AT	DEPARTMENT OF HEALTH AND HUMAN SERVICES

	FOOD AND DRUG ADMINISTRATION

	CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

	BLOOD PRODUCTS ADVISORY COMMITTEE

	63RD MEETING

	VOLUME II

	Friday, June 18, 1999

	8:00 a.m.

	Double Tree Hotel
	1750 Rockville Pike
	Rockville, Maryland

	PARTICIPANTS

Blaine F. Hollinger, M.D., Chairperson
Linda A. Smallwood, Ph.D., Executive Secretary

MEMBERS

John M. Boyle, Ph.D.
Norig Ellison, M.D.
Richard J. Kagan, M.D.
Rima F. Khabbaz, M.D.
Marion A. Koerper, M.D.
Jeanne V. Linden, m.D.
Gail B. Macik, M.D.
Mark A. Mitchell, M.D.
Kenrad E. Nelson, M.D.
Kwaku Ohene-Frempong, M.D.
David F. Stroncek, M.D.
Joel I. Verter, Ph.D.

NON-VOTING CONSUMER REPRESENTATIVE

Katherine E. Knowles

NON-VOTING INDUSTRY REPRESENTATIVE

Donald H. Buchholz, M.D.

TEMPORARY VOTING MEMBER

Paul R. McCurdy, M.D.

CONSULTANTS

Mary E. Chamberland, M.D.
Michael G. Fitzpatrick, Ph.D.

	C O N T E N T S

	PAGE
Conflict of Interest Statement:
Linda Smallwood, Ph.D.	4

	IV. Informal Presentations

Blood Action Plan:
Jay Epstein, M.D.	5

Device Action Plan:
Jerome Donlon, M.D., Ph.D.	28
Lillian Yin, Ph.D. 	38

	V. Deferral of Blood Donors for Risk of Malaria

Introduction and Background:
Mark Heintzelman, Ph.D.	48

Presentation:
Monica Parise, M.D.	60

Presentation:
Major Lianne Groshel	77

Open Public Hearing
Dr. Mary Townsend, ABC	79
Dr. Michael Busch, AABB	85

Committee Discussion	94

	VI. Development of HTLV Supplemental Tests

Introduction and Background:
Elliot Cowan, Ph.D.	138

Presentation:
Susan Stramer, Ph.D.	144

Clinical Experience with HTLV Supplemental Testing:
Michael Busch, M.D.	161

Funding Opportunities for Small Business:
Susan Pucie	183
Patricia R. Robuck	189

Open Public Hearing
Michael Ussery, Innogenetics	197
Birgit Fleurent, Gene Labs Diagnostics	200
Dr. William Andrews, Chiron	203
Dr. Tony DiMarco, Abbott Laboratories	207
Dr. Michael Busch, AABB	210

