
it struck me that a whole bunch of things came due at the same time and perhaps
if this was managed and there was a rolling sunset or a rolling review of these
things that perhaps this would help with getting more resources to your
research.
DR.
EPSTEIN: Well, I can perhaps shed a
little bit of light on that which is that there's an annual review that goes on
with standards. In other words, CBER is
a WHO collaborating center for biologics and one of the standing components of
the WHO is an expert panel on biological standardization and annually there is
a meeting convened, generally in October, of what's called an expert committee
for biological standardization.
And
so what goes on is that at that meeting proposals for these reagent standards
are reviewed, work plans are established, collaborating centers volunteer their
agreement to help develop the standard and then over the course of the year the
work goes on generally with additional collaboration from multiple expert
laboratories.
So
when you say that there seems to be convergence of deadlines, what it reflects
is the fact that there is an annual cycle for establishing the work. Every year, there's a deadline of one sort or
another. Either the deadline is for
submitting the proposal or the deadline is for review of the data or the
deadline is for determination of the potency of the standard, etc., etc. It's an ongoing effort.
With
respect to renewal of the reagents themselves, there's a certain level of
happenstance here because for example, as you saw with the blood grouping
reagents, many of them were established in the 1970s. They're only now running out. But it's not that that hasn't been
recognized. In other words, there's been
a planning process for several years how one would go about renewing those
particular reagents.
The
bottom line here is that the same could be said every year. Every year something needs renewal. Every year there's some deadline for a new
initiative. It's an annual process.
DR.
FINNEGAN: What struck me this morning is
that blood transfusions from 1950 to 2000 has gone from being a rapidly
changing learning to sort of a maturing process and it would seem to me that a
standard that was set in 1958 or a standard that was set in 1970 probably -- I
mean, I would assume that every group has the same resource problem and the
same we would rather be doing other things type of process and so it's inertia
of the entire group that's letting it go this long rather than someone saying
"Look. This is now 15 years
old. Maybe as a group we need to say for
this particular problem it needs to be moved up the scale." Does that make sense to you?
DR.
EPSTEIN: Well, I'm not sure I follow the
argument fully. What goes on is a
constant reexamination whether the available reagent still works. So for example, we participate with a
collaborative study that's organized by the Council of Europe. Every year, there is a review of serological
reagents for blood grouping and typing.
The
question is whether the current international reference material or
international standard is still operating the way we want it to and as long as
it is, it's fine. And it's only as new
needs get recognized do we generate new types of reagent and I think what you
heard today is that right now there's quite a lot of activity in new types of
reagents.
For
example, we have moved from an era solely of serological reagents to an era of
antigenic reagents and now to an era of genomic reagents and now we're looking
at genomic subtypes and of course, we also have to keep up with the evolving
evolution of agents, for example, HIV and all of the substrate of subtypes,
yes, HCV, etc. and you heard it also for Papovirus B19.
But
when you say if you have the same reagents in place for, say, Anti-A or Anti-B,
why aren't we modernizing? The answer is
we are. The answer is that standards for
monoclonal reagents are being developed.
But it hasn't made the polyclonal reagents obsolete and as long as
they're not obsolete, they're doing what they say they're supposed to do and
they haven't lost their potency and they're still available. Well, you don't need to do anything about it
except ask every year if they're still good.
I
just think that the situation is dynamic even though some reagents stay on the
scene for a long time, especially polyclonal reagents. I mean they do tend to be valuable for a very
long time precisely because of that nature and for many things, you know, the
changing in biology isn't so quick anyway.
Look at human blood groups.
They're not evolving the way the viruses are evolving but we do have new
reagents to deal with new technologies to be sure.
Is
that helpful because again I'm not sure I precisely understood your question?
DR.
FINNEGAN: I think my question was less
about the blood typing. I agree with you
completely on that. I think I was more
perplexed as to why there was depletion of so many standards at the same time
and some of those standards have been around for a long time.
DR.
EPSTEIN: Again, some of it has to do
with when they were made and some of it also has to do with the fact that as
more manufacturers may enter a field there is an acceleration in just the
utilization of reagents. But I'm not
sure that I have any greater insight than that.
You know, we tend to target something like a seven to ten year life span
for one of these international standards and so there's a certain amount of
guesstimate that goes on about the rate of use and sometimes the guess was
right and sometimes the guess was wrong.
But
to the extent that when a field kind of emerges -- let's look at it this
way. Right now, we're generating a whole
class of RNA and DNA reagents and it's happening over a relatively short span
of years. You know, over a two to three
year span of years you're going to have HIV, HCV, HBV, B19 genomic
reagents. Well, one could say that won't
they all get exhausted, for argument sake, five years from now and it will be
because there is a cohort effect. In
other words, the science has matured to the point where we recognize the need
for the reagents and we're making them, but that's all kind of happening in a
cluster.
Now
I can't tell you that a B19 reagent will be exhausted more quickly or more
slowly than an HIV reagent. But to the
extent that they all mature at the same time, that the fields do, we may see
another cohort effect a few years hence.
DR.
FINNEGAN: Why could you not monitor the
use of the reagents and figure out what's going to be depleted?
DR.
EPSTEIN: We do. Again, that's
part of the annual review at the WHO is how quickly are they being
exhausted, how much is left, are they still stable, are they still the reagent
that you want, are they fit for purpose.
So we do that.
DR.
GOODMAN: One -- I was at the committee
meeting last year at WHO about this and there was a similar portfolio of things
that each year people are taking on or identifying. But what I would say is this is another
area. It's not sexy. It's not finding the gene for disease X and
it's not necessarily -- there's not necessarily funding dedicated to it. So at the WHO level, at our level, there are
only a few places in the world that do this stuff. The Paul-Ehrlich-Institut is another one
which is a counterpart of ours in
One
of the things we've tried to do with this research management and with the
whole FDA critical path initiative is identify that this is an area of science
that needs attention and everybody benefits from that. Patients benefit on the quality and safety
end. Industry benefits on the quality
and availability end.
So
I think in a way it's good we're having this discussion. It's good that we do this work. But it's not something the world has paid the
same attention to as, let's say, standards for semiconductors or something
where there's a huge economic drive for it.
DR.
EPSTEIN: I just wanted to --
DR. DI
BISCEGLIE: Can I ask a related
question? Sorry.
DR.
EPSTEIN: That's fine.
DR.
DI BISCEGLIE: For either of you. Just the idea of the distinction between
mission-related research and mission-related laboratory work. This development of standards I would think
of more as very important, very necessary laboratory work but not necessarily
innovative, and therefore, not necessarily research. Or maybe I'm wrong and I'm just thinking
about how you measure in terms of time and effort and so on, those two types of
laboratory work.
DR.
CARBONE: Actually, in some ways I'll
reiterate what Dr. Goodman just said which is the lack of recognition of the
development of standards and assays as a science is one of the things we hope
to change.
Developing
a standard requires that you have an adequate way of measuring it. It requires that you have an adequate way of
measuring the disease. It requires that
you have an adequate model sometimes of starting out. So there are quite a few scientific creative
elements and the end product is "just a standard."
So
we define our research not -- we don't use other people's definitions of what
is quality research. We define our
research as what we need to do the job well and in many cases, there's a great
deal of science and if you will, the lack of knowledge or the science makes it
difficult sometimes to generate these standards. So the element -- the end product I agree
with you. It's a standard. It's fairly -- by definition, it's
standard. But the act of getting there
in the right manner often requires some innovative science. So from our perspective, it is counted as a
laboratory research endeavor and it gets the scientist credit.
We
do obviously the peer review publications which is kind of the standard
academic extramural NIH type measurement because we feel it's important to have
our science peer reviewed, have our science out there in public. But in fact, we measure that as important and
it's important science for CBER as well.
DR.
EPSTEIN: I would say that there tends to
be an underestimation of the scientific element of this endeavor because the
end product looks simple and everybody understands that certain aspects of it
are rote. After all, if you want it
lyophilized, how much science does it take?
That's straightforward.
On
the other hand, what goes into it as Dr. Carbone was explaining is really
multi-factorial. I mean it starts with
epidemiology. What's out there? What are we trying to measure? Why are we trying to measure it? What are the characteristics of the
assays? For what assays and what types
of assays are we trying to make a standard?
So that requires a certain kind of exploration.
Then
you can get into many, many subtleties about the assays. For example, we didn't go into the details,
but let's say you want a standard for von Willebrand disease. Well, what are you looking for? So there's a lot of effort that goes into
figuring out the standard assay as well as the standard reagent and it's full
of betwixt and betweens.
And
then you come to the reagent itself and should it be liquid? Should it be lyophilized? Should it be purified? Should it have a single specificity? Should it be multiple specificities? Should it be naturally derived? Should it be recombinant? Should it be the natural sequence? Should it be a consensus sequence? So there's a lot of judgment that goes into
relating its characteristics to its utility and of course, that requires a
scientific dialogue and often some experimental work.
Then
you come into the whole issue of now your goal is to have a physical material
that has a meaningful unitage. But when
you then characterize it with an array of assays through a scientific
collaboration what you end up with is a range of answers and then you're trying
to figure out what's meaningful in that range of answers and that gets you into
a whole set of questions about the methodology.
It raises statistical questions.
If you have an assay and it gives you an outlier result or you have an
assay and it has high variance, just exactly how do you deal with that result
when you assign unitage and what's going to be the significance of giving a
unitage that may not work in that assay and is the problem with the standard or
is the problem with the assay? And we
mustn't forget that that has a lot of implication for product potency. I mean, if that's a standard for Factor 8 and
you want to reliably dose the patient with Factor 8 or Factor 9, you want to be
very, very sure that you've measured the right thing. So you have that whole aspect to it.
So
what I'm trying to explain is that although some aspects of it may be mundane
science because it's well established. I
mean, we know we should refrigerate liquids.
Right? But on the other hand, you
get into all these subtle questions.
Should it be inactivated or not inactivated? If we inactivate it, does it change its
character in an adverse way because it's no longer a natural material and we
don't know what assay is going to come next.
So
all I can say is that a seemingly simple activity is actually laden with myriad
scientific questions that require extensive collaboration and for which the
answers are not straightforward. Just to
give you one more example, there's this whole debate about what's called
metrological traceability. If you give
an unitage which is always an arbitrary unit, should you be able always to
relate it to some actual physical measure?
For example, is an antigenic potency unit sufficient or must it be
referable to physical mass or if it's only referable to antigenic mass, is that
with a standard antibody and how do you know that the standards stayed the
same?
And
a lot of the effort goes in -- Dr. Finnegan was talking about refreshing these
reagents. The immediate question is how
do you determine sameness and sameness is very difficult to assess. You're going to have a new reagent. It's going to come from a different human
donor or a different human pool and you want to figure out whether the unit is
actually traceable to the prior unit because if the unitage turns out not to be
equivalent, when for example, Mei-Ying was explaining the unitage for the
Factor 8 standard, you don't want to have a shift in product potency because
you misidentify the equivalent unitage of the new reagent compared to the old
reagent. But then the question is how is
it traceable to the original potency and does it require merely a functional
determination or does it actually require a biochemical determination and how
exactly can that consistency be demonstrated?
So
all of these issues converge into a scientific effort and I think what you
heard Dr. Carbone say and what I've tried to illuminate is that it's actually a
science onto itself and I think that that's the point that's been
underappreciated that you do need people who understand all of the details of
that at the very, very simplest level.
You know, should it be delipidated and lyophilized to the most
sophisticated level which is is it or isn't it representative of the genomic
variation of the thing you're targeting and that's just the science. That's the science piece. Does that help?
(Laughter.)
CHAIRMAN
SIEGAL: That was very good. Thank you.
Okay. Are there any more
comments?
DR.
KATZ: That was neat, Jay. Good job.
That was not mine. This may be for
Jim because lo these many years ago I was doing site visits as well and writing
reports and actually the evolution of management of the research program is
pretty spectacular over the last ten years.
So that's one side of the field of endeavor.
But
we keep talking about the resources and I'm just wondering what the Committee
says about what anybody who's interested can do about the resource issue and I
didn't know then and I don't think I know now.
DR.
ALLEN: It's hard to say. Certainly, those of us who are not now in any
way connected except through this committee with the Federal Government, we are
certainly free to contact Congress and to advocate on behalf of the Agency and
the need for those resources. I think
that's an extremely important function that we all should be doing. We should be talking with our own
Representatives and Senators about the importance of this and trying to get our
colleagues at academic environments to do likewise.
There
isn't a good lobbying group out there for the FDA. The NIH certainly has a very broad-based
research community that is out there and has organized to assure that their
message is heard by Congress and by others.
The CDC was slow to do so, but has subsequently developed a reasonably
active public health support group.
The
FDA has a lot of industries that it regulates or is regulated by the FDA and
these groups have their own special interests.
They aren't out there in the same way as a strong support group for the
Agency and resources for the Agency. But
I think it's really incumbent on all of us to do what we can to try to get that
message out.
I'm
delighted to hear that there is an FDA review group that's out there and
certainly I assume that they have been given copies of the report. Dr. Goodman certainly indicated that he's
been talking with them.
This
whole issue of perhaps a foundation to
support research efforts hasn't come to fruition yet, but at least it's being
discussed and I think that's helpful.
Again, support from those of us who believe that that might be useful
certainly might be helpful. And I think
we just need to look at ways that we can do that to always in everything that
we do be supportive of the Agency and in particular, of the programs that are
important to us.
DR.
CARBONE: I just briefly want to mention
that as part of the total FDA review we supplied the office site visit reports
for all the offices to the Office of Commissioner. So that message certainly has been delivered.
CHAIRMAN
SIEGAL: Okay. Anybody else prepared to lobby?
(Laughter.)
CHAIRMAN
SIEGAL: Dr. Szymanski.
DR.
SZYMANSKI: I was quite impressed about
the response I think in all areas as Dr. Allen said. But I was wishing that there would be one
other area included, but I guess it doesn't belong to FDA and that is the
standards of transfusion of various products.
I think this is such a very important area clinically and it would be
lovely if some overall agency would look at this because now it seems to remain
in each hospital their own affair and I would love to see an overall scientific
review of the standards of transfusion.
DR.
KATZ: Clinical Transfusion Medicine
Committee at AABB is embarking as we speak over the next several months on a
very formal guidelines development process.
It doesn't carry force of law or regulation, but I think most physicians
would prefer that clinical guidelines come from clinical organizations as
opposed to regulators.
CHAIRMAN
SIEGAL: If there are no other comments,
then perhaps we should adjourn for lunch.
But it's actually about 15 minutes early. So that means we should come back 15 minutes
early. So let's reconvene at 1:00 p.m. You're allowed to check out in your lunch
hour.
(Whereupon,
at 12:01 p.m., the above-entitled matter recessed to reconvene at 1:03 p.m. the
same day.)
A-F-T-E-R-N-O-O-N
S-E-S-S-I-O-N
1:03 p.m.
CHAIRMAN
SIEGAL: Let's resume please. We're going to have to revise the schedule
slightly. But the topic this afternoon
is Measles Antibody Levels in U.S. Immune Globulin Products which we already
began to discuss a little bit earlier.
We're going to have an introduction by Dr. Basil Golding from FDA. Dr. Golding.
DR.
GOLDING: Thank you and good
afternoon. Before I start, I would just
like to give credit to people who provided very important input. Some of the presentation is going to involve
information that was generated at the FDA, worked on across offices, between
people in the Office of Vaccines and the Office of Blood. Judy Beeler is the virologist that does the
measles titer assays together with Susan Audet who is the first author of the
paper that was generated and a lot of that information relates to the position
that we're in where we're able to deal with this project.
And
keeping in mind what was discussed during this morning's topics, I think it's
very apt to remind people that the research that was done here was very mission
related and was very proactive because we realized that the titers were
dropping and people in the research group, in our group, Dot Scott and Mei-Ying
Yu, collaborated with the Office of Virology and started looking at the lots
and trying to figure out what was going on and that led to an information base
which we can use to formulate some kind of approach which we're going to
discuss this morning.
