DEPARTMENT OF HEALTH AND
HUMAN SERVICES
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
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.
BLOOD PRODUCTS
ADVISORY COMMITTEE
DAY TWO
OPEN SESSION
Friday, March 18, 2005
Gaithersburg Holiday Inn
2 Montgomery Village Avenue
Gaithersburg, Maryland
Proceedings By:
CASET Associates, Ltd.
10201 Lee Highway, Suite 180
Fairfax, VA 22030
(703) 352-0091
TABLE OF CONTENTS
Page
III. Study Design for Abbreviated Uniform Donor
History Questionnaire
A. Background and Introduction - Dr. Orton 3
B. Study Design - Ms. Kessler 9
C. Experience with Abbreviated Donor History 31
Questionnaire
- Ms. Bassett
Open
Public Hearing
D. FDA Perspective and
Questions for the Cmt. 66
E. Committee Discussion
and Recommendations 67
IV. Review of Site Visit Report for the LMV,
DETTD
A. Introduction and
Background - Dr. Nakhasi 106
B. Overview of
Laboratory and Diagnosis and 112
Pathogenesis
of HIV Variant - Dr. Hewlett
C. The Molecular Biology
of HIV Infection of 123
Primary
Human Macrophages - Dr. Dayton
D. Viral and Host
Factors in the Pathogenesis 132
of
HIV-1 Infection - Dr. Dhawan
E. West Nile Virus: Pathogenesis and Diagnostic 140
Tools
- Dr. Rios
P R O C E
E D I N G S (8:35 am)
DR. FREAS: Good
morning and welcome to this, the second day of the Blood Products Advisory Committee. Just to open this morning, I do have a few
brief announcements, and I would like to read the conflict of interest
statement that is allegedly brief.
This brief announcement is in addition to the conflict of
interest statement, read at the beginning of the meeting on March 17, and will
be part of the public record for the Blood Products Advisory Committee meeting
on March 18, 2005. The announcement
addresses conflict of interest for discussions of topic III on the study design
for abbreviated uniform donor history questionnaire.
Ms. Judith Baker and Dr. Liana Harvath were appointed as
temporary voting members. Based on the
agenda, FDA has determined that there are no specific products being considered
for approval at today's meeting. The
committee participants were screened for their financial interests to determine
if any financial interests existed. The
agency reviewed the agenda and all relative financial interests reported by the
meeting participants. The Food and Drug
Administration prepared general matters waivers for participants who required a
waiver under 18 US Code 208. Waivers
were granted to: Dr. James Allen; Dr.
Donna DiMichele; Dr.
Catherine Manno.
Because general topics impact on so many entities, it is
not prudent to recite all potential conflicts of interest as they apply to each
member. FDA acknowledges that there may
be potential conflicts of interest, but because of the general nature of the discussions
before the committee, these potential conflicts are mitigated.
Dr. Louis Katz will be participating as a non-voting
industry representative acting on behalf of regulated industry for this
meeting. Dr. Katz' appointment is not
subject to 18 US Code 208.
With regards to FDA's invited speakers for today's
discussions, the following disclosures will assist the public in objectively
evaluating presentations and/or comments made by the participants.
Ms. Mary Beth Bassett is the Vice President for Quality
Assurance and Regulatory Affairs, Blood Systems Incorporated. Ms. Debra Kessler is Director, Regional
Services, New York Blood Center, and a member of AABB. FDA participants are aware of the need to
exclude themselves from discussions involving specific products or firms for
which they have not been screened for conflict of interest. Their exclusion
will be noted for the public record.
With respect to all other meeting participants, we ask in
the interest of fairness that you state your name, affiliation, and address any
current or previous financial involvement with any firm whose product you wish
to comment upon. Waivers are available
by request under the Freedom of Information Act.
And that's the end of the conflict of interest
statement. At this time I would like to
ask if you have a cell phone, that you would put it in the silent mode. The person sitting next to you would really
appreciate it.
Thank you.
DR. ALLEN: Good
morning. Topic III for the meeting, the
first topic for the day will be the study design for the abbreviated uniform
donor history. This has been an ongoing
development over several years. I'm
excited that it is moving forward, and hope that that momentum will be
continued.
Our first speaker with background and introduction will be
Dr. Sharyn Orton.
Agenda Item:
III. Study Design for Abbreviated Uniform Donor History Questionnaire -
A. Background and Introduction - Sharyn Orton, PhD, OBRR, FDA
DR. ORTON: Good
morning. I'm going to give you a brief
background, a little bit of information on the work of the task force on the
full length questionnaire, some of the history of discussion on the abbreviated
questionnaire.
Now, the AABB Donor History Task Force -- in 2001 this task
force submitted to FDA a proposal to revise the full length questionnaire. And this was a very intensive work
group. They used focus groups and
one-on-one cognitive interviews to assess donor comprehension of
questions. And they developed a very,
very large package that has everything to do with the donor history
questionnaire.
So, in 2002, they submitted their final materials to the
FDA, including the full length questionnaire that had been revised, medical
deferral list, educational materials, and an abbreviated donor history
questionnaire.
In 2003, the FDA completed their review and proposed to
accept the full length questionnaire, the medical deferral list, and
educational materials, but not the abbreviated questionnaire. And this is in the draft guidance for
industry that was published in April 2004.
Comments have been coming to the docket. FDA has received them.
They have shared them with the task force, and revisions have been
submitted. Right now, that final
process is under review.
Now, as far as the history of the abbreviated donor history
questionnaire, this concept has always been endorsed by FDA, certainly long
before I even worked there. I went back
and looked. In 1993 and 1994 there was
the AIR report. It was part of the 1997
blood action plan. In 1998, the FDA
approved the first abbreviated donor history questionnaire. In 1999, the FDA approached the industry to
develop a task force to include the evaluation of an abbreviated questionnaire.
In 2000, there was an AABB/FDA workshop that also included
discussion about an abbreviated questionnaire.
There was BPAC discussion in 2001.
In 2003, a second abbreviated questionnaire was approved by FDA. And in 2003, there was very extensive BPAC
discussion.
This particular BPAC, the discussion covered abbreviated
surveys in general, survey concepts and design, and survey participant
behaviors. Particularly, John Boyle(?)
presented some information and Paul Beatty(?) from the National Center for
Health Statistics. We discussed donor
motivation or lack thereof when answering questions; donor satisfaction and
retention; impact on blood safety; focusing donor attention to recent events;
the use of capture questions versus a series of specific questions.
And a lot of discussion included: the methods of abbreviated questionnaire assessment; including
comparison to rates for deferrals; infectious disease markers; post-donation
information; biologic product deviation reporting; post-transfusion disease;
whether we should look at things historically, prospectively.
We tried to incorporate information on the biologic deviation
reports that FDA had received at the time.
There was quite a bit of data given about that; what kind of data
collection and analysis and interpretation might be appropriate; potential
study designs. And there were many
opinions given by the major blood organizations.
The question to BPAC in 2003, was does current knowledge
support the use of an AABB uniform abbreviated donor history questionnaire as
an alternative to the current donor screening process for appropriately
selected donors? And the outcome was
that the BPAC members voted 1 abstention, 2 no, 10 yes, and the non-voting
member and industry representative voted yes.
So, why not accept the task force abbreviated
questionnaire? At the time there was
the use of one capture question for new medical events. And it was:
since your last donation have you had any new medical problems,
diagnosis, or treatments including vaccinations? And at that time Paul Beatty's group did do one-on-one cognitive
interviews with four subjects. And one
subject did not provide information on a significant medical event. And that particular individual was the only
one that had a significant medical event.
So, albeit a small sample size, we were somewhat concerned
that one out of four people in a capture question didn't provide the
information that was trying to be captured.
So, at that time we determined that some sort of assessment of the
abbreviated questionnaire compared to the full length should be performed.
We certainly support measures to improve the predictive
value of the donor screening process, including use of an abbreviated
questionnaire. That is our primary goal
as well. So, the AABB task force today,
Debbie Kessler is going to propose a study design for assessment of two medical
capture questions on the abbreviated questionnaire.
In addition, Mary Beth Bassett is here from Blood
Systems. They were the second blood
center that was approved for an abbreviated questionnaire, and she is going to
update the committee and the audience on their experience with it.
So, the questions to BPAC today are: (1) does the committee agree that the
proposed study design (exclusive of sample size) is adequate to reasonably
demonstrate equivalence (or lack of equivalence) between the two capture
questions on the abbreviated questionnaire, and the 17 specific questions on
the full length questionnaire?
This is in fact 16 questions. It has been changed since I made my slide.
Two, and if yes, does the committee agree that the proposed
sample size adequate? Three, if no,
what alternative study design and/or sample size does the committee propose
would be adequate?
Thank you.
DR. ALLEN: Dr.
Schreiber.
DR. SCHREIBER:
Sharyn, could you expand on what the one out of the four were
deferred? You said it's a significant
medical event. Can you tell me what was
significant?
DR. ORTON: Debbie,
are you going to address that? She's
going to address that in her presentation.
DR. SCHREIBER: The
other question I had is when we hear the ASCP proposal, are they using the same
abbreviated form?
DR. ORTON: No, they
have their own. And Mary Beth, are you
going to address how similar it is? No.
MS. BASSETT: My
name is Mary Beth Bassett from Blood Systems.
I don't have in my presentation, an actual comparison between the
abbreviated process that we use, and what the AABB is proposing. But we can talk to those similarities. I can let you know how many capture
questions we have, what criteria we use for determining our frequent donors,
and that kind of information after we hear from Debbie and my presentation.
DR. ALLEN: Let me
just ask my question also, although it probably will be addressed in the later
presentations. And that was in the four
people, the one with the medical event or of the four that had the cognitive
interviews, I assume that none of them also then had the full length
questionnaire first. So, we don't know
if the full length would have picked up the event.
DR. ORTON: No, we
don't.
DR. ALLEN: So,
there is that. It's hanging out there
as it was something that was considered significant that came up on a cognitive
interview that wasn't picked up.
DR. ORTON: I need
to clarify too, Jim, in the cognitives, they go question by question, versus
giving one questionnaire and then given another questionnaire. It is done somewhat differently than in real
life the way the questionnaires are given.
DR. ALLEN: Other
questions for Dr. Orton before we move onto the presentations? Thank you.
Our first full presentation descriptive of the new study
will be by Ms. Debra Kessler, Donor History Task Force, and Director, Regional
Services, New York Blood Center.
Agenda Item:
III. Study Design for Abbreviated Uniform Donor History Questionnaire -
B. Study Design - Debra Kessler, RN, MS, Donor History Task Force &
Director, Regional Services, New York Blood Center
MS. KESSLER: Thank
you for inviting me today.
I'm just going to give a brief overview of where we are
today. As Sharyn mentioned, the process
to design the full length donor history form in 2000. FDA asked the AABB to work on it. There was extensive collaboration between numerous
stakeholders. We had blood centers,
including independent blood centers, Red Cross, FDA members. There were experts in creating
questionnaires. It was a very broad
group of committee members. And a
groundbreaking approach to design, and for the first time a blood screening
document was systematically evaluated.
The old uniform donor history form, which was the previous
one that AABB had was a very different document from the current donor history
form. You notice we dropped the uniform
part of it, just calling it donor history form. Questions were complex.
There were compound questions.
And it didn't follow any identifiable order of time when we were asking
the questions.
The task force made many changes in the new DHQ. Eliminated a number of questions that were
not required by either FDA or AABB.
Local blood centers could decide to put some questions back if they felt
it was important. We broke up compound
questions. Pretty much every question
asks about one thing. We simplified the
language. And we restructured the
format into time periods that begin at the present, and go backwards in time.
Changes were made with the input of these experts in the
fields of questionnaire development and reading comprehension. We had focus groups to review the new
questions, and individual cognitive interviews by NCHS were performed to
validate that the questions elicited the information that we intended to get.
In June 2002, the Blood Products Advisory Committee
unanimously endorsed the full length donor history questionnaire. And in April 2004, the FDA issued a draft
guidance. In December 2004, there were
questions to the docket about the draft guidance, and the committee submitted
responses to these questions. And we
had revisions, so that the donor history questionnaire is now Version 1.1, and
revisions also to associated materials.
And currently, the donor history questionnaire is in use in many
collection sites.
So, the next steps, AABB will receive any feedback from FDA
regarding the revisions and the new Version 1.1. We'll issue the revised materials from the AABB, and FDA should be
ready soon to issue final guidance on the full length donor history
questionnaire.
Just to let you know how it is being used so far, it is in
use in at least 19 ABC blood centers. A
survey was recently done, and currently in 2 Red Cross centers. An additional at least 28 ABC blood centers
and the entire Red Cross system will go live with the full length donor history
form in the next 12 months. So, a great
number percentage of the country will be using the full length form.
Now to the abbreviated donor history questionnaire. Just in terms of what the response was from
blood centers about whether or not they would like to use it, at least 39 ABC
centers and the entire Red Cross system plan to use the abbreviated donor form
when it's available.
Currently, all donors answer all questions at every
donation, including non-repeatable events.
The abbreviated questionnaire eliminates non-repeatable event questions;
it identifies recent changes in health, travel and behavior; and it retains
questions about risk-associated activities that might have changed since the
last donation.
There is precedent.
As Sharyn mentioned, there are two blood centers that have approved
abbreviated donor questionnaires. Mary
Beth is going to talk about Blood Systems.
But their model is exactly the kind of model that we are proposing for
the AABB form. They do have a medical
capture question that eliminates a number of medical questions on the full
length form, and Mary Beth can explain more about that to you.
What we hope to accomplish is that the safety and efficacy
is equivalent to the full length form; that donor satisfaction is increased for
frequent blood donors; and that maybe, and nobody knows if this would happen,
there would be an increase in the availability of blood, because people would
feel that the process is simpler.
The abbreviated form is based on the full length form, and
the full form is, as you know, a validated document. The testing of the abbreviated capture approach for recent
changes in health status was performed by NCHS on four subjects in one-to-one
cognitive interviews. And at that time
there was only one capture question.
This is what you were asking about before. Since your last donation have you had any new medical problems,
diagnoses or treatments including vaccinations?
The capture questions in the cognitive interviews were
performed only four people due to the lack of resources, but we wanted to get
some testing done. And while this was
not a full, large scale test, the preliminary findings generated optimism that
the approach was worth pursuing.
Now, the event that wasn't reported was a miscarriage. The question, pregnancy in the last six
weeks, is not one of the questions that is being rolled into capture
questions. It is asked on the
abbreviated form, as well as the full length form. The person who answered the question could have just as easily
missed it on the full length form as the abbreviated form. So, while that was a concern, it wasn't
exactly the issue that was captured in this interview process.
We want to have equivalent safety to the full length
form. We want to increase the donor
focus on recent events and behaviors, instead of directing their attention to
things that have happened long ago. And
as you can see, some people you may know, Alan Williams and Sharyn Orton, have
said in writing that, "behavioral risk screening needs to be optimized to
query donors about factors that best predict recent infection."
Again, with equivalency of safety, we want to increase the
donor attention by reducing the time it takes to complete the screening. Whether or not this will increase the
availability of blood, we don't know.
Maybe these factors would influence that, increase donor satisfaction,
decrease phenomenon of lapsed donors, and increase frequency of donation. That's yet to be seen.
Now, which donors will be eligible for using the
abbreviated form? The definition of a
frequent donor is someone who has successful completed the full length form at
least twice, so they have seen all the questions at least twice, and that the
next donation after, or at least one of the donations are within the previous
six months. So, they have been exposed
to all of the questions the last time within the last six months.
The donor will answer all the questions. Anecdotal evidence indicates that donors may
remember information at the second donation that they didn't remember at the
first, however, this is less likely to occur after a second experience with the
questions.
Now, in the development of the abbreviated form, again, the
full length validated form was used as the basis. We did question by question consideration. We deleted questions for a single risk in
the past. For example, from 1980-1996
were you a member of the military, civilian military employee, et cetera? So, once they have answered that, that time
period is gone now. So, we eliminated
questions like that.
We consolidated travel questions into a single capture
question about recent travel, consolidated medical questions by use of two
capture questions. After the cognitive
interviews we went from one to two separate questions. The HIV and hepatitis risk questions remain
intact. Those will not change.
As you may remember, in December 2003, as Sharyn mentioned,
the question was put to BPAC about whether the current knowledge supported the
use of the AABB abbreviated form. And
the vote was pretty strongly yes, that we should be able to move ahead with it.
Nevertheless, here we are.
FDA requested that the task force develop some kind of
pre-implementation study to compare the full length and abbreviated form as
related to the medical capture questions.
And this was based on that concern with the cognitive interviews where
the pregnancy was not brought up. But
again, maybe it wouldn't have been anyway.
So, the abbreviated donor history form study. A subgroup of AABB Donor History Task Force
met and we had representatives from AABB.
We had FDA on the committee, NCHS, and various blood centers. Actually, we had CDC on the committee too, I
just recalled.
The study objectives are to determine whether the two
medical capture questions identify deferable risks as well as the full length
form, compare responses to the two medical questions with responses to the
questions they cover in the full length questionnaire, and identify reasons for
discrepancies between the answer provided to the capture questions, and the
full length questionnaire using cognitive interviews. That is our main source of analysis is cognitive interviews.
The two medical capture questions are since your last
donation, have you had any new medical problems or diagnoses, and had any new
medical treatments?
This is the list of the questions from the full length form
that are being rolled into these capture questions. We're asking if they are on an antibiotic, if they are taking any
other kind of medication for an infection.
We're asking in the past 12 months have you had a blood transfusion,
transplant, graft, been treated for syphilis or gonorrhea?
And have you ever had a positive test for HIV, and
basically the risk questions for infectious disease, dura matter transplant,
cancer, problems with your heart or lungs, bleeding condition or blood
disease? Now, again, those are the
questions from the full length form that will be rolled into those two capture
questions.
The study sites where the blood centers have volunteered to
run the study are the New York Blood Center, Hoxworth Blood Center, Gulf Coast
Regional Blood Center, Mississippi Valley Regional Blood Center, and the Red
Cross, Lewis and Clark Region. The
centers were selected to represent a mix of the US geographic areas.
Two hundred and fifty donors from each center who meet the
definition of the frequent donor that I mentioned to you before, the sample
total would be 1,250. And the final
sample will include donors with the full range of the 6 month interval from
their last donations. So, we are not
going to just take apheresis donors. We
are going to take whole blood donors also.
The process is that the donor will be enrolled by
designated blood center staff, and given informed consent. The donor will fill out the abbreviated form
first, return it to study personnel, then they will fill out the standard full
length form. The study personnel will
evaluate the two documents for discordant responses.
During the study the donor's eligibility to donate will be
based on both questionnaires. So, if
information shows up on one, but not the other, it would be included in the
evaluation of their eligibility that day.
If discordant responses are found, the donor will undergo cognitive
interview either on-site right at the time, or as soon as possible, which we
have said should be within three or four days by telephone. And the interviews will be audiotaped.
Each center will provide two staff members for cognitive
interview training by the NCHS staff.
Blood center staff will be selected based on those with skills that lend
themselves to cognitive interviewing such as donor counselors that do HIV
counseling, et cetera.