Committee Discussion 	211

	P R O C E E D I N G S
	Statement of Conflict of Interest
DR. SMALLWOOD:  Welcome to the second day's session of the 63rd meeting of the Blood Products Advisory Committee.  I am Linda Smallwood, the executive secretary.  Yesterday, I read the conflict of interest statement that will apply to the proceedings of this meeting today.  That meeting statement is available if anyone would like to review it.
I would also like to announce that Dr. Norig Ellison has joined the committee today.  Dr. Ellison, would you raise your hand, please.
Today, the agenda will be hopefully followed as printed.  At this time, I would like to turn over the proceedings of the meeting to the committee chair, Dr. Blaine Hollinger.
DR. HOLLINGER:  Thank you, Dr. Smallwood.
We have three main topics today.  One is an informational presentation on the blood action plan and device action plan which were mandated before to see where we are with those plans.  Then we are going to talk about deferral of blood donors for risk of malaria, and finally look at the development of HTLV supplemental tests.
So, with that in mind, we will start with the first presentation.  Dr. Epstein is going to tell us about the blood action plan.
	Informational Presentations
	Blood Action Plan
DR. EPSTEIN:  Good morning, everyone.  Thank you, Blaine.
[Slide.]
The FDA has been involved with the blood action plan for about two years now and, for some of you, this may be a little bit repetitive, but, perhaps for those who haven't heard this story, it will prove enlightening.
Starting in the early 1990s, both the FDA and the blood industry came under intense scrutiny as a result of investigations into the AIDS tragedy related to blood products in the 1980s.  Much of the driving force behind these investigations came from consumer organizations, particularly the hemophilia advocates but also from the press.
There were certain landmark events.  These included a series of Congressional Oversight Committee hearings that were lead initially by Mr. John Dingel when the House was Democratic and then later by Mr. Christopher Shays when the leadership changed.
There was also the publication of the book And The Band Played On, by Randy Shilts, which was highly critical of governmental action, particularly, and then a series of articles in The Philadelphia Inquirer by Gilbert Gall which drew attention to existing deviations mainly reported through FDA, establishment-inspection reports and citations on the 483 form.
Some of these events led to a request through the Congress that there should be a study on the decision-making in the 1980s and, per request to the department, Donna Shalala funded a study by the Institute of Medicine to examine the decision-making in the 1980s related to HIV in the blood supply which led to the publication of a study in July of 1995.
Additionally, at the request of the Congressional Oversight Committees, there was a series of studies requested from the General Accounting Office, or GAO, which were conducted on various aspects of decision-making in blood and there have been several reports by the Congressional Subcommittee on Government Reform and Oversight that was led by Mr. Shays.
The issues that were raised, and I am going to summarize them on a series of overheads, briefly dealt with the following areas: first, allegations of wrongdoing by industry; second, the question of poor compliance status of the blood industry and the initial focus was on the American Red Cross although later the focus shifted to the fractionaters; the question whether there had been weak oversight and weak enforcement by FDA; the alleged failure of both industry and government to communicate the risk of blood products to consumers; the charge of poor governmental coordination and responsiveness in emergencies; and the perception of a lack of clear regulatory requirements for the blood industry.
In addition, there were a set of incidents that brought these matters to a head.  And these included the bacterial contamination of Centeon's albumin which occurred, or came to light, in September 1996, a large number of product withdrawals that were related both to manufacturing problems but also to the theoretical risk of CJD which caused great fear in the public.
And then there were other specific product concerns that came to light such as an incident of hepatitis A transmission by one of the companies' Factor VIII products.
Following a series of briefing by CBER and in the wake of comprehensive report issued by the GAO in February, 1997, then Acting Commissioner Mike Friedman directed the center to identify the key issues and develop an action plan so as to focus the agency and department attention on them.  	As a result, a blood action plan was developed in July, 1997 with the following global objectives: first, to restore public confidence in blood safety through communication, through the effective correction of deficiencies and general enhancement of the blood safety; second, to bring the blood industry and all its parts into full GMP compliance; third, to streamline FDA operations in the blood area consistent with reinvention initiatives which were also ongoing mainly under Vice President Gore's Reinvention of Government Initiative; and, finally, an attempt to bring supplemental resources into the blood program to accomplish these expanded tasks.
[Slide.]
What I am showing you here is a graph that is cited from New England Journal, February '99 issue, with permission of Jim Aubichon, one of the coauthors.  This shows the rather dramatic decline in the residual risk of infection with major transmissible diseases per unit of transfusion since the onset of the recognized AIDS era in blood of 1983.
What you can see is that there was essentially a three-log decrease in the risk of HIV, a two-log decrease in risk of hepatitis C, and a one-log decrease in risk of hepatitis B but that is on top of about a two-long decrease in risk that occurred with the screening of the blood supply since the early 1970s.
One might ask with these rather dramatic safety improvements, why is there an issue here?
[Slide.]
I call this current problem the blood safety credibility gap.  This gap in credibility can really only be understood if one understands the implication of AIDS which I have called the shadow of AIDS.  So what is the shadow of AIDS?  The problem, as I understand it, is that authorities not only failed to recognize early and warn about AIDS risk from blood products in the 1980s but, at the same time, were stating that the risk was remote while, in fact, the epidemic was raging.
Then what happened is that public confidence was shaken both by the failure to protect the public from AIDS which, of course, came to light but, also, the perception that there was a belated, if you will, admission of the risk.  I am not saying that any of this is wrongdoing.  It is just that that is what happened.
[Slide.]
Then the question is why do those problems of credibility persist?  The explanation lies in understanding a set of perceptions concerning the industry and concerning the FDA which are, in fact, the issues that we are dealing with.  What were the perceptions dealing with the industry?  That they denied their problems, both their manufacturing problems and the fact of emerging threats, that the industry operated secretively, that the industry did not function up to GMP standard, that the industry maintained poor relationships with the consumer community and that the products, themselves, were of variable safety and quality.
On the governmental side, the perceptions are that government had been slow to act in any of its dimensions, whether it was establishing policy, enforcement actions, or taking precautionary measures and emergencies.  We were accused of having worked inappropriately closely with the industry in establishing policies, having industry representatives voting on advisory committees, preannouncing blood inspections, et cetera.
We were accused of having a very confusing web of regulations and guidance, that our administrative procedures, particularly related to applications and the speed through which we could approve innovations was sluggish and burdensome, and that we were underutilizing available information on adverse experiences, reports that already existed either in the literature or at the CDC or through reporting mechanisms to the agency.
These issues were brought, in various ways, to the attention of the FDA through oversight activities.  Who are the main overseers?  The main overseers, as I have noted--we had the landmark report of the Institute of Medicine although the Institute of Medicine does not have a standing function of oversight with respect to government or the FDA, Congressional hearings where there are, indeed, committees and subcommittees empowered with an oversight function which they liberally exercise.
The Office of the Inspector General is an arm of the Department of Health and Human Services and it conducts investigations both of activities of the agency as well as allegations of wrongdoing.  And the General Accounting Office which provide reports on the model of white papers generally at the request of the Congress.
I am going to review the various recommendations of each of these bodies since 1995.
[Slide.]
First let's start with the recommendations of the Institute of Medicine in its study of July 1995.  I put this first because I think that it is, in fact, the landmark event that has changed the landscape and changed the paradigm that underlies much current thinking.
The IOM recommended with regard to the Department of Health and Human Services that it should establish a blood safety director, a blood safety council, and an expert panel.  The blood safety director was established by Donna Shalala in 1995 as the Assistant Secretary of Health, and I'm sure that most of you know that also with the current administration, the position of the Surgeon General and the Assistant Secretary of Health are merged into one position.  They are both currently occupied by David Satcher.
Additionally, a Safety Council was established.  It is called the Blood Safety Committee.  It is constituted by the Agency heads and deputies of the Public Health Service agencies, FDA, CDC and NIH as well as other components of the department.  That group meets approximately quarterly to address all emerging issues pertinent to blood safety and availability.
Additionally, an expert panel was constructed.  That is the PHS Advisory Committee on Blood Safety and Availability.  That committee has been meeting regularly since I think it was January, 1997 and periodically makes recommendations regarding global issues of public health pertinent to blood safety and availability be they economic, social choice, legal, ethical or sort of cross-cutting public health.  They have a very broad mandate to look at issues in distinction to the Blood Product Advisory Committee of the FDA which hitherto had been the only advisory group and which is really only empowered to deal with scientific questions pertinent to regulation.
So we look to this committee for scientific judgment.  We look to that committee to sort of synthesize it in the global, societal sense.
The Public Health Service was specifically advised to make better use of information coming out of the CDC Surveillance program, particularly early warnings, and to make efforts to monitor the supply and availability of blood.  We have taken steps to improve the communication link between FDA and CDC, for example.  We have a monthly conference call.  It is a group that is called the PHS Interagency Working Group on Blood Safety and Availability.  One of the key arms is liaison from the CDC and we do get routine reports on emerging issues and respond to warnings as well as coordinating our activities.
The FDA was specifically advised to rebalance the Blood Products Advisory Committee.  We did this.  We changed the charter in 1995 so as to permit consumer representation.  Hitherto, the charter required that we have only people who were qualified based on expertise in a related science.
In addition, while we still have that criterion for membership, we have a criterion for persons who represent consumer interests but who are deemed adequately knowledgeable to discuss issues.  And we have done that.  That is why we have voting members who are advocates in addition to having a purely consumer representative who is nonvoting and considered a lay representative.
We were admonished and this is, perhaps, the most important thing, to implement partial solutions wherever feasible in the face of uncertainty where we thought we would do no harm.  That has been called the precautionary paradigm and it is impossible to understand the decisions that have been made regarding HIV antigen, regarding CJD, regarding the UK donor deferral, without truly grasping the significance of the precautionary paradigm as it was articulated by the IOM.  That is the current mode of thinking.
Additionally, we were told to provide clearer regulation and I am going to go into some detail on a rather sweeping regulatory initiative, and to periodically review past decisions which we have been doing with the Blood Products Advisory Committee.  It is one of the reasons that you are more frequently hearing informational presentations so that you know what we are up to and can think about it.
The Congress was advised to establish no-fault compensation for blood injury.  That has not happened, although there have been certain bills passed, the Ricky Ray bill, for example, that have dealt with compensation for particular injuries for particular patient populations.
Physicians generally were advised to improve their discussion with patients regarding risks and therapy options.  I think most treaters know that.  And, lastly, the volunteer organizations were advised to be more careful about avoiding conflicts of interest
[Slide.]
What about the Shays Committee on Oversight?  The Shays Committee issued its first report in August of '96.  It advised Congress to establish the department's Blood Safety Committee and the PHS Advisory Committee in law.  The concern was that this was a wonderful step forward by Dr. Shalala but what happens next?  Administrations are not forever but the Congress has not followed up on this.
Additionally, the Shays Committee echoed the report of the IOM and recommended that there be creation of an indemnification system for blood injury.  The department was advised to disseminate more risk information and you may have noticed that there have been more public statements that the Assistant Secretary and Surgeon General have spoken out repeatedly, generally in the context of the PHS Advisory Committee on Blood Safety and Availability and taken affirmative positions on some of the complex issues in that domain.
The FDA was specifically advised to require look-back for hepatitis C.  This was based on the perception that the Public Health Service in the large was not responding adequately or promptly to a perceived epidemic of hepatitis C and its sequelae of liver failure and cancer and that there was a latent epidemic, if you will, of those diseases which could, perhaps, be interdicted and that since one part of it, or about 7 percent, was due to blood transmission prior to the era of screening, that we should do something about it through targeted look-back which we will discuss.
We were also advised that we should improve notification systems related to recalls and withdrawals, particularly of plasma derivatives, and we have an initiative in that area, that we should work to limit the size of fractionation pools.  Those of you with a long memory know that we addressed that issue at multiple meetings of the BPAC and that there is now a voluntary policy within the industry to limit fractionation pool size to no more than 60,000 donors per final product including any and all secondary pooling or addition of excipients such as albumin into clotting factor.  Lastly, we were advised that we should significantly strengthen our inspectional processes.
[Slide.]
The landmark recommendations of the General Accounting Office were put forward in their February, '97 report which was quite specific and came in the wake of, if you will, corrective measures that have already been put in place since 1995.  They recommended that we should create regulations to require the notification of donors who are deferred as a public-health measure presumably to prevent secondary transmissions but also to prevent such donors from coming back to redonate based on educating them to their risk, that we should test all autologous donations.
This was very controversial.  We had met many times with the Blood Products Advisory Committee but there was a report that came out of the AABB that was quite telling indicating that there were errors of unit release which were occurring from autologous collection--autologous donations do not have to meet donor suitability standards and this was perceived to create increased risk--as well as the concern over possible exposure of healthcare workers to positive units that might be drawn but not tested and recognizing that, in the face of human frailty, universal precautions might not always be followed.
We were asked to: require confirmatory tests on all reactive units.  That, of course, has been a recommendation of the FDA going back to the 1980s but was never a requirement; to require look-back for all markers, the FDA commented that we would review which markers were pertinent.  We have not fully adopted that recommendation although we accept it in spirit; to require periodic quality-assurance tests for bacterial contamination.  The Centers for Disease Control is now in the process of conducting a comprehensive surveillance of bacterial contamination in platelets as a basis for future action and we have also planned another workshop on that subject; to require universal error and accident reporting, the universality here being that it is currently a requirement for licensed blood establishments but not for the registered blood establishments which collect and process blood components and so we would be extending the requirement; to move all pertinent guidance into regulations.  We are talking about taking nearly three decades of accumulated guidance and moving them into regulations, no small task; and, finally, once again, to improve our inspectional procedures.
So that is the background.  That is why we put together a blood action plan.
[Slide.]
What is the blood action plan?  First of all, the blood action plan consists of a set of teams that are organized around a set of issues and it is managed within the agency on the model of project management.  We have a full-time project manager that tracks the activities of about sixty different working groups and the work across the agency, about 100 people.
As I said, it was developed by the FDA in July, '97.  However, it requires interagency participation and, for that reason, it was necessary to gain the endorsement of the department.  This plan was presented to the department in late '97 and then it was adopted on behalf of the department in March of 1998.
So, at that point, it became not just an FDA initiative but a departmental initiative.  First of all, we have a steering committee which we call a core team which meets monthly.  The core team, of course, monitors and directs the activity of the working groups.  Each of the issue areas, of which there are six, has a chairperson and then there are working groups in each area.
So how did we codify all this into a set of issues?  We have issues related to updating the blood regulations.  We have issues related to reinvention--this is really streamlining--issues related to emerging infections, insuring the compliance of the plasma fractionaters, notification and look-back initiatives and FDA responsiveness to emergencies and class I recalls.
[Slide.]
How have we done so far?  The first year, which is basically reckoned from March '98 to March '99, we did a number of things.  First, in terms of regulations and guidance, we published in draft form a guidance on gamma-irradiated blood and components, which is a program pilot for, if you will, deemed licensing.
This is a streamlining initiative and the main concept here is that if we publish a standard for a conventional product, that the industry shouldn't have to file a detailed application with all its operating procedures and validation data.  They should be able to simply make a showing before the agency that they are in compliance with the published standard.
We would, then, issue a license on the basis of that certification.  Now, in the long term, the concept would be, then, that nothing further happens except for periodic annual inspecting.  Under the pilot, however, we would still do 100 percent preapproval inspecting and use the preapproval inspection as the measure or the metric of whether they were, indeed, in compliance when they said they were whereas now we establish that both by reviewing their validation data as well as by going out and inspecting.
So the question is whether we can bypass the application filing.  But that is still in draft form.  It is not yet an implemented policy although if companies were to apply under the pilot, we would probably accept it on a voluntary basis.
Also, many of you, I'm sure, are aware of the change in the licensing policy for biologics whereby we have moved from a requirement for two applications, an establishment application and a product application, to a single biologics application which is harmonized with that drug application, new drug application.  We would then issue a single license.
That requirement, to file the single biologics license application, is not yet a final regulation.  It was published as a proposed rule.  We received comments and it needs still to be reissued as a final rule.  However, the agency indicated that as it published and finalized guidance for filing out the application for different product areas, we would accept voluntary filings of a single biologics license application.
The point here is that in the area of blood and components, we have now published the final guidance for implementation on the biologics license application and are accepting voluntary submissions of the biologics license application.  So we are moving forward on the streamlining initiative for application review.
[Slide.]
In the area of developing standards, we held a number of workshops.  These included a workshop on blood licensing.  This was a prelude to issuing the guidance.  We had a workshop on donor suitability.  This is part of a regulatory initiative to develop a proposed rule on donor suitability.  This is to update all of the standards that have been put in place since the 1980s such as relating to infectious-disease risk factors for hepatitis and HIV.
We had a workshop on nucleic-acid testing--this was focused on hepatitis C NAT--in September of '98 and then in July of '99, we also cosponsored with CDC a workshop on tick-born illness and we have already summarized that at a previous meeting of the Blood Products Advisory Committee.
In the area of emerging infectious diseases, we established a database of all the known significant threats to blood safety.  An update of that was accomplished in April, '99, roughly the anniversary of the plan.  And we provided in your packet the current updated database.
In addition, we have provided, in '98, a narrative summary of the PHS efforts to address these threats and we will be updating the narratives by September, '99.  Additionally, it has been proposed that we should take inventory of all current PHS activities related to blood-safety threats and we will be developing that inventory also by September.
In the area of assuring compliance of the fractionators, as you heard yesterday from Mr. Masiello, we established something called team biologics, which is a new relationship--actually, it began in October, '96--between the field force and the center for how we approach compliance in the blood area.
To make a very long story short, what we created was a specialized cadre within the field for us to deal with biologics which includes not just blood but also vaccines and biotech therapeutic products.  That cadre of about 25 people has been intensively trained in biologics law and the issues pertinent to biologics inspecting.
Additionally, they are supported by designated product specialists within the center and the product specialists go out on the inspections with them.  The main change is that the lead responsibility for periodic inspecting now lies with the field instead of the center.  The reason for that is that historically there has been more focus and training in the GMP area in the field whereas there was more product-specific knowledge in the center.
So, if you will, we have a bit shifted the balance toward the GMP side and therefore we have retained the premarket inspecting as the lead responsibility of the center that understands the products and the science and the lead for the postmarket inspecting on the field force which has the lead expertise in GMP.
We have already rolled out the problem for the plasma-fractionated products for the in vitro diagnostics in blood and for what we call the blood cadre which is a trained group of about 100 people who have had specialized training in blood and components.
Under this issue area, we also call for annual evaluations of effectiveness and those are being performed by the subgroup.  Additionally, in the area of response to emergencies, fortunately, we have not had a class I emergency since, really, the centeon incident in '96.  So we haven't been tested.  But we are very mindful of the issue of preparedness and we have had annual refresher training on emergency operations.
The most recent refresher training was just this last March.  It consists of, basically, two hours of videos and discussions live with experts via pictel link.  Once again, there is a quarterly performance review although there is nothing much to review quarterly when there are no incidents.  But, if there are incidents, they will be reviewed on a quarterly basis.
[Slide.]
So where are we, looking ahead?  In the area of regulations and guidance, we are continuing to update blood regulations and guidance and to move into guidance for implementation, the documents as the comment periods close.
I think everyone is well aware that we have a regulatory initiative on hepatitis C look-back.  Let me mention that a revised guidance--as you know, the extant guidance is September, '98--that there was a PHS advisory committee met in January '99 and recommended extending the scope of the look-back to include first-generation screening since May 1990.  We have, therefore, revised the guidance.  We put that out on the Worldwide Web, the CBER website, yesterday morning or yesterday afternoon.  You can download it off the Web and it will be expected to be published very soon in the Federal Register.
It is being published first for comment and we welcome comments.  I believe we will be requesting a 60-day comment period.  Let me just note that we have been working very aggressively to address the specific issues that were mentioned by the General Accounting Office such as updates on donor testing, donor notification, product standards for plasma derivatives and blood components, end-user notification in the face of withdrawals.
We will be working toward a proposed rulemaking in those areas and you will start seeing some of that in the fairly near future.
In the area of reinvention, as I said, we are in the process of finalizing the regulation on the biologics license application.  We will be considering additional monograph pilots for deemed licensing in lieu of filing of applications in the blood area and we have a number of candidate proposals applicable to blood and applicable to source plasma.
We will be continuing to update the infectious disease threats to the blood supply--as I said, the last update to the database was just April '99 and you have copies that you are welcome to comment on--and, again, continuing to monitor the effectiveness.
Let me just say that there are a lot of additional areas where we expect to be developing regulations codifying existing guidance.  I have already mentioned some of these such as donor suitability.  It is our current thinking that we should also address possible requirements to deal with infectious agent inactivation and removal in the manufacture of blood products, particularly derivatives, that we should probably codify labeling standards into regulations to create uniform blood labeling and, as I said earlier, extending the scope of the requirements of error and accident reporting to encompass all collectors and processors of blood and then certain of the issues related to notification in the face of recalls and withdrawals.
So that is what is on our plate.  I hope that I have convinced you that the FDA has a very serious mind set addressing these issues and that they are, in fact, highly comprehensive of the concerns that have been brought to the attention of the agency by oversight bodies as well as attentive to what I call the issues of perceptions.
Opinion can vary how real or not real some of those perceptions are, but they are certainly issues, at the very least, of communication that we do need to address.  So let me stop there.  I am happy to entertain questions if time permits.
DR. HOLLINGER:  Questions?  Jay, it was an excellent summary of the blood review plan and I think something that has really been helpful to all of us sort to understand the overview of this situation.
I might say that the transcripts of these issues are always on the website.  I don't know how late they come out, how long it is between when we have a meeting and before they are published.  It is not very long.
DR. EPSTEIN:  Perhaps Linda can answer that.  Do you know?
DR. SMALLWOOD:  To my knowledge, the transcripts appear approximately 30 days after the meeting.  They will be available on the website.
DR. HOLLINGER:  I encourage you to maybe take a look at these again on this because it is a very good summary of where we are and what we are looking forward to.  Thank you, Jay.
DR. EPSTEIN:  Let me just say, by word of introduction for the next speakers, that this concept of action plans has been deemed by the agency and the center such a great success that we now have action plans in the areas of human tissue, xenotransplants and now, also, medical devices.  You are about to hear about one of our newer action plans in the device area.
DR. HOLLINGER:  Thank you.
With that introduction, we are going to ask Dr. Donlon, Associate Director for Medical Affairs of OCBQ to initiate the first part of this device action plan.
	Device Action Plan
DR. DONLON:  Thank you.  And thank you, Jay, for that segue.  The device action plan is the newest action plan in the center.
[Slide.]
I am going to briefly give you kind of a brief history and overview of the plan and then Dr. Lillian Yin will give you some of the nuts and bolts of where we are on some of the review and performance aspects.
As you may or may not know, the Center for Biologics is somewhat unique in the FDA in that it uses all of the regulatory authorities.  It primarily uses the PHS Act to license biological products.  It also uses the FD&C Act under NDAs for certain products.  And it applies the Medical Device Amendments to certain devices which Dr. Yin will kind of bring to your attention.
So we do have a small component, primarily located in the Office of Blood of products which are regulated as medical devices under the Medical Device Amendments.  That is basically the issue of why we needed to develop a device action plan.
The device action plan, as Jay indicated, because of the successes of our previous action plan, was initiated by Dr. Zoon and Dr. Feigal last fall.  We just recently published it in April of this year.  The committee members have a copy in their folder.  For those in the audience, it is available on the CBER external website under What's New for CBER.  It has been posted there as of April 27.
[Slide.]
The genesis of our action plan came about, basically, last August and last fall.  Under the FDA Modernization Act of 1997, there was an initiative to outreach to stakeholders.  It was called the 406(b) provision in which various stakeholder meetings were held.  In the meeting in August, several of the public and device manufacturers kind of raised the issue that, under the FDAMA of 1997, there were many significant changes impacting on medical device regulations.
The Center for Devices was moving fairly significantly ahead as far as developing new procedures, new policies, and, in addition, the Center for Devices previous to that had taken an initiative in what was called reengineering of medical-device reviews.
The basic question that was presented to Dr. Zoon and to our center was if the Center for Devices has all these initiatives, where is CBER as far as implementing or using these initiatives when we regulate medical devices as medical devices.
So, to address that, we basically did two things.  First, we had our second public hearing in December in which we invited very specific industry representatives and the public to voice their opinions and concerns about how we were regulating devices.  Several things came up, some very predictable.
The issue of consistency; was the Center for Biologics consistently applying policies and procedures consistent with the way the Center for Devices had implemented things; harmonization between the two centers regarding those polices; the transparency of process for our centers as to how things were regulated, who was responsible, who was accountable, what the status of tracking, relative to that nature of that concern; whether or not we would facilitate reviews in a way that the Center for Devices had proposed of facilitating reviews and the availability and focus of various guidance documents; whether we were buying into some of the guidance documents that the Center for Devices was initiating and, clearly, communication not just between the two centers but also with the public and with industry.
So these were several concerns that were raised in these two meetings and, based on that, Dr. Zoon appointed Dr. Feigal and myself as co-chairs to develop a device action plan.  Again, it involved several--more than several--members of the center assigned to different teams to develop that plan which eventually was finalized and signed off in April of this year.
As I pointed out, Dr. Feigal was the initial co-chair of this when he was the Deputy Director for Medicine in the Center for Biologics.  Since that time, Dr. Feigal has been appointed the Director of the Center for Devices and Radiological Health.  That was not part of our device action plan, but we welcome that appointment as an indication that we can work closely with the Center for Devices in all these areas.
[Slide.]
Let me just briefly outline the issues of how we structure the device action plan and, again, we are just beginning with this so we don't really have a list of--we have some accomplishments that we can tell you about.  We don't have a large list of accomplishments the way Jay indicated with the blood action plan.
[Slide.]
There are four areas that we focused on.  One is the coordination between the two centers which, again, was a key concern of the stakeholders.  The second was our internal review performance, ways of streamlining, facilitating that, organizing that.
The issue of compliance, inspections for devices and our working between compliance in the field, the team biologics concept that Jay discussed under the blood action plan.  Finally, our ability to outreach and inreach, basically, the communications issue, the transparency issue relative to our regulation of devices.
You have the detailed device action plan in your folder.  I am just going to give you the overview of these four different teams.  The Issue and Coordination Team: initially, there have been intercenter agreements between the Center for Devices and the Center for Biologics.  The initial one was in 1982 that was revised in 1991.
Clearly, eight or nine years later, it is time, again, to revise that intercenter agreement based on several things, not the least of which is the advancement in technology and different devices, combination devices, different organizational structures between the two centers.  So we are undertaking a joint review of that document and revision of that document.  That should take several months to finalize, but we seriously need to update that to address some of the modern technical issues relative to devices and biologics.
CDRH, as I mentioned before, had initiated a few years ago reengineering efforts regarding their own process and how to establish reeingeering workgroups within the Center for Devices.  We are establishing direct liaisons with that with our staff to their staff so, as they develop policy and procedures from their reengineering group that we have an input and a knowledge of how that process is occurring and we can buy into that.
We put out, and this is one of our accomplishments, we have already published a Federal Register notice concurring with the many policies and procedures that Devices had been publishing last year.  Under the FDAMA 1997 initiatives, they had a large list of action items that they were responsible for for taking the lead on as far as publishing policies and procedures.
They pretty much moved forward very rapidly on that.  We were able to participate in some of those, but some of those moved beyond our ability to keep up with them.  So, as an acknowledgment of our commitment to those policies and procedures, we published a Federal Register notice of concurrence basically saying that we would work within those policies and procedures as well as CDRH.
CDRH, again, is implementing a training program for the reviewer and their staff based on the FDAMA initiatives.  We basically, rather than reinventing the wheel in biologics, will participate with them as they develop that again, hopefully developing a consistency of knowledge base and networking with the center.
We are developing a device web page at the center so that individuals accessing the CBER external page will find access to our device page that is under development.  That should be accomplished actually probably by the end of the summer, pretty quickly.
We do have on our web page the device action plan.  We do have available on the CBER home page a list of device products that have been previously approved.  We hope to have a list of our current devices that we are regulating as well as a linkage to the CDRH web page so people can jump to the CDRH web page for guidance documents.
The ongoing process here is that we are going to be participating in guidance development in preparation with CDRH in a collaborative way.
[Slide.]
Hopefully, the outcomes of these initiatives will lead to commitment, coordination, cooperation, communication and consistency, the "c" words.
[Slide.]
Another critical area that is a very significant part of the device action plan is our review performance.  Dr. Yin will begin to address this in her brief presentation.  Dr. Yin will have about half the time that I have because she talks twice as fast as I do.
We are currently analyzing our process, the work load and the resources we have applied to that process.  This is kind of the basic strategy to define where the resources--how we can prioritize our device review, how we can facilitate and streamline it and apply the right resources in the right way.  We have limited resources.  This device action plan does not buy us additional resources.  We have to kind of work with what we have.
This may lead to some reorganization within the Office of Blood or the Center as far as streamlining accountabilities for these processes.  This group will set review objectives and implement and manage review process.
In the center, in general, we have taken on the initiative of having a management review process for all products.  Basically, this was an outgrowth of our user-fee initiative where we had certain time frames for our user fee for other products in the biologics.  The devices do not come under the user fee here.  That is why we don't have the user-fee resources for the devices.
Yet, we are still going to use that same management review process that we applied to the user-fee products and apply it to devices and then, basically, focus on the critical guidances that the industry will need to facilitate the review, the submissions and the review process.
Again, the outcomes, hopefully, will be defined expectations and priorities, meeting our time frames and deadlines in a priority type way, but maintaining the review quality.  We don't want to sacrifice that.  As you well know, many of the devices that apply to the blood industry are very critical devices and we are not going to sacrifice quality in this process.
In the area of compliance and team biologics, again, as I said before, is addressing the issue of primarily of inspections and consistency of how we inspect our biological devices compared to how the Center for Devices inspects and the field operates.
Again, issues of policies, training, focussing specifically on an age-old question of sterility and stability of IVDs.  That has always been a point of discussion and controversy.  Finally, I think with the team biologics and this device action plan, we are going to get the resources focused on that to resolve that.