I
also want to thank the other speakers who are coming and some of them haven't
yet arrived but who are going to present certain aspects which will help inform
us and hopefully inform the Committee to make a decision regarding the
questions.
I'm
going to be talking about measles antibody levels in the United States related
to immune globulin products and the main issue that we've come to address is
FDA seeks the advice of the Committee on a proposal to lower the minimum recommended
lot release titer for measles antibodies in immune globulin intravenous IGIV
and immune globulin subcutaneous IGSC.
The
background for this is that measles antibody titers serve as a potency test for
lot release of all immune globulins licensed in the
In
general, a lot release test, what are the regulatory requirements? Well, this comes from the CFR. "Laboratory controls shall include the
establishment of scientifically sound and appropriate specification standards,
sampling plans and test procedures designed to assure that drug products
conform to appropriate standards of identity, strength, quality and
purity."
Potency
testing for immune globulins, the rationale is based on the assurance of
strength and quality and what do the specifications really provide? They allow for a measure of lot-to-lot
consistency for assurance of product integrity, especially tests that measure a
function of antibody rather than just binding and they measure activity that is
relevant to the indication, in this case, for patients with primary immune
deficiency disorders.
So
in general, what are the current
IGIV
and IGSC in measles antibodies, the measles antibody levels are a standard
measure of potency for these immune globulins.
Historically, when measles was a much more serious problem as a public
health issue, having this protection was important. Potency tests are available and correlate
with protection in normal subjects. They
are measured by bioassay and the two types of functional assay are the
hemagglutination inhibition assay and a neutralization assay which is really a
plaque reduction assay.
The
important issue that we have to face now is that declining antibody levels have
been observed in these products over the past several years. The first question is why are these
antibodies declining in donors. Well,
natural infection does result in higher antibody levels and the proportion of
vaccinated as opposed to naturally infected donors is likely to be
increasing. The vaccine was licensed in
1963 and implemented over ensuing years and naturally infected populations of
donors are aging and these people are more likely to be deferred and there are
pure donors now available who were naturally infected.
This
is from a paper by Markovitz which just compares the titers from natural
measles infection with those from the vaccine.
On the X axis, you can see time after natural infection or
immunization. On the Y axis you see the
actual titers and the upper graph shows the titers with natural measles
infection remaining higher for a longer period of time compared to the titers
from attenuated measles vaccine immunization.
So
the measles potency test for immune globulins has a history. In 1944, a paper by Stokes demonstrated that
measles prophylaxis by IGM is effective.
Around about 1953, the NIH came out with a statement that there should
be a minimum requirement for immune serum globulin. This is the intramuscular. Several lots should be effective in
prophylaxis of measles. And as measles
potency tests became available, CBER developed standards to facilitate the
potency testing of these products.
This
is the history of the actual antibody potency standard. In 1961, the
Many
years later, 1971, Lot 1 was replaced with
Incidentally,
we're not going to have time to do it, but each replacement lot was carefully
titered against the previous lot to make sure that there was a continuity and
that we weren't changing the standard and that the standards are all connected
one to the other based on actual functional assays.
So
the clinical issues. Measles prophylaxis
in PIDD patients. Measles incidence is
now rare in the
The
last major outbreak in the
Nevertheless,
measles remains an important pathogen worldwide. Twenty-one percent of disease related deaths
in children less than five years of age worldwide are due to measles. Antibodies are needed to prevent infection
while measles virus clearance is dependent on CD8 positive T cells. So this is important because antibodies are
not the entire story. Primary immune
deficiency disorder patients especially those with combined humoral and T cell
deficiencies are susceptible in severe measles disease.
Protective
titer against measles infection and this obviously comes from vaccine
studies. This is based on a study by
Chen, but we actually, the people in the Office of Vaccines, Susan Audet and
Judy Beeler, took the titers from the paper and using our standard were able to
make calculations to refer back to our own standard. So we can use this in looking at this
problem. A serum titer of 120 mIU per mL
was found to be protective against clinical disease in healthy vaccinated
individuals. But you need a higher
titer, greater than 1,052 mIU per mL to protect against infection, in other
words, to achieve sterilizing immunity.
There's
a lack of published pharmacokinetic data analyzing measles titer in IGIV
products administered and the consequent trough level measles neutralizing
antibody in PIDD patients, but you will hear from subsequent speakers from
industry that they are going to present some data today which is relatively new
data and which we should take into consideration. The protected level in PIDD
is unknown. More than 100 distinct PIDD
syndromes exist. Therefore protective
measles antibody levels may vary as well because these people may have varying
degrees of T cell deficiency.
The
rationale for new measles antibody specification. The package inserts, if you look at package
inserts for all the immune globulins, the IGIV and IGSC preparations, you will
find that they range between 200 to 800 mg of IGG per kg given every three to
four weeks. Now even though that is
correct for the package insert, from a practical point of view, most if not all
physicians that are treating these patients will use 400 mg/kg or even higher
doses.
So
in considering trough measles antibody titers for patients receiving 400 mg/kg
every four weeks, the estimated range of the measles titer would be 250 to 718
mIU/mL based on CBER testing of lots and calculated trough levels. In the paper that I alluded to earlier, they
looked at 166 lots from seven manufacturers, calculated, not calculated,
assayed them and then based on their value, calculated what the trough levels
would be if you gave a dose of 400 mg/kg to PIDD patients and that's the range
they calculated which is more than twice what is needed for a protective level.
On
the other hand, if you look at the last bullet which would be a worst case
scenario, if a physician decided to use the lowest dose on the label and used
200 mg/kg, that would achieve a trough level of 120 mIU/mL which would be 1,200
IU/mL or 0.48 times the CBER standard Lot 176.
Just
to remind you, the current lot release standard in order for the lot to pass it
has to be 0.6 times the CBER standard.
So what we're saying is even the worst case scenario if you gave a lower
dose, you would achieve a protective level at the time of trough level prior to
the next dose of product.
What
could be the possible strategies to address declining measles antibody titers
in immune globulin products? What we're
going to propose is to lower the recommended measles lot release specification
titer for IGIV and IGSC if there is assurance that the minimally protective
titers are present. Another approach
could be to revaccinate plasma donors in an attempt to increase antibody
levels, but unfortunately the likelihood of achieving substantially higher and
durable levels is estimated to be low in adults and you may see in a subsequent
presentation actual data to show you that the second immunization is not
associated with a very big increase in titer.
What
are the questions to the Committee?
First, we're not going to ask you obviously to answer but to frame the
questions so that you'll have these in mind during the coming presentations. Do committee members concur with the FDA
proposal to lower the minimum measles antibody specification for IGIV and IGSC
from 0.6 times the CBER standard to 0.48 times the CBER standard?
CBER
is considering requesting additional studies to confirm that PIDD patients will
achieve trough levels of measles antibodies above the protective level, in
other words, 120 mIU/mL, if treated with IGIV and IGSC products that meet the
proposed revised potency standard of 0.48 times the CBER standard. Do the committee members agree that this
information is needed?
Thirdly,
please comment on the need for feasibility of any alternative strategies that
CBER should consider to reduce the likelihood of failed lots of IGIV and IGSC
based on potency testing for measles antibody in order to ensure availability
of product for PIDD patients.
Thank
you. That is my talk.
CHAIRMAN
SIEGAL: Okay. Thank you very much, Dr. Golding. Are there any questions for Dr. Golding at
this point?
DR.
FINNEGAN: Do you have any idea about the
CDC patients? Were they never vaccinated? Were they older and far out from their
vaccination? Were they wild type that
had never been vaccinated?
DR.
GOLDING: I'm not sure which cases you're
referring to, but most of the cases that have occurred in recent years they've
been imported, so, in other words, somebody traveling to an area where measles
is endemic coming back to the country.
Now you're asking were those people who got the infection locally, were
they vaccinated or not. I don't have
that information. My guess is that -- I
know the vaccination is effective. So my
guess is either they weren't vaccinated or they were long time off the
vaccination. Because what happened is
that it was shown an epidemic of `89 -`91 with 55,000 or more cases who were
infected was at a stage where people were not getting two doses. So it could be that people between the first
and second dose had their titers dropped sufficiently that they are now getting
infected. But I'm not sure. But Jane Seward is going to be here from the
CDC hopefully in about an hour. So she
can answer that more correctly.
CHAIRMAN
SIEGAL: Mark.
DR.
BALLOW: I was just curious. Going over the historical data about the IM
gamma globulin, the first slide was 0.25 or something like that and then all of
a sudden it jumped to 0.6. What's that
all about?
DR.
GOLDING: Yes. For the first lot was more -- Let me
think. Was it more potent or less
potent? It was more potent. So you could have a -- Now why did it drop
over 20 years? Again, I think it's
related to there were many more natural infections at that time and the titers
in the donors -- This lot didn't just drop out of the air. It was an regular industrial manufactured lot
that we were able to acquire to use as a standard or part of it was acquired to
use as a standard. So what you're
pointing out is that it's not that it's just dropped over the last few
years. Since 1961, the titers have
dropped considerably.
CHAIRMAN
SIEGAL: One more from Mark.
DR.
BALLOW: Nell and I were just talking and
we were asking what's happening with the Hepatitis B titers. In other words, you have all these -- You use
polio, measles, Hep B titers and I can't remember the fourth one.
DR.
GOLDING: Diphtheria.
DR.
BALLOW: Diphtheria. I mean obviously with diphtheria and polio it
may not be an issue, but what's happening with the Hepatitis B surface antibody
titer?
DR.
GOLDING: As far as I know the Hep B
titers have not been a problem, but Dr. Yu looks at this more carefully than I
do.
DR.
YU: Well, there is a minimum requirement
by CBER for the Anti-HBs present in immune globulin product and that 1 IU/g of
IGG, per gram of IGG. So you have a five
percent albumin. No, five percent of
immune globulin. Then you need to divide
it, 1 IU divided 20 mL because that is 50 mg/mL. So that's a minimum requirement for us. It's very low. But in actual reality, the titer is much
higher, but it's the minimum requirement is 1 IU/g of IGG. That's what we set.
DR.
BALLOW: But has it changed? Has it changed over the last --
DR. YU:
-- Usually --
DR.
BERGER: I think the question about
Hepatitis B titers in IGIV products is whether the titers are moving in the
opposite direction of the measles titers because now the population is getting
immunized. So perhaps the titers are
actually going up.
DR.
YU: I think the titer certainly is not
decreasing. It's not. That's what we understand. It's anti-measles is decreasing, but not
anti-HBs or other markers that I know of.
But many manufacturers are here and they may be able to provide the
answers.
DR.
GLYNN: Yes. I had a question on the level of 120 that
you've been using for your calculations.
After looking at the paper, I'm not really -- Can you go over why you
chose 120 because from what I see there was a patient who got full-blown
measles at that level. So I'm not sure
why you're saying that that level is protective.
DR.
GOLDING: That level is from the vaccine
studies where they showed that that level was a protective level for
pre-exposure prophylaxis. Now it's 120
was the lowest level that was protective.
So I don't think that it's surprising that now and again you'll get a
breakthrough infection. But on
aggregate, the 120 was a protective level in the vaccine trials.
Now
I'm not saying that we should aim -- What we're proposing is to aim for
achieving a titer that's at least double that even if we reduce the titer. So if the intent of your question is say are
you happy with the 120, I would say no.
We need to have a margin of safety and what we're proposing is at least
having immune globulin products out there that are delivering a dose which
would give you at least twice that level, somewhere in the range of 240 or 250
which would occur if you're using 400 mg/kg.
DR.
KATZ: Are you actually failing lots at
this point?
DR.
GOLDING: That's a very good
question. So I can't give you details of
that because it's proprietary information.
But there have been and even in the paper that was appended to your
package, there was one set of lots that were failing based on our testing. So there are lots that are failing. It's a small number at this point. But if you're looking at declining titers, I
think we can't wait for more lots to fail because this is a very important
product for a life threatening disease.
At
the moment, I would say that there are failing lots or lots that are very close
to the cutoff and that if we waited much longer or even longer, we would start
to see more lots failing and there would be a problem of availability of this
product.
DR.
DI BISCEGLIE: Basil, you sort of used
IGSC and IGIV sort of interchangeably.
Are there any differences with regard to levels of antibody and is this
something the Committee needs to consider?
DR.
GOLDING: Okay. Well, what happens is this is really that the
answer is based on pharmacokinetics and what happens when you're giving IGIV
every three to four weeks is you get a sawtooth patent. When you're giving it every week as a sub
cut, you're getting a much flatter curve which means that your peak levels are
lower and also means your trough levels are higher with the IGSC. So if anything, the IGSC trough levels are
higher. I think it's less worrisome to
some extent with the IGSC concerning the actual trough.
But
on the other hand, you still want to have sufficient titers in those products
that are also going to have a high assurance that through the period they're
going to be above, considerably above, the 120 mIU/mL.
DR.
SCHREIBER: Do you have any information
on whether there have been any patients with immune deficiency disease that
have experienced measles while on IGG?
DR.
GOLDING: That's also a very good
question. At the workshop, we discussed
this and they're putting a registry in place.
I don't think, if somebody who was at the workshop recalls, but I don't
think anybody, we've seen cases to my knowledge in this country of PIDD
patients developing measles while they were on treatments. An assumption from that is that the current
treatment is very effective in pre-exposure, but the truth is that it hasn't
been tested very well in the last few years because as you see there have been
very few cases for the last 20 years.
DR.
GLYNN: And so do you have an estimation
of the current levels right now with the current IGG?
DR.
GOLDING: Yes. We can calculate it based on pharmacokinetic
principles. But better than that, you're
going to get these two presentations today where the manufacturers are going to
talk about the actual measured trough levels.
We don't have, as I mentioned in my slide, a lot of data especially
published data on that. So the speakers
will provide us with some information about actual levels. What we have is mainly based on what the
titer is, either product, and then based on PK principles what we expect the
trough levels to be.
DR.
SZYMANSKI: Can you tell me what
percentage of IGIV products are given to immunodeficiency patients and which
ones to other patients for other diseases?
DR.
GOLDING: I'm not sure I have an accurate
answer. I think there may be somebody in
the audience who can help. But we know
when we looked, when there were problems with the availability of the product
and we started asking treaters and major centers what is going on in terms of
IGIV usage, we found out that 60 or 70 percentage of the usage was off-label
and there are some other indications besides PIDD like ITP, Kawasaki and a few
others. So I'm guessing, but I would
think that only about 20 percent, 20 to 30 percent, is used for PIDD and the
rest is used off-label or for other indications.
CHAIRMAN
SIEGAL: Do we know what proportion of IG
product is used subcutaneously these days as compared to IV? Do we have any idea about that?
DR.
GOLDING: We have one newly licensed
product for IGIV sub cut and we have six or seven -- other manufacturers. I don't know what the market share is. I don't have that with me.
CHAIRMAN
SIEGAL: But we don't know in practice
how it's being used?
DR.
GOLDING: But do you mean to what extent
compared to the IV?
CHAIRMAN
SIEGAL: Yes. I mean you can use the same product sub cut.
DR.
GOLDING: Right.
CHAIRMAN
SIEGAL: And so the question is how much
is actually being used sub cut as compared to IV?
DR.
GOLDING: Well, I don't know offhand.
CHAIRMAN
SIEGAL: Anybody have any sense of
that? Okay. All right.
Basil, thank you very much. I
think we should go on.
DR.
KATZ: I don't see anywhere on the agenda
where I think this could be answered but I'm kind of interested in the
implications of FDA changing its criteria and maybe the manufacturers can
address this if I bring it up ahead of time.
If they are manufacturing in some way with an eye on what gets approved
in the U.S., would lowering the threshold make a difference in the rest of the
world where measles might be more common and I think probably you can give an
FDA perspective and they can talk about what they think.
DR.
