Food and drug administration center for biologics evaluation and research vaccines and related biological products



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UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
VACCINES AND RELATED BIOLOGICAL PRODUCTS
ADVISORY COMMITTEE
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MEETING
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TUESDAY,
JANUARY 30, 2001

The meeting was held at 9:00 a.m. in the Versailles Rooms I, II, and III of the Bethesda Holiday Inn, 8120 Wisconsin Avenue, Bethesda, Maryland, DR. ROBERT DAUM, Acting Chair, presiding.

PRESENT:
MARY K. ESTES Ph.D.

STEVE KOHL, M.D.

KWANG SIK KIM, M.D.

ALICE S. HUANG, Ph.D.

ROBERT S. DAUM, M.D.

DIXIE E. SNIDER JR., MDD., M.P.H.

SAMUEL L. KATZ, M.D.

DAVID STEPHENS, M.D.

DIANE E. GRIFFIN, M.D., Ph.D.

AUDREY F. MANLEY, M.D., M.P.H.

PAMELA DIAZ, M.D.

BARBARA LOE FISHER

JUDITH D. GOLDBERG, D., S.c.D

WALTER L. FAGGET, M.D.
PRESENT: (cont.)
NANCY CHERRY

Executive Secretary
DENISE ROYSTER

Committee Management Specialist
CONSULTANTS PRESENT (voting):
PATRICIA FERRIERI, M.D.

EDWIN KILBOURNE, M.D.

MARTIN MYERS, M.D.
GUESTS PRESENT:
NANCY COX, Ph.D.

COLONEL BENEDICT DINIEGA, M.D.

MICHAEL DECKER, M.D., M.P.H

DR. LANCE RODEWALD, CDC

DR. WENDY KEITEL

DR. KEIJI FUKUDA, CDC

DR. ALEXANDER KLIMOV, CDC

MS. LINDA CANAS, DOD

MR. ALAN HAMPSON

DR. JOANNA ELLIS





FDA REPRESENTATIVES PRESENT:
DR. KATHRYN ZOON

DR. KAREN MIDTHUN

MR. ZHIPING YE

DR. ROLAND LEVANDOWSKI



MANUFACTURER REPRESENTATIVES:
DR. GREG SLUSAW, PhRMA

MR. JOHN O'BRYAN, EVANS VACCINE

MR. RICHARD HJORTH, WYETH

I‑N‑D‑E‑X
AGENDA ITEM PAGE
Call to Order/Welcome 4

Dr. Robert Daum, Acting Chair
Introduction of Committee 4
Conflict of Interest Statement 6

Tara P. Turner, Pharm.D.

Executive Secretary, AVAC
Introduction and Updates

Dr. Roland Levandowski, FDA 8

Dr. Lance Rodewald, CDC 30

Dr. Wendy Keitel, Baylor 60
Presentation to Retiring Members

Dr. Katherine Zoon 81
U. S. Surveillance 85

Dr. Keiji Fukuda, CDC
World Surveillance and Strain Characterization

Dr. Nancy Cox, CDC 95
Molecular Characterization of Strains

Dr. Alexander Klimov, CDC 108
Additional reports

Ms. Linda Canas, DOD 117

Mr. Alan Hampson, WHO 134

Dr. Joanna Ellis 148
Vaccine Responses

Dr. Roland Levandowski, FDA 156
Availability of Strains and Reagents

Mr. Zhiping Ye, FDA 189
Comments from Manufacturers

Mr. Greg Slusaw 201
Options for Strain Selection

Dr. Nancy Cox 220
Committee Discussions and Recommendations 240

P-R-O-C-E-E-D-I-N-G-S

(9:05 a.m.)

CHAIR DAUM: Good morning, the meeting is officially in session. For people that don't like surprises, Dr. Zoon will not come at 8:15 to give plaques to retiring VRBPAC members, but will rather come about 9 o'clock.

So we will proceed with the Agenda and begin hearing about influenza issues, and then take a break before Dr. Zoon's presentation, and a photo-op, if you will, of the VRBPAC committee at the same time.

We will begin with the usual introductions of the committee. And, Dr. Snider, I can barely see you out there. Maybe it is my glasses, but we will maybe ask you to start, and we will go around the table and introduce ourselves.

DR. SNIDER: Dixie Snider, Associate Director for Science, Centers for Disease Control and Prevention.

DR. STEPHENS: David Stephens, Emory University, Atlanta.