Again, outcome is coordination, transparent inspection process so that there is not a sense that there is a CDRH inspection of devices and a CBER inspection of devices and it is different.  We want to have the sense that, if you are a device manufacturer using the Medical Device Amendments as your regulatory framework that you get consistent inspection and compliance actions, again, are consistent in the same way that we would have the same threshold and action items relative to compliance actions as follow-ups.
[Slide.]
The final team effort is the outreach-inreach.  This is to maintain communications, dialogue with the public, with industry, with CDRH or other agencies that we need to be in dialogue with.  In this sense, we probably anticipate having an annual CBER device open public forum where, again, people can come back, like a stakeholders meeting, and basically tell us what their concerns are and what initiative we need to be focussing on.
[Slide.]
Finally, some of the basic objectives here is harmony with CDRH for consistency, that our policies and procedures are efficient and that the communications are facilitated in all realms.
That is the overview.  My colleague and now co-chair, since David Feigal left, Lillian Yin has been named co-chair of the device action plan.  Those of you who don't know Lillian Yin, she is legendary in the agency.  She was a division director in the Center for Devices, Office of Device Evaluation, for fifteen years.  I don't know; it was a long time.  She has extensive device experience and so she is very appropriate.
She is with us now.  She is in the Center for Biologics as a specialist in devices and is certainly going to add to our implementation of the device action plan.  And it is my privilege to show her slides.
DR. YIN:  Thank you, Jerry.  It is a pleasure for me to be here with you.
[Slide.]
I just joined the Center near the end of December of 1998.  Before that, I was with Medical Devices and we used the acronym CDRH.  I note this panel is very good.  You always ask what those acronyms mean.  In FDA, we are full of those.  So the Center for Devices and Radiological Health is really CDRH.
And now I joined CBER.  I am very, very pleased to have this opportunity because I think I know medical devices and especially FDAMA because we have been initiating those programs for all those years.  Our action plan was just completed this April.
But I have the fun part.  Panel chair and Dr. Epstein please stay with me for a short ten minutes or less.  I usually try to time it.  Normally, I will crack a fortune cookie to see what they tell me to say.  But today, I don't need to.  I know I have to be short and succinct so it will make life much, much easier.
I hope you all know the definition of medical devices.  Okay; I took the opportunity to tear out a page to read it to you.  A major distinction between drugs and devices, the definition is made in the statute of 1976.  The definition of a device is recognized in the official National Formulary or the United States Pharmacopeia or any supplement to them.
The intended use is in the diagnosis of disease or other conditions or in the cure, mitigation, treatment or prevention of disease in men or other animals or intended to affect a structure or any function of the body of man or other animals and does not--and this is the key--does not achieve any of its principal intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any if its principal intended purposes, because, if it met the last statement I read, it means it should be a drug or a biologic.  So that is the difference.
With that, let me tell you the fun part.  I always get the fun part to talk about.  It is the accomplishment of what we have done since this short time, since we only had the action plan finalized in April.  The majority of devices are here with us in our Office of Blood Research and Review; OBRR, CBER.
One of the members in OBRR--now, you all know what that is--helped me make this logo.  We are so pleased.  I am so poor at the powerpoint but she made this for me.  I was so greedy, I wanted both, that one and the little square one.  That is so cute.
First, our device action plan; not only are we trying to meet FDAMA, FDA Modernization Act of 1997.  In this particular action plan, I am only going to focus on the accomplishments that we are doing here in OBRR.  I am stationed here in OBRR.  The reason is that the majority of our devices are being reviewed here in OBRR and we have sent you the list, the CBER list.
[Slide.]
There are three things that I would like to point out for this list.  This list is being prepared by Len Wilson.  He is a member of our Division of Blood Application in OBRR.  The three major parts that I would like you to pay attention to are that we listed devices by offices.  You can see the first two pages is being reviewed by OBRR.
We divided that into three divisions.  The first one is the Division of Blood Applications and reviewed by the Division of Hematology and the Division of Transfusion Transmitted Devices.  In the future, I am going to call these DH and DTTD and DBA.  Everybody must follow with me.  It took me a long time to memorize those.
This is for OBRR.
[Slide.]
The next page we have for our Office of Vaccine Research and Review and Office of Therapeutics Research and Review.  You can see from the list that the majority of the devices are being reviewed by OBRR.  That is why I am going to focus my attention to the few tasks we are already working diligently so far.  This is one of our accomplishments.  Len Wilson did it.  Dr. Donlon is going to make sure that this list will be posted, will be put on our web.
Did you notice that, under each one, we also list a contact person.  We are doing all this primarily with responding to our stakeholders comment that we receive at all those meetings.  So you can see that.  There is another place I would like to highlight that is little noted.  That is strictly for the benefit of the industry; to process applications more efficiently, sponsors may voluntarily use a submission cover sheet found at the CDRH web.
That will make the logging in of the documents much, much easier.  Okay; so we have accomplished that.  That is the first accomplishment.
[Slide.]
Before I leave this subject, we just published this regulatory submission in electronic format and if anyone would like to submit that in electronic format, we welcome that but please follow the government--if you don't follow the instructions, we have to redo it again--not we.  All of us.  So this is very good to know.
I will tell you, for the next task, I did not have slides made.  This is what we are trying to do now is to assess our review process, to see how we can streamline it.  By being able to streamline it, we hope we can review our applications within the statutory required time frame.  And that is one very important part of the regulation for the statute in FDAMA 1997.
So we are actively assessing our review process.  Our goal is to streamline the process and our review of the submission will meet the statutory required time frame.  I put it in a nut shell for you.  Task 3--and that is the part.  Pay attention because we will come to you for advice--we have anticipated that if we would develop reviewer and industry guidance documents, we can expect the quality of the submission to be improved and the reviewers may review a little bit faster or shorten the review time.
[Slide.]
So we have set up committees that will be developing those guidances.  You have seen a lot of ours already.  I am so pleased that this team voluntarily said, "I am willing to be part of it."  You can see that.  I am not going to quiz you but you see Robin Biswas is from DTTD.  Can anyone tell me what that is?  I'm bad.  I think, in my past life, I must have been a teacher.  That is the Division of Transfusion Transmitted Diseases.
I am not going to tell you the second one; DH.  DH stands for?  Beautiful; Division of Hematology.  Always remember the last one, now.  Division of Blood Application.  So we will be developing that.
The next thing I am going to share with you is that when we are doing that, we really need a lot of scientific know-how.  Guess where we are going to find them?  Right here in this panel.  So be ready.  When any one of us calls you, there is a good reason.  I don't know about CBER panel members.  In CDRH, we do pay homework for what you do for us outside the panel.
Dr. Smallwood, do we do that?  Because we believe that if we have those guidance documents, both the industry and FDA, we all know what we expect in those documents so we should not receive documents that are so empty and miscollated.
[Slide.]
Let me give you a few examples that we believe would be good to have except we don't have the resources.  But I am going to twist people's arms to do that.  The few examples they gave us--I am not going to read it since I have to learn some of those words.  Immunohematologic reagent, blending, reworking and reprocessing--we need guidance documents for those--and the product stability testing for blood-grouping reagents, anti-human globulin and reagent red cells.
[Slide.]
Examples from DH are blood collection and processing kits, anticoagulant and additive solutions used for blood collection and storage, leukoreduction filters, cell separation devices including electronics, mechanics, materials, software.  Those things are very, very dear to my heart.
The last one, although not the least, is adhesives and solvents used in blood-product containers.  I don't know how familiar you are with them but you will be very, very soon.
[Slide.]
Examples from DTTD; the guidance documents for INDs and PLAs--you all know PLA is product license applications--for hepatitis and retroviruse.  For PMAs for retrovirus assays, for 510(k)s--I hope you are familiar with PMAs, 510(k)s and INDs.  For 510(k)s for CMV, I know you all know that.  Syphilis, et cetera.  For 510(k)s for external controls for hepatitis, retrovirus, CMV, syphilis and other assays.  Those are the examples we are giving, so we are asking for comments from you, are those the proper ones to do, to start out with, and do you have other recommendations.
So, with that, I think I am not going to prolong the talk.  So let's think and let's work hard on those documents or the new ones that you are going to recommend.  So we are counting on your help and I thank you in advance.
Thank you very much.
DR. HOLLINGER:  Thank you.  Any questions from any of the committee members?
DR. BOYLE:  Based upon discussions yesterday, what I don't understand in the action plan, there doesn't seem to be any requirement for plasma fractionaters to have an automated record system for rapid review of key quality-control measures related to product safety.  If FDA did require it, as I understand it, such a system would be a medical device and then the nature of that would be regulated by FDA so that it would meet the necessary standards.
My question is, since yesterday, a lot of the discussion related to the difficulty of the time required to do reviews of key quality-control measures related to product safety which, apparently, are in large part manual records.  If the FDA required that they be automated, then the FDA would also have the ability to make sure that automated system would meet the necessary standards.
So, is there any thought being given to that?
DR. DONLON:  Part of that, I think, would address, like, the GMPs and the compliance ORA field inspection and that would come under that team as far as an inspection standard or criteria.  Before that occurs, though, I think we need to have a policy statement basically as to whether that would be a requirement or not as far as facilitating.  My guess is that, initially, before it becomes a requirement, it would be kind of like a recommendation and this is something that would have to be transitioned into by many of the industry as far as establishing it and validating it as far as that type of record is concerned.
DR. YIN:  I would also to add that we do have an expedited review process so that if any new devices like that, the company may request expedited review and we would definitely comply to that.
DR. EPSTEIN:  We have requirements for keeping the records.  We have requirements that they be durable, that they be maintained and that they be readily available.  We have always shied away from defining the mechanism of keeping the record because that changes over time as the technologies evolve.
Whether we would review and approve those record-keeping systems as devices, I think is a little bit more tricky because, if they are strictly in-house and they are not intended for commercial use, they are actually exempt from the device requirements.
On the other hand, we could, as Dr. Donlon suggested, regard the implementation of such a presumably electronic system as part of current GMP.  So I don't think we have really thought that through from the standpoint of a regulatory requirement.  I thank you for the suggestion.
DR. HOLLINGER:  We had someone from industry who wanted to speak to the question on the device action plan.  That is Steve Binyon from Baxter.  Is Mr. Binyon here?  He had asked to speak.  He is not here, so I presume he is not going to speak, then.
I am convinced to work here in the FDA, you really have to like to make documents and write a lot.  I am interested in all the words.  My mentor used to say when you were doing these things, you say it like it is.  We have words like "harmonization."  I guess that means cooperation.  And things like "transparency," which I guess means visibility.  Then we have "inspectional practices."  I think that is the same as inspections.  But all these words come up.
Does anyone have any discussion anymore about these plans?  I think they are very well presented.  It gives us some idea of what is taking place.  If not, then we will go on to the next item for discussion today.  This is a very important item on the deferral of blood donors for risk of malaria.
I am going to ask Dr. Heintzelman, Deputy Director of the Division of Blood Applications, to give us an introduction and background to the issues to be brought before this committee.  I believe there is to be a vote based upon the discussion this morning.
	V. Deferral of Blood Donors for Risk of Malaria
DR. HEINTZELMAN:  Good morning.
[Slide.]
Today, we are here to discuss the current thinking of CBER concerning the recommendations for donor questioning regarding possible exposure the malaria.  My name is Mark Heintzelman, as Dr. Hollinger said.  I am with the Division of Blood Applications in the Office of Blood Research and Review, Center for Biologics Evaluation and Research.
There was an update for this topic during the December, 1998 BPAC meeting.  Since that time, there has been additional discussion of the exclusionary criteria that a blood donor must meet.  One area in particular that has been discussed is that concerning the risk to the blood supply for donors who have traveled to an endemic malarious area during times of broad daylight.
The sense behind this situation is that if the mosquitos that transmit the malarial parasite are not feeding during daylight hours, there may not be a need to defer the donors that travel to a malarious area during the daylight.
The Centers for Disease Control and Prevention will present data concerning the feeding activity of female anopheles mosquitos and the risk of acquiring malaria during broad daylight.  The Armed Services Blood Program Office will present a brief overview of their experience with travel restrictions in the northwestern portion of South Korea and malarial deferral.
As you listen to the presentations, please remember that there are a number of interlocking factors that contribute to the safety of blood for transfusion.  Currently, there are no licensed tests to screen blood for malaria.  Instead, we must rely on the donor questionnaire to determine if someone has traveled to a malarious area and been put at risk for acquiring malaria.
The value of a donor's ability to recall where they have been and when they were there is critical to the success of our policy, both current and future.
[Slide.]
This is our current policy that is in effect.  I believe that I should use this as a stepping stone to talk about the draft proposed policy steps.  So many of you will already be familiar with this.  I am going to review it very quickly.  When I go to the proposed policy, you will see that it is essentially stepping from this point and going forward.  You will see these same items noted again.
So, our July 26, 1994 memo states, "Permanent residents of nonendemic countries who travel to an area considered endemic for malaria by the Malaria Branch, CDC, U.S. Department of Health and Human Services, should not be accepted as donors of whole blood and blood components prior to one year after departure from the endemic area.
"After one year after departure, such otherwise suitable prospective donors may be accepted provided that they have been free of unexplained symptoms suggestive of malaria and regardless of whether or not they have received antimalarial chemoprophylaxis."
[Slide.]
"Two, prospective donors who have had malaria should be deferred for three years after becoming asymptomatic.  Three, immigrants, refugees, citizens or residents of endemic countries should not be accepted as donors of whole blood or blood components prior to three years after departure from the area.  After the three-year period, otherwise suitable prospective donors may be accepted if they have remained free of unexplained symptoms suggestive of malaria."
[Slide.]
Additionally, the memo states, "Because there are no approved tests to screen donated blood for malaria, careful questioning is essential for identifying prospective donors at risk for transmitting malaria.  Blood-establishment personnel should carefully elicit the necessary information regarding travel and disease history in order to defer those at risk."
[Slide.]
At the end of my presentation, I will review the suggested exclusionary criteria for the newest version of the malaria document.  As the process now stands, we rely on a close working relationship with the Centers for Disease Control and Prevention to identify areas throughout the world where malarial risk exists.  Our current guidance identifies the Yellow Books at CDCNP as being the source of information for identification of malarious areas that require exclusion from the blood supply.
This leads to some interesting observations concerning recommendations to prevent malaria in travelers and suitability of travelers to serve as blood donors.  Guidance for travelers concerning the need for chemoprophylaxis to prevent malaria at times can appear to be in conflict with exclusionary criteria for blood donors.
One issue that is indirectly linked to our discussion today is the situation wherein someone travels to a low-risk area for malaria, does not receive guidance to take antimalarial drugs, but may be deferred as a blood donor as a result of our current policy.  While this is a separate issue, the deferral of a potential blood donor for a risk that was not great enough to require chemoprophylaxis does cause frustration to the deferred donor.
I don't know if we will be able to reconcile this issue, but I wanted to point it out as one factor that feeds into this situation.
[Slide.]
So the current draft document which is built from the 1994--everyone knows this is draft not from implementation in our current thinking.  It is recommendations for donor questioning regarding possible exposure to malaria.
[Slide.]
The introduction states that this guidance document is a compilation of prior guidance regarding recommendations for deferral of donors for risk for malaria.  In addition, the term "resident" is being defined for the purpose of malarial deferral to be a person that has resided in a malarious area for five years or longer.
These recommendations apply only to donations containing intact red blood cells or platelets.  Donations used for preparing plasma, plasma components or derivatives devoid of intact red blood cells, red blood cells or platelets are excluded.  This guidance document also provides the recommendations of the Food and Drug Administration for donor questioning regarding travel to vacation resorts located in malarious areas.
[Slide.]
FDA's recommendations for deferral of blood donors at increased risk for malaria are as follows: one, permanent residents of nonendemic countries who have traveled to an area considered endemic for malaria by the malaria epidemiology section, CDCMP, should not be accepted as donors of whole blood and blood components including platelets prior to one year after departure from the endemic area.
After a year has passed since departure from the malarious area, such otherwise suitable prospective donors may be accepted provided that they have been free of unexplained symptoms suggestive of malaria and regardless of whether or not they have received antimalarial chemoprophylaxis.
[Slide.]
Two, prospective donors who have had malaria and received an appropriate treatment should be deferred for three years after becoming asymptomatic.  And three, immigrants, refugees, citizens or residents for at least five years of endemic countries should not be accepted at donors of whole blood of blood components including platelets prior to three years after departure from the area.  After the three-year period, otherwise suitable prospective donors may be accepted if they have remained free of unexplained symptoms suggestive of malaria.
[Slide.]
Number four; persons that may possess a partial acquired immunity to malaria such as those that have resided in a malarious region for at least five years, immigrants, refugees, citizens or residents of endemic countries should not be accepted as donors of whole blood or blood components including platelets for a period of three years since their last visit to the malarious region.
[Slide.]
Now, five. Before I start into five, I would like to point out that many, if not all, of the blood-collection facilities are currently determining status for travel for individuals and they will ask if people have left the country in the last three years and begin a series of questions beyond that.
With that in mind, the fact that it is already there, we were trying to formalize this process a bit more in coming up with these questions.  This is an area that is certainly hard to define.  Many of you are aware of the problems associated with good donor questioning and getting the answers you wanted.
As we go through this process, I would encourage feedback.  We are really looking for this to be a good document and this process is very valuable to us.  So, in this area, if you have comments about what you might conceive as better ways to do it, we are certainly listening very hard.
The questions that we have proposed are; "Were you born in the United States?"  If the answer is yes, the donor should be asked, "In the past three years, have you been outside the United States or Canada?" or B, if the answer is no, the donor should be asked, "When did you arrive in the United States and, since your arrival, have you traveled outside the United States or Canada?"
There are many issues associated with where someone considers themselves to be a resident.  We define resident, for the purposes of malarial deferral for this document, to be a five-year time stay in a specific area.  An individual that may speak English as a second language really may not want to admit that they resided in an area for political reasons or any kinds of persecution reasons and may have a different feeling on this.
So this has been a very hard area for us to come up with good questions that will address these issues.
[Slide.]
If the answer to the question in A above or the second question in B above is yes, follow-up questions should be asked to determine the country or countries that have been visited.  These questions should include, for example, something along the lines of, "In the past year, have you visited any rural area including a resort in a rural area in Mexico?"  The reason that we have put that there is because there are a very large number of people from the United States that travel to resorts on either the Pacific or Gulf Coast of Mexico.
I have heard numbers of upwards of 20 million a year.  Not all of those are blood donors.  Maybe 5 percent is the average.  Maybe up to a million of them might be.  So, ascertaining whether they have gone there and knowing the risk for the areas that they have visited can have a very big impact on donor availability.
If a prospective donor answers yes to this question, determine whether the rural area or resort is located in a Mexican state considered at risk for malaria by the CDCMP.  If so, the donor should be deferred for a minimum of one year from the date of departure from the area.  The major resort areas on the Pacific and Gulf Coast of Mexico do not have a malarial risk.
Our presentations from CDC will give you a lot of good scientific background regarding parasite areas that are endemic, activity, feeding activity, of the mosquito and such and will reaffirm that fact.
Finally, blood-collection facilities should further question the prospective donor regarding exposure history to better ascertain the actual risk of exposure to malaria using the information contained in the background section of this document.  If questions persist, we advise that they call the Malaria Epidemiology section at CDC for further clarification.
Of course, when more than one deferral period applies to a donor, the longest period of deferral should go into effect.  That is the most conservative approach.
[Slide.]
The question that we will pose to the committee, and I hope everyone got a copy of it coming in, is, "Do the committee members support a change in the current blood-donor policy to allow for travel the areas endemic for malaria when travel exposure was limited to hours of bright daylight?"
I tell you that now so when you listen to the people in the audience, when you listen to the presentations that are coming, you will know where we are going.
DR. HOLLINGER:  Thank you, Dr. Heintzelman.
The next presentation is going to be by Dr. Monica Parise, medical officer for the CDC.  Oh; sorry.
DR. BUCHHOLZ:  I think that what you have presented has been very interesting but, in reference to the question as it was phrased which relates to travel in bright daylight time, it seems to me there is some very important evidence lacking or that hasn't been presented which is what do we know about mosquitos, what is bright daylight.
DR. HOLLINGER:  Don, that is going to be covered, I think, very extensively here in the next--
DR. HEINTZELMAN:  Yes; you are absolutely correct.
DR. BUCHHOLZ:  So there are data that define and support the fact that mosquitos--which must differ from the ones at my house, because they bite me--
DR. HEINTZELMAN:  You probably don't have anopheles in your house.  I believe that that is the whole sense of this.  Should you have further questions regarding it after this presentation and the next one, we will certainly be open to discussion.  That is the point in this is to determine whether you can support the purpose of the question or not.
DR. STRONCEK:  If we vote yes to this question, later on will we--there seem to be about a dozen changes there that I saw, not just this question.  Maybe we will get into that later on?
DR. HOLLINGER:  Yes; I think we will.  Does anyone else have a question?  I was going to ask one question, and I don't know if it is going to be brought up, about platelets.  Is there any evidence that platelets have been associated with transmission of malaria?
DR. PARISE:  There is.  I wasn't going to present data on this but I will say that there is.  There are published reports.
DR. BUCHHOLZ:  Could someone give the committee an idea of what the magnitude of this problem is in terms of number of potential donors that fall into this category, number of donations per year that have deferred and the number of transfusion-transmitted cases of malaria?
I think we all know that this is a problem or a potential problem, but I am not sure that I, at least, have a feel for what is the size of this.  Is it two cases?
DR. HEINTZELMAN:  No.  That number is known.  I believe that Monica will be providing you with that.  As far as the incidence of deferral for the individual blood donations, there are about 14 million donations a year.  I don't have the number from the--maybe we will have a representative from the blood associations.  Kay is shaking her head no.  It would appear that they don't have the number for us today either.  So the number of deferrals is an unknown at this time.  Is that fair to say?
DR. FINLAYSON:  John Finlayson, FDA.  I don't have the number either, but if you notice, in the presentation that Ms. O'Callaghan made yesterday, you saw that for post-donation information, the major one, numero uno, for blood donors was travel to a malarious area.  So it is at the top of the list on the call-back information.
DR. ELLISON:  The paper we were handed today does give us some numbers.  In 1998, 1255 of the 7104 post-donation reports is 18 percent for travel to malaria-endemic regions.
DR. HOLLINGER:  18 percent of the post-donation information.  That still doesn't tell us the number of pre-donation--why don't we go ahead with the presentations and then we will come back because these issues are critical issues that are brought up and they may be answered.
	Presentation
DR. PARISE:  Thank you for providing us with the opportunity to present some information here.  I would like to say that I am going to be doing the presentation but Dr. Trent Ruebush, the Chief of Malaria Epidemiology at CDC, is also here and will also be actively participating in any discussion that is addressed to us.
[Slide.]
This morning, I am going to present technical data related to malaria to anopheline mosquito behavior and then specifically to transfusion-transmitted malaria in the United States.
[Slide.]
Malaria is a protozoan parasitic disease caused by one of four species of plasmodium which include falciparum, vivax, malariae and ovale.  It is generally transmitted by the bite of an infected female anopheline mosquito.
[Slide.]
Malaria was eradicated in the United States in the late 1940s but each year approximately 1000 to 1400 cases are reported in the United States, almost all imported infections in U.S. travelers or in foreigners.  A few cases, less than ten each year, are transmitted in the United States and include about two to three cases due to either transfusion or organ transplanation, congenital transmission.
In addition, once every one to two years, we have a case or a few cases that are due to local mosquito-borne transmission in the United States.  This happens very rarely in the United States because all the necessary conditions for transmission to occur here are rarely met because there has to be a contact between a mosquito vector and an infected person who had traveled and conducive climate conditions that support the development of the parasite in the mosquito and the longevity of the mosquito.
[Slide.]
Of the imported cases that occur every year, about half are in immigrants, refugee-resident category, of people who are from other countries who come to the United States and the other half occur in U.S. travelers which includes U.S. civilians and military.
A major risk factor for the acquisition of malaria in these travelers is failure to make use of effective chemoprophylaxis.  85 percent of these cases are associated with a failure to take prophylaxis for the use of ineffective drugs.
[Slide.]
Moving on to the mosquitos, the mosquitos that transmit malaria, the anopheles, feed almost without exception between dusk and dawn, although they may feed in daylight hours in densely shaded woodland or dark interiors of houses or shelters.
This is in contrast to other species of mosquitoes such as Aedes aegypti, the mosquitos that transmit dengue, which are primarily daytime biters.
[Slide.]
The changes that occur in monitoring behavior at different times of day or night are influenced by several environmental factors which include light, which is the most important, temperature, humidity and air currents.  The changes from day to night and back again to daylight conditions have a dominating influence on mosquito behavior and affect the mosquito's level of activity and responsiveness.
[Slide.]
This activity level and responsiveness underlies all the observable patterns of mosquito behavior which include host-seeking or biting, dispersion, mating, egg-laying and occupation of resting sites during daylight hours.
[Slide.]
Laboratory experiments have shown that many cyclical changes in mosquito behavior are true circadian rhythms controlled by an internal clock which is set by the transition from light to darkness at dusk.  At dawn, environmental temperature and humidity are very uniform which means that mosquitos have to use predictive clues in the environment in the search to find daytime resting sites.  It appears that certain combinations of overhead shade and dark background provide those clues and give the appropriate stimuli for where the mosquito will rest.
Experiments have shown that once mosquitos adopt a resting site for the day, they are reluctant to move.
[Slide.]
This slide shows the biting cycle which is shown in the red line and the peak biting times which is shown in yellow for several species of anophelines in South America, Southeast Asia, Oceania and SubSaharan Africa.  It goes from 6:00 at night and goes to 6:00 in the morning.
The fact that these mosquitoes don't feed during daylight hours is so well-accepted among entomologists that no recent studies since the 1930s even comment on daytime mosquito collections.  They start work, when they are studying these mosquitos, at about 6:00 p.m.
[Slide.]
Many similarities exist between the determination of malaria risk for travelers and potential blood donors.  I will say right from the beginning, the only way that we will completely prevent all cases in travelers would be for people to never travel to malarious areas.
[Slide.]
First, I will briefly discuss what we do for travelers.  Our recommendations for malaria chemoprophylaxis, which are based on determination of geographical areas at risk of malaria, are based largely on information obtained from the World Health Organization.  This information is updated on a regular basis every one to two years.
Several factors that can place a degree of uncertainty in these decisions are involved in deciding which areas have risk and when and are the types of information we discuss with travelers when we determine risk.  Some of these include the distinction between what is urban and rural, which is especially important in the Americas and Asia because the mosquito vectors are often not present in urban areas, the time of year of travel.
For most countries, because climate conditions can vary from year to year, the exact months when malaria is transmitted or the time of peak transmission also varies.  Because we don't have detailed information in real time on these year-to-year changes in climate and malaria transmission, we generally don't vary recommendations based on season.  One exception is China as the transmission there has historically been relatively constant.
The third issue is the time of day which is the dusk-to-dawn criterion which I will get into in more detail in subsequent slides.  We, at CDC, have not had difficulties getting such points across to very large numbers of travelers and healthcare providers for many years.  Furthermore, the evidence that we have about cases of malaria that we have at CDC as well as has been published in the literature from other countries, doesn't support that.  The misunderstanding here is necessarily with the cases, but that cases occur because people don't get accurate pretravel medical advice or because they don't follow it.
[Slide.]
In our determinations for malaria chemoprophylaxis in travelers, we don't consider persons who were in a malarious area only during daylight hours and then who come back to a malarious area at night to be at risk for malaria acquisition.
If travelers stay overnight at the resort in a malarious area such as resorts in rural areas in one of the states in Mexico that has malarial transmission that we are discussing in the proposed changes in the memo, they are at risk of malaria and must be deferred.  The dusk-to-dawn criteria mainly affects the short-term traveler who spends most of his or her time in a large city or a very developed resort where there is no risk of malaria but takes a day trip to a nearby tourist site or a business site in a malarious area.
Another case scenario are Ocean Cruise travelers who are at sea at night but the boat docks during the day for persons who do sightseeing.
[Slide.]
For travelers, we aim to strike a balance between the risk of malaria and the low risk of adverse reactions to anti-malarial chemoprophylaxis drugs.  In our judgement, there is more uncertainty around other issues such as urban-rural distinctions as well as time periods between the time of travel and the time of infection which I will get into shortly than around the issue that anopheline mosquitoes bit during daylight hours.
[Slide.]
Moving on to blood donors; the only way to prevent all cases of transfusion-transmitted malaria would be to exclude any traveler who has ever been in a malarious area at any time in their life for the rest of their life.  This would severely limit the size of the donor pool.  Thus, instead, we aim to strike a balance between the risk of infection and the exclusion of as few uninfected donors as possible.
We have agreed upon time limits for exclusion that are set forth in the existing criteria and their scientific basis is the vast majority of cases of malaria will have been infected within these time periods.
[Slide.]
Mark has well covered the donor-exclusion criteria and the proposed change.  I won't repeat these.
[Slide.]
Before I review information used to develop these criteria, I am going to briefly discuss the life cycle because there are species differences that I think are important to understand.  Basically, what happens is that, in the life cycle, the mosquito injects a stage of the parasite that is called the sporozoite that is present in the salivary glands in the mosquito when it bites a person.  	These forms, the sporozoites, are very short-lived in the blood.  They are there for only about 30 minutes.  They quickly are carried to the liver where they are taken up by liver parenchymal cells.  There they grow and undergo a development process which involves multiple divisions, evolve into a form that we call a schizont that contains thousands of little forms that will later be broken out called merazoites.
This maturation process takes, on average, 7 to 16 days and then the liver cell ruptures and these forms are released into the blood stream.  Once this happens, they relatively rapidly are taken up by red blood cells and passed through several stages of development within the red blood cells.
Once this occurs, once this development occurs, that red blood cell ruptures, releases merazoites again and those parasites go into other red blood cells and the cycle repeats itself.  The cycle in red blood cells takes about 48 to 72 hours depending on the malaria species.
Some of the merazoites that enter the red blood cells develop along a different pathway and develop into the sexual stage called the gametocytes.  This is important because these are the ones that are infective for the mosquito and are the ones that have to be taken out for the mosquito to infect another person.
When an uninfected female anopheline bites an infected person, it takes up these forms and they undergo development in the mosquito which takes about 9 to 35 days, depending on climate conditions and species, et cetera, and then it is ready to pass it on again.
Let me note, also, which I will get into in the next slide, a few of the species have dormant liver stages.  I will talk about that.
[Slide.]
This is one of the major differences, this liver stage.  The two species that don't have a persistent liver stage are P. malariae and P. falciparum.  P. malariae, although it doesn't have this stage that can relapse later, it has a quality that it can remain in the blood at very low levels without causing symptoms for many years, up to decades.  Case reports have been 40, 43 years.  So the current donor exclusion criteria will never prevent these cases.
The other parasite that does not have a liver form is Plasmodium falciparum.  Most symptomatic cases of Plasmodium falciparum come up within a few months.  Persons who have lived in malaria-endemic areas who may have acquired some immunity to malaria can have parasitemia which may be asymptomatic at periods that last beyond these few months which can go up to a few years.  I will present a little more data on details of those outliers in a minute.  This is the species that is responsible for almost all of the deaths due to malaria.
The two species that have a dormant liver stage are Plasmodium vivax and ovale.  Even without treatment, the liver stage rarely lasts longer than three years.
[Slide.]
There have been very rare cases reported in the literature and that we have noted in our U.S. National Malaria Surveillance System experience that exceed these general rules.  A review of our surveillance data from 1985 to 1987 showed that, of about 7400 cases in U.S. civilians and military, information on the time between travel and onset of illness was available in about 5700 cases.