GOLDING: I think that on balance we have
to make a decision which I think we can make and have the best of both worlds
in the sense that we can lower the titer and still be reasonably assured that
the product is going to be safe and effective in preventing measles. But we may reach a point sometime in the
future where the titer had declined to an extent where that won't be the
case. As far as public health in the
CHAIRMAN
SIEGAL: Mark.
DR.
BALLOW: Just a comment. You know, even though the package insert says
200 mg/kg, I and my colleagues are actually tending to use higher doses because
of the recognition that even at 400 mg/kg some of these patients are still
developing chronic lung disease and bronchiectasis. So, for example, in patients with Bruton's
disease or X-lined agammaglobinemia the suggestion is to use 600 to 800 mg/kg.
So that means that they would be getting more measles antibody.
CHAIRMAN
SIEGAL: All right. I understand that Dr. Seward has in fact
arrived. So I would like to introduce
Dr. Jane Seward from CDC who is going to talk about the epidemiology of measles
in the
DR.
SEWARD: Good afternoon and sorry I was
late. It wasn't the weather. It was a GameBoy that got dropped down the
toilet in the plane I was on.
(Laughter.)
DR.
SEWARD: So that two hours delay for that
reason.
CHAIRMAN
SIEGAL: Terrorist attack.
DR.
SEWARD: And then we had to get off the
plane. They cancelled the plane
altogether.
So
I'm here to talk about measles epidemiology in the
As
everybody knows, I'm sure, measles is a highly contagious viral disease. In the pre-vaccine era, there was nearly
universal infection during childhood because of its contagiousness. Morbidity and mortality in the
Measles
vaccine was licensed in 1963. Almost all
the vaccine now is administered as the combination MMR vaccine and when it's
available I guess the MMRV vaccine which is not currently available, although
it's licensed. Measles vaccine is highly
effective. It's one of the most
effective vaccines that we have. One
dose administered at 12 months or older is 95 percent effective. Two doses at least four weeks apart
administered at the same age on or after the first birthday is 99 percent
effective. These effectiveness estimates are lower if measles vaccine is given
at a younger age, but this is the age of recommendation for the
In
the U.S. we give two doses of measles vaccine to children, the first at 12 to
15 months, the second dose at four to six years and two doses is recommended
for all school students, for college students or other students in post high
school educational facilities, health care workers and because of their risk of
exposure overseas for international travelers.
The
strategies to control and eliminate measles in the United States are to
maximize the population immunity to measles by delivering the first dose on
time as close as possible to the 12 months, to increase the second dose
coverage in school children, although that is already extraordinarily high as
you'll see in a minute and to vaccinate high risk adults, to assure adequate
surveillance so that we understand the risks of measles and what's happening in
the country with measles disease, to respond rapidly to outbreaks and to work
to improve global control because that will reduce the risk of importations
into the United States.
This
shows reported measles cases. Is there a
pointer? Reported measles cases in the
There
was an increase in measles in the late 1980s, around 1989 and 1990 there was a
resurgence of measles in this country and you'll see why in a few slides and
then in 1989, there was a second dose measles recommendation made and improved
first dose coverage in preschool children.
Since 1998, we've had measles incidence in the
I'm
sorry for that red color for total. I
have two slides here, one showing the total number of cases and then some
breakdown by age. You can see that in
the late 1970s there were still 50,000 to 60,000 cases reported a year. However, that dropped rapidly as there was
better implementation of school requirements.
The resurgence that you see in 1990, up to 30,000 cases reported in one
year, was mainly due to low vaccine coverage in urban communities in preschool
children and that led to an influx of money into vaccine programs and the
Vaccine for Children Program being established and then monitoring of vaccine
coverage in children 19 to 35 months.
That is the current ongoing coverage that is monitored and there's been
a dramatic improvement in vaccine coverage among preschool children since that
time.
This
shows the breakdown by age without the totals showing that in the late 1970s
the highest number of cases were in the school age children. But the resurgence in 1990 occurred mainly in
children under five.
If
you look at age specific measles incidence by less than 15 and greater than 15,
again we're at extraordinarily low levels.
So this doesn't mean a whole lot.
Most people 50 and above aren't susceptible to measles. So you can see there that incidences are very
low in both. For less than 15, it's a
little bit higher.
These
are the largest outbreaks that we've had in the
The
The
This
shows the age distribution of measles cases showing by age just the number of
cases and this shows the vaccination status, again, to show you that most of
the outbreaks have been because of introductions into small vaccine objector
groups or into groups that are not as highly vaccinated such as the adults in
This
slide is to show that as our surveillance has improved the number of cases has
gone down. We've been able to do
virologic confirmation and molecular epidemiology on all these cases and we can
show that almost 100 percent of cases now are definitely imported. We can look at the genotype and then look
globally where that genotype is circulating, know where that person came from
and say it's an importation or an import associated case if it leads to a small
outbreak in the
This
shows one of the evidences that was used to document elimination of
measles. By elimination of measles, I
mean absence of endemic transmission of measles. You know as I've highlighted I think we stay
at risk for importations in this country until those global measles are
eradicated or eliminated.
And
there will always be some spread. I
mean, you can vaccinate children under one.
One of the small outbreaks that I didn't point out a few slides ago was
in a daycare center where a little child came back after visiting with his
family in the
During
the resurgence in `89 to `92, all the viral isolates were D3 genotype.
There weren't many specimens taken for genotyping before that time. Since that time, since 1993 onwards, there
have been probably now more than 150 isolates and they're all just different
genotypes from different parts of the world.
Just
to show you the countries that these importations come from which reflects
measles in that country and also the probability of travel from those
countries. There are a lot more measles
in some other countries like in
In
the
We
can't always find the original source. We've had instances in the past where
we've had a call from a European country that some person from their country
developed measles rash and they flew through
This
just shows last year's source countries:
India at the top; Ukraine because there was a large outbreak there;
China, we have a number of children come in from China as adoptees and China
doesn't have a great program for their children and orphanages anyway and quite
regularly we do see measles coming in among their adoptees with some spread.
The
largest outbreak last year, I mentioned the
And
this shows you the cases in 2006 with the genotypes and we can just say where
every one of them comes from. We've even
been able to document exposure at Disney World and mixing there with a case
from another country and just to highlight that it's exactly the same pattern
in the year before, in 2005, and in years before that. This was the year that we had that fairly
large outbreak from
So
the evidence for elimination of endemic measles or elimination of endemic
measles transmission in the
Population
immunity is very high. There is no
endemic strain of measles virus circulating.
The
evidence for adequate surveillance to detect endemic measles are these. We have consistent detection of imported
measles cases. We have detection of
isolated cases and small outbreaks. High
level of investigative effort for measles to which we thank the state and local
health departments who work incredibly hard.
In that
Molecular
typing is consistent with elimination of indigenous genotype of measles
virus. We have very high population
immunity with high first dose coverage of greater than 90 percent since 1996
for preschool age children. First dose
coverage being greater than 97 percent of school age children. Second dose required for 82 percent of school
children as of 2001 and that's higher now, but we haven't calculated it again
recently. And then the most recent
seroprevalence data from 1999 to 2004 shows 96 percent immunity, well I should
say, antibody measured by Eliza in ages six to 49 that may or may not indicate
immunity but it's the best measure that we have.
These
are slightly older data from Ann Haines from the National Health and Nutrition
Examination Survey that were published that were presented of evidence of
immunity for the measles elimination meeting to show the dip in seroprevalence
in the age group of people born between 1967 and 1976. That was the age group most affected during
the
Now
we worry a little bit about duration of vaccine-induced immunity. It's not because we see any evidence waning
to susceptibility from our epidemiological data, but just because we're now 40
years into a program. The younger cohort
are not being exposed at all to wild measles virus, so aren't having any
external boosting and we think it's very important to monitor population
immunity including whether immunity remains above the so-called protective
level.
This
paper was published earlier this year by Charlie LeBaron and Judith Beeler who
is probably here today showing measles antibody response measured by
neutralizing, plaque reduction neutralization testing, I think, in children
vaccinated, I'm sorry about the quality here, but hopefully it's better in your
slides, children vaccinated in the left-hand graph at kindergarten, getting the
second dose at four to six years versus getting it at 10 to 12 years, showing
that there's quite a boost in immunity with the second dose at whatever age you
get, but then immunity declines again and you tend to stay in the quartile that
you were before you got your second dose.
Most of these levels are above the protective level still though.
Dr.
LeBaron then tried to model these data to project out 30 years in the future
what might happen. He acknowledges in
the paper that this is just a model and that you may not get decline at the
slope as shown there on the left, but if you did, we will have a more
susceptible population in the future and so we need to monitor this very
closely.
Another
small study that's been done following up people from a vaccine trial in 1971
and they were about 30 years after their last measles dose with no known
exposures to measles, nine percent of that small group had PRN titers of less
than 120, not considered protective but, of course, they may have good cellular
immune memory still and may be able to mount that in response to exposure to
measles.
In
conclusion, measles is no longer endemically transmitted in the
CHAIRMAN
SIEGAL: Thank you very much, Dr.
Seward. Are there any questions?
DR.
SEWARD: I would like to thank a lot of
people at CDC that provided the data for the slide. I didn't make an acknowledgment slide but
Charlie LeBaron, Susan Redd, Susan Reef and a number of people in the MMR team.
DR.
DI BISCEGLIE: You pointed out that
measles can still be a very severe disease.
What's the evidence? Is there
evidence of its increasing severity in patients with immune compromised
situations of one kind or another?
DR.
SEWARD: Well, we don't see it in those
people anymore. But, yes, my
understanding is it is more severe.
DR.
DI BISCEGLIE: People on corticosteroids
or post transplant. Is it just because
we don't know because they don't get it anymore?
DR.
SEWARD: They don't get it anymore. My understanding from the literature is that
it is more severe in those people.
CHAIRMAN
SIEGAL: Is there any boosting effect to
bystanders from MMR?
DR.
SEWARD: To bystanders --
CHAIRMAN
SIEGAL: In other words, do parents of
children just immunized have a vaccine effect?
DR.
SEWARD: Yes, that's a good
question. Not that we know of. We did a study looking at wild virus to see
if there was any evidence of subclinical transmission and boosting and there
was not with wild virus. So it would be
much less likely with vaccine virus. I
don't know that that's been looked at specifically though. It has been for wild virus.
DR.
BALLOW: And a related question. Transmission of two siblings from other siblings
that have been immunized, I mean, that hasn't been reported, has it?
DR.
SEWARD: No.
DR.
BALLOW: No. Okay.
DR.
SEWARD: I don't know the detailed
literature on that as well as I do Varicella for example. That's sort of my specific area of
expertise. But if there is, you could
count them on one hand and there have been hundred of millions of doses
administered. So it's not considered a
problem at all.
DR.
QUIROLO: Can you say something about the
PRN value of 120 and where that came from?
In the paper that we were given, the people in this outbreak that didn't
get measles all had much, much higher PRNs than 120.
DR.
SEWARD: Right. That value comes mainly from a study by Bob
Chen at CDC who was fortunate enough to find blood from a blood drive that had
been done before an outbreak, I think, in a college and examined the data and
noted that the attack rate was much higher in people below that level. That was clinical disease as I remember. I haven't read the paper for awhile and between
eight and 120 seemed to be the range for protection from infection.
I
mean, it's a small study. There hasn't
been -- I think there's another study from
I
think the immunity that we're seeing, measuring, in the community using similar
testing and the absence of measles and spread, I think, in vaccinated people
10, 15, 20 years out from vaccination would lead me to believe that's probably
it's a reasonable level.
DR.
QUIROLO: That does sound right except
that only thing that I'm just thinking about is that that may be the case in
college students who have a normal healthy immune system. But in people
who are getting IVIG who have PIDD or something, they may not have T cell
response after it. So I wonder if these
college students were getting infected but not getting clinical disease and I
don't know that paper. So it's hard to
know the answer to that.
DR.
SEWARD: I think some got infected but
they had levels between eight and 120 is my --
DR.
QUIROLO: Right. But would you not
recognize people who maybe had a level of 200 who got infected but never
progressed to clinical disease. You
would never pick up those people in this study.
Right?
DR.
SEWARD: Yes, they had bloods before and
after -- Oh. I think they did. I'm sorry.
I haven't read the paper for awhile.
DR.
QUIROLO: They didn't take everybody's
blood after the fact to see who got infected.
Every single person.
DR.
SEWARD: I think they took some who
developed measles and some who didn't to try to answer that question.
DR.
QUIROLO: Okay.
DR.
COLVIN: Yes, in that paper actually I
think they have evidence of viral replication with boosting reaction between
levels of 120 and 1052 if you have a copy of that paper. So it looked actually only levels above 1052
were protective. That's how I read the paper. So that I had asked also my question before
where the 120 came from.
DR.
SEWARD: So it protected from infection
not disease.
DR.
COLVIN: That's right.
DR.
SEWARD: Right.
DR.
COLVIN: But these were healthy
vaccinated college students. We're not
talking about immunocompromised patients.
DR.
SEWARD: Right. Maybe some clinicians would like to
comment. Many of you are. I mean measles, my understanding is that it's
more severe, but not dramatically so compared to something like Varicella. That is just extraordinarily more severe in
immunocompromised people.
DR.
BERGER: We can only imagine. We don't have data as several people have
pointed out. But certainly we must
imagine there there are one year olds in homes, immune deficient one year olds,
in homes where the four year old is being immunized when they go to
kindergarten.
DR.
SEWARD: I think there are children with
Skid who are immunized at 12 months who were late with their diagnosis.
DR.
BERGER: Right. But I mean but with Bruton's and antibody
deficiency and a lot of the other immunodeficiencies there must be kids in
homes where an -- You pointed out --
DR.
SEWARD: I think some children who are
severely immune deficient are being immunized.
DR.
BERGER: Right. This is also unquestionably true.
DR.
SEWARD: Yes.
DR.
BERGER: And we don't hear cases of -- I
don't know -- Again, we don't have any sort of accumulated data, but I
certainly have never a case of severe measles in an undiagnosed Skid patient.
DR.
SEWARD: Right.
DR.
BERGER: Whereas, for example, we hear
about Varicella in undiagnosed Skid patients.
DR.
SEWARD: Right.
DR.
BERGER: But there must be -- but you
pointed out this outbreak in a daycare in the baby room. So your implication is that there might be
one year olds whose protection by maternal antibody has waned and they have not
yet reached the age of immunization.
DR.
SEWARD: Yes. A lot of these children are --
DR.
BERGER: So there must be a lot of babies
like that in homes where a four year old is getting immunized for the second
time when they go to school and you don't hear a lot of cases like that,
although there is no systematic data of which I'm aware of.
DR.
SEWARD: About transmission?
DR.
BERGER: Yes.
DR.
SEWARD: It's not a problem. It is not a problem. We've stopped looking for it it's so rare.
CHAIRMAN
SIEGAL: Any other questions?
DR.
FINNEGAN: This may be a really simple
way to look at things, but we're here today because the protective level in the
donor blood is dropping from people who have been vaccinated. Do you not see this as a potential public
health problem down the road?
DR.
SEWARD: I was at the previous meeting
where some of these issues were discussed and my own feeling is that, right
now, the population is very adequately protected and to the levels in IVIG from
vaccinated individuals will be adequate.
I know there's another issue with the testing and pass/fail on the EIA
test that's used for the lots which is a separate issue. But right now, I wouldn't be worried about
the levels in IVIG.
Now
10 or 15 or 20 years from now, it might be a different story depending on what
happens with that graph in Dr. LeBaron's paper.
But right now, vaccinated people are absolutely adequately protected. There's no spread in this country. So I'm not worried from a public health
perspective for today. Twenty years from
now, perhaps, but we can continue to monitor immunity levels in vaccinated
people.
Measles
vaccine is just a phenomenal vaccine. It
was very, very effective and immunogenic.
We had a large mumps outbreak in this country last year with 6,000 cases
and I won't say the same for mumps vaccine.
But measles and rubella are just very, very good vaccines.
But
it doesn't mean, as I said. I concluded
by saying we need to continue to monitor.