DR. KIM: Kwang Sik Kim, Johns Hopkins.

DR. GRIFFIN: Diane Griffin, Johns Hopkins.

DR. HUANG: Alice Huang, California Institute of Technology.

DR. KOHL: Steve Kohl, Oregon Health Sciences University.

DR. MANLEY: Audrey Manley, Spellman College.

DR. DIAZ: Pamela Diaz, Chicago Department of Public Health.

MS. FISHER: Barbara Loe Fisher, National Vaccine information center.

DR. ESTES: Mary Estes, Baylor College of Medicine.

DR. FERRIERI: Patricia Ferrieri, University of Minnesota Medical School, Minneapolis.

DR. MYERS: Martin Myers, National Vaccine Program Office.

DR. GOLDBERG: Judith Goldberg, NYU School of Medicine.

DR. KILBOURNE: Ed Kilbourne, New York Medical College.

DR. DINIEGA: Ben Diniega, Department of Defense health Affairs.

DR. COX: Nancy Cox, CDC Atlanta.

DR. DECKER: Michael Decker, Aventis Pasteur in Vanderbilt University.

DR. LEVANDOWSKI: Roland Levandowski, Center for Biologics.

CHAIR DAUM: And I'm Robert Daum from the University of Chicago. Thank you.

We will now move on to Nancy Cherry, who will advise us of conflicts of interest.

MS. CHERRY: Well, first of all I will comment that we are happy to have Dr. Daum as Acting Chair today. Also, you may or may not know that FDA is in the process of appointing industry representatives to each of the committees.

And, today, we have Dr. Decker acting as a guest, but in that capacity for our Committee.

My final announcement is for any of you that are parked at the public parking lots across the street where you feed the meters with many quarters, please be vigilant, because the Montgomery County's finest are also vigilant.

The following announcement addresses conflict of interest issues associated with the meeting of the Vaccines and Related Biological Products Advisory Committee of January 30th, 2001.

Based on the agenda made available, it has been determined that the committee discussions for the influenza virus vaccine formulation present no potential for a conflict of interest.

The Director of the Center for Biologics Evaluation and Research has appointed Drs. Theodore Eickhoff, Patricia Ferrieri, Edwin Kilbourne and Martin Myers, as temporary voting members for the discussion on the selection of strains to be included in the influenza virus vaccine for the 2001-2002 season.

And I would add that we are sorry that Dr. Eickhoff could not be with us today.

In the event that the discussions involve specific products or firms not on the agenda, and for which FDA's participants have a financial interest, the participants are reminded of the need to exclude themselves from the discussions. Their recusals will be noted for the public record.

With respect to all other meeting participants we ask, in the interest of fairness, that you state your name and affiliation, and any current or previous financial involvement with any firm whose products you wish to comment on.

And I will now turn it back to Dr. Daum.

CHAIR DAUM: Thank you, Nancy. I think we will move, without further ado, right into the topic of the day, the strain selection for influenza virus vaccine.

And we will begin with a trilogy of presentations that may be broken, as I mentioned by plaque presentations and photo ops. And we will call on Dr. Levandowski of the FDA to introduce us to the topic, and present us some information about what has happened since last year.

DR. LEVANDOWSKI: Thank you, Dr. Daum. I would like to welcome everybody here to this meeting. And, as usual, there is lots of excitement, not the least of which is getting all of this together.

We are trying to present, or use, some new technology here, and hope that this is going to work. However, if our power point doesn't work I think everybody is prepared with either slides or overheads to back this up, so we will just dive in and get started.

As everybody knows we are here today to begin the process of selecting the influenza virus strains that are going to be included in the vaccines prepared for 2001-2002 in the United States.

The question to be answered by the committee is shown on this slide, and it is the same one we ask every year, and that is, what strain should be recommended for inclusion in the inactivated vaccine for the coming year.

In formulating an answer to that question I think it is helpful to review a few facts about the currently approved inactivated influenza virus vaccines. Inactivated influenza vaccines act primarily to induce the production of antibodies.

The hemagglutinins and the neuraminidases of the incorporated influenza virus in current vaccines are concentrated, and partially purified, to remove extraneous material derived from the eggs in which the vaccines are produced.

Although antibodies to both the hemagglutinin and the neuraminidases may be protective, influenza virus vaccines are standardized currently only for the content of hemagglutinin.