Only 2.1 percent of these arose more than one year after travel.  When we consider the immigrant refugee foreigner category, there were 6200 cases which we had information about 4200.  Only 7 cases--that is, 0.2 percent--arose greater than three years after travel or immigration.
Note that this one in three years that we used are the current criteria.
[Slide.]
The extreme outliers found in our U.S. surveillance system and in the medical literature are nine in 13 years, respectively, for Plasmodium falciparum, 5 in 23 years for vivax and 7 in 7 years for Plasmodium ovale.
[Slide.]
There are reasons which may be related to immigration status, why a person may not be truthful about travel.  For example, in the course of investigations of cases of alleged mosquito-borne transmission in the United States, we found that a case-patient who repeatedly denied ever having been out of the United States later admitted it.  As we consider cases, both that are in the literature and in our surveillance data where there are these very long durations between travel and onset of infection, we need to consider that there could be inaccuracy in the travel history.
Many studies in human volunteers and non-human primates have shown that this parasite, Plasmodium falciparum, rarely lasts longer than a year.
[Slide.]
Concern over the three cases of transfusion-transmitted malaria that occurred during 1996 to 1998, all of which were complicated Plasmodium falciparum infections, prompted us to review all cases of transfusion-transmitted malaria reported to CDC from the years 1963 to 1968.  I am briefly going to discuss this review because the epidemiology of transfusion-transmitted malaria is relevant to the decision-making process.
The objectives of this review were to describe the epidemiology and evaluate trends in incidence and to try to evaluate reasons why cases occurred and how to better prevent them.  In cases where an implicated donor was identified, donor suitability was determined using published FDA and AABB donor-exclusion criteria.
As these guidelines have changed through the years, we looked both at the donor suitability with respect to the criteria in place at the time of donation and with respect to current criteria.  There was very little difference between these two analyses, so, today, I am going to focus on the current criteria.
To determine the incidence of transfusion-transmitted malaria in the U.S., the cases we used were from our surveillance data.  We believe that our surveillance system is probably about 50 percent sensitive, but we tend to hear about unusual cases or cases that occur in the U.S.  So we think it is very sensitive for that.  And we derive number of units transfused from the medical literature.
[Slide.]
From 1963 to 1998, 91 cases of transfusion-transmitted malaria were reported in the U.S.  A donor couldn't be implicated in all these cases, and there were 35 implicated donors, whose age ranged from 19 to 59 years, and 80 percent were between 21 and 40 years of age.  91 percent were male.  59 percent were foreign born and the area of acquisition of infection was most frequently SubSaharan Africa, in 45 percent of cases, followed by Southeast Asia and Central and South America.
We had sufficient data to judge donor suitability for 58 of the implicated donors.
[Slide.]
36 of 58, or 62 percent, of infections would have been prevented if the current donor-exclusion criteria had been correctly applied.  The screening process failed at some point; for example, the donor didn't understand the question, purposefully withheld information, or the probing process was not adequate.
Of these cases that occurred when guidelines were not followed, approximately half occurred in immigrants and half in U.S. travel.
[Slide.]
In 22 of the 58 cases, or 38 percent, the problem was that the time period from the last travel to a malarious area and the blood donation exceeded the time limits in the donor-exclusion criteria.  In cases caused by P. malariae, P. falciparum and P. vivax and ovale, times ranged from 5 to 44 years, 1 to 5, and 1 to 7 years respectively.
59 percent of these cases occurred in immigrants and 41 percent in travelers.  The travelers included either military or persons who had previously lived in endemic areas, now live in non-endemic areas and went back to visit.  I am going to refer to these people as VFRs, visitors to friends and relatives, because I am going to get into that in a little more detail in a minute.
So, of cases that occurred in travelers, they were either military or the VFR category.  Overall, in this 35-year period, we only identified seven non P. malariae infections that occurred when the guidelines were followed.
[Slide.]
Overall, the most frequent infecting species was Plasmodium falciparum in 34 percent followed by vivax, malariae and ovale.  In cases where the guidelines were not followed, P. falciparum was most frequent species and, not surprisingly, in cases where the guidelines were followed, P. malariae was the most frequent species.
We also looked at differences in implicated donors by decade to see if there were changes with time.  Since 1980, there have only been three cases due to U.S. travelers.  The last occurred in 1982.
[Slide.]
Questions have been raised as to whether the VFRs, the persons who visit friends and relatives, should be presumed to have retained some acquired immunity and so should be treated as immigrants and not travelers in terms of time for donor referral.
In 5 of 8 such cases, the infection arose within one year.  Two cases occurred several years later that involved Plasmodium malariae and, in only one case where the donation occurred 29 months after travel where the traveler exclusions while this three-year immigrant exclusion would have prevented the infection with Plasmodium falciparum.
This case was somewhat unusual as the donor had made several long trips since his immigration which may have contributed to retaining some acquired immunity.
[Slide.]
The bars in this graph show the number of annual cases of transfusion-transmitted malaria from 1963 to 1997.  The line shows the incidence rate.  We have difficulties in obtaining denominator data on units transfused in the 1975 to 1985 years, and so that data is missing.  But, basically, you can see there has been no change in the incidence of malaria, transfusion-transmitted malaria, in the last decade and it has actually decreased since the early years of the investigation.
[Slide.]
The information I have presented explains our rationale for a dusk-to-dawn criteria.  We believe that such an exclusion can be implemented.  One may define the safe time period as the time which is after dawn and before dusk that we don't consider to have malaria risk as the time of full daylight.
Not excluding persons who have had only daylight travel to malarious areas is very likely to impact upon the category of immigrants and will only affect you as travelers.
[Slide.]
The first step in the screening process, done as part of the probing, could be to determine how long a traveler was in a malarious area.  Anyone there greater than 24 hours must be deferred as they were there overnight.  So this doesn't change anything in reference to those travelers who spent that night inside a screened, air-conditioned hotel or inside a cruise ship that was docked at port.  These people were overnight in a malarious area and they need to be deferred.
In considering persons who were there less than 24 hours, did they arrive after it was fully light and did they depart while it was still fully light.  They must answer yes to both questions to be allowed to donate.  If a traveler isn't sure or cannot remember, we do as we do in other cases of uncertainty; for example, when we can't find an area on the map, we play it conservative and we defer the donor.
Thank you.
DR. HOLLINGER:  Thank you.
I think we will have the final presentation and then we will come back to questions.  This presentation is by Major Groshel, Blood Program, Department of Defense.
	Presentation
MAJ GROSHEL:  Military duty, whether that be active duty or even reserve duty, means that a donor stands a good chance of travel to a malarial area.  Donor questions on travel history and potential exposure to malarial endemic areas take up much of our donor interview time and is an emphasis of our donor training programs.
FDA recommendations for donor questioning and areas of donor travel and potential exposure to malaria must be clear, concise and as specific as possible.
When the Armed Services Blood Program instituted a restriction on donations due to travel in areas of the northwest portion of South Korea due to possible exposure to malaria, we limited restrictions to an area north of a reference river and we exempted travelers who were only in the area during daylight hours such as day-trip visitors to the demilitarized zone.
This policy not only resulted in documentation questions from our donor centers but also in other questions like how wide does a river need to be before a mosquito will not fly across it, what is considered dawn and dusk and how does a mosquito know the difference, especially on a cloudy day.  What if the donor says they were only there during the daytime but they remembered getting bitten by a mosquito or what if the donor doesn't remember if they left before dusk.
These were just questions that came up in relationship to that policy.  Although we don't have any specific data saying that we had any errors or recalls resulting from this policy, increases in subjectivity of donor questions increases potential risk.  So we would ask that all recommendations be as clear, specific and concise as possible and expect questions that will need good supporting documentation, be very clear and specific about questions that would be expected to be included on donor cards and in follow up, be consistent with recommendations for specific follow-up questions.
The examples included in the draft guidance were very specific in wording for follow-up questions to determine if a donor had visited a rural area or a resort but did not include specific wording for follow-up questions to determine if the donor's previous country of residence was a malarial endemic area.
I think the main thing that we are asking is that the donor instructions to the donor centers be as clear and as concise and specific as possible because they are the ones that are going to have to field these questions.
Thank you.
DR. HOLLINGER:  Thank you.
We are going to take a break now until 10:30 and then we will have the open public hearing and then go into the open committee discussion.  It is now 10:03.  Be back at 10:30.
[Break.]
DR. HOLLINGER:  We are going to have the open public hearing at this point.  There are two people who have asked to speak.  There may be others that want to, but the two people who have asked to speak--the first one is Dr. Mary Townsend from America's Blood Centers.
	Open Public Hearing
DR. TOWNSEND:  I am Dr. Mary Townsend.  I am co-chair of the America's Blood Center Scientific, Medical and Technical Committee.  I am Medical Director of Coffee Memorial Blood Center in Amarillo, Texas.
ABC thanks the committee for the opportunity to present our recommendations and comments on the issue of deferring donors who may be at risk for infection for malaria.  For your information, ABC's not-for-profit, community-based members provide nearly half of the nation's volunteer donor blood supply.  Blood-collection facilities frequently have requested clarification from FDA on requirements for evaluation of donors who have visited or lived in countries in which malarial transmission occurs.
The focal nature of malaria transmission within endemic areas, the seasonality of transmission and other intrinsic characteristics of malaria as well as the wide spectrum of activities and their recall complicate evaluation of donors who have been in endemic areas.
The magnitude of the complexity is reflected in the high rate of errors and accidents reported to FDA as a result of post-donation information having to do with travel to malarial endemic regions.  In 1998, these amounted to 1,255 of the 7,104 reports, or nearly 18 percent of all post-donation information reports.
Since prevention of transfusion-transmitted plasmodial infection is the goal of donor interrogation about travel outside of the United States, the epidemiology of transfusion malaria should be the basis of our donor screening efforts as suggested by Dr. Parise of the CDC.
[Slide.]
This table is extracted from the last four CDC malaria surveillance summaries and reflects the current epidemiology of malaria in the United States.  In the years studied, only 2.6 percent of malaria diagnosed in the United States was acquired in Mexico and the Caribbean, extraordinarily popular destinations for tourists and common points of origin for immigration.
A review of the cited surveillance summary shows that none of the two to three annual cases of transfusion-associated malaria, including the three most recent cases occurring during the 1996-1998 reporting period, as reported in the April 2, 1999 issue of MMWR, could be definitively attributed to donor infection acquired in Mexico or the Caribbean.
In fact, the three donors associated with the 1996 cases all immigrated from West Africa.  Of additional interest, correct application of current FDA and AABB malaria deferral standards could and should have prevented all of the recently reported transmissions of malaria by blood components.
We attribute these failures, in part, to the increasing complexity of donor medical history.  We feel that the new proposed questions regarding country of origin and subsequent travel and immigration should greatly improve the problem of donor history failures.
The adequacy of the blood supply is marginal and we believe that adequacy is a safety issue.  Data from the AABB's national blood data resource center previously presented earlier this month to the Transmissible Spongiform Encephalopathies Advisory Committee suggest that demand for blood and blood components for transfusion will exceed the supply of donations from volunteer whole-blood donors in the Year 2000.
Under these circumstances, changes in malarial criteria for volunteer whole-blood donors must not result in significant increases in deferrals especially for travel to Mexico and the Caribbean since they would not materially reduce the incidence of transfusion-transmitted malaria.  This concern is rendered more acute by the TSE Advisory Committee's recent advice to FDA that certain donors with residence in the United Kingdom during the interval 1980 to 1999 be deferred due to theoretical concerns about transmission of new-variant CJD.
It is estimated that this action will result in the loss of 2.2 percent of eligible volunteer whole-blood donors.  We applaud, and many facilities such as my own have already adopted, the suggested mandate by AABB for a question, "In the past three years, have you been outside the United States or Canada?"  This question is unambiguous and will standardize the donor interview at blood-collection facilities.
The plan for additional and follow-up questions proposed this morning are appropriate.  A precise definition of residence is greatly appreciated.
Regarding the issue raised today regarding rural versus urban resorts; we are concerned that that determination of urban versus rural resorts in Mexico, the Caribbean and elsewhere will be arbitrary absent a definitive categorization by CDC and/or FDA that can be updated as appropriate.  Because of the volume of travel by donors in these two former destinations, an authoritative list, or at least definition, for these areas would be the most important assistance in simplifying initial donor screening we can ask for.
We oppose taking from blood-collection facilities the flexibility to inquire regarding potential day versus night exposure particularly with reference to travelers to Mexico and the Caribbean.  Many thousands of donors vacation in these areas and may be deferred by such a policy.  The CDC has provided today for you the opinion that this is a meaningful differentiation and, in the absence of transfusion-transmitted malaria from Mexico and the Caribbean will result in donor loss with no increment in safety.
Finally, the FDA must take pains to avoid providing mixed message to traveling donors that conflict with that information that they have obtained pretravel from the CDC or from their physician relying on CDC information for malaria prevention advice.  It is wrong, we think, for a donor who has been advised before traveling that that risk of malaria on a trip to a Mexican resort or a Caribbean cruise is inadequate to demand preventive medicine than to be subsequently told that he is being deferred for the theoretical risk of malaria.
Surveillance data from the CDC cited above suggests that such transmission is not occurring with a recognizable incidence using current donor-screening techniques including discretion of medical directors to assess risk.
Before any such step is taken, its impact on donor loss, both nationally and on a regional basis, should be assessed in a survey analogous to that which was undertaken to assess the impact of new-variant CJD deferrals.
I thank you very much for your time.  Are there questions?
DR. HOLLINGER:  Thank you, Mary.
DR. BOYLE:  Would you turn that back on for a minute?  I just want to be sure I understand.  Using 1995 as an example, the difference between the 32, which are malarial cases acquired in Mexico and Caribbean, and the total are ones known to be acquired outside of Mexico and Caribbean or the ones that you don't know where they were acquired?
DR. TOWNSEND:  They were outside of Mexico and Caribbean.  And then the two that were transfusion-transmitted were from Ghana and Nigeria.
DR. BOYLE:  Thank you.
DR. HOLLINGER:  Thank you.
DR. EPSTEIN:  I had a question for Dr. Townsend.  What is your thought, Dr. Townsend, about whether the absence of cases from Mexico or the Caribbean is due to effective screening?  It is a cart-and-horse problem.  You have got screening and maybe it is more accurate for persons who, say, travel to Mexico and the Caribbean or immigrate from Mexico or the Caribbean compared with the accuracy of screening for African immigrants who travel to Africa.
DR. TOWNSEND:  I think the screening has been effective.  What we are looking for is some guidance in regard to differentiation between rural resorts, day and night exposure.
DR. EPSTEIN:  I hear you, but I am quarreling with the observation that the risk for Mexico and Caribbean must be low because you don't see cases.  That might just reflect effectiveness of screening.
DR. TOWNSEND:  I wouldn't argue that.
DR. BUSCH:  But I think, Jay, the issue is is there going to be a further tightening.  Operationally, now, it sounds like most blood centers are not deferring people who have just had day visits out of the main resorts to these more rural regions.  So if there were any consideration of further tightening, then the issue is is there any transmission of the current policy.
The second person who has asked to speak is Dr. Michael Busch who will speak on behalf of the AABB.
DR. BUSCH:  My name is Mike Busch.  I am at Blood Systems and University of California, San Francisco.  I am presenting on behalf of the AABB Transfusion-Transmitted Disease Committee.
The AABB is the professional society for over 9,000 individuals involved in blood banking and transfusion medicine.  It represents roughly 2200 institutional members including community and Red Cross blood-collection centers, hospital blood banks, transfusion services, as they collect, distribute, transfuse blood and blood components and hematopoietic stem cells.
Our members are responsible for virtually all of the blood collected and more than 80 percent of the blood transfused in this country.  For over 50 years, the AABB's highest priority has been to maintain and enhance the safety of the nation's blood supply.  The Association operates a wide variety of programs to meet safety priority and is proud to have played a key role in insuring the nation's blood supply is the safest it has ever been.
The AABB appreciates the opportunity to provide its comments on the topic of deferral of blood donors at risk of malaria.  Malaria is a rare but potentially serious complication of blood transfusion.  On average, two to three cases per year have been reported to the CDC from 1958 to 1998.  Thus, three reported cases between 1996 and 1998 should not be viewed as an indication that this problem is suddenly increasing.  Nevertheless, all measures currently in place for the purpose of reducing the risk of transfusion-transmission of malaria should be examined to see if improvement is possible.
The donor interview is a critical component in determining possible malaria exposure, especially since readily available testing methods are not predictive.  The AABB publishes a uniform donor history questionnaire which has been approved by the FDA.  The question about travel asks, "In the past three years, have you been outside the United States or Canada?"
A yes answer then prompts more specific questions to elicit where, when and for how long.  We believe this question is very straightforward and the most appropriate way to obtain this information.  For donors who have been outside the U.S. in the last three years, additional questioning can determine whether the donor was an immigrant or a resident in a malaria-endemic country if FDA determines that specific deferral criteria should apply to these donors.
Adding such additional specific questions for all donors is not warranted.  It will increase the amount of time answering questions which are not applicable to most donors and will add to the length of the total time required for donation.  Additional questions that are not of high value in distinguishing donors at risk also take emphasis away from the extremely important questions.
However, should the FDA decide to add questions, these questions must be practical and nonoffensive to prospective donors.  It would be requested any such additional questions be field tested in selected blood-collection facilities prior to implementation in the entire country.
Such field testing would, perhaps, identify questions which are not clearly understood by prospective donors.  FDA should demonstrate not only that the new questions are understood but that new questions will actually result in a more appropriate deferral than the current questions.
The major issue faced by blood-collection facilities primarily lies in the proper identification of geographic regions considered at risk for malaria.  Although CDC publishes health information for international travelers, commonly known as the Yellow Book, the information is not user-friendly.  AABB requests that an easy-to-locate, readily understandable and up-to-date reference be made available, perhaps on the Internet.
Blood centers also call CDC directly for information and find it very confusing when CDC advice appears to contradict the FDA advice.  AABB requests that CDC and FDA harmonize their thinking so that there is an agreement about what constitutes malaria risk.
In conclusion, AABB will be pleased to have FDA clarify its expectations in a new guidance on deferrals for malaria and urges FDA to make this guidance practical for blood centers and consistent with advice provided by CDC>
Thank you.
DR. HOLLINGER:  Any questions of Dr. Busch?  Mike, I want to ask you just a question about from the blood-banking circumstance.  I go to Bangkok.  Bangkok is considered an urban area and not of concern, Bangkok, itself.  I decide to fly to Angkor Wat which has falciparum, in fact, resistant falciparum.  I am there just in the day.  I fly there that morning.  I to the Angkor Wat.  I come back that afternoon and go back to Bangkok.
That has to deal with a little bit of the question that we are going to be asked today.  The same thing goes with a port.  You come into a port where there is malaria in the area.  You arrive there in the morning.  You go out and you visit places out in the port and then you get back on your boat and the boat leaves versus the boat staying there overnight.
How does the blood-banking community now handle those two questions if I were there and I said, "Yes; I was here at these places."  What would you do for me in the first instance in terms of the Angkor Wat.  I didn't stay in Angkor Wat overnight but I just went there that day and came back.  How would they handle it today?
DR. BUSCH:  To be honest, I am not that involved on the front-line, how the nurses actually would handle those questions.  My sense would be that we are discriminating.  Thailand is much more of an unknown to us so my sense would be that you would be deferred in that scenario in Thailand whereas here, probably, in the Caribbean resorts, you would not because it is a much more controlled environment.
I don't know the answer.
DR. HOLLINGER:  That is the issue, basically, because Bangkok is okay but--in terms of the CDC, it is okay.
DR. TOWNSEND:  This is what we do every day.  Basically, in either of those cases, I think probably neither donor would be deferred.  What I have done in the past, when it gets complicated, I put a phone call in to the CDC and ask them and they will tell me, this donor is at risk or is not at risk.  Basically, it is based on the information that you have heard today, from a dusk-to-dawn situation.
We have similar situations when people leave the big resort and they go on a river cruise which is considered--overhanging dark trees, a little bit, high water.  So we would defer those donors but, often, it is based on a case-by-case basis and if there is a question, we consult the CDC.
DR. HOLLINGER:  So, currently, what we are being asked of the questions, and I just want to be clear here, is in addition to what is being--for example, if we accept the question as it is posed about dusk-to-dawn, as it seems like it is being utilized now, then nothing different will change.
DR. TOWNSEND:  That is correct.
DR. HOLLINGER:  On the other hand, if we vote against that, then there will be additional factors here and those people will be viewed differently.
DR. TOWNSEND:  There would be additional deferrals.
DR. HOLLINGER:  Additional deferrals to those areas.  Okay.
DR. NELSON:  I don't think you could do that trip overnight.  The airport is at Siam Reef and it is a ways, so you would probably have to stay overnight.  But, at any rate--
DR. HOLLINGER:  It's a good question, anyway.  Actually, I did look into that.  And there are planes that will get me there and get me back.
DR. NELSON:  Oh; okay.  But one of the questions I had was about the 18 percent of post-donation information that led to all sorts of complex actions.  I wondered what happened in that setting.  Did somebody just forget?  Or did they subsequently report that, oh, yeah, they stayed overnight?
Looking at those data might be--because that is really sort of what is at issue, was it a real risk or is the question too complicated now, or--I don't understand.
DR. HEINTZELMAN:  I think it safe to say it is all of the above.  Look back to your own experiences in the last year if you have been on a vacation.  Do you remember that vacation?  Do you remember where you were?  Do you remember the time of day?  Those are the questions that you have to be able to answer to address those post-donational callbacks that are related to malaria--I think the number on the document is 1,255--are places where the people forgot during the time of donation.
You can only wonder how many completely forgot and didn't remember a week or two later.  Those are very real issues.  The science for the mosquitos, the parasitology is very well understood.  I don't believe there is any question about that.  The implementation strategy and people's ability to recall is another part of this.
It is a very complex issue and there are differences of opinion in the blood community regarding this.  That is the reason why we bring it to your attention.
DR. HOLLINGER:  Is there anybody else from the public that wishes to speak at this point before I close the public hearing and open this up for the committee.
MS. JETT:  I am Betsy Jett from NIH.  I just want to talk a little bit more about that implementation piece of it because that is a nightmare for us like it is for everybody else.
I would like to see CDC publish a much more detailed map than they currently provide because a lot of our donors couldn't tell you the name of the province they were in.  So a better map would help.  A better definition of rural versus urban would be very helpful, especially in Thailand.
The last thing is not only does the questioning take a long time, but the documentation of that interview is also very cumbersome.  So I would like the policy-writing people to talk to the compliance people and kind of get together because, right now, we have to document not just that, yeah, they visited an area but we determined it was okay, we have to say where they went, all the details of the case report in our donor documentation.  That is a problem for us.  It is hard.  It is a lot of work.
DR. HOLLINGER:  Thank you.  Appreciate that.
Anyone else from the audience want to say something?  If not, I am going to close the open public hearing and we will open it up for discussion.
	Committee Discussion
DR. EPSTEIN:  I am afraid this may add to complexity but I think one of the questions for the committee is that if you are uncomfortable about the accuracy of histories, then the recommended policies should be deferral.  However, one could incorporate into that policy the concept that if one then gets more specific reliable information, one can override the deferral.
So, for example, with regard to resorts in rural areas of Mexico, it has been pointed out that all resorts are not the same and how do you define a resort.  So you could have a policy that you defer donors if they went to resorts in rural areas unless the resort is identified and it is checked with CDC or it is on a CDC list that that is not a malarial risk at that resort.
Likewise, you could have a policy that you defer for exposures in malarious areas, time of day not withstanding, unless the medical director can reliably ascertain that exposure was limited to hours of bright daylight.  It is really a question of where do you put the onus of checking.  So I just think that we can have a little bit more complex recommendation that, on the other hand, would mitigate unnecessary deferrals, but it puts the onus of validation on the medical director.
DR. BOYLE:  Could somebody just explain to me the process--the questions now about was it during daylight, or was it urban-rural, or whatever, is that part of the standardized questionnaire people are filling out or are they follow-up questions that are being asked by nurses once they have seen the first thing on the form.
DR. FITZPATRICK:  Those are follow-up questions.  The initial question is, "Were you outside the United States or Canada in the past three years?"  That is the only standard one.  Everything else is follow up that the interviewer has to draw out of the donor.
DR. BOYLE:  Is that question that is being posed to us to add this criteria to the written form or simply make sure it is a criteria that would be followed by the nurse or the person who does the follow up?
DR. HEINTZELMAN:  In that regard, if you are referring to the question to the committee--
DR. BOYLE:  Yes.
DR. HEINTZELMAN:  If the committee was to vote in favor of that and FDA was to enact that into its policy, it would probably require a fairly extensive rewriting of that entire document so it would become incorporated into the document in the areas where it is appropriate.
Does that answer your question?
DR. BOYLE:  The document being the questionnaire as opposed to the training materials.
DR. HEINTZELMAN:  The document that I am referring to would be the malaria memo.  I can't respond to what the individual blood banks are doing.  We have to ask a representative from that area.
DR. HOLLINGER:  Other questions?
DR. RUEBUSH:  I am Trent Ruebush from the CDC.  Perhaps I could respond to a couple of the questions or comments that were made.  Someone asked about why we are not seeing more cases from Mexico and the Caribbean.  Perhaps the reason that we are not seeing transfusion-induced cases from those areas is because the screening techniques are very good.
I think the real reason is there is very little malaria transmission; in the Caribbean, really only the island of Hispaniola.  Haiti and the Dominican Republic have malaria.  There is no malaria in any other Caribbean island and even the level of transmission in Mexico is quite, quite low.  So the risk is low and I think that is the reason you are not seeing many cases.
I think it was Dr. Epstein brought up the point about, perhaps, making some slight modification.  We feel very strongly at CDC that if there is ever any doubt about where a traveler is going, because we usually get involved in that end of things in terms of prevention, or if we get a call from a blood bank, defer is there is any doubt.
But, again and again, we do get calls, and I work in a travel clinic in Atlanta where we have a lot of Coca Cola executives coming in.  They are going to be traveling to Latin America or to Asia.  They are going to be staying in a four-star hotel in a big city, but they are going to take a day trip to a factory in the middle of a rice field.
We feel very comfortable telling them they don't need to take malaria prophylaxis.  Frankly, if a blood bank calls me, I would feel comfortable saying to them that person is okay.  So I think we would feel comfortable, more comfortable, perhaps, than one side or the other with some sort of intermediary point.
Someone brought up the issue that they would like to have from CDC better maps of the malarious areas of the world.  We would, too.  The problem is that, in many parts of the world, the areas where malaria is really transmitted are not well-defined.  Where it is transmitted this year or this season may be different next year or next season because of rains, floods, whatever.
I think we could do a better job in that, at least in some countries, come up with better maps.  But many, many of our questions that we get from blood banks could be very easily answered at the blood bank if they simply had the Yellow Book and a decent atlas because, basically, that is what we end up doing when we get a call.
They will tell us, "We have a potential donor who has traveled to a given country."  We will ask, "Where?"  We will pull out an atlas and then try to find the name of that city.  A lot of that could be done, I think, at the blood bank.  So we could, perhaps, help in providing better maps but something that would take care of, I think, 85 or 90 percent of the problems would just be a decent college-level atlas at the blood banks.
We do occasionally get questions about travel to places like Buenos Aires which they could certainly handle at the local level.
DR. PARISE:  We get an average of about twelve calls a day.  Some days it is six.  Some days it is twenty.  And that is all we do is look at our atlas.  I very rarely have a difficulty with it.  There are a few countries that I agree, we don't do very well, and those are Peru, Columbia and Ecuador.  There may be a few other South American countries.
So I think maybe us trying to get a more detailed map of the provinces and departments in those countries would avoid confusion because it is a headache for me when I am in the middle of my lunch and I have to look for those provinces and I can't find them, either.
But, in general, a normal atlas, we answer 90 percent of these questions.  We don't have anything computerized at all.  We just look at the atlas and the Yellow Book.
DR. ELLISON:  The suggestion was made by Dr. Epstein, I believe, that you have a list of resorts that are acceptable.  Do you have such a list now?
DR. PARISE:  We do have a list.  We can't publicize the list with names.
DR. ELLISON:  It is not a very effective list.
DR. PARISE:  When we first started these discussions a couple of years ago and we got into discussions about some specific names of resorts, those resorts were on the phone with our lawyers almost immediately.  I think it would be very unlikely that we are going to be able to publish names.
DR. HOLLINGER:  On the other hand, if we take a cruise ship, you can look in and find out what their inspection has been with a number for any of the cruise ships around, if they have had a real safety record or the value of their score is a safe score.
DR. PARISE:  I think, and there, Trent, you can comment, there are inspections of those cruise ships and CDC has information on that.  We don't have that on the resorts.  Really, we make this determination by looking at--no one will agree to us going in and inspecting these resorts and collecting mosquitos.
So we really just, from Atlanta, make the best judgment we can.
DR. ELLISON:  My second question has to do with the Yellow Book which I have never had occasion to use, but having just completed reading the federal income-tax guidelines, is there anything you can do to make the Yellow Book more user-friendly?
DR. PARISE:  I think we would be open to a dialogue with blood centers because we are so inside of it.  When I sit down with an atlas and the Yellow Book, I can answer these questions with very little difficulty.  But we would be open to a dialogue with blood centers and whatever forum might be proposed to try to do that and put it on the internet.  I don't think we are averse to that.
DR. CHAMBERLAND:  In follow up to the question about CDC's ability to publish a list of resorts, I think Monica has indicated the difficulties that we would face doing that and that we actually, as opposed to cruise ships, don't obtain objective data.
But I would add that I would wonder if it would be possible, let's say, being in a guidance document or whatever, if perhaps CDC, FDA, could amplify a little bit of disease discussion of what constitutes an urban versus a rural, a large major resort.
Clearly, when you probe on the phone, there must be some general characteristics of these resorts that you are asking about, be it size, how long they have been in existence, are they in the middle of a forest, something like that.  So I just would wonder if that is something that might be helpful and would ask my CDC colleagues if that is something that is practical or doable.
DR. PARISE:  I think that we could work on that somewhat.  Our main criteria there is that some of these resorts are really cities.  They have built a lot of hotels in them.  But they really are urban areas.  Whereas, others are resorts that have been pretty much plunked down in a rural area.
The problem there is that when a resort is plunked down in a rural area, we consider that the rural resort.  If it has been there for years and becomes very urbanized, until the map changes, we don't know.  We play it conservative and we defer.  Maybe if we went and inspected that resort and saw it, we wouldn't defer.  But, again, we don't have any data and so we do the best we can.
But we probably could come up with large urbanized resorts that have come in urban areas.
DR. NELSON:  The urban versus rural only applies to Latin America, not to Africa.
DR. PARISE:  Largely.  There are a few African cities that don't have transmission, but there are very few.  And Southeast Asia.  Southeast Asia and the Americas; yes.
DR. NELSON:  So Africa is pretty easy.  SubSaharan Africa is a problem.
DR. KOERPER:  I am just curious how long this process takes.  Does the prospective donor sit and wait in Seattle or San Francisco while the medical director calls the CDC?
DR. PARISE:  That you would have to ask the blood banks.
DR. KOERPER:  Or do they ever walk out the door and never come back again.
DR. HOLLINGER:  The answer is yes from several of the blood-banking people here.
DR. PARISE:  We place it as a priority.  If we have chemoprophylaxis calls and the person there isn't right in her office, we will take a message.  For cases of malaria and for blood-bank calls, if the person is not right there, they will page somebody.  So we do, on our end, try to do them as fast as possible and interrupt what we are doing to go look at the atlas.  But I am sure there can be many delays in the process.
DR. HOLLINGER:  On the other hand, what I am hearing here, if this is an issue, here, in this computer world, not to have this computerized--the same questions you are going to be asked, you obviously have answer for right now.  To put that on a website that is computerized and could be changed in an instant would allow them, and the blood bank, to then pull that information or put that issue in there and receive a piece of information back.  I can't understand that.
DR. PARISE:  The Yellow Book is on the Web.
DR. HOLLINGER:  And it has those sites on it.
DR. PARISE:  Right, but at a mobile site, you don't even have an atlas so the Web isn't going to help you at a mobile site.  Many of the calls we get are at mobile sites that don't have an atlas in front of them and they can't look.  So they are relying on us.
We are amenable to dialogue on what else we could put on the Web besides the Yellow Book.  That is all we use.
DR. KOERPER:  Can't you put the atlas on the Web?
DR. PARISE:  We didn't publish that, but I guess we can look into that.
DR. KOERPER:  Color code the atlas on the Web.
DR. PARISE:  We can look into that.
