Page 2
1
2
3
4
5
6
7
8 MEMBERS ABSENT:
9
10 LISA JACKSON, M.D., M.P.H.
11
12
13
14 EXECUTIVE SECRETARY:
15
16 CHRISTINE WALSH, R.N.
17
18
19 COMMITTEE MANAGEMENT SPECIALIST:
20
21
22 DENISE ROYSTER
Page 3
1 A-G-E-N-D-A
2 Open Session
3 Call to Order . . . . . . . . . . . . . . 4
4 John Modlin, MD, Acting Chair
5 Administrative Matters . . . . . . . . . 4
Christine Walsh, RN, FDA
6
Presentation of Laboratory of DNA Viruses,
7 Division of Viral Products, Office of Vaccines
8 Research and Review, Center for Biologics
Evaluation and Research
9
Overview of Research/Site Visit Process,
10 (CBER) . . . . . . . . . . . . . . . . . 10
Carolyn Wilson, PhD, FDA
11
12 Overview, Office of Vaccines Research and
Review (OVRR), CBER . . . . . . . . . . 23
13 Konstantin Chumakov, PhD, FDA
14 Overview, Division of Viral Products (DVP),
OVRR . . . . . . . . . . . . . . . . . . 34
15 Jerry Weir, PhD, FDA
16
Overview, Laboratory of DNA Viruses . . 46
17 Philip Krause, PhD, FDA
18 Q&A . . . . . . . . . . . . . . . . . . . 55
19 Open Public Hearing . . . . . . . . . . . 58
20
21
22 Adjournment . . . . . . . . . . . . . . . 62
Page 4
1 P-R-O-C-E-E-D-I-N-G-S
2 1:04 p.m.
3 ACTING CHAIR MODLIN: Why don't we
4 go ahead and call the meeting to order and I
5 guess I turn things right back over to you for
6 an announcement, right Christine?
7 MS. WALSH: Okay, thank you. Good
8 afternoon. I'm Christine Walsh, the
9 Designated Federal Officer for today's
10 teleconference meeting of the Vaccines and
11 Related Biological Products Advisory
12 Committee.
13 I would like to welcome everyone
14 to this meeting. Today's session will consist
15 of presentations that are open and closed to
16 the public as described in the Federal
17 Register Notice of November 3, 2008. Of the
18 committee members, Dr. Jackson is unable to
19 attend today's meeting and we are waiting on
20 Dr. Gilbert right now. I would now like to
21 read into the public record the conflict of
22 interest record - statement, I'm sorry - for
Page 5
1 today's meeting.
2 The Food and Drug Administration
3 is convening today's meeting of the Vaccines
4 and Related Biological Products Advisory
5 Committee under the authority of the Federal
6 Advisory Committee Act (FACA) of 1972. With
7 the exception of the industry representative,
8 all members of the committee are special
9 government employees (SGEs) or regular federal
10 employees from other agencies and are subject
11 to federal conflict of interest laws and
12 regulations. The following information on the
13 status of this advisory committee's compliance
14 with federal conflict of interest laws,
15 including but not limited to 18 U.S.C.
16 208(n)(712) of the Federal Food, Drug and
17 Cosmetics Act are being provided to
18 participants in today's meeting and to the
19 public.
20 FDA has determined that members of
21 this advisory committee are in compliance with
22 federal ethics and conflict of interest laws.
Page 6
1 Under 18 U.S.C. 208, applicable to all
2 government agencies, Congress has authorized
3 FDA to grant waivers to special government
4 employees and regular government employees who
5 have financial conflicts when it is determined
6 that the agency's need for a particular
7 individual's services outweighs his or her
8 potential financial conflict of interest.
9 Under ^U 712 of the Food, Drug and Cosmetics
10 Act, Congress has authorized FDA to grant
11 waivers to special government employees and
12 regular government employees with potential
13 financial conflicts when necessary to afford
14 the committee their essential expertise.
15 Today's agenda includes updates of
16 the research program in the Laboratory of DNA
17 Viruses, Division of Viral Products, Center
18 for Biologics Evaluation and Research, FDA.
19 Based on the agenda, it has been determined
20 that the committee discussion presents no
21 actual or appearance of a conflict of interest
22 for today's meeting. Dr. Seth Hetherington is
Page 7
1 serving as the industry representative acting
2 on behalf of all related industry and is
3 employed by Icagen, Inc.
4 Industry representatives are not
5 special government employees and do not vote.
6 This conflict of interest statement will be
7 available for review at the registration
8 table. We would like to remind members that
9 if the discussions involve any other products
10 or firms not already on the agenda for which
11 an FDA participant has a personal or imputed
12 financial interest, the participants need to
13 exclude themselves from such involvement and
14 their exclusion will be noted for the record.
15 FDA encourages all other participants to
16 advise the committee of any financial
17 relationships that you may have with firms
18 that could be affected by the committee
19 discussion.
20 That ends the reading of the
21 conflict of interest statement and Dr. Modlin,
22 I turn the meeting back over to you.
Page 8
1 ACTING CHAIR MODLIN: Christine,
2 thank you. I think we'll begin by asking each
3 of the members of the advisory committee to
4 introduce themselves and where they're from
5 and then we'll get started. I'll start. It's
6 John Modlin from Dartmouth Medical School.
7 I'm serving at this meeting as the Acting
8 Chair of the advisory committee. Not
9 everybody at once.