The data evaluation.
The audiotapes will be transcribed, and the transcriptions, and if
needed by NCHS, the audiotape will be evaluated by NCHS. The demographic and discordant responses
will be entered into a database for evaluation.
Our timeline, May 3, we have a tentative date for
scheduling the cognitive training of blood center staff. June through December we will execute the
protocol at the blood centers. In
January 2006, there will be transcription of the cognitive interviews. February/March 2006, NCHS will do the
analysis of the cognitive interviews.
And May 2006, we would hope to have submission of results to FDA.
Now, we want to focus on the fact that cognitive
interviewing is really our main evaluation tool. It's understanding how people use the capture questions, and
whether it works as well as the full length form.
The cost burden, the cost to AABB, there will be
interviewer travel for training, interviewer training and analysis of the
cognitive interviews by NCHS will be paid by AABB. They will need to have a study administrator, and do data
entry. For the blood center there is
study personnel time and materials.
This is an unfunded study, so this is all voluntary use of funds by the
centers and by AABB.
In conclusion, the abbreviated form was developed at the
request of the FDA. It received BPAC
endorsement in 2003. At the request of
FDA the task force has developed a study for the abbreviated form. This is not intended to be an epidemiologic
study. The emphasis for evaluation is
on the cognitive interviews, and post-implementation evaluation will additional
data.
And if I can also say that we have, and we'll hear from
Mary Beth about Blood Systems, in a way we have kind of piloted the whole
concept, because Blood Systems has been doing this for quite a while. So, we see from what Mary Beth will tell us,
how it's working so far.
Thank you very much.
DR. ALLEN: Thank
you for the overview.
A quick question.
On the abbreviated questionnaire capture questions, if somebody responds
yes, there has been a medical event or whatever, the process then would be to
do what? Administer the full length
questionnaire? Have the data collection
person interview them to find out what it was, and make a decision as would be
done for the full length questionnaire?
How is done?
MS. KESSLER: During
the study they will fill out the abbreviated form, and then fill out the full
length before any evaluation is made.
Let's say we were implementing, and we just had the abbreviated
form. The health historian would be
required to follow-up on what was the medical condition to determine
eligibility, as they do with many questions in the current full length form.
You may not remember, but we have support documents for the
abbreviated questionnaire including flow charts for the questions like we have
for the full length questionnaire as support material for the blood center
staff.
DR. ALLEN: And I
thought that was all very complete. I
guess my question was really much more assuming that it's accepted at some
point and implemented, what would be the process once the capture question is
flagged as a yes?
MS. KESSLER: There
would have to be follow-up interview by the health historian to determine what
was the condition, when was it, and would they be eligible or not.
DR. ALLEN: Other
questions or discussion?
DR. DOPPELT: In
regards to the discordant responses between one form and the other, are the
cognitive interviewers just asking additional medical information? Or are they specifically asking why is it
that you answered this question this way and that question that way?
MS. KESSLER: Yes,
it's the latter. They will be asking
what was their understanding of the one question, versus the full length question. It will be similar to the way NCHS did and
does cognitive interviews for evaluating answers to all questions. It was how do people understand the
questions, and what motivated them to answer one way or another.
DR. EPSTEIN: I
have, Debbie, a question about the questions, the capture questions. The first is had any new medical problems or
diagnoses. And I'm wondering how that
language was selected, and whether the alternative of had any new health
problems or medical diagnoses would be more effective. Because if you ask if someone had a medical
problem, you are asking them to make a judgment about what happened to their
health, whether it was medical. And
health I think is a little bit broader.
Now, I'm not a questionnaire expert, but the issue is how did this
particular language get selected?
MS. KESSLER: I
don't really that saying health problems was really discussed. It was always focused on medical problems or
diagnoses. But we can take that
suggestion under advisement.
DR. DI MICHELE: I
just want to first of all say that this is a major undertaking, and I really do
congratulate you on taking on this study.
And I do certainly understand why it's important to do so. I also do not want to, in my questions that
follow, do not want to do what the PPTA is going to say that we can't make the
perfect be the enemy of the good. And
I'm not going to suggest that as well.
But just with respect to study design, I have a couple of
questions. And is this an appropriate
forum to ask those questions?
DR. ALLEN: I think
let's ask for clarification now, and we'll have a chance as a committee to
discuss it. I would rather get through
the other presentations first. George
Schreiber has been asked to look at it, and he has got a brief overview. So, if we want to get into extensive
discussion of study design, I would prefer that we delay that just a little
bit.
DR. DI MICHELE:
Okay, then I'll just ask some general questions then. When the interviewer goes to do let's say
the telephone interview, how will the confidentiality of the subject be
maintained?
MS. KESSLER: The
donor has signed consent saying that they would be interviewed, possibly over
the telephone. How the tapes would be
handled, only study personnel could listen to them, and the usual
confidentiality safeguards are put in place.
But they are told up front.
DR. DI MICHELE: I
saw that consent. But like the
telephone interviewer calls and says may I speak to?
MS. KESSLER: Right,
to the name of the donor.
DR. DI MICHELE: So,
they will have the name of the donor.
MS. KESSLER: Oh,
yes.
DR. DI MICHELE: It
won't be just the study number.
MS. KESSLER: No,
they will have the name of the donor.
DR. DI MICHELE: One
other quick question. Will the method
of recruitment allow for all age demographics to be included, so that you can
look at the younger donors who is answering these questions, versus the older
donors?
MS. KESSLER: Yes,
we really intend to get as broad a representation of donors as we can.
MS. BASSETT: Mary
Beth Bassett from Blood Systems.
I just wanted to let the committee know in answer to your
question the medical capture question that Blood Systems has been using says
have you had any new medical conditions or health problems?
DR. ALLEN: Other
questions? Yes, Ms. Baker.
MS. BAKER: Thank
you.
As a repeat donor, actually the first time I was ever
confronted with the possibility of donation, I walked out after seeing the long
form, and being very intimidated by it, although I have a great deal of survey
experience myself, because I found it very awkward, no coherence, and not
somebody who is squeamish or unexposed to the medical profession for over 20
years. But I have since become a repeat
donor, and I do see that the thought of an abbreviated questionnaire would be
terrific.
A couple of questions.
For this particular study would eligibility require people who have
telephones?
MS. KESSLER: Not
necessarily, because they could be interviewed on-site if the blood center is
set up to do it.
MS. BAKER: And in
case you cannot interview them on-site, what is your timeframe for the
telephone? Is it three days, a week?
MS. KESSLER: Three
days is our intent.
MS. BAKER: But you
don't have a firm cut off for a week?
I'm thinking about donor recall.
MS. KESSLER: Three
days is the intent, but we didn't want to be completely inflexible, so it's as
soon as possible.
MS. BAKER: And
primary English speakers? If English is
not your primary language, have you given some thought to eligibility or
non-eligibility?
MS. KESSLER: That
would also be something that the local blood center would determine that they
could do, some blood centers where they might have Spanish as an available
donor history form, could do it in Spanish as well.
MS. BAKER: And did
the committee look at low literacy? And
having this go through a screening for low literacy?
MS. KESSLER: That
was thought about when we developed even the full length form. And in that case, if for any reason a donor
doesn't comprehend, because they can't read, because their language skills are
bad, the blood center can administer the form verbally. So, the health historian can just read the
questions to the donor. That can be
done with the abbreviated or the full length form, and that is part of the
user's guide and the process of how either form would be used.
MS. BAKER: Great,
thank you.
DR. ALLEN: But what
you raise is certainly a very important question in general to the whole
donation process of capturing information correctly, whether it is full length
or abbreviated.
MS. BAKER: Are
these questionnaires that we are proposing to use, are they not standard
throughout all blood collect sites throughout the US?
DR. ALLEN: No, each
blood collection center that has a license, and the Red Cross for example has
one license for all of its centers, each license holder has its own version,
and it may or may not be part of the uniform or other. But they are all reviewed and approved by the
FDA.
DR. LEITMAN: This
is a suggestion. We all grapple with
the best phrasing for medical capture questions, that most likely to make the
donor remember something that happened in an interim period. And what we use, which is extremely broad,
and just as a suggestion is since your last donation, have you been under a
doctor's care? And sometimes that helps
jog memory. It sounds like you have
validated these two also, but if again something comes up in your next study,
that tends to be more of a broad question.
MS. KESSLER: Thank
you.
DR. LEW: I don't
think there is one perfect one, because I can tell you in our medical
interviews that we do for every single patient, we also ask have you ever seen
the doctor, or had any medical care?
And then later we go on for the full review of systems dot by dot. And I can you there is no perfect
question. Sometimes they will say yes
on one or no, and then later they are all positive. You have just got to do your best.
MS. BAKER: One more
question. Can you comment on what would
be the trigger for assuming this all would pass, and we have an abbreviated
questionnaire, who would decide when the abbreviated questionnaire would be
implemented? For example, if you don't
just donate blood at one site, would it be the blood donor site? If you only went to one blood donor site,
then perhaps they would have a record and a date to validate that this is the
six month window. We could approach
this person with the abbreviated questionnaire. But if you are not going to the same site for donation, who would
determine, oh, yes, I'm within my six month window?
DR. ALLEN: Well,
the six month window would have to be within a given system. And as Ms. Bassett will tell us in a little
bit for example, you can go to any one of the Blood Systems sites and the information
is available online. Now, if you go to
another center operated by a different blood collection center, then it's a
whole different system. So, it would be
dependent on being within the same system.
Dr. Orton, do you want to address the question of the FDA
process for approval?
DR. ORTON: We have
actually a checklist. Any of the
questions or information that are required by FDA, we have a checklist
for. If any blood center chooses to use
the current AABB donor history questionnaire, and that's in recipe that they
are including that information, then we make sure that that they adhere to
it. But how exactly questions are
worded, if we have at FDA, required some wording, what order the questions are
in, we don't give information for that.
So, our checklist is basically are the items asked, not
anything to do with whether it's a compound question. Some places may have three or four questions, others have
compounded to one. We do not make any
comment on that.
DR. ALLEN: Other
questions?
DR. SCHREIBER:
Debbie, the way it's structured now with the capture questions, it's
conceivable that the abbreviated one could pick up conditions that you are not
interested in excluding people as donors.
For example, I tried it out on a couple of people, and it picked up pap
smear, mammography in those capture, and colonoscopy. But these are not questions that are on the full length.
So, are you going to do some kind of pre-screening to try
to get rid of those people, and not reflux them into the cognitive interview
before? It would seem that it's very
non-specific, and you could wind up having a lot of people that you are going
to do these interviews in that you are going to get any yield from.
MS. KESSLER: I
don't think we have actually thought about that. I think that's something that we should think about before we go
with the study. But that's a good
suggestion.
DR. ALLEN: I'm glad
you brought that up, because that was actually my major concern about the study
design, was that the capture question -- the Venn diagram has a lot of areas of
non-overlap, and certainly within the process of making a decision of whether
or not that person is eligible for a donor, that can be screened out subsequently
during the history taking process.
But the interview process, that's another one that does
need to be clarified. It may be a point
that we would want to discuss as a committee and make a recommendation on to
the AABB, I don't know.
DR. SCHREIBER: One
other question. I have to hark back to
those famous four. How were they
selected to start with? Where did they
come from?
MS. KESSLER: They
were blood donors selected by NCHS.
DR. SCHREIBER: You
just randomly pulled four?
MS. KESSLER: They were
people who fit the criteria. They had
donated blood twice with a full length form, and the last donation was within
six months.
DR. HARVATH: I'm
just curious. Did you say that you
would always have the donor answer the abbreviated history question first, and
then the full length later? And I
wondered if there was any discussion about considering randomizing of giving
the -- randomizing between some people addressing the full length first, and
the abbreviated second? I'm just
curious about that.
MS. KESSLER: No,
because we want to see if the full length captures all of those
conditions. So, we didn't want to
trigger somebody by seeing the full length form first, and then having that
contaminate the abbreviated form.
DR. ALLEN: Okay,
all of the considerations. Thank you
very much. And I'm sure that we will be
asking you further questions later.
Our next presentation is experience with the abbreviated
donor history questionnaire at Blood Systems, Mary Beth Bassett, Vice President
of Quality Assurance and Regulatory Affairs.
Agenda Item:
III. Study Design for Abbreviated Uniform Donor History Questionnaire -
C. Experience with an Abbreviated Donor History Questionnaire - Mary Beth
Bassett, BS, Medical Technology (ASCP) and Microbiology, Vice President of
Quality Assurance & Regulatory Affairs, Blood Systems, Inc.
MS. BASSETT: Thank
you for inviting me to speak on Blood Systems' continued success with the
abbreviated donor history questionnaire process. Just a little bit about Blood Systems. We are the parent company of United Blood Services. We operate 18 blood centers in 12
states. We collect about 1.1 million
units of red blood cells, and about 120,000 units of platelet pheresis on an
annual basis. We have two consolidated testing laboratories and a research
institute in San Francisco, and we are the nation's second largest blood
collection agency.
We believe that the use of the abbreviated questionnaire is
important, and has benefitted our donors and our organization. We began implementation of the abbreviated
process in August 2003, so the experience and the data that I'm going to share
with you today is from that point, current.
In the interest of my time allotted, there are some slides
that you will have in your handout that I'm not going to speak directly to
today.
In 2003, I presented to BPAC, and that presentation
included why Blood Systems had implemented the ADHQ process. I told you the reasons were to improve
customer satisfaction; increase donor retention; increase our donation
frequency; and increase blood availability.
And those still are our reasons today.
I reported on our policy for repeat, frequent donations,
and that is three allogenic donations previous, and one of those has to be in
the last six months.
I have data to provide for you for three months of data
related to medical history deferrals, temporary deferrals, biomarker deferrals,
post-donation information, and our error rate.
And that information I will update for you for current information.
And lastly, I also presented some information from a donor
survey. So, today, I'm going to talk
again about a donor satisfaction survey that we recently conducted. I'll compare some of the results from our
abbreviated, and our full questionnaire, and provide you some new data that we
have on post-donation information, and on apheresis platelet donors.
The first thing I want to talk about is the donor
satisfaction survey. This was a survey
that we conducted in fourth quarter of 2004.
It really was a study and a research that we had done that was part of a
more general survey that we had conducted about the whole donation
process. But out of that survey, 750 or
42 percent of those that we talked to actually responded to the question, if
you could change one thing about your donation process, what would it be?
This chart really illustrates what the answer to that
question is, and it really shows the desire of donors for a more efficient,
less time consuming process. You can
see that 82 percent of the time the donors were asking for some kind of change
in the donor process. Fifty-five
percent wanted it shortened; 27 percent asked for it to be speeded up. So, this data really does point us to having
a need for blood centers to find a safe way to streamline the donation process.
Now, to just confirm for ourselves that our abbreviated
process was answering some of these concerns from our donors, we actually
conducted another survey in March 2005, so this month. This survey though, was conducted with
people that were eligible for the abbreviated questionnaire.
Our objectives were to determine if the donors are more
satisfied and more likely to donate in the future if they received the
abbreviated questionnaire. We completed
250 interviews for those donors who were eligible and actually received the
abbreviated questionnaire, and also 250 were interviewed for those that were
eligible, but received the full questionnaire.
Both groups got the same interview, and the results are statistically
significant.
These are the results.
Donors from both of the groups were asked to rate the person that
greeted them. They were asked to rate
the interview process, the phlebotomist, and their overall experience. And these were asked by four different
questions. A rating of 5 was considered
excellent, and this chart only focuses on the excellent responses. And as you can see, the donors who actually
got the abbreviated questionnaire responded had more excellent responses than
those that received the full questionnaire.
This really parallels the data that I presented last time
to the BPAC, and it is relatively interesting, because the only thing that
really changed in the process was shortening the interview. But for donors who got the abbreviated
questionnaire, they rated everything as better.
Since we were doing a survey, we wanted to try to get
information about what the commitment the donors might have to future
donations. And we asked the question,
do you plan to donate blood in the coming months? As you imagine, these are really very experienced, repeat donors,
and so most of them did indicate that they would donate again.
However, there was one thing that was relatively
significant. Five percent of the donors
receiving the full questionnaire were not sure that they would donate
again. And for those that got the
abbreviated questionnaire, only 1 percent were not sure.
Now, I would like to take us into the data that we have
collected. This is an update of
information from the last time I presented at BPAC. We actually analyzed data from 3 time periods, and there are 20
day time periods. The first started in
October 2003, ending November 20, 2004.
The number of donors that presented and opportunities we
had to review the records you can see ranged from 53,000 up to 57,000. Our donor eligibility, those that are able
to have the ADHQ, remained pretty consistent at 32-33 percent. But you can see our actual usage, that means
those that were actually eligible for the questionnaire and got the
questionnaire increased from 48 percent to nearly 76 percent.
This table is really a summary of all of those three time
periods that I just talked about. What
we have here is a total number of 165,786 donors. So, these are the records we had an opportunity to review. You can see 42,644 of those are first time
donors, so they are not eligible for the ADHQ.
Our repeat donors were 69,000 and those were repeat donors that also
were not eligible. And then those that
were eligible for the abbreviated process was 53,996.
The next line down is medical history deferrals. You can see here first time donors, we had a
medical history deferral rate of 5.64; repeat donors not eligible is 2.2, and
medical deferrals for those that were eligible for ADHQ was 0.50. Now, this did not change from the last time
I reported to you, and really isn't probably surprising to most of us.
This next line, temporary deferrals is really deferrals
that are related to blood, pressure, temperature, plus, hematocrit, and really
doesn't influence the abbreviated donation process, but it does continue to
reflect that even though the donors are part of the abbreviated process, they
have been frequently screened, and therefore they are less likely to have
health issues in subsequent donations.
You can see here we had 14 percent first time donors that
had temporary deferrals. We cut that in
half at our eligible for ADHQ to 7 percent.
Confirmed positives shows similar results, 0.92, 0.13, down
to 0.02 for those that are eligible for the abbreviated process. That is about 40 times lower for abbreviated
donors.
This final row is post-donation information. You can see that that information stays
pretty consistent: 0.15, 0.19, 0.15
here. So, there isn't a lot of
difference related to post-donation information. Shortly, I've got some additional information around
post-donation information that I will share with you.
This chart just takes a closer look at the donors that were
eligible for the ADHQ. Remember, that
number was 53,996. You can see that out
of that, 32,000 or 60 percent actually got the abbreviated questionnaire, and
40 percent received the full questionnaire.
Again, moving from right to left, you can see that the
rates of medical and temporary deferrals in the donors receiving the full
questionnaire is slightly higher, but all of the numbers between both groups
remain very close and very low. There
is very little difference between the confirmed positive and the post-donation
information.
In one of our previous discussions we had the concern that maybe
the platelet pheresis were influencing some of the rates in these groups. So, we looked at that, although our size is
really quite small. The number was
again, 53,996, and we only had eligible for the ADHQ that donations were less
than 8 weeks of 8 percent or 4,274.
So, the platelet donors are a much smaller portion of our
data set. And their deferrals rates are
pretty similar. We don't think there is
really an impact on the overall documents or the overall rates. Again, the rates of the medical history and
temporary deferrals are low. The
difference in the medical history and deferral rates here though you can see is
higher. There really isn't much
difference going on between these.