But we see absolutely no evidence, epidemiologically, that there is
waning to susceptibility in any of the vaccinated populations.
DR.
SZYMANSKI: Would you in any phase
consider a third vaccination at some age, later age, when levels are very low?
DR.
SEWARD: Not unless we see waning to
susceptibility. I mean, we'll continue
to watch very closely. I think that's
the big challenge with the
CHAIRMAN
SIEGAL: All right. If there are no more questions, thank you
very much and let's proceed to Dr. William Moss who is going to talk about
measles infections and estimated protective titers in primary immune deficiency
diseases and potential reemergence of epidemic measles in vaccinated
individuals, from
DR.
MOSS: Thank you very much. I'm here in part representing Dr. Dianne
Griffin, who gave a talk at the immunoglobulin workshop in April of this year
and will be giving a similar presentation.
The title on the agenda was not my title. So I hadn't seen that title, to be honest,
before.
But
the questions regarding measles in the immunocompromised hosts are a nice segue
into what I'll be talking about and because most of what we know about measles
in immunocompromised hosts is not in children with primary immunodeficiency
disorders, as a number of people have already mentioned. I'm going to use some other examples,
particularly malnourished children, HIV-infected children and studies in
immunosuppressed monkeys to provide some insight into measles and
immunocompromised hosts.
I'll
also come back to some of the issues that have been already touched upon,
particularly this magic number of 120, that we talked about a number of
times. I also want to just reiterate the
point that was made, but there have been no documented cases of transmission of
measles vaccine virus.
So
let me just briefly run through measles in the immunocompetent host and talk a
little bit about the normal immune responses and that will set us up for
talking about measles and the immunosuppressed host. Measles has very characteristic clinical
features. It starts off with what I'll
refer to as the three Cs, cough, Coryza and conjunctivitis, then early papoules
that occur on the buckle mucosa called Koplik spots. During this time, there is fever and then the
characteristic morbilliform rash that typically starts on the head and neck and
extends over the entire body and that's typically when clinicians will diagnose
measles, though a very astute clinician can diagnose it based on the presence
of Koplik spots and these are just some photographs, a little difficult to see,
but the characteristic morbilliform rash on the left and this will be important
because we'll talk about different rashes that can occur in the
immunosuppressed host and then the child on the right a little bit of
conjunctivitis and crusty nasal discharge.
And
then on this picture again, it projects a little. It doesn't project very well, but there are
small white papoules that are seen on the buckle mucosa. Those are the Koplik spots that proceed the
rash. But what I want to point out on
the right side is that on that middle panel just summarizes briefly the
clinical manifestations we talked about. But I wanted to just mention that the virus is
very active during the asymptomatic incubation period before the onset of fever
with replicating, initially, in the upper respiratory tract and spreading to
the lymph nodes. Then there's a
generalized viremia and replication of measles virus in many organs, including
the skin.
In
addition, there's also an intense immune response and I'll come back to this,
but initial CD-4, primarily TH-1 type response, with production of interferon
gamma and a cytotoxic T cell response that starts about the time of the rash
and you can also see that when the rash is beginning, the level of virus
replication decreases. So really the
rash is a manifestation of the host cellular immune response and I'll come back
to this. But there have been a number of
cases of confirmed measles particularly in persons with AIDS without a rash,
and that makes sense understanding that the rash is a manifestation of the
immune response.
There's
initial IGM antibody response that's transient that lasts several weeks and
then an IGG response follows. It's
initially an IGG Type 1 and then switches to an IGG Type 3 predominantly and
that's the titer, the protective antibody class that we've been talking about.
The
immune response of measles virus is more complex than that. I just want to touch on it briefly. There's as with all infections an early
innate immune response with Type 1 interferon.
It appears that wild type measles virus has evolved mechanisms to
inhibit the host interferon response that are not seen in the attenuated
vaccine response and I should mention, although you all probably know this,
that the vaccine is a live attenuated vaccine that requires replication in the
host in order to induce protective immune response.
Then
there are the antibody responses we talked about, the IGM and various
subclasses of IGG that are protective.
There are also IGA responses and it's not clear what role they play in
protection from disease at the mucosal surfaces. The cellular immune responses are very
complex. I talked about CD-4 responses,
early Type 1 response and then that's followed by a Type 2 response with
characteristic production of IL-4 and IL-5 and IL-13. There is also prolonged increase in IL-10
production that may be related to the immune suppression that follows measles.
Measles
is a strong inducer of immunologic memory, particularly wild type measles. Some of the classic epidemiologic studies of
measles were done by a Danish physician named Peter Panum in the mid 19th
century on the Faroe Islands where he observed where there was an outbreak of
measles that he was called on to investigate.
The prior outbreak was 65 years earlier and no one who was live during
that prior outbreak got measles again, suggesting really life-long immunity
following wild type measles virus infection.
Dr. Seward talked a little about whether that occurs after
vaccine-induced immunity.
Measles
is an immunosuppressive virus and much of the mortality and morbidity from
measles results from secondary infection. So it's actually a immunosuppressive
virus in itself and these are just some, I won't go through this in detail,
potential mechanisms by which measles virus has been suspected or studies have
suggested how measles virus may suppress the immune system. It's unclear whether or how much measles
vaccine virus suppresses the immune system.
Some of these differences have been documented following measles
vaccination.
So
measles and the immunocompromised host, Bob Good several decades ago with others
published a paper that suggested that children with deficient antibody
production, with B cell deficiencies, would have normal recovery from measles
and would clear measles virus, but would have limited protection from
reinfection because of the absence of antibody.
But it was really children with T cell deficiencies, with deficient
cellular immunity, who had delayed viral clearance and progressive disease.
So
one way, a common way of thinking about immunity to measles, is what immune
responses are required to actually clear the virus once infection has taken
place and in children with impaired clearance, there are kind of two broad
clinical pictures. One is a desquamating
rash and I'll show you a picture of that.
That's been best characterized in severely malnourished children who
have deficits in cellular immune function and then in people and children and
adults who are most severely immune suppressed as a progression disease that
can often occur without a rash as I mentioned and with measles virus
replication particularly in the brain and in the lungs.
And
then in terms of protection, and I'll come back and talk about the difference
between protection from clinical disease and we've already touched on this and
protection from actual infection, the best correlative protection is the
neutralizing antibody titers that we've talked about.
I'm
going to be presenting a little bit of data using a rhesus macaque model. Obviously, monkeys are the best animal model
for studying measles and there have been several studies I'll show you in which
the monkeys were immunosuppressed and then challenged with wild type measles
virus. But this is just to show that
rhesus macaques developed a characteristic measles rash, a type of viremia
that's very consistent with what humans develop and measles also induced a
peripheral lymphopenia that develops that's shown here that was also observed
in macaques.
Sallie
Permar, who was at
They
followed that up with an analogous type of study, but instead of solely
depleting CD8 T cells, they depleted B cells as well using a monoclonal
antibody to CD-20 and let's just focus on the right-hand side. This is using a real time PCR assay. So you have a log scale quantitating measles
virus on the right side. The top is a
control group. The middle panel is our
monkeys depleted of B cells. So they
won't have an antibody response and then the bottom panel are monkeys depleted
of both CD8 and B cells and, consistent with the early observations in humans,
monkeys depleted of B cells had a normal clinical course of measles. They didn't have prolonged viremia or higher
levels of viremia and they had the disease progression similar to that of the
control group, whereas again the CD8-depleted monkeys had a more prolonged
viremia. So there was a delay in
clearance of measles virus.
Interestingly,
some of the monkeys that were CD8-depleted also developed a desquamating rash
and that's another type of rash that can develop in immunosuppressed hosts, as
I already mentioned and, I won't go through this in detail, but on the right
side is a picture of the rash and you can see in that small insert on C the
desquamating characteristic of the rash in the monkeys and then the
histopathology in F of that rash with inclusion bodies of measles virus shown
in the insert.
So
in humans, what we know about in children and adults who have immunodeficiencies
and fail to clear measles virus, there are two broad category of disease that
are frequently described, a giant cell pneumonitis, measles caused syncytia
formation and a measles inclusion body encephalitis and I'll come back to that. Often, as I've already mentioned, there is no
rash at the time of measles virus infection and again, this has been best
described in HIV-infected children and adults.
But there is this progressive pulmonary or CNS disease and in the
absence of rash, this is a very difficult diagnosis to make and really has to
be suspected and looked for.
The
desquamating rash was first described by David Morley who was working in
Nigeria in the 1960s, and this is a little cartoon showing the complications of
measles particularly in severely malnourished children and most children with
measles in sub-Saharan Africa die of secondary bacterial pneumonia and
diarrheal disease and then on the bottom, he describes this characteristic
desquamating rash that occurred in severely malnourished children. I primarily work in
There
have been, and we've already alluded to this, case reports, but no real
extensive case series of progressive measles virus infection associated with
various immune deficiencies both in primary immune deficiencies, usually
combined deficiencies of T and B cells.
There have been a few small case reports, particularly one of a measles
inclusion body encephalitis, of a child in whom the underlying immunodeficiency
was not well characterized. And then in
addition, there have been case reports, but again not a lot of experience in
part because the exposure has been low in the
We
have a little bit more in HIV-infected children and I'll talk a little bit
about that. Measles in HIV-infected
children was first, best described by a report from the Centers for Disease
Control back in 1988, during that last big measles outbreak that we've already
talked about, where severe and unusual measles was described in five
HIV-infected children. There were a
number of case reports out of that outbreak and about half of the children,
half of 19 co-infected children in the United States, had either an absent or
some unusual type of rash with measles.
About three-fourths had pneumonitis and about one-third of these
children died of progressive measles virus infection which is much higher case
fatality ratio than is otherwise seen.
There
have been a few small reports of HIV amongst children in
We've
conducted studies of measles in HIV-infected children in
We've
also looked at the ability of HIV-infected children to clear measles virus and
this is using an RT-PCR assay approximately one to two months after rash onset
and a higher proportion of HIV-infected children failed to clear measles virus
RNA during this time period after measles.
It's not clear whether these children are still contagious, but this
indicates that they have failure to clear measles virus.
I
did want to mention that there's been one report of fatal infection with
measles vaccine virus in a person with AIDS.
This was a young man who received a second dose of MMR. As part of the regulations for a second dose
that Dr. Seward talked about, this young man had no rash after MMR vaccination,
presented 11 months later. Really at the
time of immunization, he had no clinical evidence of severe immunosuppression
although his CD-4 count was very low. He
had been previously vaccinated against measles and he had a number of invasive
procedures that eventually identified measles vaccine virus in his lung tissue
and he died 15 months after MMR vaccination and this one case actually helped
shift measles vaccination policy by excluding people with severe immune
suppression.
I
mentioned briefly the neurologic disease that can be due to measles virus in
immunosuppressed hosts. There are a
number of different neurologic diseases associated with measles. There is an autoimmune demylinating condition
that can occur several weeks after.
That's not an immunocompromised host.
But then there's this measles inclusion body encephalitis where the
actual measles virus replication within the brain that occurs in
immunocompromised hosts and that has been described in children with primary
immune deficiencies as well as persons with HIV/AIDS. And just briefly again, one sees within brain
tissue inclusion bodies and staining for viral antigen.
As
I've mentioned the best evidence is that cellular immune responses are critical
for clearance of measles virus. There is
some evidence, though it's not strong evidence, that antibodies may play, at
least, assist the cellular immune arm in clearing measles virus. There are some studies by Don Forthal
suggesting that antibody-dependent cellular cytotoxicity is associated or
correlates with clearance of viremia.
There is certainly evidence, older evidence, that low antibody responses
predict poor outcome and some in vitro studies suggesting that antibodies can
down regulate intercellular virus replication.
So some evidence that antibodies play a role in clearance.
But
where antibodies are really critical is in protection from disease and I think
probably one of the most important questions facing the committee, for which I,
unfortunately, don't have evidence for is, what role the cellular immune arm is
playing in protection that might assist in a way the antibody responses and either
require higher or lower titers of antibodies for protection.
The
evidence that antibodies alone are protective against measles come from
numerous studies showing that young infants with passively acquired maternal
antibodies are protected against disease.
Obviously, the passive administration of immune globulin which this
committee is considering and really as we've talked about the best correlate is
this neutralizing antibody titer and I'll come back to the 120.
Just
to remind you, neutralizing antibodies are primarily to the two surface
glycoprotein of measles virus and particularly hemagglutinin which is the
larger structure shown there which is what binds to measles virus receptors on
host cells, human cells. There is also a
fusion protein on the surface and there's probably some contribution of
neutralizing antibodies to these.
So
when one is measuring neutralizing antibody titers using a plaque reduction
neutralization assay, one is primarily measuring antibodies to the H
protein. Just to show that, show how
those antibodies to different proteins vary in relative amount, we'll just
focus on the right-hand. You can see
antibodies to H there in the middle.
Most of the antibodies to measles virus are made to internal protein,
the nucleocapsid protein. So one uses an
ELISA assay to measure antibody titers, one is primarily measuring antibodies
to N rather than the functional neutralizing antibody to H.
This
is just evidence in a graphic form from Neal Halsey showing declining levels of
maternal antibodies and an increasing incidence of measles and showing just to
reiterate the fact that passively acquired antibodies from the mother can
protect the young infant and this might be one of the best ways to try to get a
handle on what are protective titers in children who lack cellular immune
responses to measles, though these would be in otherwise normal infants.
It's
known too that these levels of maternal antibody can inhibit response to
vaccine and this is one study from, again, Laurie Markowitz, showing that
seroconversion rates to the vaccine were much higher in infants who had very
low or no neutralizing antibodies to measles virus and as I mentioned before,
in order to get a protective response to the vaccine, the vaccine has to replicate
within the host and basically cause mild measles and these maternal antibodies
will neutralize that vaccine virus and prevent the immune response.
So
this is the data that each of the prior speakers has alluded to, that magical
120 number, and it was really a serendipitous discovery and I think that
explains partly why we have so few data about what the protective titers
are. There was a blood donation program
at
But
as I think as a number of people have suggested, this is not written in stone
and it's the best data we have on levels that protect and this is protection
from disease, protection from clinical disease, this 120. But you can see the numbers of individuals
were small in the group with levels less than 120. It was really the highest titer in the
college-aged students who developed measles was exactly 120.
They
did look at, as was already mentioned, boosting antibody responses. So young adults who boosted their antibody
response, but didn't have clinical disease presumably had a subclinical
infection but were protected against disease and this is where that 152 comes
from and again the number are very small.
But this is what we have, because that kind of epidemiological
circumstance has not been repeated.
In
Dianne Griffin's lab, they've done studies with a number of -- these are DNA
vaccines, so very different vaccine construct that what's used in people, but I
just want to bring up again this issue of protection from disease compared to
protection from infection and these are monkeys that got different kind of
constructs of DNA vaccines. But you can
see the neutralizing titers there and some monkeys, particularly those with a
titer of 135 or greater, had evidence of viremia without rash. So they didn't have sterilizing immunity and
then those between three and 105 had a rash as well as viremia.
But
I want to mention that titers below 120 although they may not protect against
clinical disease, they probably protect almost certainly against severe
disease. So there's an entity
vaccine-modified measles where children will get a milder form of measles if
they have some level of immune protection but not enough to protect clinical
disease.
And
the vaccine itself, particularly the first vaccine used in the
But
I think the critical question is what the impact is of cellular immunity on
these protective titers and part of the problem is the inability to really
quantitate cellular immune responses in a good way or at least in a way
analogous to antibody titers in children and certainly there are assays to
measure cellular immune responses, but there is not the same threshold that's
been identified.
In
summary, clearance of measles virus is dependent primarily on cellular
immunity. Defects in clearance are
associated with unusual manifestations of measles and those with the most
severe immunosuppression, they can have a progressive disease without rash.
Those with moderate immune suppression may have a desquamating or unusual type
of rash and we've talked about this neutralizing antibody titer being the best
protection but the data is rather limited on what those thresholds are.
And
I'll just thank my colleagues, but particularly Dianne Griffin for her help.