DR. HEINTZELMAN:  Since we have this opportunity, we are talking about dusk-to-dawn.  If that is implemented, or at least one scenario for implementation would be anywhere in the world.  I want to make sure that people aren't thinking just about Mexico or Caribbean.  We are talking about global when we talk about dusk-to-dawn.
That is the sense of this.  With the emphasis on Mexican resorts, because of the number of travelers, that's fine.  But a change in policy would be all over Africa, all over Asia, any of the really, truly highly endemic areas.
Monica did a great job of presenting the malaria number of cases that have been reported.  When you think about that, you may have noticed that there is an increase in '95 which is the last report.  There is a 15 percent increase, according to the CDC's reports.  That is imported malaria.  It is important to consider the number of malaria cases coming into the United States and then to also think about transfusion-transmitted malaria because the donor base comes from the base population which includes the imported cases.
The fact that transfusion-transmitted malaria is running at a very low percentage--it is about 1 in 4 million donations--reflects a certain trend in screening and distribution and disease infectivity.  But when you look at the amount of malaria that is coming into the country, you see that that is really a fairly significant number, very different from what you are seeing in the transfusion cases.
If you open up the door, I believe, to a broad proposal of allowing donors that have traveled anywhere in the world, to the best of their recollection, during broad daylight hours, to donate, we may find that there is a potential for a change in that distribution.
DR. HOLLINGER:  Do you view the dusk-to-dawn question as compared to what is currently being done now as something that will keep more donors eligible or lose more donors, at least for a period of time?
DR. HEINTZELMAN:  We know where we are right now.  While they may get approximately a dozen calls a day at CDC, if you look at 14 million units of blood collected in the United States over a year, roughly that is 40,000 units a day.  I am not sure that everybody calls CDC when they have a gray area and are unsure about somebody's travel.
I think that the conservative issue is usually they just defer these people.  I believe that if we go to a dusk-to-dawn, we may not decrease the donor base.  We may increase the donor base.  Increasing that donor base would be from within the population where imported malaria is evident.  In that group, the trends have been roughly consistent but within the Americas there was 100 percent increase in 1995 for imported malaria.
DR. OHENE-FREMPONG:  Just a couple of things.  One, the dusk-to-dawn question, I can't see that applying to Africa, for instance.  I can't see anybody traveling on a day trip to any part of Africa and being out to a non-endemic area before nighttime.
The second question, though, just for clarification, the transmission through platelet transfusion, is that believed to be from red-cell contamination of the platelet pool and not from plasmodium in the platelets?
DR. PARISE:  That's correct.  It is felt to be from red-cell contamination in the platelet pool.  The question in Africa--you're right.  There might be a few selected areas such as taking a day trip out of Nairobi and Kenya or a day trip out of one of the cities in South Africa to a game park and coming back.  But it would be unusual.
The other thing is, when we look at the vectors, the African vectors tend to bite very late.  So if you say there was a fuzzy area, it is probably going to hit you more in the Americas when it is an early-biting vector in general than these Anopheles gambia which bites at 2:00 a.m.
DR. EPSTEIN:  First, to clarify the issue of impacts, I think we are hearing two contradictory things and I want to try to sort that out.  Current policy does not provide an exemption from deferral for daylight exposure or for being at a resort.  So if the current guidance were to be followed, the donors would be deferred.
What I am hearing several blood-bank organizations say is that they have been querying the CDC and they have been advised on many occasions that they can exempt daylight exposure and that they can exempt travel to specific resorts.  I don't have a problem with that where it has been based on good science, but that is not the current FDA recommendation.
The current FDA recommendation would be to defer based on those exposures because we do not make those distinctions in our guidance.  So we see the proposal to the advisory committee as a relaxation of the stringency of deferral.
The second point I would like to make is that that relaxation either does or does not add risk whether you believe that the history you get about the nature of the exposure is accurate.  There is a distinction to be made about the accuracy of the history, and I would like Dr. Parise to comment on this.
In the case of chemoprophylaxis, you are dealing with the traveler just at the time of travel.  You are not asking them a year later or three years later whether they ought to have been prophylaxed.  They are telling you their travel plan and you are advising them based on current information.
The problem that we have in the donor selection process is that you may be asking that donor that question as much as three years after the travel where it would affect their deferral.  So the FDA's concern is how accurate is that information going to be.  You are potentially asking a donor who was in a malarious area whether they were exposed only during hours of bright daylight and you are, in essence, asking them did they go jogging shortly before or after dawn?  Did the cruise boat dock before dawn?  Do they remember whether they stayed over that night?
You are asking that as much as three years later.  That is part of what is concerning the FDA.  So, you see, we are really not begging the question of the underlying science.  If Drs. Ruebush and Parise tell me that mosquitos don't bite, well, I believe that.  But the question is the accuracy of the histories.
So that is why I have suggested that a way out is we could accept the scientific principle but put the burden of proof on the medical director to basically decide how confident they can be in that history.
DR. HOLLINGER:  But, Jay, just to clarify something.  Although the question is asked for three years out, in essence, for travelers from the U.S., it is really one year that you are really looking at the history and that is the only thing that they are going to have to remember.
If I traveled three years ago, that would not exclude me.
DR. EPSTEIN:  You are correct.  I am being technically precise because we have the semi-immune traveler where we are changing the policy to recognize that some of the delayed cases of malaria have been in semi-immune individuals who have, then, briefly traveled.  So yes, the majority of travelers would only have an applicable history of one year.
But, even so, w donor you recollect nine months later was it broad daylight.  Did you take that sunset walk?
DR. NELSON:  Given the nature of the risk and the geographic distribution and real risk of malaria of a Caribbean resort versus Africa or some places in Asia and the much greater likelihood of falciparum, a potentially fatal infection, being acquired from Africa, could we limit this dusk-to-dawn recommendation or could the vote be on the Americas rather than the world.
DR. HOLLINGER:  Or anything except Africa?
DR. NELSON:  Right.  Well, there are certain places in India that I think have a high risk, and certainly New Guinea.  I would say limit it to the Americas.
DR. HOLLINGER:  Dr. Ruebush or Dr. Parise, can you tell me a little bit about--since, we are talking about dusk-to-dawn, where do the anopheles rest during the daytime?  The reason for asking that, in my previous life, I was an arbovirologist so I am very well aware of mosquitos and the issues.
I remember when we were looking for a site of Culex quinquefasciatis in Corpus Christi and couldn't determine why these cases were occurring until we went down in the storm sewers and found the mosquitos all resting down in the storm sewers during the day.  Of course, anyone working in the storm sewers clearly ran the risk of being bitten by a female mosquito.
So the issue has to do with where they are resting and some of their feeding habits and so on.  Could you enlighten us a little bit about that.
DR. RUEBUSH:  During the day, most anopheles mosquitos rest inside houses, inside some sort of buildings, in relatively humid, dark, quiet, undisturbed environments.  Some may rest outdoors under bridges or things like that, perhaps under leaves of bushes where it is shaded and they are not disturbed.
But most of them, at least the ones that the mosquito collectors find, are generally within buildings.
DR. HOLLINGER:  Thank you.
DR. FITZPATRICK:  I have two questions and, for your discretion, I have what might be construed as a statement.  First, for CDC, how often is the Yellow Book updated and how do you update the world that the Yellow Book has been updated.  The other one, you mentioned a river cruise in a shaded area.  So are we going to have to ask our donors if they left the beach and took a walk in the tropical forest in the dark shade?
DR. PARISE:  In answer to your first question, the Yellow Book is updated every one to two years.  Previously, it had been every year.  The last update was two years ago and I believe the Division of Quarantine, who is responsible for the Yellow Book at CDC, is planning to do it on an every-two-year basis.  The changes that we make in the Yellow Book, we put on the Web.  They are based on the WHO.
The second question about the mosquitos in the forest, that's true.  It is possible that, in a dark forest, that person could be more at risk if they went there during the day than somebody who went to somewhere that is not shaded.  I actually think Jay's idea to--because this will increase donor availability.  I don't have an idea of how many donors it is going to be because we don't measure that here, but I think that allowing for this exposure criteria, it is the blood bank director's discretion to prove that that really was a day trip is a very reasonable cause.
I agree that the recall bias that is present in what we do with travelers versus blood donors who would mainly fall into your category is a problem.  But there are some people that we talk to that are just very clear about the timing of their trip.
DR. HOLLINGER:  You said you had a statement?
DR. FITZPATRICK:  Whenever you--
DR. HOLLINGER:  Oh; okay.  Why don't you go ahead and answer this.
DR. HEINTZELMAN:  I will be very quick.  Everyone is interested in having clear, concise guidance.  I had posed this to our field investigators, one of the biologics experts, who does blood banks and asked her how she felt about this.  And it is intriguing to note that she reflects the same concerns that everyone else has here.  They want clear, implementable guidance that can be documented so that they can inspect for compliance with the regulations and do so in a fashion that doesn't lead to confusion.
It is the same wish that the blood banks have and I am sure that it is the same that the government agencies have.  Trying to get to that point so it can be inspected and verified is a bit of a challenge.
DR. KHABBAZ:  I want to get back to a suggestion or the question from Dr. Nelson, and that question is to the FDA.  Is it possible to make a distinction between the Americas and either Asia and Africa or Africa with regard to the dusk-to-dawn question?
DR. NELSON:  I think there is really a risk, quantitative--qualitative, almost--difference in the risk between travel to Africa and Asia.  I have seen students, et cetera, that have gone to visit their home town in Africa and have come back with malaria.  It is a real risk and the risk is falciparum.
I wouldn't feel comfortable taking blood from a donor who said that he can't remember when he got back to Nairobi from the game park.  To me, I think that that is a different kind of a risk than a cruise ship.
DR. OHENE-FREMPONG:  I just want to say, as a frequent visitor to Africa, that the ultimate solution to this problem is to eradicate malaria.
DR. PARISE:  I would just speak that we would not favor a distinction between the Americas and Africa for a few reasons.  One is, as I mentioned, the vector biology doesn't really support the need although there is much more malaria transmission in Africa.  The vector doesn't support it as well as the fact that--the bottom line, here, is when you look at our data, the problem is really not in the cases that are coming from these travelers.
It has mainly been in the immigrants or the people that go to visit.  There hasn't been a case due to one of these U.S. travelers who would mainly be the people doing these day trips for the last over fifteen years.
So my impression is that it will add a level of complexity that we are already trying to simplify things and make clear.
DR. HEINTZELMAN:  Are you referring to transfusion-transmitted malaria or imported malaria, when you say there hasn't been a case in the last fifteen years.
DR. PARISE:  Transfusion.
DR. HEINTZELMAN:  Not all of the reported malaria cases.
DR. PARISE:  In a person who was one--I mean, it is typically going to be your U.S. resident who lives in the United States that goes somewhere and takes one of these day trips.  That is mainly the population that we are talking about that is going to be affected by the dusk-to-dawn.  There hasn't been a case in one of those people for many years.
DR. MACIK:  I guess is my confusion a little bit.  What are the numbers we are talking about?  What real impact is this on people who donate if you defer--outside the military, say, if you have traveled outside the states in a year and if you have, then it falls to the discretion of the blood bank director to apply certain rules to those people.
It seems like we are spending a lot of time talking about stuff that--what is really the magnitude of people that this is involving.  I know that I have donated blood recently and I know that it is quite irritating to sit through all of these questions and go on and do these things that keep getting asked to you.
It seems like there should be some bright points that fairly easily break out.  So what is really the magnitude.  And then the second point would be isn't there a way to educate the public beforehand about some of this because what we are talking about is asking the public to remember, a year later, did you go out for this or that.
Shouldn't there be some kind of thing that if you know that you are going to Africa, if you are going even to South America, you get all this information you can possibly get about where to go and what to do.  One little stand should say, "Just remember for the next year, when you get back, you need to know whether you went to this place or that place and you may not be able to donate blood," so that those people have some education of the public beforehand and not just when they are sitting down at the time of answering out a blood-donation form.
DR. VERTER:  I wonder if you could just clarify for me the review you made.  You said there were 91 cases that were reviewed from '63 to '95 or '98 and you had data on 58.  Of the 58, if I recall correctly, 36, if the current guidelines would have been followed, would have been deferred and the other 22, the current guidelines were irrelevant because the period of exposure was more than three years.
So, using the current system, if I can use the phrase, we had GMP, there would have been no change.  This addition or modification would not have changed anything for the cases that you could follow, the 58 of the 19.
DR. PARISE:  I didn't quite understand.  I'm sorry.
DR. VERTER:  I am just asking if I am correct in what I just presumed.
DR. PARISE:  About two thirds are because the process that we already have didn't work.  Those questions, although we think--I mean, even in this very last case, "Were you outside of the U.S. or Canada in the last three years," to me, that is a very straightforward question.  But it doesn't always work and in the '98 case, that specific question didn't work.
And then, in the other one-third, it is basically because the parasite lasted longer than we have set up in those criteria.
DR. VERTER:  Therefore, any modification in the current guidelines wouldn't have changed anything for those 58 cases.
DR. PARISE:  The questions, if we talk about the questions, those could potentially impact on those two-thirds that failed in that screening process.
DR. VERTER:  Then I misunderstood how you were interpreting the screening process.  I thought you meant that if the screening process, as it now stands, had been accurately followed completely, that those two-thirds would have been deferred.
DR. PARISE:  That's right.
DR. VERTER:  Which means that this question wouldn't have added anything to it.
DR. PARISE:  This dusk-to-dawn.
DR. VERTER:  Right.
DR. PARISE:  That's right.  The dusk-to-dawn; right.  Sorry.
DR. NELSON:  But put the current recommendation as a relaxation, not a stringent thing.
DR. RUEBUSH:  I just wanted to respond to the comment that was made about perhaps doing a better job from our standpoint at CDC when we answer a phone call from a physician or someone who is travelling overseas, something like that in the materials that we produce to remind people about the fact that yes, they would need to be deferred for a year.
We don't routinely do that and yes, we could do a better job in that both in terms of our direct-voice communications with travelers or physicians and what we publish.
DR. HOLLINGER:  Also, just to state the obvious, the donors are lost for one year.  That is not, as with so many other things, where they are lost indefinitely.  So we are talking about, basically, a year deferral.  Many people will not return to these areas.
Dr. Ohene-Frempong I don't think would ever be able to donate, but so many of them will be coming back.
DR. KHABBAZ:  I have a question and a comment.  Actually I have two questions, maybe.  One, the question that we are dealing is one of relaxation based on how long they have stayed in the area.  There is also a proposed addition in the FDA guidance which deals with the partial acquired immunity, basically, which proposes adding three years after a visit for people who were born or have lived an extensive period of time.
My question is what is the impact of that addition in terms of numbers that might be additionally deferred.  That was the first one.  Do we know?  We don't?
DR. HEINTZELMAN:  We have no hard numbers, if you are looking for number of donors that would be deferred.  There are no hard numbers for that.
DR. KHABBAZ:  The other comment or question; I note that the FDA is proposing a change of order of questions starting with, "Were you born in the United States?" and then querying about the last three years.  The AABB statement brought to my attention basically these questions.
If somebody who was born outside of the United States, I can see a point of asking that question.  I cannot donate blood for other reasons, but just saying, "Forget it; you don't want my blood."  So, the sensitivity of how the question--if there is a reason to ask this question ahead of recent travel, fine.  But I am missing the rationale for changing this order.
DR. PARISE:  Actually, there was one point from before that I had forgotten.  That is what I wanted to clarify and didn't.  In terms of relaxation, this is a relaxation in terms of dusk-to-dawn.  But, from our standpoint, this isn't a relaxation in terms of the resorts because the previous 1994 memo referred to what we define in our Yellow Book as malarious areas.
We have always said, in the Yellow Book, that the major resorts are okay.  So that is not going to change.
I think the issue that I can respond to from my perspective and then, if anyone from FDA or anyone else wants to comment on the questions, where we failed in some of these recent cases--we don't have hard data on what happens in that interview.  Sometimes, it is a "he said, she said," situation where the donor can say one thing and the blood-collection agency says another and we really don't know.
But it is our impression that one problem that might be happening is that, although the question is in the last three years, people who have moved here within the last three years don't consider that if they--no, they haven't gone anywhere because, since they came, they haven't gone.  But they came within three years.
Because most of the recent cases have been in people from other countries, we are trying to get at a way to know about that up front and then probe more.  There may be better ways to word that and I think FDA is open to that.
DR. KHABBAZ:  I think that is fine, but I would support piloting these questions and field testing and seeing how they work.
DR. OHENE-FREMPONG:  It is really not a question of where you were born.  It is where you lived.  I just wonder if the question could be, "Were you born outside of the United States or have you lived outside of the United States."
DR. MITCHELL:  I did want some more information about the impact of this and particularly the post-donation information.  We had asked before, there are 1200 cases of post-donation information.  I still don't have a good sense of what percentage of those are due to what kinds of answers and I was wondering if there was someone who can provide that.
DR. HOLLINGER:  I don't think so, Mark.  I don't think anyone could provide that information for you.
DR. MITCHELL:  As to what those questions are?
DR. HOLLINGER:  Yes.
DR. MITCHELL:  Then, getting back to the discussion that is under way right now, I think that it would be more sensitive to ask whether someone has traveled or lived outside of the U.S. within the last three years and just leave that as a question.
DR. HOLLINGER:  I saw someone start to stand up out there, maybe to answer.  Do you have an answer to the question?
MS. JETT:  Anecdotally, I know that some of the cases I have looked at in my own center are, the donor comes in at one visit and says, "I traveled here and there."  And then the next time, when they come in, they have a slightly different take on where they have been and what they did.  So it is the donor giving different information on the next interview that would be a post-donation information report.
DR. MITCHELL:  So the information is more on where they went.
MS. JETT:  Yes.  One time, they will report a visit and it may be the details of if it was rural or urban or maybe just having to mention this country or not that they visited on the trip.
DR. MITCHELL:  The reason I am asking that, then, is because a day trip may make a big difference.  It is my impression that people are less likely to remember if they didn't spend the night there.  If they went on a cruise ship and they stopped at two places at day, it is hard to remember all of those places.
MS. JETT:  My subjective impression is when you are sitting in the donor chair, whether you are going to give enough detail to make a good judgment on them just depends on how they feel that day or who is interviewing or if they feel like being chatty or not.
DR. BUSCH:  Comments on two issues; in terms of country of birth, we do, in the REDS group, ask donors--it is not a required question but we have been eliciting country of birth along with other special questions of donors.  I think about 3 percent of donors sort of refuse or don't answer that question.
We have looked extensively at predictors of risk, particularly incidence of infections.  Country of birth is not an independent predictor of risk of HIV or other seroconversion so there is no evidence, perhaps independent of this malaria issue, that would justify deferring.  So I would agree with the comments about residents in as opposed to country of birth probably being a more sensitive approach to that issue.
The other general point--I wasn't here yesterday but I heard feedback in terms of all of the implications of post-donation reports.  Many, certainly, of these post-donation information reports are these subtle deferral issues such as visiting areas or things like tatoos or piercing and things like that.
You can argue whether or not those deferrals are very effective and justified in the first place.  Certainly, I would suggest that it might be appropriate to make a distinction as to whether such deferrals warrant investigation after the fact.  For example, I think my understanding is FDA is not going to require, if you have lived in Britain during the period that is now being implicated as potential risk for new-variant CJD, you may be deferred prospectively but that will not be a basis for a post-donation report.
You will not have to retrieve product or investigate product donations.  So the same kind of distinction, I think, should be considered for many of these soft, if you will, deferrals, that so many of these recalls and potential investigations are driven by donors acknowledging later that they maybe had a body piercing or tatoo or something.  It may be a basis for prospective deferral, but I think it shouldn't be a basis for post-donation information investigation.
DR. HOLLINGER:  I think one of the more important things that you have provided us with, as I look at this information, was the fact that, at least recently, if you are a U.S.-born traveler, there is little danger of transfusion-transmitted malaria if the guidelines are followed or if they answer the proper questions.  Is that a correct statement basically, that most of the cases of transfusion-transmitteds are occurring in individuals who have lived in an endemic area or immigrants or refugees that, perhaps, have P. malariae or something else or perhaps, even, falciparum that might be persisting longer than the time limit.
DR. PARISE:  Let me tell you the data because I am not sure--if the guidelines were not followed, actually, about half of those are U.S. travelers.  Even our U.S. travelers are not answering the questions right all the time, and half of them are in the immigrant category, refugee, et cetera.
Of the other cases that happen because of these long exclusionary periods, those, there are very few in U.S. travelers.  That is sort of our aggregate data.  When we look at our sort of analysis in recent years, the U.S. traveler falls way down in, say, the '80s and the '90s.
DR. HOLLINGER:  For transfusion-transmitted malaria.
DR. PARISE:  That's right.
DR. HOLLINGER:  Which is what we are really dealing with here today.
Dr. Linden, do you have any comments?
DR. LINDEN:  I guess I am a little concerned with what appears to be a discordance of the information that CDC has been giving to people that isn't really consistent with the FDA recommendations.  I think that situation needs to be reconciled so that all of the federal agencies are giving uniform information.  So, whichever way we go, I think we should get together.
But, otherwise, it seems that this change is reasonable.  It sounds like, in part, it is sort of have been implemented already.  But I agree with Dr. Epstein that it should be only if you can fully document that you know this is the case and if there is any question, you certainly defer.
DR. BOYLE:  The travel exclusion questions that we are talking about are among the very few items, I believe, in terms of risk factors that are relatively easy to validate because you can get samples of people by destinations very easily and you can test your questionnaire to see what the error rates are, whether or not they are reporting what we suppose them to be.
The question is has been done?
DR. HOLLINGER:  I would guess not.
DR. BOYLE:  Then I will make my statement.  Since it is one of the few things that is relatively easy to find out what the error rate is in terms of reporting, particularly because you can pre-identify pretty much, and then those are discordant, obviously, you can follow up with, that it would be a good first step of learning a little bit about how good these screening questionnaires are.
DR. HOLLINGER:  Dr. Fitzpatrick, you had a statement.
DR. FITZPATRICK:  I will make this brief.  Jay already brought up that the current policy is to defer and that there is no dusk-to-dawn exclusion.  And I am not sure what percentage of donor centers are making exceptions or calling CDC.
In twenty-one years, I have managed six major and minor Army facilities that are donor centers and I was responsible for policy in all of Europe.  I don't disagree with the science at all.  The science is valid.  The science is sound.  But we have an implementation problem.  We discussed last meeting the problem between the interviewer, the screener and the donor and perceptions and understanding and the need for better questions and questionnaires.
We have data that says 62 percent of the transmissions were due to a failure in the screening process.  AABB and the ABC have, in both their statements, said that the donor history interview is critical and very complex.
I think adding complexity to the interview will increase the error-accident rate.  I believe that we are adding complexity to the interview.  In order to not add complexity to the interview and if current policy, as dictated by the FDA is being followed, we are not impacting the donor supply.  If we enact this, you are loosening the restrictions and increasing the donor supply.  But, if current policy is being followed, you are not decreasing the donor supply.
And I have a problem with what Jay initially told us in his interview.  In the IOM study, he stated that the precautionary paradigm is the one the FDA is following.  What we are going to hear about at TSE and British donor deferral is an enactment of the precautionary paradigm.  Yet this, to me, is in conflict with enacting the precautionary paradigm.
So Jay's suggestion of a blanket deferral with possible exceptions by the medical director may be the best approach.
So, in short, I would say that I think the dusk-to-dawn exclusion, while valid scientifically, increases the complexity of implementation, increases an already very complex difficult interviewer-donor situation, perception, understanding, communication area and I don't see that the gain is worth what we are talking about.
DR. HOLLINGER:  Thank you.
I think I am going to call for the question.  If somebody could put it up.
DR. NELSON:  The current policy allows the medical director of the blood bank to make an interpretation based on CDC advice?  What is the current recommendation?  What is it that we are going to change or vote to change?
DR. STRONCEK:  Practically speaking, if you are going to make exceptions, you really have to have your SOPs written very carefully.  You don't want to make a lot of exceptions.  You want it well documented.  That is not practical.  As a medical director, I would want something, at this level of detail, that is very well spelled out.
DR. EPSTEIN:  The current guidance makes no distinction regarding risk exposure based on time of day.  We do not recommend that that issue be further explored with the CDC, although we have always respected the need and value to consult CDC when there were questions about geographic exposures because the FDA does not monitor areas for risk of transmission.  The CDC does.
But, really, what has happened is that blood centers have gone beyond the existing guidance and asked more subtle questions such as resorts, such as time of day.  But it is not in the current FDA guidance.
DR. BUCHHOLZ:  Jay, if I look at the current guidance and I have a donor that answers that question, and I call CDC and, based on being educated or based on something I know, I say, "Okay; you are in an urban area," or, "You were only in the daylight."  And FDA inspectors come in.  Do I get a GIG then if I let that donor donate, because I got advice from CDC or things I knew such as the basis of science that have said, no problem.  Yet, I would guess that represents a compliance situation in terms of an inspector coming in and reviewing my records.
DR. HOLLINGER:  Dr. Chamberland?
DR. CHAMBERLAND:  I will ask Monica or Trent to comment or correct me but I think, and perhaps we are well aware of feedback that we have gotten that there has been disparity in information that CDC and FDA have advised on.  I think, from henceforth and maybe it has already been your practice, the appropriate technical question to CDC is is this person-donor, non-donor, traveler at risk for acquisition of malaria and does this require institution of chemoprophylaxis.
I don't think, at all, that, as an agency, we should be making decisions for medical directors of blood banks determining donor suitability.  Clearly, we don't want to be in conflict with FDA guidance or regulation in this area, so I think, as an agency, we have to be very careful as to our responses in this area, that it is probably not appropriate for us to be making decisions about donor suitability.
I think this is what is going to be the problem is that CDC, as a public-health agency will be telling individuals or medical directors, "No; this person is not at risk for acquisition of malaria.  Prophylaxis is not needed."  Blood bankers and CDC will then be faced with confusion and complexity.  That is not to say we can't work through it but, in talking with some of the blood bankers who also work as travel-clinic directors, they are going to be giving two sets of information out to people when the traveler shows up in their travel clinic, "You are not at risk for malaria based on what you told me.  You don't need to take prophylaxis.  But when you show up in my blood bank, I am not going to let you donate.  You will be deferred because you pose a risk of malaria transmission to a potential recipient."
So Trent and Monica, again, I just wanted to make sure that you were in agreement with what I just said and after the vote today and the subsequent guidance, that was probably a better way to cast our role.
DR. RUEBUSH:  We agree wholeheartedly.  I think, many times, the question comes to us from a blood bank or something like that, "Is there a risk of malaria in this area or in this situation?"  And we have based our response on the scientific knowledge and we feel a daylight trip to a malarious area when you are spending the night in a non-malarious area, doesn't represent a risk.
I think if the FDA guidance is different, we need to be very careful in the future to make a distinction when we talk with someone on the phone that, for prophylaxis purposes, we would not consider a risk, we would not recommend chemoprophylaxis, but you are calling us from a blood bank, in which case, the guidance is to do the following.  And we are prepared to do that.
DR. EPSTEIN:  Speaking to Dr. Buchholz' question what the compliance approach would be if a medical director exempted a donor when that was not in the FDA guidance.  I guess the answer is a little bit complex.  The field investigators do recognize the role of enforcement discretion.
They generally would give a fair amount of consideration to exercise of good medical judgment, especially if it was well-documented what the basis of the decision was.
Generally, we look askance at exceptions other than those that are provided in the regulations based on medical need.  So, outside of the documented medical need which is, of course, particularized to a patient, we sort of look very carefully.  These kinds of inconsistencies, when they are noticed by the field, usually would surface back to the center as a policy question, which is exactly how we get here.
So I think it is not so straightforward as that they would simply take enforcement action or cite on a 483.  More often than not, they would then call us and say, "What do you expect us to do.  Your guidance is unclear."
DR. HOLLINGER:  I am going to have just two more comments and then we are going to call for the question.
DR. CHAMBERLAND:  Before the question is called, I wondered--Jay, you had mentioned the possibility of potentially allowing for some flexibility in override or whatever for medical directors to have some discretion about deferral.  I wondered if you had crafted that in language that could be voted upon because I am also keeping in mind the statement from America's Blood Centers which represents half of the blood collectors in the United States which are also asking for that flexibility.
Yes; we all have heard comments on both sides of the question that there are people that want us to be very black and white with no flexibility, but there are others that would like that discretionary flexibility.  So I will leave it to the chairman, certainly, to decide on how the voting should proceed, but you did raise this as an option and I was just curious as how that translates into a statement that could be considered by the committee.
DR. McCURDY:  I have got a little bit of confusion that I thought had been cleared up but I am not sure that it has, now.  first, I think that difference between whether a traveler should take prophylaxis or not or whether a traveler should be a donor or not when they come back are different.
I don't think they can be answered by the same--I think you have to differentiate between those two.  The risk of transfusion malaria appears to be of the order of two to three cases per year.  This is the same order of magnitude, not quite as large, but it is the same order of magnitude as the likely transmission of HIV infection by blood transfusion in the present milieu.
I think transfusion-transmitted malaria is frequently fatal.  It is probably fatal because there is a delay in diagnosis because nobody thinks about it.  It is probably fatal because transfusions are given to sick people who will not tolerate an additional illness.
I think it is likely under-reported so the two to three cases per year probably doesn't represent the total cases.  I want to be sure that CDC is differentiating in their advice between the risk of being a donor and the risk of chemoprophylaxis where you must balance the potential problems of the drug versus the risk of malaria.
I think those are vastly different.
DR. HOLLINGER:  I think Dr. Ruebush did comment about that.  I think you are right, Paul.  They need to be distinguished.
I am going to call for a vote on the question.  The question is written up there.  "Do the committee members support a change in the current blood-donor policy to allow for travel to areas endemic for malaria when travel exposure was limited to hours of bright daylight?"
As we said before, a vote of yes means to allow travelers to malarious areas during daylight hours to serve as blood donors and a vote of no means to stay with the current proposals for deferral of travelers to malarious areas regardless of the time of day.  It is fairly straightforward.
All those in favor of this change in the current blood policy raise your hands.
[Show of hands.]
DR. HOLLINGER:  All those opposed?
[Show of hands.]
DR. HOLLINGER:  Anyone abstaining?
[No response.]
DR. HOLLINGER:  Dr. Buchholz?
DR. BUCHHOLZ:  I vote no.
DR. HOLLINGER:  Ms. Knowles?
MS. KNOWLES:  No.
DR. SMALLWOOD:  The results of voting are as follows: there were 5 "yes" votes, and that includes the vote left by Dr. Koerper.  There were 9 "no" votes.  No abstentions.  The consumer representative agreed with the "no" vote.  And the industry representative agreed with the "no" vote.  There are 14 members eligible to vote including the vote that was left by Dr. Koerper.
DR. HOLLINGER:  I think the issue that Dr. Chamberland brought up is very important regarding what one has in the guidance regarding the role of the medical director or others to make some decisions regarding this and what the ABC had indicated.  I don't know how we are going to deal with that, or if we should deal with it or anything.  I think the comments were made.
We have got a few minutes here before we break here for lunch.  But does anybody have any comments about what Dr. Chamberland mentioned or any thoughts about it?
DR. ELLISON:  I would have preferred to see some kind of a discretion.  It would have certainly have influenced by vote.  I agree with Dr. Fitzpatrick's comments as far as that question which we are asked.  I don't think the question allowed the leeway, the medical-director discretion, that I think is essential.
DR. HOLLINGER:  Right now, I think it is pretty clear.  It has clarified the issue, I think, for both the concerns that they have.
MS. KNOWLES:  I do have a suggestion in terms of maybe a tool to help with the Yellow Book being on the Web and that is that there is a really good computer program via the Internet called Mapquest.  If the two of those could be integrated, that probably would help solve a lot of those questions.
DR. HOLLINGER:  Thank you.
DR. NELSON:  I know there are a lot of travel clinics that advise people on, often, malaria prophylaxis and vaccines.  I think they rarely mention the issue of deferral from blood donation afterwards based on travel and how the risk that would lead to prophylaxis might be different from the lower risk but much greater consequence of a transfusion-transmitted infection.
I think of travel clinics, and there is now an organization of travel clinics.  They have meetings, et cetera--I think that there should be an effort to educate travel clinics about this issue.  My sense is that it has not been done very much to date.
DR. HOLLINGER:  I think we will take a break now until 1 o'clock.  We will return here at 1 o'clock for the next meeting which will be on HTLV.
[Whereupon, at 12 o'clock p.m., the proceedings were recessed to be resumed at 1 o'clock p.m.]