This next information is around the post-donation
information. We actually took the
November 1 through the 20th timeframe and looked at all of the post-donation
information that we had received. And
that was a total of 120. So, this is
not just for abbreviated or just for full.
It's all of the post-donation information that we received in that
timeframe.
What you can see here is 50 percent of the post-donation
information we got from donor call back; 34 percent we got from donor deferral
or information that the donor provided us on a subsequent donation; 11 percent
came from telerecruitment; and 5 percent were generated from third party.
Now, we wanted to ask ourselves did the donor know this
information at the time that they were giving their health history? And we found yes to that. So, there were 37 out of that 120 where the
donor really knew that information.
This 77, they couldn't have possibly known. They got flu or sick or some kind of an illness after the fact.
So, if you look at those 37, the majority of the cases, you
can see 24 here out of the 37 are related to travel or resident risk either for
malaria or new variant CJD; 4 cases were related to medicine, and 3 were
related to medical condition.
Then we wanted to take the analysis one step further. We wanted to ask ourselves how many times
might a donor withhold deferring information?
And is either the abbreviated or the full questionnaire clearly better
at discovering deferring information?
And this is what we found.
Twenty-four donors out of that 37 didn't provide
information on one occasion; 21 of those 24 didn't provide that information
using the full questionnaire; 3 used the abbreviated questionnaire. We had 4 donors that didn't provide that
information on 2 occasions; 3 of those donors were screened twice with the full
questionnaire, 1 was screened once with the full questionnaire, and one with
the abbreviated questionnaire.
We had 4 donors that didn't provide the information on
three occasions; 3 of those were screened 3 times on the full; 1 was screened 2
times on the full; and 1 on the abbreviated.
So, this slide just shows more of the same. You can see that we have 5-6 times that
donors were not providing us the information.
You can see that just on this slide, the full questionnaire failed 13
times, and the abbreviated questionnaire failed 3 times. So, really what does this mean? What is this telling us?
This doesn't tell us definitively which questionnaire is
better at discovering the deferring information, but it does tell us something
that we all know. Not even the full questionnaire
is 100 percent at getting deferring information from our donors.
This is just to provide you the error rate from the time
that we implemented ADHQ until fourth quarter of 2004, and you can see the
learning curve here. We had an error
rate of 0.23 percent; fourth quarter of 2004, our error rate is 0.008 percent.
So, in conclusion, our experience to date is that donors
want a shorter process, and they like our abbreviated questionnaire. One-third of our donors are eligible, and
three-quarters of those donors are actually getting the abbreviated
questionnaire.
There doesn't appear to be data that indicates the
abbreviated process increases risk. It
doesn't appear that platelet donors are biasing our analysis. The analysis of PDI shows that donors
withhold information during both the full questionnaire and the abbreviated
process. And our root cause and
implementation has really reduced our error rate.
Just a thank you to my collaborators who helped me put this
presentation together and really analyze the data. And my thanks to all of you for letting me share our experience.
DR. ALLEN: Thank
you very much.
I've got a couple of questions, Mary Beth. First, when you talk about withholding
information from either the full length or the abbreviated questionnaire, for
example with variant CJD, what you are talking about is somebody who says,
well, yes, if you add it all up, I was in England for a total of eight months,
and I forgot about it.
MS. BASSETT: Right,
it's those kinds of things that are difficult for the donors to actually
remember and calculate.
DR. ALLEN: And
second question, when you have got a group of donors that are eligible to
receive the abbreviated questionnaire, why do only 60 or 70 percent get it, and
not closer to 100 percent?
MS. BASSETT: It's
because of the implementation. It's not
fully implemented at all of the centers, and the rate of implementation may be
more at fixed sites than it is at mobiles.
So, we do have some population of our donors that are eligible, but not
getting it just because we are not offering it yet.
DR. ALLEN: Okay,
fine. Dr. Lew.
DR. LEW: Two
questions. One is you showed kind of
striking information, except I don't have the denominator, unless you mentioned
it, and I didn't catch it. When you
mentioned how many times the donor may not reveal deferring information, you
point out more persons who took the full form in terms of absolute numbers left
out information, compared to those who took the abbreviated form. But I don't know how many people got the
full form, what percentage of those.
MS. BASSETT: What
are you looking at?
DR. LEW: You last
couple of slides, when you talk about how many times a donor may not reveal
deferring information. And you say 21
of those who took the full form, versus 3 who took the abbreviated
questionnaire did not reveal certain information that you got back I guess on
follow-up interviews. Are you getting
what I'm saying?
DR. ALLEN: There
isn't a single denominator figure, if I understand.
DR. LEW: But then
this is meaningless. What I'm trying to
point out is that if you gave 5 million people the full form, and only 21 on
follow-up made a mistake, and then you gave 5 people the abbreviated
questionnaire, and 3 out of the 5 made a mistake, that is a huge
difference. Without a denominator, I
don't know how to interpret these two slides.
DR. ALLEN: I
basically agree with you, but let me I think explain what happened in this
instance. If somebody has been coming
in as a repeat donor, and received the full length questionnaire let's say four
or five times, and then the abbreviated questionnaire was put in, and maybe the
second time they used the abbreviated questionnaire they recalled, gee, I
forgot about the time I was a graduate student over in England. Did that really count? Yes, I guess it was 1980, so I forgot about
it.
What they did was to then go back. All right, the information came up here at
the second time of the abbreviated, so they went back and then looked at all
the prior donations, and even though the questions were asked, none of those
prior ones elicited it. So, it's not a
formal study. It is basically an
experience analysis, where suddenly you get discrepant information. And I think that --
DR. LEW: I guess I
would have preferred just to say it's clear even when you use the full form
people make mistakes, just as when you use an abbreviated form.
MS. BASSETT: That's
correct.
DR. LEW: I know,
but the way it was presented, it wasn't quite that way. The other question I had was you did show
that when you did the comparison between the abbreviated and full form, there
was just a slight, but statistically significant increase in medical deferrals
with the full form. Did you all follow-up
what those medical deferrals were?
MS. BASSETT: Dr.
Kamal, can you respond to that?
DR. KAMAL: Hani(?)
Kamal from Blood Systems. No, we don't
have a breakdown to what questions these medical deferrals were for.
DR. DI MICHELE:
Actually, my question was about the same thing, except the way I
interpreted it, and this is what I'm asking for clarification on is that with
the full length form, there were more initial deferrals; deferrals on the basis
of how the questionnaire was answered with the full length form than with the
abbreviated form. But in terms of
ultimate confirmed positives, or confirmed deferrals, they were not
statistically significant. Is that the
way I should interpret the data on those slides?
MS. BASSETT: Yes.
DR. LEITMAN: A
couple of questions. On the abbreviated
form the only travel question is 13, been outside the US or Canada since your
last donation. So, if the most common
reason for forgetting to reveal deferrable risk was a remote travel history to
UK countries prior to 1996, or residence on a military base prior to 1996,
that's not going to be brought out if all subsequent histories are taken
through the abbreviated donor history questionnaire. That jogging of the memory will only come up on the full donor
history questionnaire.
MS. BASSETT: Are
you talking about our travel capture question?
DR. LEITMAN: The
abbreviated donor history travel question.
Oh, I'm sorry. Never mind, it's
a different one.
Also, 0.25 percent error in implementing. That's interesting. Do you know what the source is of the error?
MS. BASSETT: Yes,
at that point in time when we first implemented, we were using a manual
process. It was computerized, but it
had a lot of manual actions to it. You
had to go into the computer on one screen to try to find your three allogenic
donations. And so, if you made a
mistake, what you were doing was finding somebody that maybe had done an
atallogous(?) and you counted those.
And also, the six month timeframe might have been
missed. Many times what we saw is they
missed the year. They thought it was
six months, and they didn't look at the current year. So, we knew that we had an issue going on. And how we changed that, we put corrective
action in place, and now our computerized system actually when they put in the
donor ID, it will pop up on the screen, and it says whether or not that person
is eligible or not. And then we have
double blind entry to make sure we have entered it correctly as well. So, that's why our error rate has gone down.
We still have a few errors, probably only 2-3. And that's just manual entry kinds of
issues, or not paying attention to the screen.
DR. EPSTEIN: Mary
Beth, I would like to come back to the point that was raised earlier about
medical deferrals. These are slides 12
and 13. When analyzed eligibles, either
all eligibles, or those who had donated with 8 weeks.
I'm struck by the fact that the difference in rate of
medical history deferrals is really quite remarkable. For the cohort overall it's about a third higher with the full
length questionnaire. And when you look
at frequent donors, presumably mainly platelet donors, it is four fold
higher. And both those findings are
statistically significant.
So, whereas you have pointed out that the confirmed
positive rates aren't statistically significant, without analyzing what the
deferrals were, I think it's very hard to dismiss that as an unimportant
finding. It's exactly the opposite of
what we had hoped for. I mean to say
that those aren't significant deferrals because they are not reflected in
positive infectious disease tests overlooks the fact that we may have reasons
to ask those questions. We are worried
about false negative infectious disease tests, as well as other conditions for
which we cannot test.
So, I find it disquieting, both because the magnitude of
that effect seems large, and because at least at this forum you have not been
able to tell us what those deferrals were.
So, in brief, I think these are very disturbing findings.
MS. BASSETT: I
think one of the real markers though, and maybe one of the most important
markers for that kind of thing is around your confirmed positive rates. That's really one of your main things for
sensitivity.
DR. ORTON: I think
one of the other pieces to what Jay is saying is because some of those medical
history questions that are rolled in donor safety issues. So, heart disease, lung disease, those
wouldn't be found in the marker rates at all.
So, in fact if you were as an example, drawing people who
had heart disease and weren't reporting it, and they were reporting it in a
full length versus an abbreviated, you might see that. I'm not saying that's what was reflected
here, but I think that's also another consideration, where the marker rates are
not going to capture that safety information.
MS. BASSETT: That
is correct. Dr. Kamal, do you have any
information to share with that, since you were part of the group that did this
analysis?
DR. KAMAL: Obviously,
all people who were eligible, in the prior slides it shows only 0.5
percent. So, we are dealing with a very
select group, with the lowest medical deferral, temporary deferral, and
confirmed positive. The group pheresis
or frequent platelet donors are only 8 percent of that group. And the number of deferrals here, we are
talking about 13 medical deferrals divided among the 2 groups.
We are reporting what we have seen, and as Jay mentioned,
unfortunately, we were not able -- we created this number by computer queries,
counting numbers only. So, whether they
were part of the capture question or not, we can't tell. We have about 20 out of the 35 questions are
shared between the full questionnaire as well as the abbreviated
questionnaire. So, among these groups
there is truly no difference, or the questionnaire is not a factor.
And the only thing, we looked at information about the
capture question. And as mentioned
earlier, it is a wide net catching much information that we may not be
interested in. We are getting acid
reflux disease. We are getting
hypertension. So, our capture
questions, we looked at some information, and it seems like it's not a matter
donor understanding or comprehension or sharing information. As a matter of fact, yes, we are getting
more information that non-deferring and deferring conditions.
DR. KUEHNERT: I'm
sorry if this was covered before. I had
to step out. Maybe I missed it. But just as far as the slide comparing those
eligible for the abbreviated questionnaire and then comparing those who were
given the abbreviated versus the full length, obviously they weren't
randomized. And so, what was the
determination on whether they got the abbreviated versus full? Was that it that the people who got the full
length occurred before implementation?
What was the determination on who got what?
MS. BASSETT: The
reason that we have a difference between those that are eligible for the
abbreviated, and those that received full and not is just because of the
implementation. Some of our centers in
our organization that haven't done full implementation. So, we just have an automatic really kind of
control group, because they were eligible, but they didn't have the process in
place to be able to given the abbreviated questionnaire.
DR. KUEHNERT: So,
is there a difference in geographic region or demographics between the two
groups?
MS. BASSETT: I
don't think so.
DR. KUEHNERT: I was
just trying to understand whether there might be other reasons for this
difference in medical history deferral between the two groups.
MS. BASSETT: And
we've got some implementation at all of our centers. It's just not full implementation at all of them.
DR. ALLEN: One
might expect that in fact there is some difference. I would assume that generally in each center it's implemented at
the main facility before it is on the mobile collection.
MS. BASSETT: That's
absolutely correct.
DR. ALLEN: So,
there may be rural/urban differences.
There may be as well some geographic differences.
MS. BASSETT: Mobile
versus fixed is definitely one of the rationales, because it's much easier to
implement this at a fixed site, than it is at a mobile operation. So, those are some of the differences as
well.
DR. LEW: Was there
any effort to try to find out who actually returned when you did your
comparison for full form versus abbreviated form? Because it would make sense if someone had an unpleasant
experience, as you point out in your questionnaire, that they might be a little
upset, so when they answer their questions, they say of course I'm not going to
come back next time. Versus once they
got home, they relaxed a little, that all goes away.
We all know polls aren't that accurate. So, is there any effort to try to capture
who really does come back? Because
that's the whole thing. We are trying
to make it abbreviated so people come back.
But if it really doesn't work, well, do you want to lose some important
medical information?
MS. BASSETT: We are
still doing some analysis on that donor retention and return rate from this
data that we have.
DR. ALLEN: There is
a difference between the Blood Systems history question collection process and
the AABB process in that Blood Systems, Mary Beth, is all verbal questions and
answers. There is no self-administered
questionnaire.
MS. BASSETT: No
self-administered.
DR. ALLEN: So,
there is that difference in process.
Other questions or comments for Ms. Bassett? Thank you very much.
Agenda Item:
Open Public Hearing
We will at this point move to our open public hearing. I'm aware of only one speaker who wishes to
speak. I need to read the open public
hearing announcement for general matters meetings.
Both the Food and Drug Administration, FDA, and the public
believe in a transparent process for information gathering and
decision-making. To insure 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 relationships 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 or a 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 choose not to
address this issue of financial relationships at the beginning of your
statement, it will not preclude you from speaking.
The one speaker that I have on the list for this morning is
Ms. Mary Gustavson, Senior Director, Global Regulatory Policy of the Plasma
Protein Therapeutics Association, PPTA.
She is speaking on the AABB abbreviated questionnaire.
Ms. Gustavson.
MS. GUSTAVSON:
Thank you, Dr. Allen and committee.
I am Mary Gustavson.
I am a salaried employee of PPTA.
Yesterday during the first open public hearing, the who, what, and why of us was presented, so I
won't repeat that. It's in the written
statement.
PPTA supports the implementation of an abbreviated donor
history questionnaire for frequent donors.
PPTA has been a participant in the AABB interorganizational task force
to develop the uniform donor history questionnaire. The AABB task force developed the full length questionnaire and
abbreviated questionnaire to be used in tandem to enhance the donor interview
process.
PPTA formed a subgroup of the task force to develop
questionnaires to be used to screen donors of source plasma. It was recognized that separate documents
were needed, because of some of the differences in collection practices and
donor screening requirements between whole blood donors and source plasma
donors.
The PPTA subgroup used the AABB UDHQ and made modifications
designed to elicit information relevant to source plasma donors. PPTA is currently reviewing FDA's comments
to our submission, and plans to meet with FDA in the near future to discuss
PPTA's plan for moving forward on this important initiative.
The abbreviated questionnaire is an important adjunct to
the full length questionnaire for repeat and frequent donors. While no study may be perfect in design,
scope, or size, PPTA encourages FDA to avoid making the perfect the enemy of
the good. As all of us are aware, it
has been the practice over the years to implement donor history questionnaires
with no evaluation or studies. The
current efforts of the blood and plasma communities to implement standardized
questionnaires, including an abbreviated questionnaire for frequent donors
should be encouraged and facilitated.
Thank you.
DR. ALLEN: Thank
you very much.
Questions or comments for Ms. Gustavson? Thank you very much.
Are there any other speakers who wish to make comments
during the open public hearing session?
Hearing none, the open public hearing session is now closed. We will move to open committee discussion of
the question. Dr. Schreiber, do you
want to make a brief summary presentation about the abbreviated questionnaire
and proposed study?
DR. SCHREIBER: I guess
I was asked to make some comments. To
read the questionnaires in a little bit more depth and comment. And these are strictly my thoughts related
to no one else's perception of reality.
When I look at it, the problem that we have is that the
previous version contained one medical history capture question. And the questions were then amended for test
subjects in this one-to-one cognitive interviews to try to determine the
adequacy as a substitute for the specific medical questions.
And they failed to identify this one case that we have
heard about. If we had never tried
those four, we probably wouldn't be here today. We would all be administering the abbreviated questionnaire.
So, the solution as we heard, was that the task force then
split the question into two parts. And
that is what we are now looking at is the evaluation of how those two questions
are compared to the full length. And I
have to say they have gone to a lot of problems, and have really spent a lot of
time thinking through this, and I commend the task force for all the work they
have done.
The issue is a study is proposed to "test how well the
two capture questionnaires identify relevant donor eligibility information and
repeat donors." And we are asked,
is the design appropriate to answer this question? What does the proposed study hope to accomplish? Well, as Debbie clearly said, this is not an
epidemiological study. So, are we
expecting it to be big enough to be able to test these differences? My conclusion is no, and you'll see that.
It will study discordancies between the two instruments,
the capture questions versus the 16 medical condition questions. And one of the things is that they are all
different time periods. So, one of the
questions is how well can you map one to the other in a study like this? The other thing that we have heard is that
the idea is to reflux discordant donors to cognitive interviews, to try to
understand why these differences exist.
And as Debbie said, the emphasis for the evaluation is on cognitive
interviews, and to conduct these cognitive interviews.
So, I think one of the things that we have to ask
ourselves, are there going to be enough people that are discordant to be able
to do enough cognitive interviews to make this important? And it's hard to look at this in terms of
statistical design for a full blown epidemiological or randomized trial. And I think Debbie was very clear, that's
not what the intent of the group was.
And if that's the intent of what the FDA is going to require, or feels
that's needed, I think that that has to be made right up front, so that they
know what direction to go in.
I took in the 1,250 to try to see what I would expect as
discordancies. And I said that there
would probably be a 1 percent deferral rate on the full donor history
questionnaire. As we saw from BCP,
their rate was about 0.85, so the 1 percent is probably in the right ball park.
If that is true, then we would expect to see 13 people that
were deferred. If we missed one-tenth
of them by the HDAQ, we would have 1 discordant person out of the 1,250. If there are some other criteria that I'm
missing, and there are other conditions in there at that are less sensitive to
be screened for, maybe the discordancies would be higher, but those are probably
things that we're not really interested in trying to evaluate anyway.
And that's why I was asking if there was going to be some
kind of pre-screening so a lot of time isn't spent and wasted on conditions
that are not trying to be judged in the two questionnaires. For example, pap smears or mammographies,
colonoscopies, things that would not be deferral criteria on either of the
questionnaires. But when I tried it on
a small number of people, those three conditions came up repeatedly on the
abbreviated questionnaire, that people answered yes to the screening questions.
So, then the question is, okay, how many do you need to
have a meaningful sample size? And I
just did a rough back of the envelope calculation. And I come up with about 6,200.