And, therefore, the greatest emphasis is placed on the viral hemagglutinin and in the selection. However, the neuraminidase receives consideration since it, too, may add to the protective efficacy of vaccines.

Since the use of the first inactivated vaccines in the 1940s, it has been very clear that one of the most important predictors of vaccine efficacy is the match of the vaccine virus with the influenza viruses that are causing infections.

What has also been made clear, with yearly epidemics and pandemics, is that influenza virus have great scope for antigenic diversification.

Ongoing random mutations of the hemagglutinin and the neuraminidase, which we refer to as antigenic drift, and exchange of entire genes with other influenza viruses that we refer to as antigenic shift, both participate in influenza virus evolution.

It may also be helpful to the committee's deliberations to consider answers to the questions shown on this slide. Most importantly it is necessary to know if new influenza virus is revolving in nature.

An extensive global network exists to collect and analyze information, throughout the year, as we are going to hear shortly, from colleagues at CDC and other national and international institutions, this morning.

When new viruses are identified, and they almost always are, the extent of geographic distribution helps to judge the urgency in changing the composition of the vaccine. Often antigenic variants appear, but sometimes they are dead end branches on the evolutionary tree.

As we've seen in the case of some influenza B viruses in Asia, in the recent past, they may even be spread in a geographic location without subsequent globalization of those strains.

Of course we have seen, also, just the opposite with influenza A viruses transported freely and rapidly across hemispheres by modern travel habits.

If new strains can disseminate widely it is useful to know whether current vaccines are likely to produce some measure of protection. If it appears that current vaccines could be suboptimal, then it is still necessary to consider whether there is a strain that is suitable to permit large scale manufacture of vaccine within the perennial constraints of time.

We are prepared to assist, this morning, by supplying information in each of these areas. Customarily there is a brief review of the previous year's experience.

However, this year we are going to expand on the review of the production year just past. As everyone is, undoubtedly, aware there was a serious and unprecedented delay in distribution of influenza virus vaccines in the United States during the production season that is just ending.

It is now possible to state with certainty that the amount of vaccine produced for distribution in the United States during 2000 was similar to the amount produced and distributed in 1999.

However, by all reports the disruption to the accustomed schedule for use of influenza virus vaccines in the fall months has been severe. Even though there appears to be sufficient vaccine to supply the existing demand, the lack of vaccine at the time it was expected for use, in effect, was perceived as a shortage.

And just as it takes months of planning and effort to make the vaccine, it also takes a huge effort, and many weeks, to administer more than 70 million doses of vaccine in this country.

This slide helps to demonstrate the magnitude of the delay. And to give some perspective, here, the data are included for 1998 and 1999 when similar total amounts of vaccine were produced.

The data are presented here as the cumulative percent of the total amount of influenza virus vaccine that was submitted to the Center for Biologics Evaluation and Research for testing and release.

The green bars here are information for 1998. The blue bars are information for 1999, and the red ones are the information for 2000.

What you can see is that in all three years, in June there was some vaccine that was produced for release, or it was prepared for release by that time.

However, more than 50 percent of the vaccine was prepared by August in both 1998 and 1999. While the 50 percent point was not reached until October in the year 2000.

You will note that October is also the month when nearly one hundred percent of the vaccine had been prepared in 1998 and 1999. That one hundred percent point was not reached until the end of November, to the beginning of December in this year, in the 2000 season.

In effect it took about six to eight weeks longer to prepare vaccine. And nearly 50 percent of the vaccine was ready for market only after October and November when most practitioners and recipients are now very well accustomed to using vaccine in accordance with recommendations from the Advisory Committee for Immunization Practices at CDC.

The causes of the delay have been reported previously, and I've listed them here. Although there have been several other instances in which one or another vaccine manufacturer experienced an event that delayed manufacturing, there has never been an occurrence when three of the four licensed manufacturers were delayed at the same time.

I think that is the real answer to what happened during this past year.

At two of the manufacturers, Parkdale Pharmaceuticals and Wyeth deviations from good manufacturing practices were discovered during FDA inspections of facilities.

One of those manufacturers, Wyeth, was able to make corrections in time to permit production of vaccine. Although the vaccine distribution began late in 2000.

The other manufacturer, Parkdale, was not able to complete their corrections in a timely manner, and they withdrew from further production.

Another manufacturer, Aventis Pasteur, experienced early difficulties with one of the two new viruses included in the vaccine. And I want to emphasize that there were two new strains that were recommended for the past year.