	A F T E R N O O N   P R O C E E D I N G S
	[1:05 p.m.]
DR. HOLLINGER:  We will begin the afternoon session on Development of HTLV Supplemental Tests.  Those speaking, we will keep you to your assigned times.  If you were not assigned a time, then we will assign you one.
This is an important issue, the development of HTLV supplemental tests so we want to have plenty of time to have some discussion if we need to.  We are going to start out with an introduction and background by Dr. Cowan, Senior Staff Scientist, Laboratory of Molecular Virology, DTTD.
	Development of HTLV Supplemental Tests
	Introduction and Background
DR. COWAN:  Thank you very much.
[Slide.]
I would like to begin by presenting to you the goal for this last session of the meeting which is HTLV supplemental testing.
[Slide.]
That goal is, to promote to the best of our ability, the submission of INDS for HTLV supplemental tests.  There are currently no licensed supplemental tests for HTLV to follow up specimens that are repeatedly reactive on HTLV screening tests.
It is our intention to work with manufacturers of research-used tests to remedy that situation.  To that end, you will hear the following presentations.
[Slide.]
You will first hear a series of presentations on HTLV testing of U.S. blood donors.  I will present an overview addressing some of the issues related to HTLV supplemental testing.  Next, Dr. Susan Stramer will speak about the resolution of reactive HTLV screening test results with estimates on the number of specimens that would require supplemental testing.  Dr. Michael Busch will then speak about clinical experience with HTLV supplemental tests.
After this discussion of clinical HTLV testing, you will hear two presentations that may offer funding opportunities to support licensure of HTLV supplemental tests by Susan Pucie from NHLBI and Pat Robuck from the Office of Orphan Products Development at FDA.
[Slide.]
To begin with the overview, why are we concerned about HTLV.  There are two reasons.  First, HTLV is associated with disease.  By HTLV, of course, I am referring to HTLV I and HTLV II, retroviruses that are closely related to one another.  HTLV I is known to be the etiologic agent of primarily two diseases, adult T-cell leukemia and HTLV-I-associated myelopathy, tropical spastic paraparesis, although other disease associations have been described as well.
HTLV II also appears to be associated with a HAM/TSP-like disease.  The second reason that we are concerned about HTLV I and HTLV II is that they are transmitted very efficiently by transfusion with the rate of approximately 63 percent for HTLV I.
As a result, on November 29, 1988, FDA issued a memorandum to blood establishments recommending testing of donations of whole blood and cellular components for transfusion for antibodies to HTLV I with licensed FDA tests.
[Slide.]
Subsequently, on August 15, 1997, FDA issued the guidance to industry on donor screening for antibodies to HTLV II recommending that blood establishments implement donor screening for antibodies to HTLV II using licensed tests.
[Slide.]
The testing algorithm for donor screening for antibodies to HTLV introduced in the 1988 document is shown here characterized colloquially as a "two strikes and you're out" algorithm.  Primary screening of blood donors is performed using an EIA.  A donation that tests repeatedly reactive by EIA is destroyed but the donor is not notified of the test result.
The donor is also eligible for future donations and non-reactive donations may be used until another repeatedly reactive test result is obtained on a subsequent donation even if there had been a series of intervening non-reactive test results.
At this point--that is, the second repeatedly reactive test result, the donor is indefinitely deferred from donating blood.
[Slide.]
An additional testing algorithm was introduced in the August 1997 guidance document to industry on donor screening for antibodies to HTLV II.  In this case, a specimen from a single donation that tests repeatedly reactive using the primary screening test may be tested by a second licensed screening test of a different type for HTLV II and HTLV II antibodies.
However, if the specimen tests repeatedly reactive using the second screening test, then the donation is destroyed and the donor is indefinitely deferred and counseled on the basis of test results on this single donation.
If, on the other hand, there is a non-reactive result using the second screening test, then the unit is destroyed but the donor remains eligible for future donations as in the single EIA testing algorithm.
[Slide.]
However, there is an important piece of the testing algorithm that is missing.  As stated in the August 1997 document as well as an earlier statement from FDA, donors with repeatedly reactive donations should be permanently deferred whenever additional, more specific tests confirm that the donor has antibodies to HTLV I or HTLV II and utilization of investigational additional more specific tests may be useful in notification and counseling of donors with repeatedly reactive screening tests for antibodies to HTLV I or II.
Having said that, we are now at the issue of the matter at hand, and that is, at the present time, there are no FDA-licensed additional more specific tests for antibodies to HTLV I or HTLV II.  This statement is taken as a quote from the 1997 guidance to industry on donor screening for antibodies for HTLV II and it still holds true today.
[Slide.]
As you are aware, supplemental tests provide more specific information about EIA reactivity, defining that reactivity in terms of antibodies to particular viral proteins as opposed to general reactivity to various populations of antibodies or false positive reactions.
These tests are typically immunoblots such as Western Blots or strips continuing viral peptides or recombinant antigens.  The lack of availability of licensed HTLV I-II supplemental tests impacts at least two sectors which you will hear more about later.
First, blood banks are suffering the indefinite loss of valuable donors who cannot be reentered into the donor pool.  Second, blood donors cannot be counseled appropriately following a repeatedly reactive screening test.  Dr. Stramer and Dr. Busch will speak directly to this issue.  The impact of a false-positive test result on a blood donor cannot be ignored.
[Slide.]
Why are there no licensed supplemental tests for HTLV I and HTLV II?  One historical reason is that research use, or only RUO tests, have been used for donor counseling.  However, I must emphasize here, as I have in a previous presentation before this committee, that RUO tests should not be used for donor or patient-testing or counseling except under the terms of an IND exemption, this according to the Code of Federal Regulations.
Another reason for the absence of licensed HTLV I-II supplemental tests is communicated to me by a number of individuals in industry on numerous occasions is that the number of samples that would require supplemental testing may simply be too small to justify the expense of licensure.
This is due to both a low incidence of HTLV I and HTLV II in the U.S. and to the specificity of the currently licensed HTLV I-II screening tests.  Dr. Stramer will be addressing this point next.
[Slide.]
I would like to end with the following request from the committee; as you listen to the various presentations in this session, I would ask that you please provide us with general comments on strategies to promote the development of licensed supplemental tests for HTLV.
Thank you very much.
DR. HOLLINGER:  Thank you.
The next presentation is going to be Dr. Stramer from the American Red Cross.
	Presentation
DR. STRAMER:  Thank you.
[Slide.]
This is the topic that I was asked to cover today, resolution testing of HTLV screening tests repeatedly reactive blood donor samples.  I will take you through an evolution of a process leading to where we are today with the dual EIA algorithm.
[Slide.]
As far as background, as Elliott Cowan just reported, currently there are no routinely available supplemental tests for anti-HTLV I-II confirmation.  Data I will show you shows that those that are available under IND, which includes one test, has indeterminate rates greater than 70 percent.
As Dr. Cowan also mentioned, an HTLV I-II algorithm is proposed in which repeat-reactive donations from the primary screen are then tested using a second licensed EIA of a different type and the use of this dual EIA algorithm was coincident with the implementation of HTLV I-II screening in February, actually February 15, of 1998.
According to this dual EIA algorithm, concordant repeat reactives are then tested by an investigational Western blot and the investigational Western blot is manufactured by Cambridge Biotech.
[Slide.]
The American Red Cross notified FDA of its intent to perform this algorithm on February 10, 1998 and, again, I said it was meant to be coincident with the implementation of HTLV I-II screening.  We received verbal approval and then received written approval on March 15 of this year but, within our approval letter and relevant, as you will see, to some of the results I will show you, is FDA asked us to change the interpretation, the interpretive criteria, recommended by the manufacturer of the IND reagent.
The IND reagent states that you need to have two gene products of HTLV reactive; that is, one from core, p24, and one from envelope which can be recombinant GP21e which is a recombinant protein or the viral lysate protein directly which is gp46.
This is relevant because p21e has high rates of nonspecific reactivity and that will come through in the data.  But what FDA requested is that we maintain the Public Health Service criteria which is not what the IND requires but what uses a positive interpretation requiring p24 and gp46.
[Slide.]
For the dual EIA data that I will show you--that is, data subjected to the dual EIA algorithm--approximately $7 whole-blood donations were screened using an anti-HTLV I-II kit and we used Organon Teknika as our primary kit.  Repeat reactives were then tested by a second licensed HTLV I-II kit, Abbott.  Concordant repeat reactives were tested by the investigational Cambridge blot, as I stated.
When we initially implemented this test, we worked with Community Blood Center of Greater Kansas City to also qualify the reverse of this algorithm; that is, for blood centers who begin with Abbott and then would use, as their reflex test, Organon.  So I will show you a small amount of data showing how the reverse algorithm looks.
Then, in a larger study that we just completed, looking at what is the supplemental test reactivity of discordant EIAs, we have looked at that in the presence of both directions of the algorithm; that is, we took 200 samples from blood-systems laboratories in collaboration with Mike Busch and Sally Caglioti and they were tested first by Abbott and then by Organon.
With Red Cross samples, we took 128 Organon repeat reactives and then tested them by Abbott.  All samples were tested, whether they were concordant EIA-reactive or discordant EIA-reactive, by both the Cambridge investigational western blot and also by a research test-kit referred to as a strip immunoassay or recombinant immunoblot assay RIBA, which is the same technology that was recently licensed for hepatitis C.
[Slide.]
To give you first some historical perspective on what our expectations are for HTLV, this shows you Red Cross data that I have shown at BPAC committees previously.  It covers the year-and-a-half period of time between 1996 and 1997 before the Red Cross made some changes in their screening test methodology.
Here you can see what the prevalence of HTLV that we would expect in a blood-donor population is relative to 10,000 donations.  So our expectation is 10 per 100,000 donations.  You can see here how that fits relative to other viral markers we screen for.
[Slide.]
When we made a switch from the Abbott HTLV I kit to the Cambridge HTLV I kit, we noticed a dramatic change.  Now, we changed vendors in June of 1997 and both algorithms involved a screening test followed by the Cambridge Biotech western blot.  The issue with our change was the Cambridge EIA contained the exact same antigens as the western blot.  Therefore, one would infer that what is repeat-reactive by the antigens of I would still be repeat-reactive by the antigens of the second test.
In fact, that is exactly what happened.  So, if you compare two three-month periods of time, the three months just before we stopped the test and the three months when we introduced the new test, what is really compelling here are two points; one, that no matter what we do on western blot, we always see high rates of indeterminate.
Secondly, when we went from the Abbott test to the Cambridge test, all of a sudden, the number of positives we were reporting doubled.  So that is a significant problem because we can't ignore a positive test result.
[Slide.]
Looking at the quality of the blot, you can see why the indeterminate rate is so high.  What I am going to show you are manufacturing defects in the blot that occur during the electropheresis in construction of a western blot.
Here you can see what is referred to as smiling.  That is when the glass plates generally aren't clean and we see antigens not electrophoresing completely linearly.  The other thing you see on this blot are a tremendous number of viral bands that indicate not true positivity in these cases but, in fact, false positivity.  There are HLA bands here.  There is just background on the blot.  Generally, they are poor quality.
[Slide.]
Here you can see another blot batch.  Here you actually see a hole in the gel so this is on the positive control although it doesn't affect the area that you read.  Again, non-specific viral bands--this is probably the only true positive of all the strips that I have shown you.  Here is the p21e recombinant reactivity.
[Slide.]
The next three graphs are the ones that have the line that is very important to see.  It is in pink.  This shows you historically what has now happened when we switched EIAs.  One would expect, under CGMP testing, using an FDA-licensed product on a relatively stable population, that, week-to-week, lot-to-lot, our numbers should be consistent and should be not fluctuating.
With the Abbott product, during each fall, we would see a rise in initial and repeat reactivity due to cross-reactivity of flu-shot vacinees so that would occur in the fall.  Then, when we switched to the Cambridge EIA, our repeat-reactive rates skyrocketed as well as the initial rates.  We were pleased when we switched, then, to Organon because, on the first two months, the rates went down.
But then what happened, in response to a request from FDA to increase the sensitivity of the kit based on a lot-release number, we saw a tremendous increase in repeat reactivity here.  You can see a mean during these weeks of greater than 0.2 percent.  As Elliott said, without supplemental testing, we have to tell donors something about these results.
Then they were allowed to recalibrate their kit to not exceed the levels that FDA requested it to on the lot-release panel and we saw a decrease.  But now, what is happening, is we are seeing another increase.  So the point in showing you this graph is that the screening repeat-reactive rates are not stable product-to-product.
[Slide.]
When we switched to the Organon HTLV I-II kit, we wanted to make sure that the sensitivity of our primary screen and the reflex screen, the second EIA, were comparable.  So we asked the manufacturer for some assistance.  What the manufacturer did was provide us their most weekly reactive samples out of their clinical trial.
You can see this from S/COs of 1 to 2.  Then, when tested on the Abbott kit, they showed very comparable sensitivities so we could see out of the FDA validated clinical trials the most weekly reactive confirmed-positive samples had equal strengths on both kits.  So we felt confident that we could proceed forward.
[Slide.]
The data to date, for 7 million whole-blood donations is as follows with the dual EIA.  I will now show you its stability over time.  The Organon Teknika; again, we screened 7 million blood donations with a repeat-reactive rate of 0.12 percent.  So this is the number that we start with.
Over this period of time, which is over a year, that includes 8,661 blood donors, we then tested those donor samples by Abbott.  Only 35 percent were concordant repeat-reactive.  So, just by doing the second EIA, we eliminated over half and, in this study, 65 percent of samples from unnecessarily being tested by western blot.
If you look at this as a concordant repeat-reactive rate, that is about a 0.94 percent repeat-reactive rate which is really what we would like to see for the reactivity of the primary screen.  Those samples were then taken on to western blot and here you see, if you look at the percent concordant repeat-reactive, what the outcome of the blot results were.
Again, 73 percent indeterminate.  So it is this blot that is generating a lot of problems regarding high numbers of indeterminate.  The non-reactives, as Elliott also said, are not tested further by the second EIA and those donors remain eligible for a second donation, although their repeat-reactive donation is destroyed.
[Slide.]
I wish this were clearer because this slide speaks a thousand words.  These represent samples per week that are required for confirmatory testing.  That sample, incoming samples into my lab--I run a confirmatory lab to the Red Cross--represents the fluctuation that we see week-to-week from product-to-product with HTLV.
This represents, initially, what we started with with Abbott.  This represented the increase with Cambridge.  Then we went to Organon.  We saw a dip.  Then we saw the increase and then another dip and now another increase.
[Slide.]
To look at the impact of the second EIA--and, again, I apologize regarding the colors--the blue, again, represents the number of incoming samples.  The green line represents those samples that are non-reactive by the second ELISA or ones that we do not have to do supplemental testing on.  So, again, this represents 65 percent and it represents probably false positives from the primary screen.
The red or pink line down here represents the total number of concordant repeat reactives that go on to western blot.  You can see that this line is relatively stable and that is because we are screening out most of the false positives with the second EIA.
[Slide.]
Looking at true positives following western blot, just western blot positives, this is what we see over the three tests.  You will see the impact of the false positives on the supplemental or Cambridge western blot.  With the Abbott test, over time, we generally saw, as I said, 10 per 100,000 donations as confirmed positive.
When we converted to Cambridge, that number skyrocketed to 23 per 100,000.  Again, we believe that is an artifact using the same kit for screening and confirmatory.  Now that we are back with Organon using the dual EIA algorithm and the western blot, we are back now to 10 per 100,000.  You can see that relatively stable over the Organon product.
[Slide.]
As I said when we first started this testing, we also qualified the reverse algorithm.  These are the data from Community Blood Center of Greater Kansas City in collaboration with Gary Tegmire.  These were the Red Cross data from the first five months.
We initially saw a primary screening repeat-reactive rate of 0.10.  Then, at that time, only 45 percent of those were repeat-reactive on the second EIA for an overall repeat-reactive rate of 0.05 percent.  This is a little bit lower than what I have shown you on the previous slide of 35 percent.
But, going from Abbott to Organon, in the beginning when Abbott was first licensed, the specificity wasn't so good.  So the importance of the second EIA was very, very needed because it eliminated 90 percent of the false positives, a much higher number than here, and yielded an overall repeat-reactive rate by both directions of the algorithm that was relatively comparable.
[Slide.]
Looking at this now in a more recent study, also qualifying both sides of the algorithm, it is going from Abbott to Organon and Organon to Abbott, what we tested were 200 samples from BSL, Blood Systems Laboratory.  They were Abbott repeat-reactive, Organon nonreactive.  We actually tested all of the discordant EIAs by supplemental testing so we could see if there were any positives not detected.
Of 150 that were discordant, or 75 percent, none of them were Western blot positive.
[Slide.]
Looking at a similar study from the Red Cross, we had three samples here out of 128 total screened that included 93 that were discordant EIA-reactive.  We, unfortunately, had three that were RIBA positive.  This is the RUO test.  A certain explanation of this is that they are false positives so we investigated further.  These samples, actually, by western blot had only very strong p21 reactivity according to PHS criteria but extremely strong p21 reactivity.
We tested them by another construct of p21e that has a piece of the recombinant protein truncated that is supposed to represent the non-specific region.  All three samples were nonreactive with the more specific 21e construct.  They also were negative by immunofluorescence and by RIPA in the state of California.
[Slide.]
So if you put all the data together for BSI and Red Cross in this first study of 200 screened in 128, only about 25 percent were concordant repeat-reactive similar to the overall Red Cross number I showed you of 35 percent.  Similar results were obtained by RIBA and western blot for confirmatory testing also similar to those that I showed you from Red Cross experience total, which included about 24 percent being positive.
Now, when we looked at the Red Cross samples, there was one sample here that was western blot indeterminate and RIBA positive.  Is that a false negative or a false positive.  That sample is undergoing further study.
[Slide.]
This now combines a larger dataset of 200 Red Cross samples and 200 BSI samples, just to look at a two-by-two table comparing the performance of western blot to RIBA. When we did a statistical analysis to say, are these methods similar?" the statistics said no, they were significantly different.
The reason that these were significantly different was because of this cell that represented 47 percent of the data that is western-blot indeterminate, those problem samples that I showed you that were all RIBA negative.  This would all be well and good if we had concordance on positivity for both assays, but, on this testing, we have 12 western-blot-positive samples that were RIBA negative and we also had one western-blot-indeterminate sample that was RIBA positive.
So, in order for us to assess the sensitivity of these methods, further testing needs to be done because there appears to be some discordance.  But the methods were primarily not related because of the high numbers of western-blot indeterminates.
[Slide.]
So, summary and conclusions; the unavailability of HTLV supplemental tests having validated sensitivity and specificity have forced alternate strategies to be examined.  Fluctuating repeat-reactive rates and screening test-kit performance have placed further pressure on the need for HTLV supplemental tests.
Screening and supplemental tests should not contain the same manufacturer antigens.  The dual EIA strategy reduces the number of samples requiring western blot by at least 65 to 75 percent, consequently greatly reducing indeterminate rates.
[Slide.]
And even with the use of the dual EIA algorithm, high numbers of samples require further supplemental testing.  The availability of HTLV I supplemental tests is limited and the quality of the one available is poor and RIBA may offer a more specific alternative to western blot once sensitivity has been fully qualified.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Stramer.  Any questions for Dr. Stramer regarding the information she presented?  So the percentage of positives that are EIA--I mean, with a different test, the number that you are left with, finally, how does that make.  How many donors?  What percent of the donors would, therefore, under this circumstance, be ineligible?
DR. STRAMER:  From the small study we just did with BSI and with our small number of samples, that was 25 percent.  So it is 25 percent of the repeat reactives which is 0.12 percent.  25 percent is 0.12 percent of 0.04 percent.
DR. HOLLINGER:  Okay; so the 0.04 percent.
DR. STRAMER:  Which is really what I reported for the concordant repeat-reactive rate.  So it is about 0.04 percent is the total demand for supplemental testing.
DR. HOLLINGER:  If you had supplemental tests, how many would that further reduce?
DR. STRAMER:  The supplemental test would then divide the samples into negative indeterminate and positive and the answer to your question would be it would depend on the performance of the supplemental test.  We would hope that all of them would be negative with very few positives, but we know that is unrealistic.
DR. HOLLINGER:  Thank you.
DR. KHABBAZ:  I have a question for Sue.  Clearly, from the time that I knew HTLV better than now, and was involved with HTLV, things seem to have deteriorated with regard to supplemental tests.
My question is what happened with the western blot that had I- and II-specific glycoproteins whose performance, as I recall, and I don't have the numbers, was much better than what you have now.
DR. STRAMER:  You are referring to the Diagnostic Biotechnology blot which is now referred to as the GeneLabs blot.  In your era of HTLV, there was the version 2.3 which is now the 2.4 soon to be the 3.0.  But, anyway, that product was distributed in the United States under RUO labeling and it was being used for blood-donor counseling which is against the CFR that Dr. Cowan replied, so the product had to be removed from circulation.
They weren't following the guidelines as Cambridge was.  They never filed an IND.
DR. NELSON:  Will these supplemental tests--will the western blot or RIBA differentiate HTLV I and II?
DR. STRAMER:  The one problem with the Cambridge blot and actually reported in the U.S. Public Health Service guidelines is it says that one guide to differentiate HTLV I from HTLV II is p19 or p24 reactivity.  That is really not the way to do it.
The RIBA does have, and I should have mentioned this but didn't, HTLV I and, separate, HTLV 2 enveloped glycoproteins.  So you can confirm and distinguish HTLV I from HTLV II by specific peptide which the blot does not have.  The blot that Rima referred to did differentiate but that is no longer available in the United States.
This western blot that I showed you is probably absolutely first-generation.
DR. KHABBAZ:  The other one had a I- and II-specific glycoprotein recombinant or peptide--
DR. STRAMER:  Right.
DR. OHENE-FREMPONG:  Is there a nucleic-acid test in development?
DR. STRAMER:  HTLV is a cellular-associated virus.  It doesn't circulate freely in a viremic phase the way HIV does or HCV, so we can't do a plasma-based PCR.  You can do cellular-based PCR but that requires cells and it is not something that is conducive to routine supplemental testing
There have been reports of serum-based HTLV PCR, but that has not been very well reproduced.
DR. NELSON:  Have the donors been followed?  Are most of the HTLV donors from endemic areas and the IIs are drug users?
DR. STRAMER:  I think the epidemiology of HTLV has been pretty consistent.  We see a predominance--and I don't want to use Red Cross data because that is based on p19 and p24 and I have zero confidence in that reporting methods.  But, from REDS data, and I think Michael may hit on this, we believe most of them are HTLV IIs still and risk factors, drug use.  I think the epidemiology for HTLV has been pretty consistent.
DR. HOLLINGER:  The next presentation will be by Dr. Busch on the clinical experience with HTLV supplemental testing.  Dr. Busch represents Blood Centers of the Pacific, Irwin Center.
	Clinical Experience with HTLV Supplemental Testing
DR. BUSCH:  Thank you.
[Slide.]
I am glad to be able to address this topic.  It has been one that has really been a problem for ten years or more and it is a more general problem than just HTLV.  The issue of adequate supplemental assays for donor infectivity screening tests has continued to be a problem for all of the markers where, basically, as the companies bring forward more sensitive screening tests, there is not much incentive financially or from a regulatory perspective for them to invest in the appropriate supplemental test to complement the screening test.
So we have really been handcuffed in terms of the donor notification site of this for a number of years for all of the viruses.
[Slide.]
So I am going to slightly more generalize my comments and, unfortunately, I had distributed some papers to FDA that I thought would be distributed and they weren't.
But, in any event, I would refer you to an editorial I wrote several years ago that really tried to focus on the adverse impact of the lack of adequate supplemental tests on our blood donors.  As you can imagine, from all these tests put together, well over a percent of blood donations are detected as reactive on one or more of these screening assays and the donors are usually deferred and have to be notified and counseled and, often, in the absence of adequate--and, certainly, adequate FDA-approved supplemental assays.
A couple of just general, fundamental problems.  One is that as the companies, again, bring forward enhanced screening EIAs, the lack of capacity to bring forward complementary enhanced supplemental tests to adequately notify these donors.
What we have been documenting over the last few years is a fairly high rate of false-positive supplemental-test results.  This have been well-documented now in the context of HIV where, in the range of about 10 percent of all donors who were being notified that they are HIV western blot-positive in fact have patterns that are indicative, and a high proportion of those represent non-infected donors who have non-specific patterns on HIV western blot.
On HTLV western blot, again, in the range of probably 10 to 20 of donors who are scoring positive on the Cambridge biotechnology blot are actually false-positive blots.  I will get into that as well.
On both HIV and HTLV immunofluorescence assay, false positivity has now been well documented.  For hepatitis B surface antigen and p24 antigen neutralization assays, there is a fairly high rate of false positivity.  For HIV, there are probably 20 false neutralization tests for every true neutralization positive that has been reported.
Even with some of the earlier recombinant tests, like HCV RIBAs, there was interpretive criteria that resulted in false-positive notifications and, indeed, as we have begun to evaluate the new-generation HTLV supplementals such as the Biotechnology blot or the HCV HTLV I-II RIBA, those do have much lower rates but still have some problems with false-positive results.
You can just imagine the impact on donors, many of whom are told they are false positive and only years later do we really understand this issue and the dilemma of going back to these donors who were told they were infected with these viruses and coming back, years later, and trying to tell them that we made a mistake, if we ever get to the point of retesting all those samples and sorting it out.
Another big area that has been just a chronic problem is, as Sue alluded to, the very high rates of indeterminate results using these viral lysate-based assays.  So we are running in the range of 30 to 50 percent of blood donors who are repeat-reactive for HIV are reported out as indeterminate on the FDA-licensed western blots and, using, again, viral-lysate assays such as the Cambridge or the spiked blots from Biotechnology GeneLabs, we see 70 to 80 percent of these donations are reactive on one band or another and the donors are being notified that they have an indeterminate test result.
Then, in terms of discrimination of viral subtypes, for none of the viruses, HIV, HTLV or hepatitis C are there approved methods for detecting subtypes which, in some cases, have great clinical relevance.
Now, the problem here really has to do with sort of the economics and regulatory issues around supplemental assays.  There is a fundamental problem simply economically in that the market for supplemental tests is much, much lower than for screening assays.
So the companies focused their resources on getting better competitive screening tests developed, manufactured and licensed and tend to minimize the focus just enough to get them through the trials.  And test like HTLV, where the market is relatively low, where the whole world doesn't screen, the numbers of screened donations that require supplemental testing are so low that the companies basically are not willing to go through the continued developmental and regulatory channels.
As a result, in addition, the FDA's policies, I think, have been somewhat misguided in this area.  Usually, the FDA looks at licensing a supplemental test in concert with approving a donor reinstatement protocol.  So they are very critical of the assays requiring that they have head-to-head or improved sensitivity compared to the screening assays and, also, obviously, good specificity.
So that has resulted in very intense scrutiny of the assay sensitivity during the regulatory process which takes years and during the time that a company is trying to get approval for a supplemental test, there is a new screening test that comes along that has to build in type O or has slightly better window-phase sensitivity.
So a supplemental test that really was excellent and still is a great improvement over what we have is not able to get through the regulatory hoop.  So we are basically, at this point, in terms of many of these agents--really, there are, to my knowledge, no really state-of-the-art supplemental tests going to FDA for HIV, HTLV, even though these assays are being widely used elsewhere in the world and they have been developed and are much better than the current viral lysate or no approved assays that we are dealing with today.
So I think, to my mind, one important consideration to FDA would be to look at approving these assays for donor notification and counseling as an initial step independent of the issues around donor reinstatement that have implications for blood safety because what we really need--in fact, none of the large blood programs reinstate donors because it is such a regulatory risk that, if the FDA comes in and you reinstated a donor inappropriately, you really get nailed.
So most of the blood programs are not reinstating even though there may be an acceptable algorithm.  So we would rather see the focus on getting methods for donor notification and counseling and potentially, downstream, through later validation studies, could the reinstatement issues be addressed.
The other issue, again, is that the supplemental tests become obsolete as a type-O antigen detection or other improvements in the screening test come forward.  This leads FDA to put reinstatement programs on hold and so a test that might have been approved for donor reinstatement is no longer adequate.  So FDA cancels the reinstatement program.