DR.
BALLOW: If I may, I have several
questions for you. Thank you for that
presentation. It was really an excellent
overview.
DR.
MOSS: Thank you.
DR.
BALLOW: You mentioned that in order for
the measles vaccine to be productive there has to be replication of the virus.
DR.
MOSS: Right.
DR.
BALLOW: So we give a booster
immunization at preschool age. Correct?
DR.
MOSS: Right. Well --
DR.
BALLOW: And presumably they have
antibodies. So is the virus still able
to replicate and what's happening? Is it
boosting up the cellular immunity as well as the ambient response of the IGG?
DR.
MOSS: The -- I may let Dr. Seward
respond. But I'll just say that the real
reason for the second dose is not a booster dose. It's not to booster antibody titers. The reason for the second dose is twofold and
it's part of a measles -- the second dose is critical to measles elimination,
to really interrupt measles virus transmission, so to obtain a very high level
of population immunity.
So
the second dose is really to do two things and I think more globally it's often
referred to as a second opportunity by WHO and it's to immunize those children
who never received the first dose to provide an opportunity for those children
and to immunize those who don't respond to the first dose. So at 12 months of age, it's 95 percent is
kind of the dogma, the percentage of children that respond. But that leaves five percent of children
aren't responding to the first dose. So
that second dose is to immunize those five percent.
I
don't think of the second dose as -- the purpose behind it as boosting the
antibody response.
DR.
BALLOW: But there must be data though.
DR.
MOSS: There is some. So there is some boosting and the amount of
boosting will depend upon, is a function
of the pre-existing antibody titer. So
those who have had some waning of immunity, you'll observe more boosting of the
antibody response. Those who have very
high titers, you may not see an increase in the antibody response with the
second dose.
DR. BALLOW: That makes sense. The second question; with HIV children, do
they take away the recommendation to give MMR vaccine?
DR.
MOSS: For HIV-infected children, it's an
interesting history because prior to the 1989 -- I'll talk about for the
Then
when these severe cases were described during late `80s and early `90s, there
was kind of this shift toward providing MMR.
It was recognized that it was very important to protect HIV-infected
children against measles. That case
report that I showed you actually changed the policy back. So the current recommendations are not to
give the MMR vaccine to persons and particularly children with HIV who are
severely immunosuppressed, defined as a CD-4 percentage less than 15.
DR.
BALLOW: Less than 15?
DR.
MOSS: Less than 15.
DR.
BALLOW: Wow. Okay and then the last question to get back
to patients with primary immune deficiency, as we enjoy the day and engender
some conversation about now and what's going to happen over the next 10 or 15
years, one wonders whether it would be beneficial to give patients with
antibody deficiency, not T cell deficiency, but antibody deficiency, even
recognizing that some of those patients like CVID may have some subtle T cell
abnormalities but nevertheless to give them MMR vaccine to try to elicit or
enhance their T cell responses so that if there is an outbreak at least they'll
be able to clear the virus more readily.
DR.
MOSS: Right.
DR.
BALLOW: But at the same time, since all
these patients are IVIG, one wonders whether they will be able to actually
develop a T cell immune response, given the fact that they have measles
antibody.
DR.
MOSS: Right.
DR.
BALLOW: I guess we don't know unless we
try it.
DR.
MOSS: Right. That's a very interesting question and the
tools for measuring measles virus specific T cell responses have just really
been developed and perfected over the past couple years. Before people would do
lympho-proliferation-type assays but you can really do very precise assays
now. So I think we now have the tools to
begin to measure some of those responses.
There
are a number of groups and Dianne Griffin's group is one that are working on
new measles vaccines that are nonreplicating vaccines and not all people in the
measles world agree that that's a -- certainly as has been mentioned, the
current measles vaccine is highly effective and it's a great vaccine, a very
safe vaccine. And some people question
the need for a new measles vaccine, but that might be a population where, if
you could immunize with a non-replicating vaccine, a DNA-based vaccine or there
are alpha virus-based vaccines, there is a whole array of different types of
vaccines that are development, that might be a select population where that
might be useful for inducing T cell responses.
Yes.
DR.
DI BISCEGLIE: I have a question if I
may. Are there any antiviral agents
effective against measles virus that might be given to immune-deficient -- I'm
thinking of Ribavirin in particular.
DR.
MOSS: Yes. Obviously, there have been no large trials or
studies, but there are case reports of using a number of agents particularly
ribavirin is the most experience with and people feel that -- or certainly that
has been used in that situation and some people have used it in combination
with alpha interferon.
CHAIRMAN
SIEGAL: Thank you very much. That was a nice talk. Next we'll hear from Toby Simon from CSL
Behring on measles antibody titers in plasma donors.
DR.
SIMON: Thank you. I'm very grateful for the opportunity to be
here on behalf of my colleagues at CSL Behring and also speaking for our
industry group, PPTA. It was also a
pleasure to work with Dr. Scott and the group from FDA on the workshop and to
work on developing this issue for presentation today.
I'll
just set up the stage quickly. With the
information that you've already seen, in the pre-vaccine era, there were
approximately 500,000 cases per year in the
The
measles vaccine was introduced in 1963.
By the 1970s, most states started requiring it for school entry and that
was pretty complete by the 1980s. And in
1989, the two-dose vaccine requirement was phased in. In 2001, 96 percent of states required two
doses for school entry and the median coverage was 97 percent.
Our
problem, as you have heard, is that the antibody titers as quoted here from a
text on vaccines "elicited by vaccination do decline over time as do those
induced by natural infection and may become undetectable." Vaccine-induced antibody titers are typically
lower than those induced by natural infection.
So as younger donors enter our donor programs, they come in with lower
titers than what we had seen in our older donors.
And
we have been measuring these titers in our donors using the ELISA method for
measles IGG. The particular methodology
that we'll be using in the report today is from the Eddie Mac system,
manufactured by Diasorin with an internal calibrator that we have developed
using the WHO 66/202 standard. The
reporting range is 0.5 to 10 IU/mL and the coefficient of variation goes from
2.7 to 14.7 percent and that, unfortunately, is higher at lower concentrations
which means we lose sensitivity in those donors who have very low values. We have correlated this with in-process
testing by our manufacturer's assay aboard using the Dade-Behring ELISA and it's a very high
correlation of 0.95.
And
this is the data that we showed at the workshop, which shows that the donors
depending on the birth year as you see on the left side of the slide, the
donors who are older and then with the introduction of the vaccine in 1963,
which is that inflection point before it goes down, we get to very low levels
with universal employment of the vaccine below 0.5. Many of the donors will actually have a 0.0
level on this test and so we assign them a low value of 0.1 to get the mean.
This
is based on a random sample of 4,356 source plasma donors conducted in three
snapshots, March of 2006, December of 2006 and then March of 2007. So the aggregate picture here is of falling
levels of titers in the donor population and then as young donors replace the
older donors we see a falling or decline in those titers in the product made
from their donations. Based on the
current age profile of our donors, the group that has greater than 1.5 as the
titer shown on the left of the slide constitutes about 20 percent of our source
plasma donors at the present time. By
2010, if the age profile remains the same, they will constitute less than 15
percent of our donors. So we're rapidly
moving to plasma that will reflect our current younger vaccinated donors with
the lower titer.
And
that gives us the problem that we face in terms of making product with a higher
titer that's currently required. Now
about 20 percent of the plasma product in the
Now
you might ask why aren't we recruiting more older donors and we would like to
do that. However, source plasma donation
is relatively physically demanding. It's
about an hour and a half process and our donors can donate twice a week. The
typical donor donates four or five times a month in contrast to the normal
whole blood donor who donates once or twice a year or up to about six times a
year. So it's a more physically
demanding process and what we find is as people age they tend to leave the
donor pool and then younger donors come in and, of course, one of our most
successful recruiting areas is among students.
I think it will be with great difficulty that we will make very
significant change in that age profile over time.
When
we presented this data in the workshop, Dr. Scott and Dr. Epstein asked that we
go back and measure titers using the neutralization assay and the reason for
this is twofold. First, that is the
assay that we use for the product release.
So we do have a disconnect here, this assay that we're using to screen
donors versus the viral neutralization or functional assay that we use for
product release. In addition, we do have
the problem of the very low levels in donors and the doctors pointed out at the
workshop that they do get measurable levels in individuals who have been
vaccinated of about 1 IU/mL using the neutralization assay.
So
for this reason, we conducted an additional fourth snapshot of our donors on
June 20, 2007 in order to compare the enzyme immune assay with the viral
neutralization assay and we set this up using our statistician's advice on how
to conduct mini-pools. The
neutralization assay is much more technically demanding than is the EIA which
is the reason we don't use it to screen donors.
It's more difficult to perform.
It's performed on tissue culture systems. It's more expensive to perform and therefore,
in order to practically do this, we needed to create mini-pools.
So
this is a snapshot actually of 520 donors based on the statistician's advice of
how many donors to have in each age group, based on the data that we had
previously obtained. And then on each
group, we sampled a certain amount for the mini-pool. So in the older age groups we were sampling
one in three or one in five for the mini-pool and the younger age groups one in
ten to one in eleven. We constituted a
mini-pool for each of the age groups and then we took five aliquots from each
of the minipools and sent them to the laboratory in
I'll
proceed now to show you that data and this graph shows the five datapoints, one
from each of the aliquots for each of the age groups based on birth year and
for those individuals born before 1962, the first two groups on the left, you
can see a relatively high level of approximately 4 IU/mL. Then the next group, during the years when
the vaccine was first introduced, individuals born in 1963 to `67, a reduced
level, but still higher than the younger individuals born after the vaccine had been completely
introduced in the
And
then this slide we've put the data from that one snapshot in June of 2007 for
both the EIA assay and the viral neutralization. The viral neutralization are the higher
numbers shown in red and with the one standard deviation above and below the
mean shown on the graph they are consistently higher and the statisticians tell
us that that is consistent and that the difference is, of course, greater in
measurable units at the higher levels than it is at the lower levels. So this data does give us more confidence in
the younger individuals who have the lower levels of antibody.
And
for the ELISA test, we have shown both the minipools that we measured by ELISA,
comparable to the minipools that were measured by viral neutralization, plus
all the individual units, individual samples, that were measured on the ELISA
assay as well, and those values are quite close, and a very consistent picture
emerges. So individuals born before
1963, before the introduction of the vaccine on the ELISA still have a
measurement of around two IU, on the functional assay about four IU. That falls on individuals born between 1963
and 1967 to about two to three IU on the viral neutralization assay, about one
on the ELISA, and then below one on the ELISA for the younger individuals, and
slightly above one, about one and a half, for the younger individuals on the
functional assay. So what you see on the
right will be the donor pool that will emerge as time goes on.
And
to show you the impact on this, we've created this histogram from the May 2006
measles snapshot using the EIA. If you
look to the right, that would be the percentage of individuals that are below
10 IU/mL. And then as you move to the
left, we go to lower levels. So if you
focus at about two, two and a half IU/mL, you can see among what we call the
senior donors, the individuals born before the introduction of the vaccine,
that about 60 percent of them, or about half, will be below this level, and
about half will be above the level.
If
you look at our junior or younger donors, you can see that 90 percent of them
will be below that level, so would not be able to constitute a pool of around
two to two and a half IU/mL, which is what we calculate we would need to reach
the current CBER standard. And as you
can see, the total donors are beginning to approximate the curve that we have
shown for the younger donors.
So
the message that we're trying to give you is that the donor pool is moving over
time to represent the vaccinated population with the lower level of antibodies
that will, in turn, be reflected in the product, making it more and more difficult
for us to produce product to meet the current CBER requirement for release.
Now
the next obvious question is, why don't we go ahead and immunize donors,
because many of you may know that plasma centers are capable of doing this, and
we do this for several products. This
was analyzed by one of my medical colleagues, who was with the organization
before I was, who looked at 2005 as the problem started to become acute,
whether an immunization program was practical, and concluded that it was not.
First,
I think we have what I have termed here the "ethical issue." If there's no clear patient benefit to offset
the donor risks, then we have a problem putting donors through the discomfort
and risks of the immunization. And I contrast this to our rabies program. In other words, what we heard at the workshop
from the clinicians who treat patients who are immunodeficient is that measles
is not a significant clinical problem, and that we could not tell donors that participating
in one of these immunization programs was making a difference in either quality
or quantity of life for the patients.
By
contrast, if one of you were to be bitten by rapid animal, the injection of a
rabies immunoglobulin would likely be lifesaving for you. So we can certainly tell our donors to whom
we give the rabies vaccine that we are producing a product that is likely to
save human lives. So I think that is one
thing to keep in mind.
Another
very practical point is that the measles vaccine is constituted with live
attenuated virus, and we do not conduct, at the present time, vaccination
programs in our centers with live attenuated vaccine, and have some issues
doing so. The virus replicates in the
body for six weeks, so there would be issues in drawing those donors while they
have a replicating virus, particularly for an immunoglobulin product for that
virus.
The
side effects are slightly higher with the measles vaccine than with some of the
other vaccines that we use, and the handling and management of the vaccine is
more complex than is the case with our other programs. The vaccine has to be protected from light, it has to be shipped and
maintained at refrigerated temperatures, and while these may seem minimal for
clinics and hospitals, for a busy donor center, it creates more complexity from
the program than our other vaccination programs do.
And
importantly, in our discussions at that time with the experts from Merck who
manufacture the vaccine, there was significant uncertainty about the levels
that we would achieve in order to make a product that would have adequate
antibody. Their estimate was that 25 to
50 percent of the individuals would boost to the high levels that we were
looking at, and there was a question about how long that would be maintained,
and as has already come up in the discussion, there was question about the
effectiveness of the second dose in helping with that. So we have concluded that an immunization
program is not the way to go here in order to create a more effective product.
It
was brought up in the workshop of, why don't we seek out individuals who are
vaccinated, and the couple of instances were brought up, for example, military
recruits who are frequently vaccinated, and further discussions with the
military, and I realize we have an expert that can amplify on it here today,
indicates that they generally get the vaccinations at the end of their basic
training, shortly before they're shipped out, and as you know, many of them now
are being deployed to foreign locations, and it's questionable whether
individuals preparing for combat would want to enter a plasma apheresis program
at that time.
Health
care workers were also suggested. One of
the speakers from Johns Hopkins said that hospital immunizes health care
workers if they have low immunization levels, but that is not the common
practice in the
Therefore
in summary, falling measles titers are anticipated over time in normal donors.
It's about a nine percent drop per year in recovered plasma, perhaps a little
bit higher in source plasma. It's
increased when we have times of significant growth, when we're bringing in more
younger donors, and we have verified that by snapshot data, particularly in our
source plasma donors on four different occasions in the last year and a half.
Reductions
in the plasma titers currently being seen will make it very difficult for us to
achieve product specifications in the future, and it's already creating some
difficulty currently. Immunization
programs pose significant issues, and are not seen by us as a solution to the
problem.
And
therefore, we believe that measles antibody specifications for the
immunoglobulin products need to be reconsidered, as has been done by the
Agency, and we certainly would support movement to the lower standard that's
been recommended, and I think based on the data from the donors, and I think
some of the data that you're going to hear from my colleague who has data on
the patient side, it might be possible to even move to a slightly lower level
for the specifications, as well.
This
presentation does represent the efforts of a global group at CSL Behring. The serology work was done in our lab in
CHAIRMAN
SIEGAL: Thank you, Dr. Simon. Are there any questions for Dr. Simon?
DR.
SZYMANSKI: I just wonder what effect the
multiple donations have at the titer level.
Do they go down in the young donors, and what about the older donors who
are naturally immunized by natural virus?
Do they go down, or is there any difference? Do you understand?
DR.
SIMON: Yes. Of course, with the snapshots we have newer
and older donors all included at a given
point in time. All the protein levels
are subject to decline over time, and donors, depending on their frequency of
donation, we do monitor this every four months.