The 6,200 would assume a deferral rate on the HDHQ of 1 percent, and
that the ADHQ misses 10 percent of the deferrals. Even there, what you would find is that we are not going to get
any that are deferred by the DHQ and not the ADHQ.
So, I weighted it so that we were assuming that we're not
going to miss so many. And here we
would we would have six, which would give us the statistical power. And kind of the rule of thumb that I'm always
told by the statisticians is that you need five in a cell to be able to take a
statistical difference. So, that what
we are really comparing is the six versus the zero. And here, this would yield your six that you would have for your
cognitive interviews.
This assumes that the HDHQ and the abbreviated one are
equally sensitive. If they are equally
sensitive, they would both miss the same number. And there is no pointer here, but in this case we would miss one
on either, so we would have two that would be refluxed to the cognitive
interviews. So, we are half as good now
as we were with the four.
These are my expectations.
The study is not designed to provide evidence of comparability. And as they said, really in the selection of
sample size and the design, that's not what the intent of the design was. I would predict that discrepancies between
the two instruments will be found. And
before I saw the BPC data, I thought that the 17 questions would pick up more
positives.
My other prediction is that whatever the findings are of
this study, it will probably lead to another cycle of DHQ revisions. And then my question would be, are we going
to be back here in a year, in 2006 designing another study, because we found
that we had to do some rewording on the HDAQ because of discrepancies that were
found in the limited number of subjects that were identified?
I think that the degree of discordancies will be on the
order of less than a half of a percent.
If you take that into account, we always look at the exceptions, but we
have to look at and realize that there is a 99.5 percent concordance. If we figure that we're only going to have,
as I had in my other calculations, a tenth of a percent, then we are going to
be picking up 99.9 percent concordance between the two instruments. Which I think that when you are looking at
this type of a survey or an instrument that has its problems that we all
realize, that's a pretty good degree of concordance.
The sample size requirements to demonstrate statistical
dependency or statistical discrepancy between the two instruments is on the
order of 6,000. And I don't think that
by any stretch of the imagination would the resources that are available to the
AABB and this group, that an ambitious undertaking like that could be actually
achieved. I don't think the resources
are there to do that.
The ADHQ contains two general capture questions relating to
time since the last donation. The DHQ
instrument contains questions that have specific time periods, past 12 months,
ever or current. With these
differences, it's difficult to design a study to demonstrate equivalency or
lack of equivalency of the two history forms.
So, I think in summary, we need to, in reviewing what's
been put forward to us, keep clearly in mind of what the objectives are. And then I think in my mind, one of the most
important questions is what degree of difference is willing to be accepted to
be able to initiate the abbreviated donor history questionnaire in our
screening population?
And I think now the community has been waiting for several years,
and have been tackling this question.
And if we do continue studies, at what end will be able to stop and
actually go out and administer the questionnaire? And I'm not sure that we know that answer. We hear, as Jay raised from the BCP
questionnaire and their administration, we find a small difference. The more people we administer the
questionnaire to, the smaller that difference has to be to remain statistically
significant.
So, if we administer that questionnaire or that test to 2
million, you probably have that a statistical difference of 0.01 percent would
be highly significant. Here we saw that
we had about three-tenths of a percent difference between the two
questionnaires. Which also keep in mind
that it's not the same questionnaire here, because this is a further revision.
But I think that one of the questions we just have to keep
on asking ourselves is how far do we go?
And where do we stop? What is
FDA willing to accept in terms of an evaluation? So, that's my random thoughts on the question.
DR. ALLEN: Thank
you, Dr. Schreiber. Questions or
comments specifically for Dr. Schreiber?
DR. DI MICHELE: Is
it possible for me to ask him some study design related questions?
DR. ALLEN: We will
get into general discussion. I think
right now let's focus on clarification or questions on his presentation or
perspective. We're only a couple of
minutes away.
DR. KUEHNERT: That
was a nice presentation. I just wanted
to ask you about the difference between -- you sort of distinguished between
demonstrating equivalence and demonstrating discordancy. And so, what are the differences between
those two concepts?
DR. SCHREIBER:
Well, one, when you go into the design, you design it and do your power
calculations that the two instruments are going to be the same. The other is that you design it expecting
that there will be a difference. And
you need bigger numbers to demonstrate equivalency than to you do to demonstrate
differences.
DR. BIANCO: Celso
Bianco, America's Blood Centers. This is
just a comment that I think can contribute to the discussion. We are comparing the long donor history questionnaire to the abbreviated
questionnaire or the other way around.
But if we try to compare the abbreviated questionnaire to the
abbreviated questionnaire, the long history to the long history, I'm sure that
we would find the same degree of differences.
If we look at the RAD study and the surveys that were done,
for instance the one that I recall very well from Alan Williams as the first
author, found that 1.8 percent of the donors that received this survey revealed
risks that they had not revealed at the time of the interview, at the time of
donation; much higher than all the numbers that we are talking now about.
DR. LEW: I just
wanted to comment that I agree with Dr. Schreiber that 17 questions to 1, you
know you are going to find a difference, anyone who objectively can think about
that. And to me, the bottom line is not
oh look, there is a statistically significant difference, because there was,
and you expect it.
But I guess getting back to the presentation, the two
important distinctions that I wanted to hear was those who were missed, why
were they missed specifically? Was it
something very important? Versus how
many more people did you get back to come to donate blood?
Those are the two important questions to me. And would the study that is being design
potentially answer that? No, it won't
address that. Maybe going back to it,
then this study is no longer valid, I don't know. The key is that this survey was -- a lot of time and effort has
been spent in developing it. It seems
reasonable as it is now. I'm not the
study that is going out will tell us.
DR. KATZ: I feel
very strongly both ways. Celso's
comment about the 1.9 percent undisclosed deferrable risk I think is very
important, and at my blood center we have done some things attempting to reduce
that, that we believe work, that have nothing to do with the length of the
questionnaire, and that I consider to be probably more important for
transfusion safety over the long haul, because they are really attempting to
get at recent risks in a certain sense.
But that's one aside.
There is another issue here that I think is
fascinating. And that is in the ABC
centers only 29 out of 75, 76, 77 whatever we are this week. There is enormous diversity already. Most of the centers are using completed
unvalidated materials to screen their donors.
We have recently moved to the long uniform donor history
questionnaire. And our preliminary two
months of data suggests very strongly that we are picking up stuff due to the
nature of the questions, the ordering of the questions and time that we missed
with the previously approved.
So, I want to consider in the absence of data, and recognizing
that Blood Systems' abbreviated questionnaire was not designed and validated in
that fashion, that it may be very difficult to prove equivalence, inferiority,
superiority, but it almost certainly better than the way we have been doing
things over the last long interval of time.
And I would just ask the question, is the study needed at
all? And it is a question. As I disclosed, I'm one of the
investigators. My center is one of
them. I would love to do this
study. I'm not sure at the end of it
all, I did the same sample size calculations as Dr. Schreiber, so statistical
significance is not going to be demonstrated with the resources available to
execute this study. And a number of
discordances in the sample size that we have proposed may well not give us the
information we want, and as George said, we'll be back here.
DR. ALLEN: Thank
you for the comments. I'm going to just
make a couple of brief comments, and then ask Dr. Orton to come back and give
us the FDA perspective and questions for the committee. We'll get into the broader discussion.
The abbreviated donor history questionnaire, which we all
have in our packets actually has 30 questions on it, give or take one or
two. I think I've got the most recent
version. And it starts out, are you
feeling healthy and well today? It's
got the other specific questions with regard to have you taken aspirin,
headache and fever, which we all recognize as being the West Nile virus
question that probably is not that useful.
It's got a question for female donors about pregnancy,
donation history, and 16 weeks. And
then it comes to the two capture questions, any new medical problems or
diagnoses, any new medical treatments?
And then it gets into questions about medications, on the medical
deferral list, and again, people have a chance to look at that list now, which
I think is much preferable to having somebody reel off a list of questions or
doing it in some other way.
It asks for travel outside the United States or Canada, the
contact with blood, needle stick and HIV and AIDS questions, sexual history
contact. All of that, Tab 2, ear or
body piercing. It's not just the two
capture questions standing out there alone.
And these are donors that have donated at least a couple of times, the
last time within 6 months, gone through the full questionnaire.
This is a select group of donors. I think we'll get into the discussion about the issues that were
raised by Dr. Schreiber and Dr. Katz's last question of is this even needed at
all, and what's the next process? We
do, if we possibly can, want to move this whole process forward. And that's what our discussion today should
be aimed at.
Dr. Orton, would you provide our summary, and then we'll
get into the more in-depth discussion, and attempt to resolve the issue of the
questions.
Agenda Item:
III. Study Design for Abbreviated
Uniform Donor History Questionnaire - C. FDA Perspective and Questions
for the Committee
DR. ORTON: Yes, I
want to stress the FDA as well wants to move forward in the appropriate
path. I'm actually the liaison on the
abbreviated task force, again as a regulatory liaison. We certainly have tried not to tell the task
force what path they need to take. And
so, any recommendations, we clearly want to hear.
If a study needs to be done, or if there is something in
implementation measurements we can take that we think are adequate, we
certainly want to hear them, analyze them, and then within the regulatory
framework that gives us some restrictions, move forward. So, it's important to us, the opinions of
the committee today.
So, the first question is does the committee agree that the
proposed study design exclusive of sample size is adequate to reasonably
demonstrate equivalence or lack of equivalence between the two capture
questions on the abbreviated questionnaire, and the 16 specific questions on
the full length questionnaire?
DR. ALLEN: Open for
general discussion. Dr. DiMichele.
Agenda Item:
III. Study Design for Abbreviated
Uniform Donor History Questionnaire - E. Committee Discussion and
Recommendations
DR. DI MICHELE:
Well, if we are going to discuss the study design with respect to issues
exclusive of sample size, there are two questions I had. The first was if we are using the
abbreviated questionnaire as the test document, should the study design
actually incorporate the use of the test document into ultimate donor deferral
as part of the study measures, which it plans to do.
Because one would think -- again, in a strict study design,
that you would use the approved questionnaire to actually make the deferral,
and would not use the answers to the abbreviated questionnaire to help in
making that deferral process, because I'm not sure that it would not confound
the results of the study.
The second is that if the cognitive interview is the most
important aspect of the study, and that's what I wanted to clarify with Dr.
Schreiber, because I was thinking that if it is important, then although it's
incredibly labor intensive, and I can see why it wouldn't be done this way,
should the interview not be done with all participants, whether they have
discordance or not, in order to ascertain understanding of the questions, if
that's what is truly important? And I
think those are my two major study design issues.
DR. ALLEN: Dr.
Klein.
DR. KLEIN: Well,
first of all, I would just like to remind the committee that this committee
voted 10 to 2 with 1 abstention to go ahead in December. Having said that, I think, unless I'm
missing something, I just heard an hour's discussion that this study wasn't
designed to tell us about equivalence or non-equivalence. I think from the very beginning that's what
I heard.
So, in some ways the question is not helpful to me. I thought the importance of the study was
try to find out when there were discordant answers in a subjective way from
experts, in doing so, what the perceptions were that made people answer
differently. And I think that's all we
are ever going to get out of the study.
Now, if we think that's important, obviously we should go
ahead. But if we think that we'll get
that subjective information and come back three months from now, and vote 11-1
with 1 abstention and still it won't go forward, then I think we are wasting a
lot of time.
DR. ALLEN: Thank
you.
Ms. Kessler stated this is not an epidemiologic study. Dr. Schreiber re-emphasized that point. So, to me it is much more of a descriptive
study, if you will, to try to identify through the back-to-back administration
of the two questionnaires with discrepancies defined by the cognitive
interviews.
Is there concern that we can document that the abbreviated
questionnaire is missing a significant number or significant types of
medical-related issues that would otherwise defer this fairly select group? And to me, that's the real issue. And I fully appreciate we are asked to make
our discussion now, absent discussion of study size.
But it seems to me that although I've got minor points
about the study design in terms of the back-to-back administration of the
questionnaires and that sort of thing, it seems to me that it's a useful,
descriptive analysis to try to do. And
I would think we ought to go ahead.
Dr. DiMichele.
DR. DI MICHELE: I
was just going to ask, is there a difference between this not being an
epidemiologic study, and this being a validation of an instrument study? That is what I'm thinking of it as, not an
epidemiologic study, but an instrument validation study. And that is the basis of my comments. Is this not how we should proceed? Maybe we should get some clarification on
that.
DR. KATZ: I think
that's pretty accurate.
I just wanted to make one thing -- the study instrument,
both instruments are the instruments of record. A deferrable answer on either one results in deferral of the
donor. So, they are really double
screened during the study. The reason
that the ADHQ was first was so as not bias responses on the ADHQ by coaching
off the long form. But we don't care
about colonoscopy or pap smears. Those
are not deferrable answers. They will
come up on the ADHQ, and we'll say that's not deferrable. Those won't be discordant.
So, it's really pretty simple, and it's basically designed
exclusive of sample size to see whatever discordance we dredge up, is there a
way to address those by making the process better in subsequent iterations,
would be my understanding.
DR. ALLEN: Yes, I
think that's a very important distinction.
Some of the questions as answered on the questionnaire probably would
result in deferral in and of themselves.
The medical screening questionnaires, they are capture questions that
then result in a subsequent history interview process, that if this were
implemented on a routine basis, it would still go through that same
clarification process to try to elicit is it information that is important to
make a decision about whether this person can donate today.
So, it's not the questionnaire itself that is going to
result in the deferral, it's primarily a capture questionnaire.
DR. KLEIN: Jim, I
just think that my frustration is the same one that I felt yesterday, that the
question is kind of setting me up for the wrong answer. I look at the question, and we have just
heard an hour's discussion saying the study wasn't designed to do that. So, how in the world can you say that the
study is going to do that?
And we have all discussed what the value of the study might
be or might not be. But to me, it
doesn't seem to have any relevance to the question that we're being asked. If I'm missing something here, perhaps
someone can explain it to me.
DR. ALLEN: The
question, I agree with you, in order to reasonably demonstrate equivalence or
lack of it, that would require an epidemiological study to do that. And yes, I concur with you on that point.
DR. KUEHNERT: I
just wondered if in addition to this proposed study, if there is formal plans
for evaluation of the questionnaire on an ongoing basis? And this question came up the last time this
topic was discussed by BPAC. What are
the plans for evaluation? Because the
data from Blood Systems are very helpful, but they bring up in some ways, more
questions than answers.
And so, is there a way to assure that there is going to be
an ongoing process for evaluation that would be complementary to what this
study would do, which I think will be important, but obviously will not answer
everything.
DR. QUIROLO: My
concern is that it's not really a study.
It's a validation. It's not
statistically significant. So, it's up
to subjective analysis. And somebody in
the FDA or somewhere is going to decide whether they think they are equivalent
based on this data. If they don't, are
we going to be back here again in a few months with a different questionnaire,
doing the same thing?
And further, if the questions need to be changed again,
well, then we have to do another study or some other kind of validation measure
for each one of these revisions. I
don't quite understand what the process is going to be.
DR. SCHREIBER: I
think from what has already gone on, and from the numbers that we have seen, we
know that the instruments are equivalent.
They are equivalent at a 99.5-.7-.8 percent. So, we know that they are equivalent. How much inequivalency are we willing to accept? But when you have that small of a percentage
that you are trying to ascertain a difference for, we have to remember that we
are screening out all of the negatives as negatives, and there is a high degree
of concordance with the instrument.
So, that what we are really trying to do is find the cases
that are not picked up or picked up wrong with that, and then try to find out
whether some wording can be changed in the questionnaire. And if that's what the objective is with that
1 percent deferral rate for the medical histories. And that's what was said that was trying to be evaluated. We are not going to get enough to be able to
look at it in any sense, with only three or four or five cases.
DR. LEW: I would
like to make it real clear. The data we
saw had nothing to do with the form that is going to be tested. They use a different process, the
presentation we heard. So, I like the
data, because it does help us a little.
It is a similar but not exact abbreviated form. So, we really can't say what this abbreviated
form which we are voting for, is going for.
But the other thought to it is I guess I have to agree with
Dr. Katz. If all FDA was looking for
was an equivalent study, this is not it.
And so, the point is moot. And
do we need this study? I think we will
have to think very carefully. Again, it
is a different form. Maybe we need it
just so we can say we have semi-validated a new form.
I still think the question that Dr. Allen brought up, is
this form going to unfortunately not capture some important questions that
should have deferred an important deferral question? We need to look at that issue.
And then again, it would be nice to know, since the blood
banks do want people to come back or be satisfied, that those be incorporated
into whatever mini-study that is done.
DR. KUEHNERT: I
guess I just have to ask this question, because I think it's probably on
everybody's minds. What is it going to
take to actually get the abbreviated questionnaire approved? Because I think that's what people are afraid
of, is holding this up. And there are
many things that can be done to evaluate it once it's implemented to see
exactly what the differences are. And I
think clearly the impression is this is going to be better than anything we
have out there.
So, I guess I'm trying to understand what are the processes
for approval that we are being asked to sort of help FDA decide on? And it's sort of a black box that I think is
making at least me sort of reluctant to vote any particular way.
DR. ORTON: Can I just
add one thing to clarify, I think that will be helpful? As we described for the full length
questionnaire, every single question had focus group and cognitive one-on-ones,
every single one. We modified. We retested them with the focus groups, in
some cases the cognitives.
Part of our concern was we have two new questions that have
had no study. Now, I agree and
understand that it's based on a somewhat validated, for lack of a better term,
instrument. But that was our
concern. We have two questions that
have not been tested at all to determine whether -- just the fact I think that
Jay brought up, should it say health included with medical, hasn't been tested
at all. So, that was one of our
concerns.
I think that the use of equivalents -- and after we had
kind of gone through what the questions are going to be, the little red flag
started going up when we say equivalents, we're going to be thinking about tens
of thousands, an epidemiologic study.
So, I think that this is probably an unfortunate set of wording, which
is where we get into an alternative design, perhaps.
DR. KUEHNERT: Can
it be changed?
DR. ALLEN: Let's
come back to that point.
Dr. Katz.
DR. KATZ: Well,
nobody responded to Matt when he asked about ongoing study. And I can't speak for all five of the
centers that have agreed to do the study.
Our plan was in fact because we were going to have two really bright
people trained as cognitive interviewers, to then do cognitive interviews on
every ADHQ -- presuming it's approved -- donor who in fact gave us
post-donation information, or was subsequently deferred for something that we
should have known.
And we were going to do that ongoing, until we either
realized that's the nature of asking thousands of people questions, or we found
patterns that suggested a need to suggest alternations in questions. And I suspect there will be more than one
place that would use that approach.
MS. KESSLER: Well,
my comment follows that. If you
remember in 2003 when this was discussed, the AABB task force committed itself
to post-implementation follow-up of whatever kind seems to be appropriate,
including post-donation information, new health information, maybe doing
cognitive interviews. So, we did commit
ourselves to follow-up study.
DR. ALLEN: Let me
just throw out alternative wording for the committee's consideration, and also
for FDA consideration. Does it help if
we modify the question to read, does the committee agree that the proposed
study design, exclusive of sample size, is adequate to be reasonably certain
that the abbreviated donor history questionnaire will be a satisfactory
screening questionnaire for the eligible donor population? Dr. Schreiber does not like that.