The other issue is that blood banks, as a consequence, some of them have taken a very, I think, donor-adverse approach to the notification and are not even doing confirmatory testing for some agents although, as Jay said, there has been somewhat of a mandate and I think we are waiting for an FDA regulation to require supplemental testing.
At this point, it is not required and, given the absence of FDA-approved assays, some blood banks are actually notifying donors based on repeat reactivity which I think is totally unacceptable.
[Slide.]
Specific to HTLV, actually we did a study early on in the REDS group that looked at a very large number, I think around 500 or 600 HTLV repeat-reactive donors by PCR and a number of other assays.  In fact, what we discovered was that the routing supplemental algorithms that were kind of built when the tests were first licensed, by Abbott in particular, were really extraordinarily accurate.
What they were doing is they were actually doing parallel western blot and radioimmunoprecipitation which is a labor-intensive sort of research-mode assay.  And then many blood banks were supplementing that with early available peptide-typing assays.
What this study showed was that those methods were 99.9 percent sensitive to detecting true infection.  A small fraction of indeterminates were really infected and none of the negatives were infected.  So, really, the early supplemental-test algorithms that were available through the company reference lab channels were very accurate.
Over the subsequent years, companies did begin to develop and market RUO tests that were improvements.  I will show some examples of those.  There were peptide and recombinant p21 EIAs available.  There were very enhanced antigen spiked western blots as well as what we will see in a few minutes, both Chiron and Innogenetics have been built completely recombinant peptide-based strip immunoassays.
Roche, actually, for a three or four-year period did have an RUO HTLV I-II PCR assay out on the market.  But what happened was that none of these companies were willing to pursue the regulatory channel because, again, of these cost issues downstream, that there simply wasn't enough recovery envisioned downstream and the regulatory issues were problematic, as I alluded to.
So this has led people to develop the strategies, such as Sue described, doing alternative EIA-type strategies or using these older, first-generation viral lysate western blots and trying to report type differentiation based on p19, p24 band intensity which we now know is very inaccurate.
[Slide.]
I will show you a little bit of data about how these results have resulted in artifactual observations of false positivity.  I just wanted to show you a few of these newer blots.  This is the one that Rima was addressing, the GeneLabs Diagnostic Biotechnology western blot that was first developed and reported back in the early '90's and has since gone through a few generations of improvement.
[Slide.]
Let me show you a representative figure.  This assay, in addition to a viral-lysate-type western blot and the recombinant p21e antigen, which is a very sensitive antigen that cross reacts with all the virus, they added type-specific antigens for a particular envelope region.
So this allows one to differentiate whether the donor harbors HTLV I or HTLV II in the same assay.  In the early-generation studies, the antigen that was the p21e antigen actually had nonspecificity, the same as the Cambridge blot.
[Slide.]
So we and others reported on problems with that assay reporting out a low rate of false-positive western blots.  And the GeneLabs group actually went on to identify within that HTLV I p21e antigen the immunodominant-specific epitope versus the non-specific region.  And they later have modified the blot to include a new revised antigen that is called GD21e which is very specific and does not have false positivity associated with it.
So, in the background, companies have improved and these assays are manufactured actually overseas and are widely distributed worldwide.
[Slide.]
A Belgian company has developed an assay called the INNO-LIA test which is a complete recombinant peptide base supplemental test for HTLV.
[Slide.]
It has control bands and then it has HTLV I-II generic antigen so a p19, p24 and several enveloped antigens that react with HTLV specifically but do not define the type.
But then there are three type-specific antigen, a gag and two types of specific enveloped antigens which give you the type of the donor, be that I or II, among the seropositives.
[Slide.]
There has been a series of recent papers.  This is just one of them I won't go through but the critical value of these tests is really that they eliminate the indeterminate results that were such a problem.
They are very accurate in terms of sensitivity and typing and they reduce the rate of indeterminate results by 80 percent compared to what one sees with a lysate western blot.
[Slide.]
This is the Chiron assay which we have been beginning to collaborate with them on that similarly to INNO-LIA assay has a series of strips.  It is very similar to the HCV RIBA.  There is also an HIV one to RIBA that has been in development.  But basically it uses the same p21e antigen and then uses type-specific subsets of the p21e antigen to type the individuals or peptides and then a combined HTLV I-II gag test.
[Slide.]
So just to point out that these improved assays have been under development but they have not been implemented.  In fact, if anything, we have gone backwards on HTLV.  This became apparent to the REDS group as we were monitoring the epidemiology incidence prevalence of virus in the donor pool, all the other viruses, the incidence and prevalence has declined whereas what we observed for HTLV was an actual increase in the prevalence among first-time donors of HTLV over the period '93 to '95--
[Slide.]
--as well as a sudden increase in the point estimate of the incidence, although not significant.
[Slide.]
We wondered whether this was real or not.  What we did was to look back at the confirmatory assays and criteria.  What we documented is what you have heard, that the Red Cross, in part because of some regulatory issues, moved away from using the p21e EIA and the RIPA assays going back to the only assay that has been submitted under IND, the Cambridge assay, in 1993, late '93, whereas the non-Red-Cross centers actually went the other way.  We started to use this Diagnostic Biotechnology blot which has good specificity, supplemented by RIBA.
[Slide.]
So then we looked at the REDS data separating it by the Red Cross and non-Red-Cross centers.  What we could see was that that increase in prevalence was limited to the three Red Cross regions and really probably coincided with this change to inferior, less specific supplemental tests.
[Slide.]
To further validate that, we did a study where we took 260 donations that the blood centers had called confirmed positive over this period of time.  Those were tested by PCR, by peptide EIAs, and by the HTLV RIBA test.  Using the very stringent criteria that all of these test had to be negative or the RIBA could be indeterminate, we identified 30 percent of these samples as false positive.
When we look at the frequency of false-positive results over time, we see that they really only began to be reported by the blood centers in '94 and '95.  Now, as I say, about 30 percent of what blood centers are reported out are false-positive results until the most recent change which is now the Red Cross is precluded from using the p21e antigen.  So, now, nobody is being told they are positive.  Everybody is an indeterminate.
So it is really a haywire situation.
[Slide.]
The last thing I wanted to mention is some comments about the impacts of false-positive and other test results on donors.  This is an area that I think we have all kind of talked about and waved our hands about but REDS, over the last several years, has tried to do some formal surveys to try to quantitate the impact of false notifications and true notifications on donors.
We actually published a paper several years ago that looked at the psychological impact on notifying donors who truly were seropositive for HTLV I and II compared to normals and could document significant psychosocial impact on infected donors who were being told they had a virus that probably would never get them sick, that maybe they could transmit to others but we couldn't do anything about it, so kind of the problems about telling somebody they have one of these infections.
[Slide.]
But recently we have done another survey of about 4,000 donors who were told they had various test results including various false-positive patterns.  I just want to share a few slides of preliminary data from that survey.  These surveys are organized mostly by Allen Williams.
What this summarizes is for some of the more common false-positive patterns, HIV indeterminate, HTLV indeterminate, HCV indeterminate, HCV RIBA-negative and anti-core reactive donors who were notified that they were deferred due to anti-core reactivity, what the impact was on these donors in their answers to questions such as this: "Were you confused when you were informed of these test results?"
You can see that 80-plus percent of these donors were confused with about half of them being very confused and half somewhat confused.
[Slide.]
Are they still confused?  These surveys were actually administered about a year after these donors were notified.  You can see that, still, a high proportion of these donors remain confused over the test results a year or more after the notification event.
[Slide.]
Did the notification emotionally upset them?  Again, about 80 percent of these donors who were told that they had what we, in fact, think are mostly non-specific results and try to reassure the donors--and, of course, for many of these viruses, we really can't help them further, or their doctors don't know anything about HTLV, so these donors are basically anxious over these test results.
Again, this was a persistent finding in a high proportion of those donors.
[Slide.]
Many of them went on to seek--even though our counseling messages say, "You are not infected; it is okay," many of them on to see physician follow up after these notifications.
[Slide.]
Finally, within the REDS group, we have tried to address this problem and talk to FDA about potential strategies.  So, over the last year, we have compiled some panels, large panels, of pedigreed samples from donors with well-characterized HTLV infection status.
We have begun to develop collaborations.  We have been working recently with Chiron, one of the manufacturers of the peptide EIAs although this company has now decided to discontinue making that test so they are no longer interested in studying this, it seems.
And Innogenetics, we have now started to collaborate with them to try to do preliminary evaluations of their tests and then, together with a company after we felt that the test that they have is adequate, try to file and IND because the companies are not willing to file this on their own accord or fund and pursue a clinical trial.
So we have pursued the strategy somewhat analogous to NAT to try and file and IND with the company and then continue to test under IND doing some additional clinical studies but with an understanding with FDA that realistically this may not evolve to a full application but will at least allow donor notification while testing under IND and the concept of probably broadening the testing to several of the larger testing labs to allow the availability of these results for all donors.
Thank you.
DR. HOLLINGER:  Thank you, Mike.  Any questions of Dr. Busch?
DR. TABOR:  I really regret that I have to correct a number of very careless comments, or comments that appear to be very careless in the early part of your talk.
First of all, you gave the impression that confirmatory tests or supplemental tests for several of the viruses that are tested for in blood have a very high rate of nonspecificity quite apart from the indeterminate results.  I don't believe that that is really connotatively verifiable.
Second of all, you gave the impression that companies are beating down the door at FDA to try to get us to approve supplemental tests that are new and improved.  That is certainly not the case.
Third, you gave the impression--in fact, you stated--that the development of new screening assays for things like HIV group O, that was a specific example you gave, immediately invalidated confirmatory tests that had already been approved by FDA.
First of all, we are still not testing for group O because the companies have been slow to develop screening tests for group O and, even if you had a screening test for group O, it would certainly not invalidate a validated confirmatory test or supplemental test for the vast majority of the HIV that is detected in this country.
Finally, you made the careless mistake of referring to RUO tests that are "on the market."  RUO, in case anybody missed it, stands for research use only and the companies are not supposed to have those on the market, even though they do, in fact, get cost reimbursement for them.  They have to have an FDA license or approval in order to be on the market.
DR. BUSCH:  I am sure my mother will disagree with you.  The first point, I think I could share with you a series of manuscripts published from the REDS group and others in terms of the false-positive problems with the current supplemental tests.  Obviously, they are most serious in the donor setting.  In any kind of high prevalence, high-incidence setting, they are fairly trivial.
But, in the blood-donor setting, I can show you published papers for HIV, HTLV, p24 antigen, surface antigen, that document what I think are unacceptable 5, 10, 15 percent rates of false-positive results coming off these assays in the blood-donor setting.
In terms of beating down the doors, I think what I said was that there are no tests in the pipeline or, if there are, they are stalled.  I discussed these issues extensively with the companies and, basically, they won't bring tests in because they can't afford the cost of these trials to them get to the market that is so small and the unlikely regulatory path that is reasonably likely to be aborted because of the third issue which is that, although group O may not have invalidated the license status of the licensed western blots, any test for supplemental assays, it is my understanding, that would come forward now for supplementing donor screening would have to have group O represented.	
So, if a company had a test well in development or through clinical trials, I think they would have to go back and, it is my understanding, incorporate group O into those to get them licensed downstream.  I am not certain about that.
The last issue, RUO; I guess it is the definition of market.  We were able to purchase and run the biotechnology blot several years ago for research use only.  The preclusion became that we were told, "Yeah; you can buy it and do research with it but you can't tell people the results."  It is a definition of market.
DR. NELSON:  Are these supplemental tests--would they classify as an orphan drug?
DR. BUSCH:  I think you will about potentially that.
DR. NELSON:  As I understand it, that category of drug was used to deal with the disincentives to develop important diagnostic and therapeutic reagents based upon only economic considerations.  Here it seems to me to be pretty remarkable.
The other issue with some of the supplemental tests is that--and it may be based, and I guess it is, on economics--the costs of, for instance, the RIBA for the hepatitis C that the company cites make it impossible to use this for research.  It is like $100 an assay or something ridiculous.
I don't know what the blood banks are paying or if this is part of the equation or part of the problem, but I know for use in research in a non-blood-bank situation, it is just not feasible.  They are important, obviously, because false positives in a research setting can generate data that is not--
DR. BUSCH:  I agree.  I think strategies such as Sue has developed of using alternative EIAs to save that cost on a large number of samples is great.  I think FDA early on wasn't terribly supportive of using alternative EIA strategies, but I think recently they have been receptive to that.
DR. KHABBAZ:  It is a comment and not a question, Mike, but if my memory serves me right, screening for HTLV I a decade ago, as I remember, was pushed because the tests were there.  The manufacturers made them.  They were there.  We weren't sure about the disease and what we were preventing but they made these tests, screening tests, and pushed and we did.
It is easy for us to sit here in the era, as Jay eloquently defined, the precautionary paradigm and say it is good because we are preventing disease with one little bit and with two possibly very little.  I won't get into that argument but, at the time when they pushed these tests, as I recall, they offered--part of the deal was to offer supplementary tests.
You mentioned that, Mike.  That was done.  To get to the economic incentive, clearly the incentive--the screening assays is where the economics come into play.  Somehow it seems that we have had, over the years, a separation whereas the screening tests--and you have improved tests--are there and where the money is to be made.
Yet, the manufacturers of these screening tests have kind of divorced themselves from the supplemental assays and you are left with what we are left with, talking about orphan tests.  They are, in a way, but they are not if you link them to the bigger picture of screening.
DR. EPSTEIN:  I agree with what Dr. Khabbaz just said.  The agency, however, was criticized for, if you will, holding up the pace of development of screening tests by holding the companies to the standard of having available supplemental tests, at least as in-house services, at the time of approval of screening tests.  So the arguments cut both ways.
On the question of whether we could change the approval standard to approve HTLV or other tests as diagnostics independent of the whole question of donor reentry, well, of course we could.  But our approvals process is geared toward the product claim.  The question is what is the intent to market?
The problem isn't that we couldn't approve them in their own right as diagnostic, it is that if they are being used to follow up donor screening by EIA, then, in order to understand the false-negative rate, you have to compare it to the sensitivity of the EIA.
So it is more a scientific issue than a policy issue.  In other words, we could approve with different labeling tests that had lower sensitivity than EIAs but what exactly do we say in the labeling claim if we don't have a requirement to know the answer?
And then I would make one other observation about trials which is that there is a paradox here because it has been stated repeatedly, well, we had these great RUO tests.  But, if they were that great and people believed it--presumably, they believed it because of data, and the question is why couldn't those data be brought before the agency. If they are so convincing as all that, why can't they be compiled?
So we always get into this conundrum where the test that is not studied through official mechanisms, legal routes, is always touted to be better than sliced bread.  But somehow no one can show the agency the data.  I think that we ought to ask that question, that if those tests are that good, what prevents them from that being demonstrated under IND or the data otherwise provided.
I think that is important issue.  Then one last point about the economics.  As you showed, the positive rates of screening, the repeat-reactive rates, aren't all that different for some of the other markers compared with HTLV.  But there is a big difference in the size of the market for the supplemental tests.
The reason for that is sort of external to the blood system.  It is because there is a public-health testing role for the other screens whereas, for HTLV, there is no mandate for routine public-health screening in essentially any context for HTLV.  That is why there is not a collateral market.  It is not that the blood system better supports the economic profitability of the supplementals for some of the other agents, it is just that there is a larger global market that has very little to do with blood screening.
These are just additional observations.  I am not really criticizing anything one way or the other, just that these are some of the factors that the committee needs to be aware of.
DR. KHABBAZ:  Just for the record, my comments were not meant as criticism to FDA.
DR. HOLLINGER:  Thank you, Mike.
The next speaker is Susan Pucie from NHLBI on funding opportunities for small business.  That will be followed by Patricia Robuck.
	Funding Opportunities for Small Business
	Presentation
MS. PUCIE:  Thank you.  As I am getting the slides set up, I just to let you know this will be noncontroversial because I am here to show you the money.
[Slide.]
Thank you for inviting me to talk about the small-business funding opportunities at NIH.  We appreciate every chance to publicize these programs.  In the next few minutes, I am going to give you a lot of information but don't worry about taking notes because hard copies of the slides are available.  I tried to hand them out and then there are some on the chair in the front.
The National Institutes of Health has two programs reserved for small business.  They are the Small Business Innovation Research Program or, for short, the SBIR Program, and the Small Business Technology Transfer Program, or the STTR Program.
[Slide.]
Briefly, the SBIR Program sets aside 2.5 percent of the NIH extramural budget to support innovative research conducted by small business that has potential for commercialization.  We do anticipate that that percentage will increase over the next year.  The STTR Program sets aside 0.15 percent of the extramural budget to support innovation through cooperative R&D carried out between small business and research institutions.
[Slide.]
In Fiscal Year 1999, the NIH expects to award $1,520 SBIR and STTR grants for approximately $325 million.
[Slide.]
To qualify for an SBIR or STTR award, the small business must meet these four criteria.  You must be an independently owned, controlled and operated for profit U.S. business.  You have to have a principal place of business in the U.S., the control of the research facilities where the research will be conducted and you must have 500 or fewer employees.
[Slide.]
In addition, to qualify for an STTR award, the small business must be a partner with a research institution and at least 40 percent of the STTR work must be performed by the small business and at least 30 percent by the research institution.
[Slide.]
Why pursue SBIR or STTR funding?  Because over $300 million are available; because this is seed money to fund high-risk projects; and this is not a loan.  There is no repayment of the awards.  The company retains the intellectual property rights.  You get recognition and visibility.  This is a potential leveraging tool to attract capital.  And NIH is interested in doing business with you.
[Slide.]
Here is a little information about program mechanics.  There are three phases to the SBIR and STTR programs.  Phase 1 is to evaluate the scientific and technical merit and feasibility of an idea and the awards are for six months for up to $100,000.  Phase 2 is to expand on the result of and further pursue the development of phase 1.  SBIR awards are for two years for up to $750,000 and STTR awards are for two years for up to $500,000.
Phase 3 is for the commercialization of the results of phase 2 and it requires the use of private sector or non-SBIR federal funding.  I just want to mention here that the numbers that I quoted, $100,000 for phase 1 and $750,000 and $500,000 for phase 2, NIH is flexible about those figures.  If you need more time and dollars, if you justify that in your proposal, that will be considered.
[Slide.]
There are three receipt dates for each of these programs.  Applications for the SBIR Program are due on April 15, August 15 or December 15.  Applications for the STTR Program are due April 1, August 1 and December 1.
[Slide.]
For projects with a very clear development path that have already attracted outside interest, there is also a fast-track parallel review option.  This allows for concurrent submission and review of phase-1 and phase-2 proposals.  The funding gap between phase 1 and phase 2 is eliminated or reduced.
The key requirements are that the phase-1 application contain clear measurable milestones and the phase-2 application contains a product-development plan.
[Slide.]
Now, I would like to say a few words about my institute which is the National Heart, Lung and Blood Institute and our SBIR Program.  The NHLBI Program fosters research on pharmaceuticals, medical devices and implants, biologics, informatics and biotechnologies for the causes, prevention, diagnosis and treatment of heart, blood-vessel, lung, blood diseases and sleep disorders.
[Slide.]
In Fiscal Year 1998, the NHLBI awarded 162 SBIR and STTR grants for over $35 million.
[Slide.]
Now, more specifically, the NHLBI is very interested in receiving strong proposals from small business in technologies and methods to improve the safety of the nation's blood supply.  The following four slides highlight some of these areas.  But I will just mention, for example, our interest in assays or agents that cause transfusion-transmitted disease.
[Slide.]
Equipment and procedures for the collection, separation, processing, preservation, storage, distribution of blood and blood components, computer-assisted systems to improve the blood-donor screening process, management and education systems for more effective and appropriate use of blood products, and methods and technologies for inactivation or removal or microorganisms from blood, blood components and plasma derivatives.
[Slide.]
If you are interested in learning more about the SBIR and STTR Programs, or if you would like to discuss a specific application, please call, fax or E-mail my office and I will be glad to help you or put you in touch with program staff with the right expertise to discuss your ideas.
[Slide.]
I would also like to encourage you to visit the NIH Small Business Funding Opportunities page which is on the Web.  Let me mention there is also a model or a sample application there if you are new to writing one that is very helpful to new applicants.
[Slide.]
Finally, you can obtain hard copies of the official solicitation documents for these programs at this address.  The SBIR Program is sort of a fuchsia colored book and the STTR is a blue book.  All of this is on the Web but it is easier to see in hard copy.
I hope this information has sparked your interest and I thank you for your attention.
DR. HOLLINGER:  Thank you very much.
The next presentation, then, is by Patricia Robuck, Office of Orphan Drug Production.
	Presentation
MS. ROBUCK:  I have to say that Susan took one of my lines, but I have a couple more.  The next one is, "I am here from the government and I am here to help you."  That always gets a chuckle.
And Dr. Nelson, are you a plant?
DR. NELSON:  No; I am an animal. [Laughter.]
MS. ROBUCK:  Oh, no; as in planted in the audience.
[Slide.]
I am from the Office of Orphan Products Development.  The one thing that I don't have on here that I should have put on here is my phone number, so any of you that are interested.  You should have copies of this as well.  My phone number is 301 827-0984.  That will get you right to my phone.  Or 301 827-3666.  That will get you to the office.
[Slide.]
As some of you, obviously, already know, we were brought into existence in 1983 to try and help industry and the academic community to make products available to persons with rare diseases and disorders.  This was signed into law, as I said, in 1983.
[Slide.]
The definition of this; there are two definitions.  The original definition was for products with little or no commercial value.  It took less than a year for us to realize that that was a very difficult definition.  And, therefore, the definition was amended to include disease or disorders that affect fewer than 200,000 persons in the United States.	
This is a prevalence figure.  It is not an incidence figure.  But, for example, in the subject that we are talking about today, incidence would be appropriate use of this and we would be looking at yearly incidence in this particular case.
So we are not looking at the number of people that, perhaps, are HTLV-positive in the United States.  What we are looking at is the population of intended us.  So, if the population of intended use for this product is fewer than 200,000, then you would qualify.
[Slide.]
Of importance today--I hear people saying that you need some incentives and you need some help with money--is that our office supports only clinical trials.  We can't help you, but the SBIR can, in the beginning stages.  But we will give money for clinical trials only.  These include studies of drugs, biologics, medical foods and medical devices.
The incentives, and there are other incentives under the Orphan Drug Act, are limited to drugs and biologics but the Grants Program goes further.  They are to determine safety and efficacy.  And the data that is derived from these clinical trials is intended for potential use by the agency.
So what that means is that they must be done under an IND or, in the case of a device, and IDE.  We, unfortunately, do not fund basic research.  I was intrigued by the amount of money that the SBIR Program has.  We have about, I think, $11.1 million this year.  But maybe it will be up next year.
[Slide.]
So, as I said, the goals of the Grants Program are to accelerate products getting to the marketplace.  We want availability of products under the whole guise of the Orphan Drug Act, but we want to get these products to the market as fast as we can. As I said devices and medical foods are part of this.
[Slide.]
So what is the process?  The first thing we do is we put out a Federal Register Notice.  I will tell you at the end, so you have to pay attention when that is coming up.  Our office does a review of the application.  One of the most important parts of the RFA and the application is the IND or the IDE.  It will state very clearly in the RFA that your study must be clinical trial, it must be done under an IND or an IDE that has been submitted to the appropriate division of the FDA at least 30 days prior to the application deadline.
This is a change that has taken place over the last few years.  The reason is that we need to make sure that you are ready to start your trial when the funding begins.  We also need to make sure that when we review the application that it is a study that can go forward.
The 30 days is so that you are not calling the appropriate division of the FDA every day saying, "When is it going to be approved?"
Once we get the applications in, we get category-specific reviewers and we form ad hoc panels to review these grant applications.  Typically, we get about 100 applications.  Sometimes, we get a few more, but it guarantees that the applications, for example, that have to do with blood and blood products will not be reviewed with applications that have to do with other disorders, orthopedics or neurology.
We will do literature searches and we will find the experts in these fields so that even if a product does not get funded that particular year, we will prepare a summary statement and tell you what you need to do to get it funded, perhaps, in the future, where your science is off.
Then we take it to a national advisory council and the grant is awarded.
[Slide.]
We award approximately 20 to 25 new studies a year.  It really depends on how much money we have in a given year and where we are going with that, how much money has to go to continuing studies.
The program review criteria that we do, just so that you know exactly what we are looking for in the application is, of course, we have to be sure that your prevalence is under 200,000.  We ask you to document that.  I have already told you that you have to have an active IND or an IDE.
[Slide.]
And then, when it goes to ad hoc panel review, this is a scientific and technical-merit criteria that we ask for.  It is important to note that we get all of our reviewers from the academic community.  We have no one from business on our committee.  It is an anonymous process that we never reveal the names of our reviewers for any ad hoc panel.
We do this so that we get the best review and because, a lot of times, there are only a handful of experts in that field.  We don't want to discourage anyone.  If we are asked to reveal the names of our reviewers, we will give you the names of everybody in our reviewer database, which is presently about 600 reviewers.  But it changes.  Every year when we have a new panel, we make it up of new people.  And we have a rule that we cannot have the same panel twice.  So there will always be new members that will be added to this.
These are just the normal things that you would expect to see.
[Slide.]
We look for adequacy of the resources.  This is where something like an SBIR other sources of funding take place.  I haven't told you yet.  The dollar amounts are not great for funding a clinical study.  They are $200,000 per year for up to three years but you are also allowed indirect costs.  So it can be substantially more than that.
So it is perfectly okay and it is very much encouraged that you seek other sources of funding as well.  Our grants can go to either for-profit or non-profit organizations.  It makes no difference to us.  We limit it to small businesses, however that is defined.
We want to make sure that you do have the product, that you have justified that budget and that, if you tell us that you need a million dollars and you have only asked us for $200,000, where are you going to get the rest of the money for the study.
Of course, you have to have informed consent and IRB approval.
[Slide.]
We anticipate that the FY 2000 RFA is going to be coming out sometime in July.  Right before I left here, I got an E-mail saying that it had cleared general counsel.  So I anticipate that it will be in the Federal Register in the very near future.
As soon as it gets up on the Federal Register, then we will also put it on our website.  So if you are looking for it, you can call the office.  You can E-mail us and we will send you a copy of that.  We will have two due-dates.  The first one is November 15 and the second one is April 1 of the Year 2000.
Our money is tied to fiscal year which means that we have to spend all of our money by September 29 of the year 2000 when the money becomes available.  We will do just that.  So it really makes very little difference if you apply in November or whether you apply in April of any year.  What it will do, if you have a stupendous score when you go to the ad hoc panel, you might get funded about two or three months before the grants that were submitted in April.
But we take all of the applications and we put them all together and we fund until the money goes out.
There is one other point that I would like to make and that is if you do get a grant or if you need any information about grants or if you have an orphan product, we have a staff of people--it is not a huge staff--but we have a staff of people that will help you walk through this whole process.  We are delighted to have all comers and we would welcome applications or phone calls from anyone that is interested in developing these products.