I think that sometimes has been missed in some of the reports, or some of the conversations.

Although the A/Panama/2007/99 strain grew quite well in eggs, the early yield through the process, as is often true for new strains, was low. However, as is usually true for all manufacturers of influenza vaccines adjustments were made in handling the virus, and eventually satisfactory yields were obtained.

Unfortunately manufacturing is not only labor, but it is also time intensive. And time lost is just simply not regained. During the months that followed the recognition of the situation, FDA, CDC, NIH, and the manufacturers all worked together to develop strategies to minimize the impact of the delay, and to maximize the production and use of vaccine.

In order to give a further explanation of the public health service activities that went on, I'm first going to present some additional data on production.

Following that, Dr. Lance Rodewald, from the National Immunization Program, will discuss some of the CDC activities related to vaccine supply and distribution during 2000.

And, finally, Dr. Wendy Keitel of Baylor College of Medicine in Houston will discuss clinical studies that were sponsored by the National Institutes of Allergy and Infectious Diseases during the past year, to re-evaluate dose response of inactivated influenza virus vaccines.

This slide shows an abbreviated version of the influenza vaccine production cycle. And here I've placed the vaccine use at the top of this little pyramid, since that is what most people see from the production effort.

What is not always obvious for everybody is that there is a continuous effort and a lot of work that goes on to support the preparation and use of the vaccine. And that is what is shown in blue and in black at the bottom of the slide, here.

Working down from the top, the vaccine can't be distributed until it is produced, obviously. Trivalent vaccine is formulated, however, from monovalent components that are produced individually from virus strains having different optimal conditions for growth and purification.

The amount of trivalent vaccine is limited by the poorest yielding strain, as is often pointed out to us by manufacturers. So a great deal of their effort goes into development of seed viruses.

The seed viruses are proprietary for each manufacturer, and they are produced by carefully controlled consecutive passage and eggs. Although each seed virus is unique, all seed viruses are antigenically identical to the referenced strains from which they are derived.

Those referenced strains are recommended by the actions we are undertaking here today. And although the recommendations occur somewhat point events, they really are supported by all that shown below on the slide, here, underneath the recommendations occur at specific time intervals.

But the activities to support that are going on, basically, continuously.

Manufacturers use only strains consistent with the recommendations. But it is sometimes possible to have more than one choice, either from different appropriate wild type viruses, or from multiple high-growth reassortent viruses that are produced specifically to support manufacturing of vaccine at large scale.

The global activities needed to prepare for the recommendations in northern hemisphere countries in January through March, and in the souther hemisphere countries in September through November, help to focus attention and to smooth out the vaccine preparation in many ways, mainly by forcing us to get busy.

Well before the recommendations are made, however, surveillance by CDC and other WHO laboratories identify potential new reference influenza viruses, and it is possible to explore the potential of those new strains for use in producing vaccines well before any of the committee meetings occur.

This slide shows the most recent recommendations. The recommendations on the left are the ones that were made by this committee for the 2000 production year. And the recommendations on the right are those that were made by the World Health Organization for the 2001 production year in the southern hemisphere.

Please note that the recommendations for the H3N2 strain, and the H1N1 strain, which were new for the 2000 vaccine in the United States, are the same as those recommended for 2001 in the southern hemisphere.

In fact the WHO recommendations for the southern hemisphere in 1999 that preceded our 2000 recommendations also included an A/Moscow-like and an A/New Caledonia-like strain.

The current effective recommendations differ only in the B strain, which has been updated in the southern hemisphere to include a newer strain, the B/Sichuan/3799 strain, and the actual strains that are being used for manufacturing right now are the B/Johannesburg 599, and the B/Victoria 504/2000 strain.

This slide shows the timing by month of the year of distribution of strains for the last five new strains that were recommended by this committee since 1998.

The blue filled squares denote reference viruses that were distributed to manufacturers, and the red filled squares denote potency reagents that were distributed for vaccine manufacturing.

The little yellow bars in between indicate the months during which strain recommendations are mad in the United States, just for reference.

What you can see from this slide by Gestalt is that for the two new strains that are recommended for 2000, distribution of the referenced viruses and the potency reagents was as early, or earlier than for previous new strains.

For the A/Panama/2007/99 recommendation four newly prepared high growth reassortants with hemagglutinin and neuraminidase from the A/Panama/2000/799 virus were distributed to manufacturers by the end of January.
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