DR. SCHREIBER: The
other thing that I heard from Sharyn is that the concern was that all the other
questions had been cognitively tested.
If that is the concern that was raised with these two questions, we can
very easily do cognitive testing with nine people each on each of those
questions, and test and come back with the same degree of cognitive testing
that went into the whole rest of the questionnaire.
So, if the FDA concern is at that level, there is no sense
to go forward with something as costly and time consuming as this, where we
could do in a week, the cognitive testing of those two questions. And remember that no one was tested -- the
questionnaire has never been validated.
The word "validation" in my mind is a misnomer here. What we did is we tested comprehension of
the questionnaire, and then we call that validation. We never looked at people that had conditions, and see if those
people were picked up with those particular questions.
So, just go to back again, we could do a much easier job
and quicker and less strain. And if we
follow this time schedule that Debbie has laid out, it's going to be next June
when we have the results to look at again.
And then we are going to be reviewing that and say, gee, maybe we should
ask the questions a different way.
And I think Dr. Leitman raised an issue about whether the
questions are worded right. Well, we
could take various deviations of that now and test those in these cognitive
interviews to give them the best chance to go forward. And if that's what it takes, I think that's
what we should recommend.
DR. KUEHNERT:
Another point I don't think has been brought up is equivalence might be
bad, because we don't know -- you brought up the issue of gold standard. We don't know what the gold standard is
other than confirmed positives. And Jay
brought up the issues that the deferral may be picking up things that testing
are not. But on the other hand, they
may also be false positives, so we just don't know. So, I think that's part of our challenge here, is that there is
no gold standard for comparing this.
DR. ALLEN: All
right, well, either that or -- Dr. Epstein, did you hear Dr. Schreiber's last
comment?
DR. EPSTEIN: I'm
afraid I had other business. I got
distracted.
DR. ALLEN: Okay,
the committee is a bit hung up on the wording of question one, and that fact
that it in fact really does presume, I think, that this is an epidemiologic
study with statistical equivalents being determined. I think the committee is not certain that that is: (1) either necessary; or (2) achievable.
George, do you want to re-describe or make your comments
again?
DR. EPSTEIN: I
understand that point. What we can do
is perhaps substitute the word "comparable" for equivalence, because
equivalence is a rigorous statistical standard. Comparable sort of leaves it open to judgment, what's an
acceptable difference based on the outcome of the data. It leaves you scratching your head, because
you haven't pre-defined a delta that you would live with. But I think it's closer to what will really
happen.
Another way of asking that question, I guess it's back to
George, if you have 1,250 data elements, what is the smallest difference that
could be detected with statistical significance? Because what you have said is you need a study of 6,000 to show
equivalence with a delta I think you said of 0.5 percent. But the other way of looking at it is what's
the power of the study as proposed, and could we live with that as a more
qualitative measure?
DR. SCHREIBER: I
think another issue came up concerning Sharyn's comment. These questions have not been tested
cognitively. And the only test on any
other portion of the abbreviated questionnaire has been the cognitive
testing. And I guess my question was
not dealing with the sample size issues, but could we just do cognitive testing
on a variety of capture questions to the same degree that we have done on the
other instrument, and live with that?
You raised the issue about the questions not being tested,
the capture questions. Another issue
came up while you were out of the room, whether there were better
wordings. So, we could do cognitive
testing a lot quicker, and it would be a lot cheaper, and probably give us the
same yield in results.
DR. EPSTEIN: Well,
I certainly would be in favor of cognitive testing of capture questions. I don't see how anyone could object to
that. I think the real trade off here
is whether something done prospectively on the model proposed adds much value
compared to the kind of post-use testing that has been done by UBS. I think that it's obvious that the power of
those post-market -- it's not really an approval process -- but phase IV analyses
is much greater.
It's just that you run the risk that if you find
significant deficiency of the abbreviated, then you have potentially
compromised the safety of the blood supply.
So, that's been the whole dilemma from the start. But the answer to it is not an underpowered
study.
So, again, I come back to the question of how gross must
the difference be for a study of 1,250 subjects to detect it? Would you have to miss 50 percent? Would you pick up a 20 percent
difference? In other words, what is the
actual power of the proposed study?
DR. SCHREIBER: I
think the power of the proposed study is pretty close to zero. I would say that you probably would have to
miss -- your estimate of 50 percent is probably more in the right ball park.
DR. ALLEN: In part,
the fact is that you've doing this on a very highly screen population already,
so that the probability of there being any deferrable condition is extremely
low. If you were doing it in the
population with a higher frequency of deferrable conditions or underlying
medical conditions, your power is much greater. But that's the population you want to use this on. So, that's your conundrum of to get
appropriate power, the sample size goes way up, and you are going to have lots
and lots with no discrepancies at all.
DR. EPSTEIN: So I think
that perhaps a better pathway would be to obtain a commitment that those
implementing the ADHQ would commit to doing what UBS has committed itself to
doing, which follow-up evaluations with some randomization to full length. And to continue to monitor the significance
of those outcomes.
I do think that before we would sort of go live I would
like to see a breakdown of the medical deferrals that occurred at UBS, so that
we could get some handle on significance.
It's a finite number. I think it
was less than a combined total of 250.
So, in some reasonable period of time we could actually cull those
records and find out what it really was.
And as long as we were not worried by the source of those discrepancies,
I think we could go forward.
So, I'm just expressing my view, and it shouldn't unduly
bias the committee, but I think the proposal to get cognitive evaluation of the
capture questions is very important.
And I think that if you will, transforming the study design to a
post-implementation design would be superior, because then we won't have this
problem of small numbers. Because if we
go forward with a study that's underpowered, either we are going to kid
ourselves, or get an answer we don't like, that we have to redo the study. So, there is not a lot of value.
And then I think that we have to have, if you will, some
belt line that as phase IV is done, that if the missed rate of deferrable
conditions is higher than X, that we'll pause and reconsider. So, I think that's a path forward.
DR. ALLEN: Do you
want us to perhaps complete our discussions, take a break while we reword that
question, and then come back and vote on a reworded question?
DR. EPSTEIN: Well,
I think the rewording is easy enough.
It's just to change equivalence to comparability. But I think it would help if we had some
statistical understanding of the limited power of the study. In other words, if it's 80 percent power to
pick up a 50 percent difference, then that is what you are voting on. You're asking whether a study with that
power to pick up that magnitude of difference is worth doing. I don't know how readily you can do that
calculation, but that would be my concern.
MS. BASSETT: I just
wanted to respond to Jay's request that Blood Systems would look at that information
in more detail. And we have committed
to ourselves to do that even before here, so that we would have the information
of what's behind those numbers of increase.
So, we would be glad to do that and get that information to the FDA or
whoever else that that information would need to go to.
DR. EPSTEIN: Thank
you.
DR. DI MICHELE: Can
I just ask Dr. Epstein, are you saying then that you would still want something
prospective looking at comparability, but look at equivalence in a post sort of
implementation fashion? Or are you
happy with just a post-implementation study?
DR. EPSTEIN: I'm
not trying to pre-judge the vote of the committee. I think the committee should decide whether the study, as
proposed to demonstrate comparability is acceptable. And I think the committee has in essence proposed that there at
least be cognitive testing of the capture questions. If the committee votes in the negative, that this is an adequate
study for all the reasons discussed, then I'm proposing as an alternative, that
the game plan would be a well designed post-implementation study with clear
stopping rules.
DR. ORTON: And I
think the question number three addresses that, Jay, exactly what you are
saying. If your answer to one is no, we
are asking for alternative --
DR. EPSTEIN: But
again, question two does suggest an alternative, which is a higher powered
study which is done prospectively. But
then that begs the question of to what extent was the full length validated in
this way. That was Lew's point earlier,
I think.
So, I think we've got the right set of questions here. We just need to move off calling it
equivalence, because it is clear that it's not designed as an equivalency
study. So, we shouldn't be asking you
whether it's an adequate equivalency study if it's not an equivalency
study. And I'm suggesting that a softer
term that is a little bit more qualitative enables you to vote yea or nay on
the study as presented.
And if you vote it down, then your choices are to redesign
a larger prospective study, because you are very worried about going live with
the abbreviated. Or to say well, we
have enough experience with abbreviated donor questionnaires. We think it's okay to go live, but we want
belt and suspenders. And so we are
going to want a well designed, post-implementation study that is statistically
powered, has well defined prospective endpoints and clear stopping rules.
DR. ALLEN:
Certainly, that enables you to get to the point as Blood Systems has --
Mary Beth, total number of ADHQs you had was up in the 53,000?
MS. BASSETT: In
this group, 53,996 was what we had looked at here. But those were at three different time periods.
DR. ALLEN: The
point is since implementation you have done hundreds of thousands of donors
using the abbreviated questionnaire.
DR. EPSTEIN: Right,
and I think the important point is that that yielded only a couple of hundred
comparators of eligibles who then got full length or abbreviated. And with the caveat that they may not have
been a random assortment either, because of this confounder about mobiles.
So, it's going to take a very large post-implementation
study to really answer a non-inferiority or equivalence question. I think that that's just where we are. The question is whether the committee feels
that something less statistically powered that gives you some qualitative
assurance that it's not awful, it's not missing 80 percent. Maybe it's not missing 50 percent is needed
before you go live. Mind you, we have
already approved two of these. I mean
there are two large systems doing this now.
MS. BASSETT: I just
want to make one clarification too. On
one of the slides I think I wasn't sure which slide he was looking at when I
responded earlier, but Jay, I think the one slide you were talking about where
things were twice or four times was related to different groups. One was not eligible for ADHQ. They were the repeat donors, and one was
eligible.
So, what you were looking at where the pheresis donors?
DR. EPSTEIN: Well,
the slides that concerned me were slides 12 and 13. Slide 12 compares the medical history deferrals for eligible
donors who either receive the abbreviated or full length questionnaire. And in that data set, the rate of medical
deferrals was 0.45 percent for the abbreviated, however, it was one-third
larger, 0.59. And that was
statistically significant. P equals
0.001.
And then if you looked at the donors whose last donation
was than or equal to eight weeks, you found again for eligibles the rate of
medical history deferrals was 0.22 percent for abbreviated, but it was 0.89
percent, about four fold higher for full length. And that's I think, somewhat concerning. It suggests that the people who donate
frequently and get abbreviated questionnaires tell you less. And I don't exactly understand why.
And the other point that I was making is that if you look
at slide 12, it took a study size of almost 54,000 in order to cull out a grand
total of about 270, which were then compared with abbreviated and full
length. So, it requires very large
follow-up to learn anything meaningful here.
So, again, I'm just stating my bias, which is that with
your own analysis of the statistical power here, there is not a lot to be
gained from such a small study. I would
say the only reason to do it is if we're so worried that it could be a dismal
step, that you want to try to pick up a 50 or an 80 percent difference, because
that you should be able to see with 1,250.
DR. KLEIN: I think
this a good example of a controlled trial, because I think we said that while
you were out of the room, Jay.
DR. EPSTEIN: I
apologize for bringing you the long version.
DR. ALLEN: And
again, I think rather than simply focusing on a fairly short study period, it
will be far more meaningful to follow-up on people whose call back with
deferral information, people who have a positive laboratory test after having
gone through the screening questionnaire, you will have selected populations,
and I think it's much more important to get detailed information on that group,
rather than focusing on a small number during the study.
Dr. Epstein, I had one other question. The question as given to the committee, if
you look at the bottom part of it, the question focuses on the two capture
questions on the abbreviated questionnaire, and the 17 specific questions on
the full length questionnaire.
It seems to me that what you really want to do is to
validate the whole abbreviated questionnaire.
And I just wondered if you would have objection to rather than focusing
on the two capture questions, to focus on the abbreviated questionnaire versus
the full length questionnaire in terms of comparability?
DR. ORTON: I just
want to clarify that with the exception of those capture questions, if I'm not
mistaken, Debbie, the rest of the questions are the same. So, the only things that are different are
these two capture questions.
DR. ALLEN: I guess
my point being that it is the entire questionnaire, however, that is important.
DR. ORTON: So, even
if these questions are the same, you would like to see?
DR. ALLEN: It just
seems to me that what we are doing is putting the emphasis on the abbreviated
questionnaire, rather than simply on the two capture questions.
DR. EPSTEIN: I
think that that's a fair point, because people may respond to the questionnaire
as a whole in a different way, even though the remainder is the same. If we were to go that route the revised
language would be does the committee agree that the proposed study design
exclusive sample size is adequate to demonstrate comparability or lack of
comparability between the abbreviated questionnaire and the full length
questionnaire?
DR. ALLEN:
Committee response to that?
DR. KUEHNERT: Just
a point of clarification on the difference between comparability and
concordancy, because I thought what George spoke on was equivalence and
concordance/discordance. And now we
have another word, comparability. I'm just
confused about what that means.
DR. EPSTEIN: Okay,
what we are saying is that the rates of deferral would be in the same ball
park. And by saying comparability, we
are not passing judgment on how large a difference we might accept.
DR. KUEHNERT: So,
it sounds like a similar thing to discordancy.
DR. EPSTEIN: Yes,
it's discordant rate without having set a delta. You haven't decided how bad does it have to be before you
reject. Now, again, this is not the
most rigorous way to approach a study.
Usually you pre-decide how much of a difference will cause rejection of
the conclusion.
But if you are looking at this more as a survey, then you
are really looking qualitatively at what kind of rates are you getting, and
then you make some kind of belt line decision.
We might have to come back to the committee and say, do these differences
cross your belt line?
DR. BIANCO: Just to
express that I'm very happy with the way Dr. Epstein changed the focus very
much from just this study to a post-implementation study. And what I think would be very useful to all
of us in the task force and everybody involved in the process is to hear your
discussion of what the post-implementation studies would be, more in the detail
of this study. It seems that it's not
going to fly, right?
DR. ALLEN: Okay,
other comments or discussion? Does
anybody on the committee have a concern with the reworded question? Or is that a satisfactory question to
accomplish what we need?
DR. DI MICHELE: My
only question now is whether this is a study at all?
DR. ALLEN: Well,
it's a study. It's not an epidemiologic
study. It's not one that has got
statistical validity. It is a
study. You are looking at it. You will be getting qualitative-type
information that you can use to make a decision on. It's not going to be one that's got statistical rigor to it, and I'm
comfortable with that.
DR. LEITMAN: The
committee is not being asked when this study would be done. It might be either after implementation or
before? So, what I hear is before. We are only voting on before?
DR. ALLEN: I
believe that -- well, Dr. Epstein.
DR. EPSTEIN: What
you are being asked is whether there should be a prospective study before FDA
might act to accept the abbreviated uniform donor history questionnaire. So, it's prospective, prior to
implementation.
DR. LEW: Could I
make a proposal that we have the cognitive studies done on the questions that
are new, and then redesign a post-implementation study? Since the full form is already being used,
and the big question is, is this consolidation worthwhile, I think even though
it's not equivalent, I recognize it's not equivalent, the other abbreviated
form, there is enough data there that it makes me comfortable that this is
going to be somewhat equivalent. Then
maybe we should just go into implementation if that's possible, but design a
study to see how much difference there is.
DR. LEITMAN: I get
the feeling that in the UBS study, if there were some very important medical
deferrals that we were not picked up on your abbreviated questionnaire,
deferrals that truly impacted the safety, purity, potency of units collected,
Mary Beth, you would have known. That
would have come out. It would have been
brought to attention of quality assurance leaders and medical directors.
So, my feeling -- there is no data -- is that these medical
deferrals were I forgot I had a squamous cell cancer removed on my face four
months ago or something like that. Are
things that might defer the donor related either to the donor's health, or they
are just in your SOP for deferral, but you don't really know what the
implication is. But not the male having
had sex with the male, or IV drug use are the very big ones recently that we
are concerned about, because that would have come to your attention. Am I wrong in thinking that?
DR. KAMAL: No,
actually all of the high risk questions are word for word on the abbreviated
questionnaire as they appear on the full questionnaire. Because of time limitation we show the
difference between platelet donors and red cell donors. It's basically less than eight weeks. When we looked at the full questionnaire and
the abbreviated questionnaire, in donors whose last donation is greater than
eight weeks, the difference was not significant.
But because asked last time around if platelet donors would
have an effect or bias the information, we showed you what you asked for, for
donors whose last donation was greater than eight weeks, which would be red
cell mostly, the difference was not significant.
DR. LEITMAN: What I
was trying to get at, what is the real concern with a post-implementation
surveillance or study? And the concern
seems to be the slides that were shown on the difference in medically deferring
conditions that were detected by the full questionnaire versus the abbreviated
questionnaire. That questionnaire is
not one I have seen though. I have only
seen the AABB task force questionnaire, so I can't quite comment on what the
difference in questions was.
But the feeling that I get is that we shouldn't be that
concerned about. Concerned enough to
request a study of this kind before implementation. Just like Dr. Lew said, I feel very comfortable with cognitive
testing of the two capture questions, and whatever size is deemed reasonable to
validate those questions, determine if there is a problem with them. Review of that data, and then proceed with
implementation and a study such as this on a sample that is large enough to get
at whatever you are asking for, comparability, concordancy.
DR. ALLEN: I think
the question that Dr. Epstein was raising with regard to the Blood Systems data
is if you've got a medical deferral at this level with the abbreviated, and at
this level with the full, there really isn't an evaluation process to look at
what is in between.
Mary Beth did talk about the post-donation information that
comes in. And it comes in on all the
donors. It comes in at about the same
level. And I think generally a lot of
that has to do with travel deferrals.
Am I correct? We don't have
people coming in with, as best I understand it, with major issues that they
failed to defer themselves on. It could
happen, certainly, but I don't think that has been a major problem.
MS. BASSETT: The
data that I had pulled up just for those 120 that we did, 24 of those were
related to travel or resident kind of risk.
And as Jim stated, the post-donation information for all the groups that
we have looked at has stayed relatively consistent throughout the whole study.
DR. ALLEN: Can I
see a quick show of hands by the committee of people who would like to see the
question with FDA approval revised to talk about cognitive evaluation and a
post-implementation evaluation study, rather than a pre-implementation
study? If you would like to see it that
way. Okay.
Dr. Epstein, are you comfortable with revising the question
to indicate that?
DR. EPSTEIN: I
think a suggestion for cognitive evaluation is sort of a stand alone issue, and
trying to lump things isn't going to be helpful. But I certainly don't have a problem with revising question one, as
I suggested earlier. I think we have
already heard a suggestion from the committee that cognitive evaluation of
revised capture questions would be appropriate. We can put it to a vote, but I think we already got that advice.
DR. KLEIN: Jim,
perhaps that could be our answer to question three if we go through the
questions as it's written here.
DR. ALLEN:
Okay. Is there further
discussion on question one as revised, or are we ready to discuss it? Basically, it's does the committee agree
that the proposed study design exclusive of sample size is adequate to
demonstrate comparability between the abbreviated questionnaire and the full
length questionnaire?
All right, Dr. Freas, would you go ahead and call the roll,
please? Excuse me, Dr. Quirolo, did you
have another comment?