Thank you.
DR. HOLLINGER:  Will you write the grants, too?
MS. ROBUCK:  No; but I might be able to tell you what to put in there and what not to put in there.
DR. HOLLINGER:  Thank you very much.  Appreciate it.
We are under a little time constraint here and I really must apologize to the committee and everyone here.  But, apparently, there is something outside, a class reunion or something, that is going to be barging in here before too long.  We have got a little bit of extra time, but I do want to give everybody a chance to talk and then we will have to come back to this.
So if you will bear with me, let's go through--we have several speakers who have asked to speak on the HTLV supplemental test.  They have five minutes, each one, no more than that.  The first one is Dr. Michael Ussery from Innogenetics.
	Open Public Hearing
DR. USSERY:  I have slides for ten minutes, so I will cut it.  Dr. Busch has actually already mentioned our product.
[Slide.]
This product was just approved on the 15th of June in France on the basis of three studies that I will mention and that are published.  They are retrospective studies of multiply reactive samples.
[Slide.]
It is a line immunoblot assay for the confirmation of antibodies to HTLV.  You can use either serum or plasma.
[Slide.]
There are control lines on the strip as well as the confirmatory lines that Dr. Busch mentioned to you and the discriminatory lines that allow a determination of a HTLV I or II infection.  I did provide handouts to the committee.  It looks like most of you have them.
There are a few slides that are not in those handouts and I will be happy to E-mail anyone a powerpoint including those.
[Slide.]
This is a description of the controls.  I think that might not be in the handout.
[Slide.]
There is a semiquantitation that is allowed by the strip but it is certainly not a quantitative assay.  The different antigens, either recombinant proteins or synthetic peptides that go up to make the materials that are on the strips.
[Slide.]
The test procedure involves an overnight incubation with the sample.  Often, that is started as soon as the reactive result is gained on the initial test.  Once that result is there, the labs often put these on overnight and then a couple of steps the next morning.
[Slide.]
This is an example of a result on a strip that shows that HTLV I pattern.  So it is positive in the confirmation lines in the middle, the last two, and in the first two, one specific discriminatory line in the bottom panel.
[Slide.]
This is one of the studies that was used for approval in France--this is from the Rega Institute in Belgium--looking at a number of samples, comparing them with the GeneLabs 2.4 assay.  In this case, you can see a negative that was called positive by the GeneLabs.  This was confirmed negative by PCR.  All of the discordant results that we have here were confirmed by PCR when we had cells.
There was a call of a 2 with the GeneLabs.  That was determined to be a 1.  And that was additionally confirmed by serotyping.  We didn't have cells to do that.
[Slide.]
One of the big problems with the 2.4 western blot as well as the 2.3 is the number of indeterminates.  We determined that 24 of those were negative and confirmed all of those by PCR.  There are a few other differences in the chart that you have.  Those were all confirmed.
[Slide.]
This western blot of indeterminate was confirmed to HTLV II both by the INNO-LIA and by PCR.  A number of indeterminates, most of them fall out as negative.
[Slide.]
Obviously, the LIA is not a western blot.  It is a plastic-bag strip.  It can be automatically read as well as manually read with our auto-LIA and our scanning procedures.  There are control lines and antigen lines fixed on the membrane.
[Slide.]
Just some characteristics, semi-quantitative.
I think that is all the slides.  In the interest of time, there are two other studies that were used and I only received the publication for one study on Monday that was from the Journal of Clinical Microbiology in May of this year.  That study was in Brazil.  There we had 18,000 donors that we looked at which 292 repeatedly reactive samples.  And, by western blot, there were 172 indeterminates out of that 292.  And we were able to show and confirm by PCR that 153 of those were actually negatives.
There were 54 samples that were nontypable but we were able to type.  There were actually 69 typables.  Our test could type 54 of those 60.  There was one other study that was performed in France, and I have the reference for that as well, that was done on commercially available samples.
So I think, in the interest of time, I will stop.
DR. HOLLINGER:  Thank you very much.
The next speaker is Ms. Birgit Fleurent from GeneLabs Technology.
MS. FLEURENT:  Good afternoon, everyone.
[Slide.]
I am going to put some overheads up but I think I will probably save you three minutes of time because, kindly, most of the presenters earlier did talk about the GeneLabs blot and I think the blot has been used, certainly, in other parts of the world as well as in the U.S.  So I am not going to go into detail on the performance of the product but just give you an overview of some of the issues that we have faced.
[Slide.]
Just to reiterate, the product is available in the United States for research use only.  The labeling has been approved both by CDRH and CBER as a research-use-only product and is offered as such.  We do sell this product, as Dr. Busch pointed out, widely throughout Europe.  It is approved by the French Agence de Medicament as well as the Portuguese Inframed.  We sell the product additionally in Latin America and it is registered in various parts of Asia as well.
[Slide.]
We have faced two major issues hindering the submission of a license application.  Both of these were pointed out earlier so I will just go briefly through.  We certainly value the importance of having a research-use-only product used the way it is designated to be used.
One of the problems we had in 1997 when the product was first held and relabled is the length of time it took to go through that process.  There was a disconnect, we felt, between CBER and the local compliance office.  It actually took six months to go through the relabling effort and cost us significantly both in the relabling process and in the loss of revenues.  So that was an issue that we worked through but that did cause a significant delay for us.
[Slide.]
And then, as already pointed out, the economic feasibility is questionable.  I was very pleased to hear the presentations just now by Susan and Patricia and I am sure you will be hearing from us next week.  But, because of the population, and going through internally the development costs that would be needed to meet the current regulatory criteria, the potential revenue just doesn't justify the expense.
[Slide.]
We have considered options internally.  Some of these were just mentioned.  The orphan products grants I think is something we do want to pursue at this point.  Individual investigator INDs have been discussed but we haven't taken any of these to the agency as of yet.
[Slide.]
Then, last, again as has been discussed earlier today, we would like to have assistance.  We do realize and we believe that there is diagnostic significance and benefit to both the laboratory and the patient in having supplemental tests approved.  So we would like to see more public awareness or contribution and commitment towards some of these additional sources of funding.
Thank you.
DR. HOLLINGER:  Thank you, Birgit.
The next speaker was to be Dr. Bentley Moyer, but I think Dr. William Andrews is going to speak in his behalf for Chiron.
DR. ANDREWS:  Hi.  My name is Dr. Bill Andrews and I am currently a development scientist in the Blood Testing Division at Chiron Corporation.  I would to thank the committee for the opportunity to provide a statement regarding the availability of the supplemental tests for the detection of anti-HTLV I, II.
Several years ago, Chiron Corporation, through its joint business with Ortho Clinical Diagnostics, began development of the supplemental test for the detection of anti-HTLV I, II.  This test, which is based upon Chiron's RIBA strip immunoblot assay technology utilizes both recombinant antigens and synthetic peptides encoded by the specific strains of HTLV I and HTLV viruses.
Our early development data indicated that the performance of the tests could provide accurate and meaningful results to blood bankers and clinicians in the counseling of donors and patients who are repeatedly reactive by an anti-HTLV I, II screening test.  However, further development of this RIBA EIA test for HTLV I, II as well as an automated system for completing RIBA SIA tests was halted due to our limited resources and the concurrent need to complete development and bring to market our supplemental test to serve a greater public-health need, that is HCV.
While it is now possible to turn our attention to developing new products that fulfill other public-health concerns, we are obligated as a business to understand both the scientific and economic feasibility of fully developing a product which meets the requirements of the healthcare community and the FDA.
With respect to our anti-HTLV I, II supplemental tests in development, a recent collaborative study with Dr. Michael Busch of the Blood Centers of the Pacific and Dr. Sue Stramer of the American Red Cross has indicated that the specificity of the test is a significant improvement over a current means of supplemental testing such as secondary EIA, IFA or research western blots.
Even so, we believe that further development of the test may be required to fully meet the needs of the blood banking and healthcare communities.  Our difficulty has been to further justify any continuing product development or licensing efforts through the allocation of resources given two very significant factors.
First, the anticipated need for such a product in terms of numbers of tests required per year at an expected cost per test is such that our costs for product develop in clinical study would not likely be fully recouped within a reasonable time period.
Associated with this is the lengthy and arduous regulatory approval process.  While we believe that the regulatory requirements, themselves, are, in principle, appropriate for blood-screening products, the reality of this process is such that it adds a significant additional cost to the development of the product.
Unfortunately, the combination of a low anticipated market need and a lengthy regulatory approval process has put Chiron in the position of making a difficult decision moving forward.  As it stands today, the Chiron Ortho joint business is capable of fulfilling this public-health need.
However, the above-mentioned factors effectively preclude us from moving forward into an environment of both greater public health and business needs.  In spite of this, Chiron would be willing to have further discussions with the FDA in order to understand and further evaluate any creative pathways for streamlining the regulatory approval process.
Furthermore, in consideration of the circumstances surrounding the need for supplemental anti-HTLV I, II tests, we believe that it would be important for some federal funding to be made available to help offset the costs of product development and clinical study similar to what has been done with the development of nucleic-acid tests for blood screening through the grants from the National Heart, Lung and Blood Institute.
Assuming that a suitable product could be made available, Chiron believes that it would also be appropriate to grant some extent of market exclusivity following FDA approval of the supplemental anti-HTLV I, II product through a program such as or similar to the Orphan Drug Act.
Through these mechanisms, we believe that there may be a sufficient incentive for potential manufacturers to pursue the complete development and FDA approval of a supplemental anti-HTLV I, II test and, thus, fulfil the identified public-health need.
Thank you.
DR. HOLLINGER:  Thank you.
The next speaker is Dr. Tony DeMarco from Abbott Laboratories.
DR. DEMARCO:  Good afternoon.  I am going to actually talk about more of a follow up to Dr. Sue Stramer's presentation on the dual EIA algorithm.
[Slide.]
Consistent with the two EIA testing algorithm presented by Dr. Stramer, we would like to present data obtained using the two-test algorithm that utilizes the Abbott PRISM HTLV I, HTLV II test following its approval in the United States and the currently licensed HTLV I, HTLV II EIA.
[Slide.]
A description of these two tests is shown on this slide.  The Abbott PRISM HTLV I, HTLV II test is a viral-lysate-based direct chemiluninescent immunoassay with a repeat-reactive rate from U.S. clinical trials of 0.07 percent.  The Abbott HTLV I, HTLV II EIA is an indirect enzyme immunoassay with a repeat-reactive rate of 0.16 percent from reporting sites in the United States, year to date 1999.
We believe that these tests fulfil the criteria established for different tests as defined in the recent FDA guidance document for HTLV testing.
[Slide.]
The evaluation of this two-test algorithm is performed by testing approximately 2200 random donor blood specimens at four geographically distinct testing sites around the United States and one site in Canada.  Specimens that were repeat-reactive by the PRISM HTLV I, II test were tested by the Abbott HTLV I, II EIA and, according to the algorithm, concordant reactive specimens were evaluated by western blot.
The results of the testing algorithm are shown on the next slide.
[Slide.]
In this evaluation, there were sixteen specimens or 0.07 percent of the total number of donors tested that were repeatedly reactive by the Abbott PRISM HTLV I assay.  Twelve of those specimens were nonreactive in the HTLV I EIA test and no further testing would be required according to the algorithm.
Four of the specimens, or 25 percent, or 0.02 percent of the overall number, were repeat-reactive by the Abbott HTLV I EIA and those went on for further western blot testing.  Two of those were negative and two were indeterminate. 	
Although the data are not shown here, the reverse algorithm was also evaluated where we tested the same set of specimens by the EIA first followed by the PRISM HTLV test.  In that case, all of the discordant specimens--that is, the specimens that were repeat-reactive on either of the tests were evaluated by western blot and by the RIPA.  None of those samples were found to be positive.
Because there were no true positive specimens among this set of donors, we evaluated a large set of previously identified positive specimens using this algorithm.
[Slide.]
In this study, we took 601 specimens that were identified previously to be positive for HTLV I or HTLV II.  It was actually approximately an even mix of the two types.  100 percent of the specimens were repeat-reactive by the PRISM test and by the EIA test.  Of course, all were positive upon western blot testing.
[Slide.]
In summary, the PRISM HTLV I, HTLV II test shows high specificity at 99.93 percent.  When used in conjunction with the Abbott HTLV I, HTLV II EIA as a second screening test, only 0.02 percent of donor specimens would require testing by western blot.
This dual-test strategy, employing the PRISM and the EIA test, will reduce the overall number of samples requiring western blot, thereby reducing the number of samples with indeterminate results.
So, in conclusion, the data are similar to those presented by Dr. Stramer except that the number of specimens requiring supplemental testing is expected to be lower with the introduction of the PRISM HTLV test.
Thank you.
DR. HOLLINGER:  Thank you.
The final person who asked to speak today is Dr. Busch who is going to talk from the AABB viewpoint.
DR. BUSCH:  Let me just go to the bottom line here.  I think you were all distributed the statement which basically Steve Kleinman developed and walks through all the issues we have heard today.
Just to go to kind of the bottom line, I think the unavailabity of appropriate confirmatory tests has not only precluded appropriate donor notification but it has also hindered epidemiologic surveillance of HTLV in the donor base.  The AABB encourages FDA to consider the following options.
First, to encourage manufacturers to improve the specificity of FDA-licensed screening tests.  The downside of that, as you have just heard, is these alternative EIA strategies and better specific tests leads to an even smaller market for the supplementals, so it is even more problematic issue around bringing the confirmatory tests forward; license screening tests that improve specificity as compared to those available today; encourage manufacturers to develop supplemental test strategies such as those used in their clinical trials for FDA approval; continue to allow the use of alternative supplemental testing strategies such as the dual EIA testing algorithm; and provide regulatory pathways that both encourage manufacturers to develop supplemental-test kits for use under IND and then provide streamlined mechanisms for their widespread availability to the marketplace.
This must include simplified approaches to clinical trials, systems validation and FDA licensure mechanisms.  If FDA considers that issues of donor reentry or consignee notification would interfere with the development of a streamlined approval mechanism, then we recommend that FDA consider using such mechanisms to approve the use of supplemental-test results for donor counseling and not for regulated manufacturing function.
DR. HOLLINGER:  Thank you, Michael.
	Committee Discussion
DR. HOLLINGER:  I am going to open this up for committee discussion at this time.  I am going to close the public hearing.  Any discussion from the committee?  Any issues.
I have some difficulties with these assays.  What is often done is an EIA or a regular test is done.  You get some repeat-reactives.  Then, the non-reactives, you sort of ignore as if the gold standard has been the EIA test.  Then you go down this group over here and you find that some are positive and some are negative, and so on.
Really, I guess if you are setting something up like this, you would want all positive western blot.  If you  say the western blot or RIBA or whatever the assay is, any of the strip assays and so on, if they are the gold standard of what is a true positive assay, you would think that you would start with those and then go and look and see how the regular tests come out, because this idea, often, of using a couple of different EIA tests saying, "Well, one is good and the other one is maybe not so good.  Which one are we going to count on?  Which one is going to be our gold standard?"
Can somebody go over this with me, help me to understand this a little bit?
DR. BUSCH:  I think you are referring mostly to this concept of trying to use an alternative EIA strategy.  Indeed, I think Sue Stramer remarked on that with first showing that the two EIAs seemed to be head-to-head sensitivewise.  So if you took two positives that were kind of borderline reactive on your screening test and then you tested them with the alternative licensed HTLV test, they were reactive on that test, too.
But then she actually started to use it and, in fact, was uncomfortable doing further testing on the discordant EIA nonreactives out of concern that if some of those were found to be positive, and suspect that many of them might be false positive because of the supplemental test, that it would be a regulatory problem.
So it is for that reason that the study should describe we actually did, as an unlinked study, and we did take on to confirmatory testing both the RIBA and the western blots, even the samples that were alternative EIA nonreactive to ask that question of was this alternative EIA actually missing some true infections.
What we found was a handful of false positives on some of these supplemental tests but we further took them on to IFA and RIPA and the new GeneLabs antigen and showed that they were false positives.  So those are the kinds of studies that do need to be done but they have to be done with caution because there are regulatory implications in the donor setting.
But I am convinced, at this point, that the alternative EIA strategies are sensitive meaning that the true infections are being sorted into the dual reactive group.  In the donor setting, only about 20 percent of those dual reactives are real.  And that is why we need, beyond that, a supplemental--
DR. HOLLINGER:  I guess that is what I wanted somebody to--I guess, again, maybe, Sue, you can straighten it out for me again.  Let's just take the two that are positive, the ones that are concordant, and what their response is on the strip assays and so on and then the ones that are discordant with either one, in either direction, and what theirs were on the strip assays, how they came out in terms of positives and negatives.
Were there positives in some of the groups that were discordant?
DR. STRAMER:  Yes.
DR. HOLLINGER:  And were there positives in the ones--and what are the percentage of positives in the ones that were concordant?
DR. STRAMER:  For concordance, what I showed is about 24 percent whether it was from the 7 million donors that I showed or the smaller study we did with blood systems.  It was pretty consistent between 10 and 25 percent of concordant EIA repeat-reactives were western blot or RIBA-positive.
So whether we use the recombinant immunoblot or western blot, between 10 and 25 percent confirmed positive which we believe is still an overinflated number.  So, if you look at the discordant category, the only ones that we did further supplemental testing were for the 200 BSL samples and the 128 Red Cross samples.
For the samples on supplemental testing that were discordant from BSL, there were 150 samples.  Of those 150 samples, none--zero--were RIBA-positive, were Chiron RIBA-positive.  None.  So all of the discordants were either negative or indeterminate, and indeterminate is something that you would expect.  So, zero out of 200.
For the Red Cross part of that equation, there were 128 samples.  93 were discordant.  Of those 93--that is, reactive only by one EIA and not another--three, we found as RIBA-positive.  When we found those as RIBA-positive, I called Mike and I said, "Why did you get me involved in this stuff?"
And Mike says, "Well, maybe they are true positives."  And I said--I won't repeat what I said.  I said, "We need to investigate these further."  So then, what we did, is we know that p21--first of all, we did a western blot on them.  On western blot, they all showed incredibly strong p21e reactivity which is what drives the positivity even on the RIBA test.
So we knew that there was something in common, which was p21e.  Because p21e has historically been associated with false positivity, that is why we tested it then on the GD21 which is the GeneLabs construct that has eliminated this area of p21e that has been associated with false positivity.
So all three samples we found to be GD21-negative.  Because I was still concerned that p21e is not the only criteria we should use, we further sent them to what I still consider the gold standard for HTLV which is radioimmunoprecipitation assay.  The only person on the planet that I know who still does this testing is California State.
So we sent them to Janice Diggs at California State and she did a viral lysate HTLV I and HTLV II immunofluorescence assay and also did RIPA.  And they were negative on those.
So all we had, basically, was isolated p21e reactivity in the discordant EIA-reactive samples.  Really, if you look at the donor demographics of these individuals, these are normal, routine blood donors who have absolutely no risk of HTLV.  In fact, most of our confirmed positives fall in that category as well.  So even if I showed prevalence of 10 per 100,000, if I go further back into the Red Cross history, that is really where Mike started.
Mike started showing the Red Cross data where, in the beginning, when HTLV tests were first licensed, we used two supplemental tests, either western blot or RIPA, and then we substituted the western blot for a single p21e test which is also used in combination with RIPA.  HTLV is a very difficult agent to get a good supplemental test for.
There just has not been--well, it is the same thing.  There hasn't been good development and commercialization of that.
So I hope I answered your question.
DR. HOLLINGER:  I appreciate it.
DR. NELSON:  Have all of these assays been evaluated in populations that have higher prevalence and that is known, like Japanese populations for HTLV I or the Indian--the places where HTLV II is endemic?  Is anything known about the population where the rate of true infections is higher, all of these assays?  How do they perform there?
DR. BUSCH:  The published papers that there are on each of these tests have looked at large numbers of endemic pedigreed, PCR-pedigreed, infected people from all these different geographic settings.  So they seem to have very good sensitivity, to my read.
DR. HOLLINGER:  I think something has come out here from some of the people who have spoken is this idea of what is available from the government standpoint in terms of funds.  I think that is an important issue that has been brought here and, hopefully, they will be utilized.
Anyone else have any comments?  I am not sure, Jay, other than to get this issue out in the open, what you want from the group here.
DR. EPSTEIN:  We have been frustrated for some time, really since 1988, about the lack of development of commercial supplemental tests for HTLV I and now HTLV II.  We wanted to bring forward our best thinking on the dimensions of the problem trying to illuminate what the apparent obstacles are and what the apparent remedies might be.
We are really just looking to A, make this public and B, to see if there are any additional suggestions from the committee members.  My own view of the situation is that the remedy that is needed is really economic.  FDA historically does not deal directly in that area.  I think what is needed is to find a way to subsidize the tests under GMP manufacturing.
One dimension that really didn't come out today--a lot was said about the cost of trials, but that is a one-time, up-front cost.  It gets amortized over a period of years.  The real problem is that the GMP manufacturing can't be paid for by the sales.  So the question is how do you subsidize continued manufacturing under GMP.
I don't know the full answer but, to my way of thinking, one possible answer is to figure out a way for screening to subsidize supplemental testing.  There are many ways that one could try to do that whether those would be fund transfers from organizations, surcharges at the blood unit, vertical integration of screening companies.
You can think of ideas, but the bottom line is that the money lies in screening but there is a need for confirmation.  The demand lies with the blood community.  There should be a way to figure out how to link these things up.
The other thing that I would say is that FDA can show flexibility in terms of the trial requirements based on what data we can accept for review.  What I am hearing is that there is lots of clinical data.  It just hasn't been gathered under INDs.  That doesn't preclude the agency from examining it if it does meet standards; in other words, if the human subjects of investigation were treated in accordance with Helsinki accords, if there are evaluable records, if the product can be shown to have been consistent during the course of the trial, et cetera, et cetera, et cetera.
So one shouldn't assume that because the data that exists weren't already obtained under IND or they were foreign data that we can't look at those data.  We potentially can but it still has to meet U.S. standards.  So I think there is a set of issues and I think it is very encouraging that there is continued development in the industry.  We just have to figure out a way for the products to be developed under U.S. law.
DR. NELSON:  Could the FDA somehow require that a screening instrument go beyond the purpose of just excluding potentially high-risk donors to the point of not only excluding them but also notifying them of their health status, therefore requiring some sort of a supplemental evaluation of a positive screening test.
In other words, the approval would not be only the initial screening test but some sort of a process that would affectively deal with the potential false positives in that screening.
DR. EPSTEIN:  Again, we took that approach in the mid-80's.  We were successful initially with the HIV test in that the companies offering the EIAs offered in-house testing services for supplemental testing.  The quality of those tests was highly variable and there was a lot of criticism over false-positive results and false-negative results of those tests that had not been evaluated as rigorously as the screen.
We then attempted to do the same thing in the arena of HTLV but we were heavily criticized for holding up HTLV screening.  So we allowed them to go their own way, partly with this result.  And then, also, as you see, there is the problem that when we have taken the compliance posture on unapproved tests being marketed that were approved for research-use-only and then were commercialized for clinical use, the market then dried up.
So the problem is that we need to figure out a way for companies to play by the rules.  But we can continue to encourage the companies that have screening tests to provide supplemental-test services.  I am not sure that the best mechanism is FDA regulation.  I think the consumers should demand it.
If they didn't sign contracts with test-kit providers of the screening tests unless they offered supplemental testing, this environment would change.  I think that there is a lot of power in that kind of market leverage.  It doesn't mean that the screening-test manufacturers have to manufacturer it.  They could create business partnerships with other manufacturers that know how to manufacturer it.
So I just think that all the possible options haven't been exercised and that not everything needs an FDA regulatory solution.
DR. HOLLINGER:  When you have something like an orphan drug or something like this where you finally license to one company and you sort of prevent, basically, competition from others so that they can actually get a toe hold--if you have several companies there, then that creates a little problem, particularly if you are looking at this where I think the last one I saw was you take 20,000 and you get 16 positives, so that would be what, out of 2 million?  It was be 1600 positives, and so that would be maybe 8,000 positives maybe out of the blood supply.
If you have to separate that out into four or five different companies, it is going to be tough.  It seems to me that if you are going to do this, then you are going to almost have to do, like the orphan drugs sometimes.  You say, "We are going to license this to one company."  And that's it, to me if you are going to have anything that is commercially feasible.
Or the government is going to have to make their own test which is something you haven't gotten into.  But for something like this, that would be the other thing, that the government do this.
Any other thoughts?
DR. FITZPATRICK:  Since Organon is not here and Abbott is, I just had one question since, obviously, Organon and Abbott won't qualify for an SBIR or an STTR, are you partnering or involved in providing research money to a small company to develop a partnership for this to help offset it?
MR. KLAMRZYNSKI:  Matt Klamrzynski from Abbott.  We continually have collaborations with firms but to give you any specifics right now, no; we don't have any.
DR. HOLLINGER:  But that is a possibility, I suspect.  Wouldn't it be?
MR. KLAMRZYNSKI:  Yes.  It would be a good way to work, a large company work with a small company, get the SBIR money and provide them their expertise in helping develop the assay.
DR. STRAMER:  Just to address some of Dr. Epstein's comments.  Having been with industry now in the blood banks, kind of you do see both sides of the equation.  I have called all of the companies.  It has been very impossible to tie these to contracts because neither large manufacturer doesn't have supplemental assays for all markers.  Some may have for one, and some may have for the other, so it is very difficult to get a full plate of exactly what you need.
The companies are moot as far as answering the questions.  Whether the companies partner with small companies to provide, as the comment was just made, additional incentive, well, we at the screening test wanted partner either with RIBA or with Innogenetics--we have tried that route as well.  It has not been successful.
So then, as Mike said, in the AABB comment, well, now we think maybe if do partner INDs like we do for NAT, we can take some of these small companies and show them that the FDA obstacles are not insurmountable and, with good data, we can get the job done.
So we are trying, now, to pursue the dual IND strategies.  But all the small companies are so fearful of what manufacturing costs they have to do, the cost of clinical trials, and what happens if we get a false negative in our clinical trials?   So what I have responded to them is, so you put it in your labeling.  That is what you have got.  And then, "Buyer beware."
We just have to deal with it from that.  At least something would be available.  But there is a tremendous amount of inertia because of the fear that is involved in moving forward.  I don't really know what that is there, but it is.
DR. HOLLINGER:  Any other comments?  You can see that this is, obviously, Jay, a real problem, as she has just spoken to, the fact that the small companies are concerned about not being able to make it.  A large company could probably do it and write it off, possibly write it off on these small areas of things like this.  You buy things in the supermarket that are writeoffs--with small stuff like this.
A lot of money is made in other parts of their products and one has to consider that, too.  Sometimes, you have to step up to the plate, do the right thing.
DR. OHENE-FREMPONG:  What is the precedent for the CDC establishing a test that may not be available commercially but which could serve blood banks, in this case.
DR. HOLLINGER:  Sort of as a reference lab?
DR. OHENE-FREMPONG:  Like a reference lab.
DR. HOLLINGER:  With that small number, it could be like a reference lab.
DR. KHABBAZ:  I really have no comment.  There are a number of other examples of areas of orphan diagnostics and orphan vaccines and others that we struggle with.  There are no easy answers.
DR. HOLLINGER:  You don't have an answer.
DR. KHABBAZ:  No.
DR. NELSON:  They do for parasitic diseases.  That has been one area--or unusual diseases.
DR. KHABBAZ:  But they are rare.  You are talking about--we heard the screen results and we heard the numbers.  This is larger than any other disease or agents that we have offered reference to.  There is no precedence, given the numbers and the size of this, for offering reference confirmatory--
DR. HOLLINGER:  If there are no further comments, then I am going to close the meeting at this time.  The next meeting of the BPAC is September 16 and 17.  We will let you know where it is going to be.
[Whereupon, at 3:10 p.m., the meeting was adjourned.]
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