I don't actually monitor the total protein at each donation using a
refractometer. We use the serum protein electrophoresis every
four months, and individuals are rested when their protein levels fall below a
certain level. But there is an element
of decline involved in frequent serial donations.
DR.
SZYMANSKI: But also the measles
titers. Right?
DR.
SIMON: Well, all proteins.
DR.
SZYMANSKI: Yes. All proteins.
DR.
SIMON: All the immunoglobulins are
subjected.
DR.
SZYMANSKI: Do you think they go the same
way?
DR.
SIMON: Yes. I think they -- our data indicates they all
decline pretty much the same.
DR.
SZYMANSKI: Thank you.
DR.
GLYNN: Could you please quantify a
little bit more? You're saying, if we do
not do anything, if nothing is changed, what is going to be the impact on the
amount, the supply, of the IGG products, I guess? I have a hard time understanding. It's going to be difficult, but is it going
to be possible, or is it going to be impossible, and it's going to be going
down by 10 percent, 20 percent? I mean,
can you quantify?
DR.
SIMON: I think maybe one of the industry
speakers on the product side after me, perhaps, could do a better job of
quantifying that. Perhaps Don Baker
could do that. But what will happen over
time is that more and more lots will fail the specification, and if they can't
be released, then they will be unavailable for product for patients who need
the product. So the exact quantification
is difficult. Obviously, our product
people do everything they possibly can to mix the product to meet the
specifications, but we've been seeing increasing difficulties in the last
couple of years, which was what caused this whole subject to come up for
discussion, why the FDA organized and included it in the workshop, and have
brought the question today. So more and
more lots will fail over time, and that will be progressive problem.
DR.
GLYNN: And I guess you asked the same
question before, but how many right now are -- what's the failure rate right
now, I guess?
DR.
SIMON: I think the product side would
have to answer that. I don't have a
specific number on that right now.
DR.
KATZ: Toby, it looks to me like you're
kind of approaching the asymptote now that I'm actually surprised that 20
percent of the donors were from that higher titer age cohort. I couldn't tolerate plasma apheresis, and I'm
just a kid. So it looks like most of the
impacts been seen in the titers, if I'm looking at the histogram that you showed
correctly.
DR.
SIMON: Yes. We try to do what we can to make up the product
and to enrich it with the older donors to the extent possible. But it's simply a progressive problem.
They constitute, as I said, about 20 percent right now. In 2010, approximately 15 percent, by 2025,
zero percent. We have a 65 age
limit. So you can see it simply becoming
progressive, and I think it became a big problem as this group entered their
40s in the last few years, and that's when we began to see it.
CHAIRMAN
SIEGAL: Thank you very much. The next speaker will be Don Baker from Baxter
Healthcare, measles antibody levels over time in licensed product, and patients
with primary immunodeficiency diseases.
DR.
BAKER: Okay. We've had a lot of discussion so far today,
and I bet if I turn this -- is this mike on?
I can't tell.
We've
had a lot of discussion today about the potential for decreasing measles
antibody titer in final products, and now I'm actually going to show you some
data on decrease over time. Longitudinal
studies are conceptionally one of the most simply studies you can do. You just study a variable over time. However, everyone knows that, despite their
simplicity in concept, they are tremendously difficult in actually carrying
out.
And
what this study today is going to do is, we're going to examine the change in the
measles antibody titer and Gammagard S/D IGIV for the period January 1997
through June 2007. This is a product
that has been in continuous production at Baxter since 1994. The reason I didn't go back to 1994 is
because I didn't have the data in electronic format that allowed me to easily
recover it for the time since 1994.
Now,
Gammagard is produced from two plasma flavors, our source plasma donors, these
are apheresis donors, and this is the demographics of our source plasma donors.
And as you can see, the cohort that are currently naturally immunized to
measles is somewhere probably south of 20 percent of our total donors.
I
didn't have the same demographic data for our recovered plasma donors. These are the donors where the plasma is
collected and recovered from a whole plasma donation. This data I got from the Red Cross. However, you can see obviously the same
general decline in the older donors with time.
I would estimate that the recovered plasma donors, there's probably
about -- the prevalence of this, as Toby put it, the senior donors, is probably
about twice what it is in our source plasma donors. So if we have somewhat less than 20 percent
in our source plasma donors, who are naturally infected with measles, there's
something little less than 40 percent in the recovered plasma donors. But again, time will gradually result in a
total reduction of these naturally infected individuals.
Okay. What do we assume in a longitudinal
study? We are assuming that the only
thing that is changing is the percentage of donors that were naturally infected
with measles. In terms of the other
potentially confounding variables, the assay, we have used the hemagglutinin
inhibition assay continuously to test the measles antibody titer in our final
product. There has been no change in the
assay. In the assay site, all of these
were performed at our plant in
The
standard has been the same, the CBER reference, there's no change there. The process, we have obviously tweaked the
process over the last ten years.
However, I did go back and take a look at the significant process
changes. Obviously, all of these were
evaluated at the time to not impact the product, and in going back over them, I
would conclude with that original evaluation.
I don't see that there's any reasonable likelihood that any of the
process changes would have impacted the measles antibody titer.
And
the donors. There has been no change
there. The majority of donors over time
on the source side were from our Baxter Source Centers, and we used ARC
recovered plasma. So by in large, the
donor screening questions, the donor testing, the donor selection criteria,
there have been minor changes over this ten year period, but again, nothing
that I think would impact the demographics or the measles titer.
This
is just some selected characteristics of Gammagard S/D, just for those of you
that may not be familiar with the product.
Okay. So what do we see? This is the source plasma product. As you can see, the specification is 0.2
relative to the NIH 176 reference standard, and for those of you that are
baffled by numbers, why do you see 0.2 as opposed to 0.6? The 0.2 is the adjustment for protein
concentration. This is a five percent
protein concentration, IGIV concentration.
The reference standard is 16.5 percent, I think. So the 0.2 is an adjustment for the protein
concentration.
As
you can see visually, there appears to be a decline in titer. If you look at the trend, you do see a more
or less consistent trend, or the rolling average, again, a consistent trend
downward over time.
The
situation with recovered plasma, again, is somewhat similar, and exactly what
you would expect given that the percentage of donors is older. The older donors are more represented in the
recovered plasma. So there the titers
are somewhat higher. But again, the same
trend decline over time, and the same trend in decline in the rolling average.
So,
the data from the longitudinal study does support the hypothesis. The decline of donors with a history of
natural measles infection is leading to a decrease in the titer of antibody
measles virus, and absent a change in specification for measles antibody or any
mitigating step, we will have IGIV lots that will begin to fail the measles
titer requirement.
Now
there was a question from one of the committee members about how many lots are
we losing. The fact is that right now we
don't lose any lots, because the measles antibody titer is not required in
However,
the issue is, for our company, for example, the vast majority of this product
is distributed in the
Okay. That was it.
CHAIRMAN
SIEGAL: Thank you. So we have time for a couple of questions.
DR.
COLVIN: I'm curious as to what is the
measles incidence in
DR.
BAKER: I don't know.
DR.
COLVIN: Because I'm assuming, based on
what we've heard before, it's a bit higher than it is in the
DR.
BAKER: It is higher than in the
DR.
COLVIN: So in other words, I'm just
throwing something ethical out at you for a second. So you're saying that when the measles titer
is lower, perhaps not reaching the level that people who have an
immunodeficiency might need to, in fact, prevent infection with the virus,
you're sending now this product to try to protect people from infections in a
place where the incidence of this infection is actually higher than it is here.
DR.
BAKER: You know, there's two responses
to that. Number one, the European community
and the regulators in the European community have taken a different perspective
on measles antibody titer. They feel
that the titer that we have in the product is adequately protected. So that's a difference in regulatory view,
and I'm certainly not going to get into that right now.
Secondarily
again, we have not seen, in the primary immunodeficient patient population in
DR.
COLVIN: Or it could be that most of the
time they're getting European source plasma that actually has a much higher
titer because it has more naturally infected patients donating.
DR.
BAKER: Fair enough.
CHAIRMAN
SIEGAL: Anybody else? Okay. Very good. Thank you very much. Now Othmar Zenker, M.D., from Behring.
DR.
ZENKER: Good afternoon. I am representing CSL Behring. I'm head clinical research in
A
short introduction. I think this is all
repetition. We have heard this this
afternoon. Falling measles titers are
anticipated over time in normal donors.
The measles antibody titers serve as a potency test for immunoglobulin
lot release, with a cutoff level of 0.6 times the CBER standard. We've heard a lot about the history of this
cutoff level in the previous talks. This
should usually not lead to any issues.
But here, one has to think about, is the lower measles titer that will
come into the product into the future.
Can patients be protected against measles?
If
there are more and more lots that will not fulfill the current cutoff level,
there is an increase of immunoglobulin shortage.
Now
back to the patients. The titers for immunocompetent persons that are
protective are known. This is 0.12
IU/mL. This has been associated with a
protection against the clinical measles disease in several outbreak studies. We mentioned a study by Dr. Chen published in
1990.
Currently,
there seems to be no concern for primary immunodeficiency patients with respect
of measles. Even in Europe, where there
is currently an outbreak in
What
we did is we used retention samples from two of our clinical studies and tested
these samples at the trough levels in functional assay and with ELISA. This obtained us results on anti measles
trough levels after subcutaneous and intravenous immunoglobulin treatment in
PIDD patients.
These
are the methods we have used for the ELISA.
We used a commercial kit, and calibrated it with in-house plasma
standards against the 3rd WHO standard. The neutralization assay is the assay we use
normally for a lot release, and we measure the measles antibody in relation to
the reference immunoglobulin in
So
now to the clinical studies. The first
one is a subcutaneous study. We have
chosen 20 subjects with available retention samples, analyzed them by the
neutralization assay, and in addition, 60 samples by ELISA. The demographic data of these patients are
typical for primary immunodeficiency patients, as shown here with respect to
IGG trough level, and also the weekly subcutaneous dose. The treatment was given every week, and for
this analysis, we have calculated the anti-measles specific dose in units per
kilogram per week by using the lot release test.
As
a lot could have been changed during this study, so a patient could have been
treated with several lots. Even just prior to the drawing of the samples, we
took the four last infusions into consideration, the four infusions that were
given prior to the trough level sampling, and used the mean of these values. This takes into consideration the half-life
of three to four weeks of the immunoglobulin, so that we have no carryover, or
less carryover effect from different lots.
Here
you see the results of the dose response in the neutralization assay. On the X axis, we have drawn the anti-measles
specific dose, and on the Y axis, the anti-measles titer. At 0.12, we have drawn a line which
represents the minimum protective level in healthy patients, not to develop
measles disease. It's obvious that, here
in this study, all patients are well protected.
There was no single patient that had an anti-measles titer below one
IU/mL. The mean titer in this patient
population is 3.17 IU/mL. So I would say
at least two to three times higher than the usual donors, as shown previously
by my colleague. Just for your
information, this is a graph that shows the IGG trough levels, and the
anti-measles titer. As expected, there
is also a correlation between the dose and the trough levels.
Now
to our second study, the results after the intravenous infusion. Again, we have chosen retention samples here,
53 subjects, 58 of the samples were analyzed by neutralization assay, and 140
samples by ELISA. As you can see from
the numbers, we have some repeated measurements in some of the patients. Again, the demographic data are typical for
primary immunodeficiency patients. Here
the treatment was given every three to four weeks. In this case, the dose was the dose of the
three weekly treated patients were intercollated to monthly dose so that we can
compare the three and the four weekly dosing groups.
Again,
to avoid any carryover effect of different lots, we have chosen here for this
study samples only if the same lot was given on three consecutive infusions
prior to the sampling. Here you can see
the result of the neutralization test assay.
Again, all patients are protected.
They were well above the 0.12 cutoff level.
The
mean titer here is 2.98 units per mL. When you compare these results between
the intravenous and the subcutaneous administration route, there seems to be a
higher anti-measles titer during subcutaneous treatment. This is not unexpected. I think we have just discussed previously
that the difference between the intravenous and the subcutaneous administration
route is that, by the intravenous route, we have a high trough level and a
somewhat lower -- a high peak level, sorry -- and a somewhat lower trough level
than compared to subcutaneous administration.
In
the following, I will present to you a simulation, a trough level
simulation. We have the important
question "how do the previous shown results translate into trough levels
when we are using a lot with a lower anti-measles titer than given in this
study?" For that, we had to do some
assumptions.
The
first assumption is that we use a hypothetical lot with a potency of 0.3 times
the CBER Standard Lot 176. We calculated
the dose of anti-measles antibody given to the patient according to this
hypothetical lot under the assumption of a linear dose titer correlation. We did not take into consideration that some
of the patients would probably have some endogenous anti-measles antibody
titer. So in our view, this is a very
conservative approach.
We
did a simple mathematical model, and I will show you now the results. Or I will show you graphically how we did
it. You see the red line. For one of these patients, this is the
patient 1010. He had an anti measles
titer of a little bit less than one in the retention sample. We drew the line through the zero calculated,
the hypothetical dose. With a lot of 0.3
times the CBER standard, here this is approximately 30 units per kg per month,
and so now that, with this interpolation, the patient would have at least an anti-measles
titer of 0.15.
So
we did this with all the patients, with all the dots you see here in this
graph, except of one. We had to exclude
one patient where we saw no dose trough level correlation in the ELISA
test. Here you can see that, even with a
higher dose, the patient showed no increase in the trough level. Therefore we have excluded this patient from
the following chart.
So
this is the result of this simulation.
Again, all the patients would be protected. They would have shown a trough level that is
above the 0.12. The difference between
the cutoff line and the calculated numbers is not so high as in the real
samples that should be considered. But
once again, we have to mention that this is a conservative approach as the
endogenous production of anti-measles immunoglobulin was not taken into
consideration.
So
let's summarize. All the tested samples
were well above the protective level of 0.12 unit per mL. Treatment with subcutaneous immunoglobulin
results in a higher trough level than intravenous immunoglobulin. Three or four weekly IGIV treatments with
product under the current specification of trough levels is far above the
protective titer of 0.12. Even a
hypothetical lot with a potency of 0.3 times the CBER Lot 176 would be sufficient
to protect patients in the study, as shown by the linear interpolation.
The
FDA has proposed to lower the cutoff level to 0.48 times the CBER lot
standard. With this data, this cutoff
level -- or it could be taken into consideration to lower this level of 0.48
even more. So the data show that
patients are protected with a lot of 0.3.
These
are my acknowledgments. Thank you.
CHAIRMAN
SIEGAL: Okay. Thank you very much, Dr. Zenker. Are there questions for Dr. Zenker?
DR.
EPSTEIN: First, thank you very
much. These are the first data that
we've seen on trough levels in primary immunodeficient patient, so it's very
much appreciated.
My
question is about the methods for estimating administered dose. Did you base the calculation of administered
dose in a patient on the actual known content of the product lots administered,
or did you simply assume that they were at 0.6 times CBER standard? Because in
reality, many of those lots might have been much higher than 0.6 times CBER
standard, and then you would have had an incorrect extrapolation for a lower
potency.
DR.
ZENKER: No, we have used the actual dose
--
DR.
EPSTEIN: The actual dose.
DR.
ZENKER: -- that were given in the
analysis.
DR.
EPSTEIN: Okay.
DR.
BALLOW: On the patients that were
receiving immunoglobulin by the intravenous route, I noticed your trough levels
-- I think that was a trough level. It
was like 971 mg/deciliter. Was that what
I saw?
DR.
ZENKER: The average trough level, the
immunoglobulin trough level?
DR.
BALLOW: Yes.
DR.
ZENKER: The average trough level was
970, yes.
DR.
BALLOW: Yes. I mean, that's extraordinary. That's much higher than many of our patients
achieve unless we infuse above 700 millirems per kilo. So in the real world, I know that was part of
a study, but in the real world, I mean those are trough levels much
higher. So I'm a little bit worried
about using some of the data, given that high of a trough level, because we
just don't see that in our patients.
DR.
ZENKER: So these were the data from a
clinical study which was performed mainly in the
DR.