DR. QUIROLO: I just
wondered if the way we are going to vote, if the way the hands just went up, it
sounds to me like we are going to vote no on one, no on two, and propose new
studies.
DR. KUEHNERT: I'm
sort of equally confused. I mean you
could -- never mind.
DR. DOPPELT: If I
understand what Dr. Epstein was saying, the question for this is do you expect
the addition of these two questions to somehow roughly result in the same kinds
of answers or complete catastrophe? And
if you don't expect it to be a complete catastrophe, which I don't think any of
us do, then why even do it?
DR. ALLEN: Before
we call the role, I think thank you for the clarifying question. I think the way I had interpreted the last
exchange of discussion, I was going to vote yes on one, leaving it to the FDA
to decide how to implement, whether it was pre-approval or post-approval. But I think with the revision in the
question, with the understanding that the FDA has heard the committee
statements about cognitive validation of the questions as written, does the
committee believe that this study design is adequate?
DR. DI MICHELE:
Well, I just wanted to ask another question, maybe to the blood banking
industry. One of the issues of doing
any kind of study has been an issue of cost.
When you look at sort of the cost of this study, I suppose whether you
train interviewers to do 1,200 interviews or 6,000 interviews, I'm not sure
whether that cost is different. But
certainly, study coordination, data accumulation, data collection, data
analysis is certainly quite expensive.
On the other hand, Blood Systems has just done this
post-surveillance study of 53,000 or 60,000.
And I'm just trying to understand the costs of doing the kind of
post-surveillance that has been done on a wide scale basis, and whether that
cost is even greater than a prospective study.
And if not, why that is. Why
it's much more cost effective to do the same kind of data collection
post-implementation for 70,000 donor than the other way around?
DR. BIANCO: Thank
you for thinking about cost. There are
two types of costs associated with that.
One, there is the cost of doing business. There is analyzing data that is generated in the normal
operations to analyze deferrals. This
is something that we should all be doing.
And it's hard sometimes, because our computer systems have not gotten
there yet. They swallow a lot of data,
but spit out very little, like any other computer system. But this is part of what we do in terms of
monitoring deferrals, monitoring whatever.
The other studies, that is when we need a special informed
consent, specially trained people that fall outside the operations, those are
much more difficult. So, the initial,
this study proposed in one is much more difficult, resources-intensive than
simply a study of monitoring of data that is generated during the normal
activities of the blood center.
DR. DI MICHELE: Can
I ask a follow-up question? Then my
other question is, the task force has also put in a lot of thinking into these
two medical questions. But what we are
hearing from the Blood Systems report preliminarily is what has been missed --
let's say we're concerned about implementation before a study or whatever, and
it appears that the little information we do know about the medical deferrals
is that they are mostly on the basis of travel.
The question is, would the task force consider, if we
suggest sort of a cognitive validation of these questions, would they consider
putting in a third question related to interval travel?
DR. BIANCO: That's
already there and was validated by --
DR. DI MICHELE: So,
it's already in the abbreviated?
DR. BIANCO: It's in
both.
DR. ALLEN: Yes, it
asks about travel outside the United States or Canada in there interval period.
DR. DI MICHELE: So,
then really the issue of what's been missed in the abbreviated questionnaire is
something on the basis of a question that is already in the abbreviated
questionnaire? Is that what you are
saying?
DR. ORTON: No.
DR. KATZ: The way
the questions are now is in the long form you get asked about everything, every
time. The ADHQ then changes that to
since your last donation. Then you have
the opportunity that somebody either forgot the last time they got the long
form, isn't asked about past travel on the ADHQ. And I think it's something that we have concerns about.
We know that post-donation information, there are the flus
and the colds and the runny noses and all that. But the killer of course is, well, I told you I went to Cancan
last time, but I didn't tell you I left the resort and now I'm telling you
that. And then you have to go back and
trace units and do all this craziness.
DR. ORTON: Would it
be helpful if I actually read you the questions that are --
DR. DI MICHELE: No,
I just missed it. That's okay.
DR. ALLEN: All
right, let's go back to the questions.
As I am interpreting the question, we have changed the wording to
comparability. It is excluding
statistically significant demonstration of equivalence. The committee should vote, is this study
design adequate or not, yes or no? I
would think that the instruction from the committee to the FDA is this is not
necessarily an endorsement of pre-implementation use of the questionnaire. That's a decision that the FDA should make.
They have heard the other discussion, that with appropriate
cognitive evaluation of the questionnaires, that the committee individually --
members of the committee individually at least, believe that post-approval
implementation and evaluation could be an adequate alternative. And we can discuss that further under
question three. Is that adequate
clarification, Matt?
DR. KUEHNERT: That
last part, you are saying that the two are not mutually exclusive. I was just trying to understand if a
committee member were to think well, what we really want is
post-implementation, to cognitively test the capture questions the way the
other ones were done, and then do post-implementation data collection, then how
would we vote?
DR. ALLEN: I am
going to vote yes on question one, and the statement that I as an individual
will give to the FDA is this might be modified and implemented as a
post-approval evaluation, rather than as a study of 1,250 in only 5
centers. But I think the basic study
design is adequate. It's got the
restrictions of sample size, and it doesn't have statistical power. I think it will answer the questions that
need to be done. I think the suggestion
of cognitive evaluation of the questions before you do that is a good thing to
do under any circumstances.
DR. DI MICHELE:
But, Jim, the study as it's proposed is also a prospective,
pre-implementation study. So, I think
given everything you have said, I would vote no on what I've heard, and then
get to question three. But just as a
clarification so when this vote does come up, everybody understands.
DR. ALLEN: What I
would suggest, these conversations are recorded, and people are taking
notes. I would suggest that with your
yes or no, that you provide whatever qualifications that you want to along with
your vote.
Dr. Freas, let's go ahead.
DR. FREAS: Okay,
I'll go around and call the votes.
Before I do so, I want to clarify there are 12 voting members at the
table at this time. And at the end of
the voting members' polling, we will ask for the opinions of the non-voting
industry representative, and the non-voting consultant.
Calling the roll now, Dr. DiMichele.
DR. DI MICHELE: No.
DR. FREAS: Dr.
Kuehnert.
DR. KUEHNERT: Yes,
but I don't think it's needed.
DR. FREAS: Dr.
Harvath.
DR. HARVATH: No.
DR. FREAS: Dr.
Klein.
DR. KLEIN: I don't
believe this study will provide any useful data to the FDA, no.
DR. FREAS: Dr. Schreiber.
DR. SCHREIBER:
Ditto, no.
DR. FREAS: Dr. Lew.
DR. LEW: No.
DR. FREAS:
Dr. Quirolo.
DR. QUIROLO: No.
DR. FREAS:
Dr. Allen.
DR. ALLEN: Yes, but
I don't believe that the study is necessary pre-implementation if the cognitive
evaluation is done.
DR. FREAS: Ms.
Baker.
MS. BAKER: No,
ditto Dr. Allen's statements.
DR. FREAS: Dr.
Manno.
DR. MANNO: No.
DR. FREAS: Dr.
Doppelt.
DR. DOPPELT: Yes,
and I would agree that it doesn't have to be done pre-implementation.
DR. FREAS: Dr.
Whittaker.
DR. WHITTAKER: No.
DR. FREAS: Could I
have the opinion of the acting industry representative?
DR. KATZ: I think
that my opinion is that cognitively evaluated capture questions should be
included in the ADHQ, and a post-implementation study to be agreed upon by the
interested parties should be allowed by the FDA.
DR. FREAS: Thank
you for your comment.
A comment from the non-voting consultant?
DR. LEITMAN: I
think Dr. Katz stated it perfectly, and I would ditto his comments.
DR. FREAS: So,
polling the voting members we had 3 yes votes, and 9 no votes.
DR. ALLEN: All
right, we have made significant comments about the sample size. Dr. Epstein, given the results of that las
vote, do you need a vote on the sample size question?
DR. EPSTEIN: I
don't think so. I think that the sense
of the committee is that a post-approval study would be more meaningful, and
that it remains to be designed. We'll
seek appropriate epidemiological, statistical, cognitive input into that in
cooperation with the industry.
Again, I think on question three, if there are specific
suggestions on study design, we would really like to hear that.
DR. ALLEN: All
right, we are now open on question three for any additional comments,
recognizing that there has already been a lot that has been given.
DR. KUEHNERT: I
think what Dr. Katz expressed was what I would agree with.
DR. QUIROLO: I
assume there is -- I doubt that you would need it, but some kind of a stop
rule, where if you realize that there was a significant difference between the
two forms, that the study would be stopped, and they would be re-analyzed?
DR. KATZ: Yes, I
think that's important. I think Jay
actually made the point fairly clearly that that would be required. And I'm pretty sure I don't want to try and
design this study or the sample size right here, but the task force --
everybody that needs to be represented, is represented. I think we could come up with it pretty
quickly.
DR. LEITMAN: I can
anticipate a finding where the discrepancies were almost entirely due to the
memory jogging effect of remote historical travel by the donor. So, if that shows up in a year or two from
now, how important will that be? Will
the fact that you got more of a memory jog effect for travel to Europe or
whatever, or residence on a military base, would that derail this?
DR. ALLEN: Well,
that's not a question for the committee to answer, unfortunately. I suspect that the advantages of an
appropriately implemented designed and implemented abbreviated questionnaire
will not be derailed by such things as that.
And just as to me the way in which the information is asked and
accumulated will be refined over time, I think as it has been for medications
and other things. This is complex. We need better ways of identifying travel
histories. And it seems to me that the
best way is not to ask somebody.
I couldn't begin to tell you how many actual weeks I've
sent in England. I know it's well under
90 total days, but it is an important question, and I don't think that the
efforts to figure out better ways to acquire the information from donors should
stop at this point.
DR. KLEIN: In
reference to question three, I entirely agree with the way it was summarized by
Dr. Katz, and with the stopping rule. I
also think that it is important for a post-donation study, although not
necessary, to evaluate the impact on donor retention. If those data could be collected at the same time, I believe they
would be very valuable.
DR. ALLEN: Thank
you. That's an important comment. Other comments or questions?
All right, we will take a break at this point. Why don't we try to be back in 10 minutes,
and then we'll go into our last section, which is the review of the site visit
report from the Laboratory of Molecular Virology.
[Brief recess.]
DR. ALLEN: We will
now move on to topic IV., which is the review of the site visit report for the
Laboratory of Molecular Virology. The
site visit was conducted on October 29, 2004.
We will have a series of five presentations by the staff of the laboratory,
the first being the introduction and background by Dr. Hira Nakhasi, who is
Director of the Division of Emerging and Transfusion Transmitted Diseases in
the Laboratory of Molecular Virology within that division.
Agenda Item: IV.
Review of Site Visit Report for the Laboratory of Molecular Virology, DETTD
- A. Introduction and Background - Hira Nakhasi, PhD, Director, Division of
Emerging and Transfusion Transmitted Diseases, OBRR
DR. NAKHASI: Good
afternoon. Thank you, Dr. Allen.
I think the purpose of my talk here is to set the stage for
the individual investigators to talk about their research projects with
relation to the mission of the laboratory.
And I will just give you a brief introduction, and then the people will
talk about the individual projects.
In the office in the Division of Emerging Transfusion
Transmitted Diseases is located in the Office of Blood Research and Review,
OBRR. Dr. Epstein, as all of you know,
is the office director. We have a new
deputy director now, Dr. Paul Mied(?).
Mary Beth was acting for the time being. She is Associate Director for Regulatory Affairs, which is her
second hat here.
And also Dr. Linda Smallwood -- this is now quite a bit
changed here. Dr. Linda Smallwood has
already retired. And then Dr. Ed Taber
is the Associate Director of Medical Affairs.
The office has three divisions, the Division of Emerging
Transfusion Transmitted Diseases, the Division of Hematology, and the Division
of Blood Applications. The focus today
is the scientific review in the Division of Emerging Transfusion Transmitted
Diseases.
The division is organized in three major laboratories
relevant to the subject matter, the Laboratory of Molecular Virology, who is
headed by Dr. Indira Hewlett. This is
the laboratory which will be discussed today.
And our science review of that laboratory will be discussed today, and
Dr. Hewlett will talk a little bit more about the work that is being done in
the lab in the introduction.
And then we have a Laboratory of Hepatitis and Related
Emerging Agents, a Laboratory of Bacterial, Parasitic and Unconventional Agents,
and we also have a product testing staff which does the lot release testing.
The responsible mission of the division is to first of all,
insure the safety of the nation's blood supply by reviewing, evaluating and
recommending various test kits for blood-borne viral, parasitic, bacterial and
now transmissible spongiform encephalopathies or prions.
Also, the mission is to conduct research applied to insure
the safety and efficacy of these products, which basically results in the
development, manufacture, and understanding how these pathogens work, and then
the test kits and developing of the assays.
In addition to that, as I said, our responsible is the
lot-release testing of all these investigational tests and the licensed
products, and develop reference materials for lot-release testing, and also
develop standards for validating tests.
And in addition to that, the staff does the inspection of the
manufacturing facilities where a lot of these test kits are manufactured,
provide the scientific and technical advise to other agencies and the
government components, and also presents the issues to bodies like this and
other advisory committees.
The personnel and the budget of the office in 2004, as you
see, the total staff is 58. There are
11 senior investigators which are supported by biologists, staff fellows, staff
scientists, regulatory scientists and administrative staff and post-doctoral
fellows. The total budget is
approximately $400,000, and last year there were 41 publications and some book
chapters published.
The regulatory activities, obviously, the major component
and last year which included all sources of applications, and with the total we
had around approximately 374. And also,
we did lots of lot release testing, and performed inspections and laboratory
investigations.
The purpose of this whole thing is to give you an idea of
what our workload, both in the research, as well as the regulatory arena. The research priorities of the division are
two fold. One is to focus on the areas
where we deal with the safety and efficacy of these test kits for blood-borne,
viral, bacterial, parasitic agents. And
understanding the pathogenesis of for example retroviruses, West Nile virus.
Other parasitic agents which are being studied are malaria,
leishmania and Chagas disease, and some of these bioterrorism agents both viral
and bacterial, and also hepatitis-related agents such as HCV, HBV, HAV, and the
pathogenesis of the prion proteins and bacterial agents.
The second important component of the research is the assay
development. I think the assay
development is for new technologies for detection of retroviruses, or
characterizations of new forms of variants of the new pathogens. And then lot-release as I said, development
of lot-release panels and standards for existing, as well as new and emerging
pathogens.
Also, looking at the new technologies which come down the
pike, we are actually engaged in that, because that is one of the issues, as
you heard yesterday about the critical path issues, to understand what are new
technologies or new way of thinking how we can help industry stakeholders to
overcome the issues which could be resolved earlier on.
For example, use of microarray DNA technology. Now we have heard nanotechnology, and there
are other newer technologies where we can multiplex some of these tests, and we
can test many more pathogens in one swoop, such as developing the TSE
methodologies and detection of validation methods for TSE agents, and bacterial
agents.
So, how does it fit in to the critical path initiatives,
which you heard obviously? Whereas, you
heard the nice story about the West Nile virus, how we engaged in how that
helped in developing the test.
Similarly, studies were done with the smallpox and blood safety issues,
HIV surveillance study in Cameroon, which may hear from Dr. Hewlett.
Studies were initially to find out the sensitivity of
various HBsAg tests and HBV NAT, and developing as I told you, the
oligonucleotide based microarray chip, and other concepts of parasitic and
viral agents. So, that's what we hear
from what is going to be coming down the pike, and how we can work with those
issues.
In addition to the critical path initiative, we also have a
mandate about some of these counterterrorism initiatives, developing laboratory
expertise in new technologies, as I mentioned earlier, nanotechnology,
microarray technology, and any other new technologies that come down the
pike. And then developing panels and
standards, lot-release testing, and also understanding how these pathogens
work.
With that, I will close my summary. After me, Dr. Indira Hewlett, she is the
Chief of Laboratory of the Laboratory of Molecular Virology. She will be talking too, talking first about
the laboratory, and then her own project.
After that Dr. Andrew Dayton will talk about his work, and after that
Dr. Subhash Dhawan will talk about his work.
And last but not least, Dr. Maria Rios will talk about her work.
Thank you.
DR. ALLEN: Okay,
thank you very much, Dr. Nakhasi. And
he has basically introduced the staff.
I would just ask the presenters please try to keep within the time
limits, since we are running a little bit later, and we want adequate
discussion time for the committee.
Dr. Hewlett.
Agenda Item: IV.
Review of Site Visit Report for the Laboratory of Molecular Virology, DETTD
- B. Overview of Laboratory and Diagnosis of Pathogenesis of HIV
Variant: A Progress Report - Indira
Hewlett, PhD, Chief, Laboratory of Molecular Virology, OBRR, FDA
DR. HEWLETT: Good
morning. I'm going to be presenting an
overview of the Laboratory of Molecular Virology. And that will be followed by just some highlights of my own
research program in this lab.
Just to note that we are one of the three research
laboratories in the Division of Emerging and Transfusion Transmitted
Diseases. This lab was created during
the CBER reorganization of 1992, and at the time it was given responsibility
for all HIV tests that were based on synthetic peptides and molecular probes
and recombinant DNA technology. In
1999, we acquired responsibility for all retroviral products, and from 2001, we
actually added on West Nile virus, vaccinia, and software reviews for the
division.
The lab is organized into five groups. Four of them conduct research, and they are
actually manned by individuals who are researchers and reviewers. So, they do both research and review. And we currently have a product review
section which is composed of individuals who do exclusively regulatory review
of product applications.
The regulatory mission of the lab is to review and license
applications for all in vitro tests, that is donor screening and diagnostic
assays for HIV, HTLV and other retroviruses in blood, plasma and other body
fluids, for example, oral fluid. We
also review West Nile virus donor screening assays, and this has been going on
since 2003, when implementation under IND took place.
We perform concept reviews for smallpox submissions. And this is only a small part of the
activity, but it does exist in this laboratory. We also perform software and instrument reviews for the division,
as I stated earlier.
The regulatory product area is a review of applications for
convention antibody, antigen, and nucleic acid tests, rapid tests for
diagnosis, patient monitoring assays, genotyping assays, and drug resistance,
and home use assays, although we don't have any activity in this area at the
moment.
We also perform inspections of test kit manufacturing
facilities. We develop guidelines,
review criteria and standards for validation of tests, and our staff are also
involved in developing policies related to their use through interagency,
industry and BPAC discussions.
So, to support the regulatory mission of the laboratory, we
have research programs. And the
research is basically focused on HIV viruses, HTLV, West Nile, and vaccinia
virus. We conduct laboratory
investigations of disease transmission and pathogenesis. Our staff are involved in developing and evaluating
new technologies and methods to insure blood safety from transmission of HIV,
HTLV, West Nile and vaccinia.
And another important aspect of our laboratory activity is
standards development. So, we are
constantly engaged in some type of standards development activity for licensure
and surveillance of retroviral tests, and more recently for West Nile virus
assays.
And just to give you some key points of each of the
programs -- you will hear more about this from each of the individual principal
investigators -- in my own group we are looking at genetic diversity and the
impact on diagnosis and pathogenesis of some of these variants. We are developing reference reagents for HIV
NAT assays. There is an individual in
my own section who is working on vaccinia virus as a model for smallpox. And we have looked at viremia in vaccinated
individuals, and we are starting out some work on the molecular basis for
myocarditis induced by smallpox vaccination.
We have Dr. Dayton's lab that is looking at the molecular
biology and gene regulation of HIV in infected primary human macrophages.
Dr. Dhawan is looking at diagnosis and pathogenesis of HIV,
focusing on host and viral factors in disease transmission and
progression. And he is also developing
diagnostic tools for viral detection.
And Dr. Rios -- this is the youngest program in the
laboratory -- has actually been highly productive since she joined the lab, and
has been developing programs for diagnosis and pathogenesis of West Nile virus,
looking at genetic characteristics, tropism and standards development for
licensure of West Nile assays.
So, in summary, this lab has actually had product
responsibility for HIV tests for a fair length of time. It's actually over a decade now. We have had new product responsibilities
including West Nile virus, vaccinia, software and instrument reviews. And we have actually maintained and
initiated some new research programs to support these regulatory activities.
So, that's the end of my overview. Are there any questions? Or should I move on to the next part of my
presentation, which is actually my own work that is going on in my own group.
As I said in the overview, the major areas of investigation
in my group are actually three major areas.
That is diagnosis of genetic diversity of HIV, and its impact on
diagnosis. We are also looking at
pathogenesis of these variants, subtypes, HIV-2, multi-drug resistant viruses.
And we have a program on standards development. We have developed standards for HIV-1, and
we are now looking at subtypes and HIV-2.
These standards would be for blood screening and to monitor therapy in
vaccine trials. And finally, we have a
small program on vaccinia and smallpox as it relates to blood safety.
In regard to the first area with HIV variants, the study
goals were to evaluate the sensitivity of existing and new blood screening
assays for diverse subtypes with sera from Cameroon. We chose to work in this area because it is known to harbor diverse
HIV strains. We have characterized and
genotyped several variants from this area.
We are now investigating the pathogenesis of some of these
major variants, and we are trying to identify samples to serve as candidate
reference materials from this study. I
would like to say at this point that actually NHLBI, just a few weeks ago,
informed us that they are providing us with funds to actually continue this
very work in Cameroon. So, we are
looking forward to actually pursuing this in a more aggressive manner, and to
be able to characterize these viruses completely, and of course to look at
their impact on blood safety.
The conclusions from our study were that the FDA licensed
tests were able to detect additional positive specimens than those identified
in Cameroon. We found that EIA results
from different manufacturers did not always agree with each other. The Western blot may not always resolve some
of the discordant results. This is when
you are looking at non-B subtypes in African sera.
We found that CRF02_AG was the most prevalent viral strain
in Cameroon. This is about 70 percent
of the viruses circulating in Cameroon are CRF02_AG. This is different than the picture that was seen about maybe six
or seven years ago, where the discrete subtypes were actually predominant and
those were subtypes A and D. So, we are
seeing a very different picture emerging over time in terms of the predominant
viral strain found in this particular area.
We have also identified new circulating recombinant
forms. These are unique forms. There is actually one isolate of each, so
that's AC, AF and GF. The good news is
they were all detected by the nucleic acid tests that are licensed in the
US. So, from a blood safety and diagnostic
point of view, they were not an issue.
We have identified in the study, several discordant
samples. And we are now analyzing these
discordant samples as well as some negative samples with degenerate
primers. We are also looking at PCR-RT
assay. This is in collaboration with a
group in the Office of Vaccines.
We are also looking forward to using some new technology to
look for new viruses in this set of samples.
And in fact, with the funding we are getting from NHLBI we will be
initiating a collaboration with Phillipe Niambi(?) from Cameroon to acquire
some very interesting samples that are cross-reactive with SIV peptides, and
start looking for cross-species transmission, as well as new variants that
might be evolving in this area in the course of time.
We have a proposal to look at microarrays, viral discovery
arrays for identifying genotypes, subtypes in new viruses. Since we have sequence data of these
recombinants, we can validate this using the sequence data that we have already
acquired.
And from the pathogenesis point of view, we are looking at
both tropism and apoptosis by molecular cloning of envelope genes of specific
unique isolates to see if there are any differences in these properties of
these variants relative to the known subtype B viruses.
In another type of variant that we are looking at are HIV
drug-resistant viruses. And the goal
here was to look at their replication capacity, tropism, genotype, apoptosis
capabilities, and chemokine and cytokine product. It's essentially co-receptor usage as a function of virus
evolution in patients who are on antiretroviral therapy.
We also wanted to examine whether there was correlation
between genotype co-receptor usage and virus replication. In this study we isolated viruses from
patients who were naive and patients on prolonged antiretroviral therapy. And we have found that actually they
continue to use classical chemokine co-receptors CCR5 and CXCR4. So, there aren't any new receptors that are
being used by viruses from patients on antiretroviral therapy.
There might potentially be a switch to co-receptors, to a
specific co-receptor. In this
particular case it was switched to CCR5 after they were on prolonged
antiretroviral therapy. And that's not
unusual, because that co-receptor usage is associated with less pathogenesis
than the CXCR4 using viruses.
Tropism was not apparently related to CD4 count, viral
load, genotypic mutation in the whole genes and the C2V3 region, which is
actually the major region that dictates the tropism of HIV viruses. We are now planning some future studies on
cytokine regulation, the ability of drug-resistant viruses to cause apoptosis,
since we would expect that if they are less pathogenic than naive viruses, they
could potentially be less capable of inducing apoptosis.
Of course we have all heard about this unusual virus that
was isolated in New York a couple of weeks ago, and David Ho is actually
working on this virus to see how different it is than the standard
drug-resistant strains.
In the standards development area, we have developed a
subtype panel. This has been
formulated, and is available for manufacturers to use to standardize their
assays for either quantitation or qualitative detection of the major HIV
subtypes.
We have also developed an HIV-2 panel. It is actually in the final stages of
development. We have data from several
manufacturers who have validated HIV-2 nucleic acid tests, because we see this
as being the next virus on the horizon.
Although it's not a huge public health issue in the US per se, but there
is a need to have HIV-2 NAT assays in blood screening, because we already have
HIV-2 antibody testing, and this is probably where the next round of product
development is going in terms of multiplex NAT.
So, that is pretty much where we are with the HIV
projects. In regard to smallpox vaccination,
this area was actually initiated about two years ago. The reason we started this is because there were concerns for
blood donation. There was some talk
about mass immunization at the time of the 9/11 incident, and concerns were
raised about whether these mass vaccinees could present as blood donors.
There was concern about potential viremia in vaccinated
individuals. And the concern was
heightened due to lack of data on virus transmission by blood. So, studies were needed to determine the appropriate
deferral period for vaccinated donors.
The second issue had to do with potential false positive
reactions with sera from smallpox vaccinees similar to what was observed with
flu vaccination many years ago. And
this of course would be an issue, because if there was a very significant rate
of false positivity, you could have a major impact on blood availability due to
increased numbers of donors being deferred as a result.
The conclusions from our study, we have actually looked at
plasma, and at this point we have looked at cells from vaccinated
individuals. Our findings are
essentially negative. We were not able
to isolate vaccinia virus from both cells and plasma using actually a very well
validated culture method that Dr. Srinivasan in our lab developed.
And what we have found is that plasma from vaccinees may
not pose a significant risk for virus transmission. In fact, even the cells based on culture studies, seem to be
lacking virus that's detectable by our technique.
In regard to availability, what we have observed is that
with most donor screening assays, we did not see significant interference. We looked at 13 assays, and out of the 13
though with 4 we actually did see at certain time points post-vaccination, some
false positivity. And we are now
investigating that further to see in fact if they are real. So, that's where we stand with the vaccinia
study.
So, in summary, our lab has been investigating the
molecular epidemiology of HIV strains in a country with high viral
diversity. We have actually expanded
this collaboration to other areas where virus evolution is occurring,
specifically in the Russian territories.
This is through the Biotechnology Engagement Program. So, that project is going to be initiated in
the next couple of months.
We are also looking at potentially setting something up in
the southern part of the India where there seems to be some virus evolution
occurring.
We are looking at the diagnostic impact of HIV
variants. This is by acquiring these
samples and testing all the licensed blood screening assays, as well as we hope
in the future to look at the rapid tests that are used for diagnosis, because
in fact those tests are used more in developing countries than here, and in
those areas where we see higher viral diversity than we have seen in the US to
date. So, this issue is actually more
critical we think in countries outside the US.
But it is an issue that needs to be looked at from the standpoint of
AIDS pathogenesis and prevention.
So, we are continuing to look at virologic characteristics
of drug-resistant variants. We are
developing reference materials for HIV-2, as I mentioned. We are also looking at developing reference rate
for CRF02_AB, which is the predominant viral subtype in some parts of the world. And we are pursuing some studies on
vaccinia, specifically on identifying the -- actually to look for viremia in
these vaccinated individuals by a Taqman assay.
In the area of new technology we have just been funded by
the Office of Science to start some work in developing or to evaluate
nanoparticle technology for its applicability for pathogen detection. We are starting by looking at HIV and
potentially West Nile as the first phase of the evaluation of this technology.
So, I'll stop there.
Thank you.
DR. ALLEN: Thank
you, Dr. Hewlett.
Clarification questions from any of the committee members
for Dr. Hewlett? All right, we'll move
on to the presentation by Dr. Andrew Dayton.
Agenda Item: IV.
Review of Site Visit Report for the Laboratory of Molecular Virology, DETTD
- C. The Molecular Biology of HIV Infection of Primary Human Macrophages -
Andrew Dayton, MD, PhD, Section Head, LMV, OBRR, FDA
DR. DAYTON: Good
afternoon. I'm Andrew Dayton.
The work in my laboratory for many years has been -- at
least since I have been at the FDA, has been focused largely on the molecular
biology of HIV infection of primary human macrophages. As many of you know, the macrophage is a
central cell in the body involved in the pathogenesis of HIV and the clinical
course of AIDS. It is one of the first
cell types to be infected during a transmission.
It is a conduit for bringing HIV across the blood-brain
barrier into the brain. And it serves as
a reservoir for virus throughout the clinical course of the disease. That's largely the reason why I have been
focusing on it. Also, we can study it. It's a very interesting cell type in that
you can have a lot of replication without a lot of cytopathic effect. So, you can look at what happens to these
cells.
Now, most of the work comes from our key project, which has
been identification and characterization of macrophage genetic pathways
regulated by HIV infection and/or individual HIV genes. Mostly we have focused on the HIV Tat gene,
which is known to affect a large number of cellular genes.
We have gotten into some corollary projects as a result of
this. We have looked at genes that have
seemed to be of interest, and they have taken us into related fields which are
all relevant. In particular, we have
been looking at the regulation of apoptosis in and also by macrophages. I'm going to summarize some of that data in
a minute.
We have recently obtained a grant from the Office of
Women's Health to study gender bias in HIV infection of common blood cell
populations including macrophages. And
also that grant covers the effects of antiretroviral agents in HIV infection of
macrophages. I should say as a footnote
here for mission relevance, one of the hats we wear is regulating HIV
drug-resistant genotype assays.
We have also been looking at flavivirus replication in
macrophages. We have been doing this in
collaboration with other members of the laboratory, in particular Maria Rios
and also Indira.
We have historically worked -- this recent collaboration
with others in the lab has been on West Nile virus. We have worked on dengue in the past, and have reported dengue
replicons, which may be useful for vaccine development. And we are also looking at co-infections of
HIV and West Nile virus in macrophages.
And in general, we are interested in the basic molecular biology of the
HIV autoregulation.
So, the work on apoptosis derived from looking at genes
which were regulated by HIV infection.
And a very interesting finding we made is that HIV infection or Tat
protein upregulates the expression of TRAIL which is TNF Related Apoptosis
Inducing Ligand. It's a factor which is
secreted and causes apoptosis in nearby cells.
And this is of tremendous interest, because TRAIL, which is
produced by macrophages, could contribute to bystander mediated apoptosis. When we did this work it was a theoretical
connection. Shortly therefore in the
SKID(?) human-mouse model other investigators actually showed very convincingly
that we were having a lot of apoptosis induction in that system by TRAIL and
not by direct infection. So, we were
very happy to see the groundbreaking work of ours turned out to have some
relevance.
We also found that the HIV infection and Tat upregulate in
macrophages at least, Bcl-2, which may contribute to protection of macrophages
from apoptosis.
More recently, we have been looking at a very interesting
finding that again came out of our microarray analysis actually, looking to see
which genes were upregulated by HIV and Tat.
And this is the upregulation of the IL-7 receptor alpha chain at the
levels of both RNA and protein.
I'll show you data on this briefly, but what the data is
going to say is that the upregulated IL-7 receptor is exposed on the exterior
of the plasma membrane. It is
functional, and this upregulation appears to be in a predominant population of
macrophages. I won't actually show you
the data for that today.
This is the key data.
We won't go into all the details.
But if you look at the protein data, uninfected cells have a very low
level of IL-7 receptor. But if you
treat with Tat protein or infect the cells, you get induction of the receptor
at the level of protein. This is an
inhibition of Tat by an antibody, just showing the specificity.
The same thing is seen at the level of RNA in these two
portions of the gel. These are
normalization controls. The critical
data is right here. In uninfected cells
you do have a background of RNA for the receptor. But when you infect with HIV, you get a big upregulation.
Similarly, you see the same thing with Tat, the use of
normalization controls. You get a small
amount of production if you don't add Tat to the cultures. But when you add Tat to the cultures, you
get an induction at the level of RNA.
Then this data shows that the newly induct IL-7 receptor is
functional. And it just shows that it
phosphorylates or activates STAT-3. The
question arose, okay, we are upregulating the receptor. But can it do anything? Maybe it's defective. But the answer is it does do something.
These are Western blots probed with antibodies to activate
its STAT-3. And you can see that what
these have done, these cells are grown.
Then you get rid of all the cytokines, put them in serum-free
medium. Then you blast them with the
IL-7 cytokine to look for intracellular signaling. And when you blast uninfected cells with IL-7 for 20 minutes, you
don't get any signaling. But if they
have been HIV-infected, you do get signaling.
These are controls.
Similarly, you see the same thing with Tat treatment. If there is no Tat treatment, you blast them
with IL-7, there is no detectable signaling.
If you blast them with IL-7 and they have been pre-treated with Tat, you
get signaling. So, the upregulated IL-7
receptor was displayed on the surface and it's functional.
This is the data that ties this into a novel positive
feedback loop. And all this says is if
you dump IL-7 cytokine into these cultures, you increase the amount of
HIV. And this is a dose response curve
with increased amounts of IL-7. These
are physiologic levels.
So, the basic observation is HIV upregulates the IL-7
receptor. And IL-7 stimulation through
the IL-7 receptor upregulates HIV. So,
you have a positive feedback loop. And
just to lead you through that, this is what it looks like presumably. There is IL-7 cytokine floating around in
the supernatant when you are in plasma.
When you infect with the HIV and starting HIV products, one
of those is the Tat protein, which feedbacks back, and we believe it stimulates
IL-7 receptor transcription. That gives
you IL-7 receptors on the surface, which now signal from the IL-7 cytokine that
is kicking around. And that signaling,
we believe, goes back into the nucleus and regulates genes which influence HIV
replication. It may be at the level of
entry, we don't know.
So, to give you an idea of where we are going to take this,
since the site visit we have actually been awarded a grant to pursue this work
and others by the National Institutes of Health. It's an intramural H targeted antiviral grant. And part of that is to do mechanistic
studies on HIV upregulation by the IL-7 system in these cell types. And part of it is to study the effects of
Nef on primarily human monocytes and macrophages.
The grant is centered around the use of transfection in
monocytes, which is a new technique that we have actually developed, and it's
giving the potential to do a lot of experiments which haven't been able to be
done before in macrophages. And that
will enable us to do the mechanistic studies.
This is just my rogue's gallery of macrophages transfected
with yellow fluorescent protein, which you can see is green. And you get all sorts of things. You nice stretched out fibroblastic
macrophages. You get some classic fried
egg morphology macrophages and small round ones. So, we are getting a nice transfection.
Just to remind you of the flavivirus biology that we have
done. We have developed dengue virus
replicons expressing exogenous genetic material, including HIV proteins. These are potentially useful for vaccine
vectors. It also gives us a good
background to go into some basic molecular biology of West Nile virus, if we
can get outside funding for it.
And we have also been looking at replication of West Nile
virus in macrophages with Indira and Maria.
Finally, I mentioned that we had a grant from the Office of
Women's Health for gender bias in HIV replication in blood cells. This is looking at the effect of hormones
and HIV replication, and also looking at the effect of hormones on specific
drugs and their ability to inhibit HIV.
And that is pretty much it. If there are any questions, I would be glad to answer them.
DR. ALLEN: Thank
you, Dr. Dayton.
Questions, clarification for Dr. Dayton from the committee?
DR. LEW: Would you
venture just an hypothesis on why infection with macrophages does not always
induce apoptosis as compared to the two tropic viruses that tend to infect and
also kill?
DR. DAYTON: It's
tremendously system-dependent. I really
can't say anything other than that. You
pick your experimental system and you work with it, and it just varies all over
the place, so I really can't answer the question.
DR. DI MICHELE:
Will you be looking at the role of Bcl-2 upregulation in these
macrophages in some of the malignant complications of HIV?
DR. DAYTON: You
mean how does it achieve the upregulation?
Or what is the significance?
DR. DI MICHELE: The
significance, and whether it actually has a role in the malignancy potential in
these patients.
DR. DAYTON: We
really haven't had the resources to pursue that. Of course, we would love to.
Macrophages, as you probably know, are very resistant to apoptosis
anyway, so there is some question about whether they really need the
Bcl-2. But it was an interesting
observation. The observations on TRAIL
I think have much more significance than the observations on Bcl-2.
DR. ALLEN: Thank
you, Dr. Dayton.
Our next presentation is by Dr. Subhash Dhawan.
Agenda Item: IV.
Review of Site Visit Report for the Laboratory of Molecular Virology, DETTD
- D. Viral and Host Factors in the Pathogenesis of HIV-1 Infection: An Overview - Subhash Dhawan, PhD, Section
Head, LMV, OBRR, FDA
DR. DHAWAN: Well,
good afternoon committee members and everyone present here. There is a lot to talk about, but the time
today will permit me just to give you a flavor of what we have been doing in
the past four years.
The title of my brief talk will be, "Viral and Host
Factors in the Pathogenesis of HIV-1 Infection." Besides being involved heavily in the review of product
applications and inspection of manufacturing facilities, my research interest
has been in studying the following studies.
We examined the role of HIV-Tat protein in viral pathogenesis, as Andy
mentioned before. We worked to
understand the involvement of host factors in HIV pathogenesis, and also
developed strategies to enhance sensitivity of diagnostic assays.
These studies highly relate to our mission, because we
heavily regulate vaccines in our center, and the Office of Blood primarily we
regulate the diagnostic tools.
So, briefly, the Tat protein is one of the regulatory
proteins of HIV-1. It's a very small
protein, about 6 kilodalton. It is
believed to be involved in the progression of HIV infection, the co-factor for
Kaposi's sarcoma, and also is involved in the apoptosis of normal cells and in
neurological disorders.