BALLOW: No, I understand that.
DR.
ZENKER: -- these are reflecting the
treatment in this clinical study in the
CHAIRMAN
SIEGAL: Anybody else? Dr. Szymanski.
DR.
SZYMANSKI: I have a question for
you. Now, when measles is so rare, and
so what do you think? Is it necessary to
protect these immunocompetent individuals all the time, so that they will all
the time have good titers, anti-measles titers, or would you let them go down,
and when there is a problem, increase, give them more immunoglobulin?
DR.
ZENKER: Maybe this is more a question to
the clinicians here. From the data we
have seen, it should be possible to reduce the measles titer in the product,
and when we all assume that the 120 is a sufficient cutoff level, then we can
reduce the lot specification. As I
stated before, in
CHAIRMAN
SIEGAL: Anyone else? I would certainly agree with Mark that most
of our patients don't achieve a trough level of 900 mg. It's more like the
lower limit of normal, if we're lucky.
So that might make a difference in terms of the titers that are actually
achieved.
Anyone
else? Okay. Well, thank you very much. Now we're already about 20 minute
behind. I don't know how the committee
feels about it, but I know that some of us have to make planes and trains, and
that perhaps we ought to forego the break and move onto the rest of the
program. Is there a sense that people
need to take a break for a moment?
(Off
the record comments.)
CHAIRMAN
SIEGAL: Do you want to do five
minutes? But really a five minute
break. Okay. Not 25.
Off the record.
(Whereupon,
at 3:36 p.m., the above-entitled matter recessed and reconvened at 3:41 p.m.
the same day.)
CHAIRMAN
SIEGAL: On the record. Let's get started. Because we are having an open public hearing,
I'm obligated to read an announcement for such meetings concerning conflict of
interest.
Both
the Food and Drug Administration (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 that it
is 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 statement to advise the committee of any
financial relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting. For example, the financial information may
include the company's or group's payment of your travel, lodging or other expenses
in connection with your attendance at the meeting. Likewise, FDA encourages you at the beginning
of your statement to advise the committee if you do not have any such financial
relationships.
If
you chose not to address this issue of financial relationships at the beginning
of your statement, it will not preclude you from speaking. With that in mind, I understand we have two
representatives. The first will be Mary
Gustafson from the PPTA, the Plasma Protein Therapeutics Association. Dr. Gustafson.
DR.
GUSTAFSON: Thank you very much. And in terms of conflict of interest, I am a
salaried employee of PPTA. PPTA is the
international trade association and standard setting organization for the
world's major producers of plasma derived and recombinant analog
therapies. Our members provide 60
percent of the world's needs for source plasma and protein therapies. These include clotting therapies for
individuals with bleeding disorders, immunoglobulins to treat a complex of
diseases and persons with immune deficiencies, therapies for individuals who
have Alpha 1 antitrypsin deficiency which typically manifests as adult onset emphysema and substantially
limits life expectancy and albumin which is used in emergency room setting
which is used to treat individuals with shock trauma, burns and other
conditions. PPTA members are committed
to assuring the safety and availability of these medically needed
life-sustaining therapies.
PPTA
agrees with FDA's proposal to lower the minimum titer for measles antibodies
and immune globulin intravenous (human) and immune globulin subcutaneous
(human) recommended for lot release. The
original measles antibody release requirement was related to a standard
obtained from a donor population with different immunologic profile.
In
the 1960s, the immune globulins were licensed by FDA. Today's immune globulin products are used by
people with immune deficiencies to protect them on a day-to-day basis from
pathogens in their environment. Routes
of administration are intravenous or subcutaneous. As in the 1960s, the antibody composition of
the immune globulin products reflect the herd immunity of the population from
which the source material is collected.
Today's donor is more likely to have been immunized against childhood
infections including measles rather than having had the illnesses.
Both
demand for and production of immune globulins are rising. In 2006, the distribution of intravenous
immune globulins in the
Manufacture
of immune globulins is complex. It is
important to recognize that it can take up to 12 months to manufacture a single
batch. Failure of a batch to pass lot
release specifications has serious ramifications. It is important that each lot release
specification is relevant and realistic.
The
proposal by FDA to lower the minimum titer for measles antibody is based on
both clinical relevance and the realities of manufacturing immune globulins
from today's donor populations. And if I
could add, based on data in Drs. Simon's and Zenker's presentations, we ask
that the committee and FDA consider if an even lower titer is clinically
appropriate to help ensure the continued sustainability of the product. Thank you.
CHAIRMAN
SIEGAL: Thank you, Dr. Gustafson. The next speaker will be Marsha Boyle from
the Immunodeficiency Foundation.
MS.
BOYLE: Thank you, Dr. Siegal and the
committee for allowing me to present.
The
Immunodeficiency Foundation is the national patient organization for the
primary immunodeficiency diseases. Many
of our patients depend on regular infusions of life saving preparations of IVIG
in order to replace the immunoglobulins and antibodies that they themselves are
unable to produce because of a genetic defect involving their immune system. The primary rationale for using this
treatment is that these products contain sufficient titers of antibodies to be
effective in preventing and treating a broad range of infectious diseases to
which our patients are likely to become exposed.
When
the original potency standards for immune serum globulin, IGIM, were
established, they were based on the titers of antibodies to measles, diphtheria
and polio. These potency standards have
subsequently been applied to the preparation of IGIV and IG subcutaneous.
IDF
has been aware for some time of the concern by the FDA and the industry about
the gradually falling titers of anti measles antibody in the general donor
population that has been reflected in similar reduced titers and preparations
of IGIV.
Along
with the FDA, we were pleased to cosponsor a workshop held at the NIH campus on
April 25 and 26 of this year. The
workshop brought together experts from the FDA, CBER, industry, academia and
the CDC to explore in the detail this problem and potential solutions. BPAC's consideration of this issue today is
very timely. From what we understand, it
appears that we're nearing a time when newly manufactured lots of IGIV may need
to be rejected solely because they did not meet the standard for titer of anti
measles antibody.
The
supply of IGIV has been tight for several years. In addition, the amount used by other
disorders has been increasingly substantially, further adding pressure on the
supply of this lifesaving treatment for patients with primary immune
deficiency. Measles is a serious disease
and the protection of our patients from measles via immunoglobulin replacement
is highly desirable but it is only one of a myriad of infectious diseases
against which our patients need the protection afforded by this treatment.
If
new loss of IGIV or IGSC products are rejected because this single specificity
is below the potency standard originally established for IM that was given in
much lower doses than currently possible with IGIV, we fear shortages of these
products would inevitably occur. This
could then result in infections with many other organisms with predictable
consequences for patients with antibody deficiency.
In
addition to these supply issues, we're encouraged that the levels of measles
immunization in the general population has been sufficient to keep herd
immunity high enough to prevent epidemic outbreaks of measles during recent
years in this country. Certainly the
risk that a primary immunodeficient patient would encounter, wild type measles
is much lower than their risk from other agents that are not part of the
potency standard. And we also encourage
CBER to continue efforts to define the specificities of different antibodies in
the products.
We
therefore urge that the BPAC accept the recommendations of the CBER staff to
lower the potency standard for anti measles antibody in preparations of IGIV
and IGSC. IDF further urges the CDC to
continue its surveillance program for outbreaks of wild type measles in this
country. Efforts must continue to
determine whether patients with primary immunodeficiency are among the cases
reported and, if so, determine the immunoglobulin replacement status of those
patients.
We're
pleased that CBER is maintaining the current measles standard for the IM
preparations and we feel that it would also be beneficial to our patient
population if CBER could consider the feasibility of having available
preparations of immunoglobulin that are manufactured, IGIV that are
manufactured, to contain higher than standard titers of anti measles antibody and
some other specificities as well for short term use by patients who need to
travel to areas of the world where these infectious diseases are endemic such
as Africa or the Middle East.
We
would also like to see continued and expanded research to more fully understand
the roles of the various components of the immune system in protection against
measles to help clarify the relative risk to patients with antibody deficiency,
cellular immunodeficiency or combined forms of immunodeficiency.
Also
I forgot to say at the beginning that I personally have no conflicts. But the Immunodeficiency Foundation does
receive unrestricted educational grants from many of the companies that produce
immunoglobulin. Thank you.
CHAIRMAN
SIEGAL: Thank you very much. Is there anyone else who wishes to make a
statement during the public part of the meeting? If not, we'll proceed. Thank you very much.
Now
we need to address our questions. You
can all read them. The first question is
do committee members concur with the FDA proposal to lower the minimum measles
antibody specification as described. Is
there discussion on this matter?
MS.
ELGIN: May I?
DR.
SZYMANSKI: I would like just to bring up
a couple of issues. We discussed
here. We learned that about 60 percent
of patients who receive immunoglobulin receive it not because they are
incompetent and the measles antibody I don't think matters in those cases.
So any level of measles antibody would be fine to treat those
individuals.
Now
I think the Swiss presentation sort of was quite convincing that even if you
lower the antibody level even more than it is proposed now the patients were
not at the risk for measles in even incompetent patients. So I think it seems to me that it does not
present a great danger if you lower the level to 0.48 from 0.6. I just wonder what anybody else is thinking.
DR.
EDWARDS: May I? On this same question, I have actually a
burning question. First of all, in
answering the question, I felt that from the presentations and the literature
that we've had so far that there is no reason why we shouldn't lower it to the
0.48. But my question and I'm hoping
that someone in the audience if not my colleagues here around this table might
answer this question. As we've seen,
we're saying that we get better vaccine from those who have had the disease
naturally and the question that keeps coming to my mind is that while we have
seen less incidence here in the U.S. and therefore don't have the numbers here
that have natural measles and therefore can't develop vaccine from that, why is
that we're not talking about developing vaccine from those countries where we
still see measles as a major disease there and occurrence in that
population? Is there any specific reason
why we're not going outside of the
DR.
GOLDING: I think -- Well, the issue
there is collecting plasma outside the U.S. and there is a whole host of
problems for doing that that we only accept products that are made from U.S.
licensed plasma because of the way that donors are deferred and infectious
disease risk from those donors. So I'm
not saying it's impossible, but it is huge problem to ask for non
CHAIRMAN
SIEGAL: Are there any other comments
concerning this?
DR. DI
BISCEGLIE: Just a question. I
don't see -- I'm in agreement with the idea of lowering the measles antibody
specification. But I'm not sure about
the number, 0.48. Is there some basis
for that and why that?
DR.
GOLDING: There's a lot of mathematical
calculations based on what a protective
titer would be. But starting from
a protective titer of 120 IU/mL, what we found and what I presented is based on
pharmacokinetic calculations. You would
expect that if you dropped the titer to 0.48 you dropped the lot release
requirement instead of 0.6 to 0.48 of the standard, you would end up in
practice of having immunoglobulin preparation that if you gave them at 400
mg/kg which is probably from a point of view of the standard the lowest dose
you would end up with a trough level that's, if our calculations are correct,
around 240 mIU/mL which is twice what we think is the protective level.
Part
of our thinking is that in the immune deficient population, we don't have data
to know what is protective in that population.
We heard from several speakers that T cell immunity may also be
important. So we want to have a margin
of safety here for that population. So
some of this is -- A lot of this is based on estimates because we don't have
the data.
We
saw today from CSL with very high trough levels which we're going to ask, being
a continued discussion with them and try to look at that data more
carefully. But based on what we knew
going into this meeting, the 0.48 level seemed to us a reasonable
estimate. It also means that based on
all the lots we've been looking at over the last few years that 100 percent of
those lots would pass the lot release test. So it ensures from the point
of view of the FDA both having continued supply without problems of lots
failing and at least double the protective level in the lowest dose that is
used clinically.
DR.
DI BISCEGLIE: A follow-up if I
might. Is that okay, Mr. Chairman? Sorry.
So by choosing 0.48 given that the titers are failing, might we be
facing a similar hearing five years from now to say we can't keep up any
longer?
DR.
GOLDING: I think that is possible and I
think we can look into those calculations.
But I think there is the one way of addressing that which is saying you
have to give higher doses. But there's a
problem with that because there's cost involved and there's also availability
involved with higher doses. So if the
titers continue to fall, we could end up five years from now that 0.48 is not
sufficient. But we may be --
DR.
DI BISCEGLIE: So it's incumbent on I
think maybe both the agency and the manufacturers to prepare for that now by
getting some of the data that might support saying we can go even lower or we
cannot go lower.
DR.
GOLDING: Well, I agree with you, but I
think one of the things we have is in the question is to ask -- One of the
questions is to actually do pharmacokinetic studies, asking the manufacturers
to do studies to get actual data and to then compute that and then look at that
in terms of the falling titers and see maybe there is a more realistic number
for the next five years.
MS.
BAKER: I had some questions for Dr.
Baker and the other manufacturers. You
had mentioned that when some lots seemed to be in danger of failing that you
have a policy to ship them overseas and I'm wondering -- I didn't hear you
clearly. If you could clarify. Is this something that is currently
occurring? At what antibody
specification do you make a decision to ship overseas? How often has this occurred? When did it start? In what proportion of the lots has this
occurred?
DR.
BAKER: Sure. I can answer that. In terms of the lots that have failed, we
have had one and it was marginal failure.
I think I took the question in a more hypothetical sense that if we have
a large number of lots failing what could we do and in a hypothetical sense
since we don't have a requirement that is similar to the measles antibody and
titer we could divert those products to
CHAIRMAN
SIEGAL: I have a question for the FDA
actually. Dr. Epstein perhaps. I just want to know whether there's a
absolute requirement that we use measles antibody levels for certification of
this product in the long run or could that be changed and therefore sidestep
the whole issue in the long run?
DR.
EPSTEIN: Okay. Well, the answer, first of all, the
regulations require a titer for intramuscular immune globulin. It has been a policy and consistent practice
to apply the same titer and principle to the intravenous and subcut
preparations but that's not actually in the regulations. Whether we need to maintain that policy is up
to us and the Director of CBER has discretion where to set the threshold for
lot release if we maintain that.
But
I think your question leads to your suggesting do we need this at all which was
your opening remark and I guess that's a question we could ask this
committee. Is there the sense that this
is playing a protective role or not? And
I guess having heard Dr. Moss' presentation the question arose in my mind in
the following way. If you believe the
monkey data that the natural history is essentially identical from an immune
deficient to an immune competent subject as long as there's cellular immunity
intact. What does that suggest? It suggests that if you didn't have this
titer in the product you wouldn't be putting at risk the immunodeficient
patients who have cellular immunity.
Conversely,
if you do have deficient cellular immunity, the question is whether given a
replacement to achieve titers that are less than associated with sterilizing
immunity, that is to say, prevention of infection plays any role at all and I
think what we saw here is that although a large of proportion of subjects who
get these higher replacement levels exceed roughly 1,000 mIU/mL or 1 IU/mL that
at the projected lower titer, in fact, you don't expect very many to be
anywhere near that level.
So
the point is in actual practice we're not giving patients enough product to get
sterilizing immunity which raises the question of whether we're actually
benefitting the people who are cellular immune deficient. So I think what's really going on is that the
PID population is being protected by the herd immunity of the general
population and there's rather an open question whether the low level
replacement compared to sterilizing immunity places any role, whatever. In a certain peculiar way, that suggests to
us that we can be a little bit less worried about lowering the titer because
its punitive benefit may not be an actual one.
CHAIRMAN
SIEGAL: That's clarifying. Thank you.
DR.
EPSTEIN: Sorry. I know it was a little circuitous.
CHAIRMAN
SIEGAL: No, it was very good.
DR.
EPSTEIN: But I'm trying to assimilate a
lot of results here.
DR.
CRYER: It seems to me that with taking
all the data today that we've heard that it's pretty clear that we could
support a yes to No. 1 and not really worry about it again unless one of three
happened and the three things would be that some of the donated units start
falling below the 0.48 level. The second
would be that some of the people getting those units started getting measles. And the third would be that the epidemiologic
studies start to show penetrants into the population who have been immunized
when there are some of these sporadic outbreaks. So it seems to me -- I mean this seems pretty
clear cut from a commonsensical point of view.