The evidence published in the literature shows that high
levels of anti-Tat antibody relate to low viral load and seropositive
non-progressors. So, the higher the
level of anti-Tat in the body, the slower the disease progression. It's very well documented now.
So, these studies actually led us to focus our studies to
develop a strategy to target the functional domains that are involved in the
progression of infection by neutralizing them, and use them as a therapeutic
approach, like a therapeutic vaccine.
And I was just happy that I just shared with Dr. Allen the e-mail I saw.
Dr. Luke Montaya(?) recently endorsed how useful the
therapeutic vaccine could be, as opposed to the preventive vaccine, which none
out of 30 are showing any promising results.
So, that gives me really good feedback to focus more on our studies, and
confidence to believe what we are doing.
I think that something could be meaningful.
So, Tat, as I mentioned, is a small protein. So, we mapped the entire Tat protein into
multiple domains and figured out the two key domains representing 21-40 amino acid
residue, which is cystine rich, and the other one is arginine rich domain,
which ranges for 53-68 amino acids.
They are key domains that made pathogenesis.
As you can see, there are multiple cytopathic effects. Notice when the cells were treated with
these two synthetic peptides and then challenged with HIV, the results were
quite similar to what we observed with the common and Tat proteins.
In a panel over here we demonstrated not only the
recombinant Tat, but these same domains up here, they promoted the formation of
new blood vessel formation in the CAM assay, like chicken ellen(?) toy(?)
assay. So, these two domains represent
a key domain and are the key target for neutralization in order to slow down
the progression of infection.
But before we could use these domains in the form of a
therapeutic vaccine, we must modify these domains, because they are
pathogenic. If you don't modify and use
them just as is, well they will induce immune response. Eventually you neutralize those
domains. But before they could do that,
they will cause more adverse effect, because they will potentially be given to
infected individuals. And the cells
that already are infected will produce more virus.
So, in order to do that, we modify. We may very selective changes in the side
chain of cystine and arginine. And by
this slight modification it completely blocked their pathogenic activity, and
yet retained their immunological characteristics.
Since we last had a site visit, we raised antibody in mice,
and we got very encouraging results. We
used those antibodies and tested them in the infected assay, and we were able
to demonstrate somewhere in the order of 40-70 percent inhibition of HIV
application in monocyte by macrophages even in the absence of Tat proteins.
So, we are trying to do now is to use them in -- preferably
there is a mouse model available. We
would like to test it out, otherwise we are in collaboration with Dr. Chris
Morty(?) in San Antonio, Texas. We are
trying to test their immunological capability in rhesus.
And these are the results which I just said, in one
slide. The modification that we made in
the cystine site chain, and also in the arginine over here completely blocked
the angiogenesis, as you see clearly in your handout.
So, a summary of the results are the cystine rich and
arginine rich Tat sequences, they represent key domains in the HIV Tat protein
that made pathogenesis. Synthetic Tat
MPC now multiple MPCs from multiple peptide conjugates, what we did was we used
these domains and made a synthetic construct, because this blood type will not
be able to raise antibody as it is.
So, in order to increase the size, we used the synthetic
backbone of lysine, and then put these domains on top of them, and they were
able to induce effective immune response.
So, antibody inhibited induced cytopathic effects. It's very interesting results.
And selective sites for modification I mentioned. They completely blocked the functional
domain. And this modification retained
large (?) characteristics, but completely blocked their pathogenic effects.
In another project which is quite related to the mission in
the Office of Blood is develop tools to increase the sensitivity of an
assay. It's very important to increase,
have a diagnostic test that have high sensitivity. Typically in the EIA we use a secondary antibody reconjugated to
enzyme, either HRP or alkaline phosphalyse or any other label.
But the limitation is the availability of the functional
group, because these are conjugated through either amino or cystine group. And the antibody can have only X number of
these functional groups. So, we now
increase the binding of or conjugate more of these enzymes of the labels. I artificially created a number of primary
means by using a lysine chain. In this
for example we used 20.
So, for each amino group, I created 20 groups, and then
conjugated HRP. And similarly by
selectively cleaving the antibody for the sulfide reducing, this sulfide group,
I conjugated two of those in order to increase the number of labels per
antibody molecules.
And the results briefly were shown here, very
encouraging. This is actually the
Western blot showing the ability of these conjugates to detect even the bands
that were not even visible in the conventional conjugates, we were able to
detect those bands here. Now, by the
way, this is a commercially available blot.
We didn't create it in our laboratory.
We just simply tested our conjugate that we prepared, the ones where we
artificially increased the amount of label on each of the antibodies.
So, we couldn't pursue this due to the lack of funding and
lack of resources. So, basically this
work was done nearly two or three years ago, and basically I could not do
anything more on this.
So, to summarize, the signal amplification conjugates, as
just stated, increased the sensitivity of immunoassays. I plan to, given the funding situation, I
plan to apply this to the same technique to develop a NAT. You can do the same thing in nucleic acids
as well.
So, in the future plan we will try to immunize, depending
upon the funding. We will use this Tat
MPC. We will challenge them with SHIV
89.6, effectively infect the rhesus macaques and study the progression of
disease. Also, for the diagnostic
purposes we plan to test commercially available panels of normal serum, and
whatever we require the manufacturer to do to demonstrate their efficacy of
test kits by using multiple commercially available panels.
That's basically it.
So, thank you very much.
DR. ALLEN: Thank
you, Dr. Dhawan.
Comments or questions for Dr. Dhawan from the committee
members. That's very exciting research.
DR. LEW: Using your
genetically altered Tat, have you found that it can, instead of stimulating
TRAIL production, it actually does not stimulate TRAIL production? Because if TRAIL is the cause of bystander
cell death, that would be very, very interesting. And technically, the use of antibody to the Tat, potentially that
could prevent again TRAIL upregulation and bystander cell death.
DR. DHAWAN: Oh,
well, sure. This is what Andy talked
about in his presentation. You're
right.
DR. LEW: I didn't
hear him say he was going to use those particular ones.
DR. DHAWAN: We
don't know. What he has demonstrated is
if he uses the antibody against Tat protein, it will neutralize Tat induced
effect. And he very clearly
demonstrated that. Now whether or not
those domains are involved in the inhibition of TRAIL, we don't know. But we know is -- see, we are talking two
different questions here. The one you
are talking about, the upregulation of Tat protein that mediates other pathogenic
effects primarily in the neurological disorders.
But what I am talking about is how it progresses the
infection or the virus application in cells that are already infected. So, if we can block the domains that are
responsible for promoting viral infection, even though the Tat may bind to the
cell, because the binding site is different, blocking the functional domain
that induces response in individuals' binding sites are or receptor sites,
which we don't know for Tat, can block the Tat induced signaling in the
infected cells.
Also, not only the infected cells, it can block the signaling
in the uninfected cells, because Tat not only promotes the viral pathogenesis,
it also activates normal cells and makes them more susceptible to HIV
infection. It works in two ways. So, it works in endocrine(?) fashion, and it
also works in a paracrine(?) fashion.
Blocking this effect can block both the functions.
DR. LEW: That's why
I find it interesting. Tat has many,
many different functions, and that's clear.
But I just think it's very interesting, we don't know how Tat works to
induce TRAIL production. And just
giving Tat we know can induce it without the HIV infection. You have the constructs. It might be worthwhile to just see its
relationship to TRAIL.
DR. DHAWAN: Yes,
that would be great. Let me clarify,
the construct that I mentioned is not recombinant. It's totally synthetic.
We made it in the laboratory using totally ad hoc synthetic chemistry.
DR. ALLEN: Thank
you very much.
We'll move onto our last presentation for the morning, Dr.
Maria Rios.
Agenda Item: IV.
Review of Site Visit Report for the Laboratory of Molecular Virology, DETTD
- E. West Nile Virus: Pathogenesis
and Diagnostic Tools - Maria Rios, PhD, Senior Staff Fellow, LMV, OBRR, FDA
DR. RIOS: Good
afternoon. What I have to talk about is
the new program in the DETTD. And it is
on West Nile. This program was
established two years ago, and that is what we have been doing so far. I don't think I need to keep you up-to-date
on what is going on, because we know that West Nile in the US has reoccurred
for six consecutive years, which is unheard of in the West Nile field. And actually, from the first epidemics to
the 2004, was going up and up and up, and we don't know where it's heading.
These six consecutive years of epidemics has accounted for
over 16,000 human cases of disease, and 600 deaths reported to CDC. It is estimated that about over a million
people have been infected with West Nile.
The transmission by blood transfusion was documented in
2002, and led to a series of actions mainly by the CDC and FDA, and jointly
with the test kit manufacturers and the blot community to expedite development
and implementation of screening assays for West Nile within eight months of the
identification of the issue.
The research plans were to develop a standard reagent
material well characterized to use with the purpose of regulatory issues in
licensure of tests. We also engaged in
studying genetic variation for the evolution of West Nile virus. So, why is that important? It's because the viral isolation characterization
would allow us to investigate whether the tests are picking up any potential
variant that may occur during this period of epidemics.
To study viral infectivity and pathogenesis, including the
cellular tropism, and to perform infectivity in large animals, non-human
primates that could simulate blood transfusion, address outstanding questions
regarding blood transfusion issues.
So, we got the standard material in reagents. We have developed a prototype panel, and
evaluated it in collaboration with other laboratories. The panel is composed of 14 members with a
broad range of viral copy numbers. We
used two different isolates. The first
isolate was the flamingo NY99 that CDC had available at the time of test
development.
But with our folks in FDA we isolated, completely
characterized a human isolate from 2002.
So, it is characterized genetically in the infectivity level to use for
the licensure and lot release purposes.
We distributed it to different laboratories, some of which were capable
of performing quantitative assays to assign final copy. And these studies are under epidemiological
investigation to find copy assignment.
As a result of these studies, we have seen that there is a
great variability in performance when the low copy numbers panel, like 5 and 10
copies per mL are used. But in the
qualitative assays we tried the ones used for blood screening perform much
better than the quantitative assays.
And that is where we stand regarding standard reagents right now.
To study the genetic evolution, I ready said why it's
important to perform this study, because viral mutation may affect the
performance of these nucleic tests. And
it may also affect pathogenesis, and have an impact in vaccine
development. So, it's fully aligned
with the CBER main mission, not only of the OBRI, but the CBER main mission.
And we engaged in collecting samples and isolating virus
for full sequention genetic analysis.
And because of the limitation of material, we investigated whether if we
isolate the virus from something like viracells, whether it would induce any
change in the material that would interfere with what we were intending to do
with the panels.
And we did investigate three pathogens, and we have seen no
variation in the structure of the genes compared with the countered virus to
the original virus in the plasma. This
was done in one or two specimens that we had in large volume to sequence this
straight from the plasma.
Right now we have sequenced all the 25 isolated, the fully
structured gene. And two isolates are
not fully sequenced. Now, we have three
I just learned from the post-doc that is helping me with this work, that we
have two human genome West Nile isolates from human plasma fully characterized,
and we are planning on using these to evaluate this viability.
What are we planning to go on with? To continue this study for full genetic
sequence, and try to correlate that with pathogenesis. We have a repository with the help from the
blood centers, mainly Red Cross and Blood Systems Laboratory. We plan on going on with these sequencing
studies to expand these studies to obtain samples from patients that had West
Nile, not blood donors, because our studies have been biased so far, because
all these samples that we have isolated virus and sequenced isolates based on
the available screening assays.
So, what we want to do is to get non-biased samples which
allow us to investigate where the isolates that we identify in these samples
could not be missed by the current screening assays.
So, we are using microarray technology to expedite
genotyping determination, and to identify potential point mutations. We have developed a fully structured gene
microarray already, and we are planning on going on and including 11,000 base
pairs of virus in the microarray for quite detection of variants. And these obviously will help us to evaluate
the assays and their performance.
In terms of infectivity and pathogenesis, the outstanding
question at that time was the cellular tropism for West Nile infection was
unknown following the blood transfusion.
We know that when the mosquito bites, the way that the virus enters the
human body is through the resident monocytes of dendritic cells and so on. But we did not know which would be the cell
that will be capable in circulating blood to attach the virus harboring
initiative replication.
So, we engaged, based on the similarities that the resident
macrophage would be the target for primary infection to study monocyte derived
macrophage in collaboration with Dr. Dayton that had the system in place, to
ask the question of whether that would be a target for West Nile replication.
We also engaged in looking at other human blood cells,
peripheral blood mononuclear cells in general, T-cells and B-cells, and to
investigate the host factors involved in pathogenesis. That includes chemokines and cytokines in
human host factors. And these would be
very relevant for CBER for treatment and analysis and vaccines and so on.
What we have achieved so far regarding the viral tropism is
that now I have data that shows that early stage culture monocyte -- not only
macrophage-derived monocytes, but early culture monocytes can be infected by
West Nile. In tests in the supernatant
indicates productive infection. The
viral loads go as high as 10 to the 6th in the supernatant.
The value of the application persists for 27 days in 9
experiments, 9 of the 10 experiments we have performed. And actually, we have not one experiment of
up to 47 days, but we have three experiments that we followed the tissue
culture for 47 days. And it is still
producing virus, and these virus are infectious intraviral cells.
So, we have shown that macrophage can be infected, and
produce virus which are infectious. And
what is interesting about this culture is that there is no morphological
alteration in the monocyte during the course of infection. So, it seems that the cell does not get
harmed with the viral infection, at least in a gross way of looking at it.
So, these data suggest that human monocytes in macrophage
could play an initial role in replication following blood transfusion, and that
would be important obviously to understand.
The last thing we are planning to address, and we have been
engaged heavily in trying to gather funding, as you all heard about funding, is
to perform the infectivity studies in large non-human primates. And are planning on doing it in
baboons. And why is that? Because the baboons can get a large volume
of plasma that would simulate the human transfusion, as opposed to small
animals that would not have the capacity of taking high intake of plasma that
has low viral load.
The major focus here is to look at units that have not
positive IgN positive, meaning low viral load in the presence of antibody, so
that we could define first of all, the minimal infectious dose with non-human
primates. And then address the
infectivity of human plasma in the presence and absence of antibody, which is a
very critical question to address now.
We have no information.
We have information that the three previous stages that defined not
positive Ig negative were high tider of virus are infectious, but not the two
of the IgM and IgG in low viral tider.
And I would stop here and just acknowledge the group that
has been working. Dr. Hewlett's group
has fully supported me in these short two years, and that's why we have
achieved so much.
Thank you.
DR. ALLEN: Thank
you, Dr. Rios.
I would just like to point out that when Dr. Rios came to
the FDA, less than three years ago, her background was in red cell molecular
biology. And I think she had intended
to continue pursuing investigations in that area. West Nile virus had erupted.
The FDA needed to get studies underway, and Dr. Rios volunteered. So, you made a remarkable transformation.
DR. RIOS: And
actually, when I was hired it was to work with the retroviral HGIV and HIV,
which was my background field that I have addressed in red cells, because I
have been very interested.
One thing I didn't mention was we are looking at blood
partition, and we have found that red cells carry almost a log more compared to
the paired plasma. So, maybe we are not
looking at the proper specimen for viral screening. And that's one of the things are addressing now, is to look what
is the idea sample for screening, whether it's whole blood or plasma.
DR. ALLEN: Okay,
any other questions quickly?
DR. DI MICHELE:
Maria, I wanted to congratulate you and everyone else for all of the
excellent work that they have presented.
Just out of curiosity, your laboratory is doing this work on West
Nile. What percentage of all the work
on West Nile does this laboratory represent?
Is there a lot of other work on West Nile virus?
DR. ALLEN: You mean
at the FDA?
DR. DI MICHELE: No,
elsewhere, just in general.
DR. RIOS: There are
laboratories. CDC is doing a lot of
work, and the blood centers are doing a lot of work. The group Mike Bush and Sue Stream(?) actually the infectivity
studies which we are having a hard time in getting funded will be fully
supported by the blood community providing samples from which we would isolate
and characterize the virus, and try to correlate the non-human primates'
response and things that we cannot address in human with that.
And then the state department of health and some other
laboratories more focused on treatment have been addressing that.
DR. DI MICHELE: No,
I understand the US collaborations. But
elsewhere in the world, are there other laboratories that focus on this?
DR. RIOS:
Russian. And actually, we are
engaged in trying to get money from bioterrorism. If you are not aware of NIEAT(?) just listed West Nile as
category B agent, but it can be easily manipulated in the lab and spread. And there is a program that helps us, to
link us, the American government to the Russian government, mainly scientists
that have been working in bioweapons to develop some of these studies. So, Russian has been working on it.
Israel has some work on it. Australia has done a lot of work on Kungi(?) virus, that is the
West Nile equivalent for them. And West
Nile has spread now to Mexico, Puerto Rico, and it is going downwards. I would imagine that because of bird
migration, South America soon will be hit.
And we know from Russian data that the birds migrate from Africa to
Siberia in Russian, and you have episodes of epidemics of West Nile even in
Siberia, where the climate is cold. So,
we need more.
DR. ALLEN: Thank
you.
DR. NAKHASI: Donna,
I just wanted to make a clarification here.
I think the research that Maria Rios presented today is really a
critical path issue, because the issues for example, panel development, the
areas of looking at the genetic variation, that type of research is not done
outside. And that's the reason she is
focusing on that. And also the
pathogenesis issue, because it is not the issue of looking at pathogenesis, but
it is the issue of looking at which component of the blood replicates, because
it's important for us in blood products.
So, I think it's very important to concentrate on that
whether any other labs or doing it or not.
But these type of areas in which she is focusing is more of a critical
path issue, which is relevant to what we are doing.
DR. RIOS: Thank
you, Hira. Actually, if I had
understood this question in the way now, there are very few studies in genetic
variation which focus on a very small fragment of the envelope region, about
200 base pairs. But we know now that
the NS5, that it's a non-instructor region.
It's critical to differentiate West Nile from Japanese
encephalitis. So, no, there is not much
focus on that outside.
DR. KATZ: Dr. Rios,
can you describe how you intend to get the unbiased sampling? Are you going to use mosquito pools or birds
or clinical cases outside the blood screening, or all of the above?
DR. RIOS: I have
been contacting actual just the last West Nile conference in San Jose, I have
contacted some health department people.
And I get some promise, not real samples. But what I would like to do is to get samples from health
department laboratories that come from confirmation of disease that are not
associated with the blood, and see if there is any extra variation for those.
As you all know, West Nile virus is a very unique virus in
the sense that 80 percent of the infections are fully symptomatic, but 1
percent is highly fatal. It is people
that develop neurological symptoms.
Between 10 and 14 percent of people died. And in the last West Nile conference it was reported by the State
Department that West Nile death, it's not accounted for. And these slides will be posted on the CDC
Web site. Because the physicians do not
follow when a donor dies, whether or not West Nile was a potential case.
DR. ALLEN: Okay, we
didn't hear a discussion about the FDA flamingo farm.
Thank you all very much.
Thank you, Dr. Rios. It's almost
1:00 pm. We are going to very briefly
into closed session, which means committee members and senior FDA staff only
please.
[Whereupon, the open session of the meeting was adjourned
at 5:00 pm.]