DR.
GLYNN: But I think that also brings the
question of travel in those patients. So
what is usually done when someone with immunodeficiency is going to be
traveling. Do you give them a dose just before
they travel? What's the usual practice?
CHAIRMAN
SIEGAL: Well, in practice, you can
simply up the dose.
DR.
BERGER: I think if a patient with an
immune deficiency who is maintained on immunoglobulin replacement is going to
travel most of us would probably give that patient a dose before they departed. But it also raises questions about how long
they're going and can they get a dose while they're overseas and so on?
DR.
GLYNN: And do you think your practice
would change if we decreased the dose of the titer or you would just give --
DR.
BERGER: Well, if somebody is going to --
It also depends -- It's not totally clear to me that if we vote to advise the
FDA to carry out positively on question one whether we're also going to change
the specification for IM. Because if we
don't change the specification for IM which is not indicated, then you may say
if you're going to a measles endemic place, take an IM dose before you go. So that possibility would remain open as
would the possibility of giving a higher IV dose before they go or subcu and
ask for a subcu dose or something like that.
DR.
GOLDING: I just wanted to add, the IM,
we would think might be used for normals.
But the problem with IM is the same.
We're going to have to deal with it separately. We are going to have to deal with the titers
are falling down in the IM as well. So
it's not necessarily going to be a solution.
CHAIRMAN
SIEGAL: Last comment I hope.
DR.
FINNEGAN: You're not going to like the
comment. I am very concerned that we are
being asked to answer a question for which we have been given almost no
scientific data for a problem that is still theoretical although it is
approaching and for people who are significant risk of dying if, in fact, we
guess wrong. And I think we're setting a
precedent that really concerns me. I
mean I have not heard good scientific data today I don't think.
CHAIRMAN
SIEGAL: Further comments?
Louie.
DR.
KATZ: My only response to that is that
IVIG in particular and "subcu" immunoglobulin are used for important
things than measles now and to start losing lots over the risk of measles as
somebody who has to ration intravenous immunoglobulin from our distribution hub
pretty much constantly for several years I don't measles to be the reason that
I have to tell somebody they can't some.
DR.
FINNEGAN: But are there other ways of
handling it besides dropping down to 0.48?
In fact, the woman for Immune Deficiency said can we have a higher level
if we're going to travel. Can you have a
lower level that you just put on that does not work for measles?
DR.
KATZ: I think that gets to question
three which I hope we'll have time to discuss as a separate kind of --
CHAIRMAN
SIEGAL: Well, I'd like to get a vote on
this question first and I'd like to go around the room. So I'm asking people whether they agree or disagree. Let's start with Mel Berger.
DR.
BERGER: I agree.
EXECUTIVE
SECRETARY JEHN: So we'll go around the
table here. So Dr. Berger, you're a
yes. Dr. Ballow.
DR.
BALLOW: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Colvin.
DR.
COLVIN;: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Cryer.
DR.
CRYER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Di Bisceglie.
DR.
DI BISCEGLIE: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Edwards.
DR.
EDWARDS: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Finnegan.
DR.
FINNEGAN: No.
DR. GLYNN:
Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Glynn, yes. Dr. Quirolo.
DR. QUIROLO: Yes.
EXECUTIVE SECRETARY JEHN: Dr.
Schreiber.
DR.
SCHREIBER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Szymanski.
DR.
SZYMANSKI: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Whittaker.
DR.
WHITTAKER: Yes.
EXECUTIVE
SECRETARY JEHN: Ms. Baker.
MS.
BAKER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Siegal.
CHAIRMAN
SIEGAL: Yes.
EXECUTIVE
SECRETARY JEHN: Opinion from Dr. Katz?
DR.
KATZ: Yes.
CHAIRMAN
SIEGAL: Let's proceed to the second
question for which we need to vote as well.
CBER is considering requesting additional studies to confirm that
primary immune deficiency patients will achieve trough levels of measles
antibodies above 120 mIU/mL if treated with IGIV and IGSC products that meet
the proposed revise potency standard of 0.48 times the CBER standard. Do the committee members agree that this
information is needed?
DR.
FINNEGAN: I think a preliminary study
before that is what exactly is the level that's needed to prevent infection
because I don't think anybody knows.
It's somewhere between, it looks like, 200 and 1,000, but nobody seems
to know what the real level is. So I
would say that a more basic step would be that.
CHAIRMAN
SIEGAL: Mel.
DR.
ALLEN: I think that data like the data
presented by Dr. Zenker is achievable and so if we had data comparing the titer
and lots that patients were given at least with the trough levels, if not, the
formal pharmacokinetics of the whole pharmacokinetic curve, then it would be
possible -- We would be on much firmer ground to make a mathematical
extrapolation that any given titer in the product this and this trough level
would be achieved. So that's something
that when we have to revisit this five years from now or if the data that she
just talked about were available one could at least make a mathematical
projection of what titer in the product would give a trough titer in the
patient that would be satisfactory. And
that data is certainly available from patients being treated now. You just need a sample of the lot they're
given and a sample of their trough level.
DR.
GLYNN: I think it would be really
important to those data because everything we've seen are just
simulations. So I think we need to actually
check that the numbers pan out the way we thing that they would.
CHAIRMAN
SIEGAL: From what we've heard Dr.
Epstein and from what we've been thinking about it, it strikes me that part of
the problem is that the really susceptible population are the kids with
combined immune deficiency and others with C-8 deficiency and things of that
sort for which there are no data at all.
And that really probably what we need to do for populations like that is
to provide sterilizing protective antibody immunity and it's clear that you
need much higher titers than the FDA standard proposes to achieve that so that
if we're going to look at that, we might be looking to do this with specialized
immunoglobulin preparations that are exceedingly high titered. You can't do that with the IM stuff because
you just can't give enough. So IM immunoglobulin was traditionally
protective against measles because it modified measles in healthy adults
really. Isn't the genesis of the
standard? And that wouldn't apply to a
kid with severe combined immune deficiency actually confronted with the virus I
think anyway.
But
I personally agree that we should do -- we should find out what actual peak and
trough levels are and that would be a useful and relatively simple study to do
and it's already been partially provided to us.
Other comments? If not, we can go
around the table again.
DR.
QUIROLO: I have just one question for
you. I don't give IVIG. So on the label or in the insert, does the
manufacturer state what the antibody levels are? Is there some way to find out?
CHAIRMAN
SIEGAL: I haven't read a package within
30 years.
DR.
QUIROLO: Would it help you, would it
help the clinician, to know because I noticed that in one of the papers there
was a huge difference between the manufacturing processes as to how much
antibody there were in each of these different products? So would it help the clinician to know
whether the titers were in these products?
CHAIRMAN
SIEGAL: It would but it's never provided
and, of course, as has been pointed in this meeting, there are other titers
which would be much more helpful than the measles titer because measles hasn't
been our clinical problem the way pseudomonas antibodies would be or other
encapsulated bacteria antibodies and so on.
All
right. So let's go around the table.
EXECUTIVE
SECRETARY JEHN: Before we go around the
table, I just want to summarize the first one.
It was 13 yeas and one nay.
For
question two, Dr. Berger.
DR.
BERGER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Ballow.
DR.
BALLOW: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Colvin.
DR.
COLVIN: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Cryer.
DR.
CRYER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Di Bisceglie.
DR.
DI BISCEGLIE: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Edwards.
DR.
EDWARDS: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Finnegan.
DR.
FINNEGAN: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Glynn.
DR.
GLYNN: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Quirolo.
DR.
QUIROLO: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Schreiber.
DR.
SCHREIBER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Szymanski.
DR.
SZYMANSKI: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Whittaker.
DR.
WHITTAKER: Yes.
EXECUTIVE
SECRETARY JEHN: Ms. Baker.
MS.
BAKER: Yes.
EXECUTIVE
SECRETARY JEHN: Dr. Siegal.
CHAIRMAN
SIEGAL: No. I'm just being contrary. Now the last question is please comment on
the need for -- I'll change my vote by the way.
Dr.
Katz. I'm sorry.
EXECUTIVE
SECRETARY JEHN: He's not a vote, but
it's just an opinion.
DR.
KATZ: My guts tell me that we can
talking about measles and IGIV in the
I don't think we have a clue and I think while
120 correlates with something. That does
mean it's the cause. So I'm not sure how
far in a time of virtually zero incidents in the
CHAIRMAN
SIEGAL: And again, in the Chen study
from which that number is derived, that was done in healthy adults, not in kids
without CD-8 cells.
Okay. So please comment on the need for and
feasibility of any alternative strategies that CBER could consider to reduce
the likelihood of failed lots of IGIV and IGSC based on potency testing for
measles antibodies in order to ensure availability of product for primary
immunodeficiency patients. Mark.
DR.
BALLOW: I have to assume that there is
variability from lot to lot, that some lots have higher levels than other lots
because from what we've heard there are lots of failed and they are either
discarded or they are sent to
DR.
BERGER: I would also like to support
this idea. In the workshop, several
examples were brought up not only about pneumococcus but about, for example,
the problem of chronic Enteroviral Meningoencephalitis in Bruton's patients and
so on and it's easy to see that the issue raised now about measles because
measles is the one that's written into the law we're going to face the same
issue with Varicella zoster for example and that's going to be much harder to
control natural exposure because people will get Shingles unless there's
incredibly high penetration of the new zoster vac.
So
I would suggest two things at least be considered some time in the future. One is the idea of having some sort of agreed
upon assays and labeling lots or product according to their antibody content
against a variety of diseases and then the second issue was raised which Mark
also touched upon is the issue raised by the tremendous use of IGIV for "off-label
uses." And it sounds very funny to
say should we label some of the lots to be used only for off-label use but, in
fact, we could label them for use in ITP.
Several of the products are labeled for ITP. Of course, we have very little --
I
think one of the most impressive things out of the workshop and this session
today is how little we know about IVIG or IGG products and how they work in the
patients and however little we know about it in PID patients is a lot more than
we know about it in the autoimmune and neurological diseases that actually
constitute the majority of the use. But
at least an interim strategy or as a strategy at some point in answer to issue
number three is to consider the potential of labeling lots as not for use in
PID. Then those lots could still be on the market and could be used for other
indications.
CHAIRMAN
SIEGAL: I hope we're taking notes on
this.
DR.
CRYER: Yes, I have a similar
comment. I think if I have the process
down right, then all of these units have to be measured anyway. So it's just a matter then of recording the
antibody levels for the various things on each unit. I think what that allows is even if you
didn't begin selecting out units for certain things at the beginning you would
at least have a registry that allowed you to correlate the levels of individual
antibodies with the outcomes in specific patients that you could then make
generalizations on later about what you need to do. If you're already doing it anyway, it's just
a matter of writing it down and sticking it on the bottle or the bag. It seems pretty simple to me.
CHAIRMAN
SIEGAL: Dr. Szymanski.
DR.
SZYMANSKI: We voted yes for the number
two, but even it's difficult to do the study unless you know how much antibody
you have. So even for that purpose you
had to have measured level in the bag to know how much to increase the
titers. So labeling is important.
CHAIRMAN
SIEGAL: I think one of the things we don't know at all, really, is how much
variation there is in the repertoire from one batch of gamma globulin to the
next except insofar as the subclass changes from one manufacturer to another
which is documented in one of the papers that we received.
DR.
COLVIN: As a small aside, something else
from the FDA, if you look at how the labels are on bottles like this, that
tells us exactly how much vitamin A. It
sort of makes sense to me that we would do the same thing in the case where it
might actually have a real impact as opposed to drinking this.
DR.
DI BISCEGLIE: A little off track, but I
think perhaps important for the Agency to consider is one of the uses of I
think the intramuscular preparation is post exposure prophylaxis of Hepatitis A
and the Agency may know the answer and I don't need a response from them but I
suspect that the titers of antibody to Hepatitis A in lots are declining as
with measles and it's something that I think should be looked at.
DR.
YU: We do have some data which is not
yet published and the HAV levels indeed are a little bit low and also depends on
type of plasma, if it's source plasma or versus recovered plasma. So recovered plasma a little bit lower.
DR.
GOLDING: Can I just mention that in
reference to a previous remark that in the Audet paper that is part of the
handout sheet, they studied 166 lots from seven manufacturers and the mean
values or the standard deviation are given there and they are close to a
threefold difference between the lowest levels of measles titer and the lowest
-- lots with the lowest levels to the highest levels. It's about a threefold difference.
CHAIRMAN
SIEGAL: But we don't know the
pneumococcal antibody titers for Type 3 Pneumococcus for example in those same
lots, do we?
DR.
GOLDING: No. I thought you were talking about measles.
CHAIRMAN
SIEGAL: I'm thinking in general about
the heterogeneity of antibodies that ones find in a given pool and how that
ends up in gamma globulin and how different each lot is with respect to that
because we're really -- I mean gamma globulin is essentially a black box and for
off-label uses it's certainly a black box unless we're talking about how much
anti-big D there is or how much isoglutinin there is at random there. But we don't even understand how it works as
was pointed out, and for most of the off label uses.
DR.
GOLDING: We agree with you and there was
a paper published by the FDA by my group which looked at titers of H. flu and
Strep pneumoniae among a large number of lots from different manufacturers. So there was a paper last year where we
looked at that, but we have been talking to the manufacturers to try and
encourage them to develop their assays and to use those assays for PK studies
to try and get to the point that I think you're aiming at and we have the same
goal.
DR.
BALLOW: One thing we haven't talked
about is education. So if we move
forward with this, I think we have to educate at least those individuals who
use gamma globulin and patients with primary immune deficiency disease to make
them aware that there are circumstances like travel abroad or mini epidemics
that might come along in certain geographical areas to be aware that they have
to increase the dose or give extra doses of gamma globulin in order to protect
our patients based on some of the data that we've heard. I think a lot of my colleagues probably don't
appreciate that at this point. So there
may have to be some education or maybe an addendum to the package insert of
these products.
CHAIRMAN
SIEGAL: One strategy that we could use
as clinicians is just to send off titers for 14 serotypes of pneumococcus in
our patients and see what we're getting.
All right. Are there any other
comments in this third question?
DR.
QUIROLO: I think your statement
underlies the fact that there should be labeling for the titers because the
clinicians say who was in a measles epidemic would know which product to
use. If you have no idea what you're
giving, how can you decide whether you're going give 400 or 800 mg of product
that maybe has a low titer?
DR.
BERGER: In all fairness certainly seeing
a higher titer might lead you to use a certain product in a certain situation,
but as we also see with measles, understanding the correlate of a titer done
with any given assay doesn't necessarily directly translate into predicting the
clinical efficacy of that preparation.
So this whole issue, I think, is a little bit more complicated than just
measuring titers by ELISA and putting them on the bottle like the vitamin
level.
CHAIRMAN
SIEGAL: Anyone else? All right.
Dr. Epstein, do you have any other comments or needs from us?
DR.
EPSTEIN: No. I wanted to make a very small comment in the
current context because the question was asked about is 0.48 times CBER
standard good enough for the future looking forward five years or ten years
from now and we have a little bit of information about that which is the
neutralizing titer of plasma pools in the birth cohort 1968 to 1972. That's close to 40 years post vaccination and
there is gravitation toward a level of 1 IU/mL or 1,000 mIU/mL in the pool
which correlates with the level that Dr. Golding said is what you would need in
order to end up with projected trough titer of 120 per mL in the recipient. So
I think that suggest to us that it is in fact a level that would remain robust
over time.
But
I couldn't agree more that if we have actual studies on administered dose and
trough levels obtained, we'll be in a much better position to predict where
things will end up. But that's just a
small comment in the larger context.
I
appreciate the deliberation of the committee and I think that FDA has obtained
the feedback that we need to go forward.
CHAIRMAN
SIEGAL: In that case I thank you all for
coming and this meeting stands adjourned.
Off the record.
(Whereupon,
at 4:29 p.m., the above-entitled matter was concluded.)