10 DR. STAPLETON: My name is Jack
11 Stapleton. I'm at the University of Iowa.
12 I'm the Director of the Division of Infectious
13 Diseases.
14 DR. ROMERO: Jose Romero, from
15 University of Arkansas from Medical Sciences,
16 Arkansas's Children's Hospital Division of
17 Pediatric Infectious Diseases.
18 DR. SANCHEZ: Pablo Sanchez. I'm
19 at UT Southwestern Dallas, Pediatric
20 Infectious Diseases and Neonatology.
21 DR. DESTEFANO: Frank DeStefano,
22 RTII of Atlanta.
Page 9
1 DR. DEBOLD: I'm Vicky Debold.
2 I'm with the National Vaccine Information
3 Center, Director of Patient Services.
4 DR. HETHERINGTON: Seth
5 Hetherington, Senior Vice President of
6 Clinical and Regulatory Affairs at Icagen.
7 MS. WALSH: Is there anyone else?
8 DR. GILBERT: Peter Gilbert. I'm
9 a Professor of Biostatistics at University of
10 Washington and I'm at the Fred Hutchinson
11 Cancer Research Center.
12 MS. WALSH: Thank you, Dr.
13 Gilbert. This is Christine. I just want to
14 welcome you to the committee. This is Dr.
15 Gilbert's first meeting with us. Welcome
16 aboard.
17 DR. GILBERT: Thank you.
18 DR. DEBOLD: Welcome, Dr. Gilbert.
19 ACTING CHAIR MODLIN: Do we have
20 anyone else? If not, Dr. Gilbert, let me add
21 my welcome to the committee. We'll go ahead
22 and get started. The purpose of the meeting
Page 10
1 today is to review the site visit report for
2 the site visit for the Intramural Research
3 Program and specifically the Laboratory of DNA
4 Viruses in the Division of Viral Products,
5 OVRR, as Christine had mentioned. We have
6 three hours to conduct the review. I don't
7 believe it's going to take anywhere near that
8 amount of time, but at least we do have the
9 time to, I believe, take a somewhat careful
10 and a reasonable approach to this. I'm going
11 to begin by turning things over to Dr. Carolyn
12 Wilson from the FDA who will give us the
13 overview of this site visit process. Dr.
14 Wilson?
15 DR. WILSON: Thank you and welcome
16 to the advisory committee. And I want to
17 start by thanking the members of the site
18 visit committee who came and did the site
19 visit of the laboratory. My talk is going to
20 focus on an overview of how CBER views
21 research in fulfilling its regulatory mission
22 combined with how we manage our research
Page 11
1 resources and finish with some specific
2 information that the site visit needed to
3 consider in its writing of the report and that
4 would be helpful background for you all to
5 consider as well.
6 So to start on the second slide,
7 CBER's mission is to ensure the safety,
8 purity, potency and effectiveness of
9 biological products, including vaccines, which
10 is obviously the topic most relevant to
11 today's review for the prevention, diagnosis
12 and treatment of human diseases, conditions or
13 injury.
14 The next slide is the vision,
15 which is to protect and improve public and
16 individual health in the U.S., and where
17 feasible globally, facilitate development,
18 approval and access to safe and effective
19 products, in harnessing new technologies and
20 to strengthen CBER as a preeminent regulatory
21 organization for biologics. And underlying
22 all of these points is that we are very
Page 12
1 actively engaged in keeping on top of
2 innovative technology and applying it where
3 feasible to advance public health.
4 So, on the next slide if you're
5 using animation you'll see that CBER's
6 approach to regulation is that obviously we
7 work under the laws of the Food, Drug and
8 Cosmetics and Public Health Service Acts
9 combined with regulations that are promulgated
10 from those laws, but underneath of that we use
11 a variety of tools, such as external
12 discussion, active research at CBER, review of
13 data submitted to the IND, as well as internal
14 CBER discussion, and the point here is that
15 the research is a critical component for - I
16 don't know if you have that drumroll on yours
17 or not - rational policy and decisionmaking.
18 So that the point is that the
19 research is critical for us to be able to
20 fulfill our mission. And the way we do this
21 is by having individuals that we call
22 researcher regulators. These are
Page 13
1 approximately 10 percent of our entire CBER
2 staff and these are integrated into research
3 and review activities. They do all the same
4 type of review activities that a full-time
5 reviewer would do, which includes review of
6 INDs, BLAs, going on inspections, writing
7 guidance documents, developing policy and also
8 making presentations and organizing advisory
9 committee meetings.
10 And the point here is that because
11 these research scientists are actively engaged
12 in the review process they have an
13 understanding of the relevance of how their
14 expertise can be applied in a timely and
15 useful way.
16 So in the next slide is an
17 overview of how we manage our research
18 resources. And we start - it's really a
19 cyclical thing, but we'll start on Number 1,
20 which is to first look at what are our
21 regulatory and public health needs, and that's
22 looking both in-house and what our current
Page 14
1 portfolio of regulatory work involves as well
2 as what we call "horizon-scanning." Looking
3 ahead, what are the products that are likely
4 to be coming to us in the near future and how
5 do we prepare for those? A lot of them have
6 very challenging scientific issues that they
7 bring with them.
8 And from that we derive our
9 center-wide research priorities and from that
10 each office then looks again at their own
11 internal portfolio and aligns their research
12 plans and priorities in line with the center-
13 wide priorities. Research programs are then
14 evaluated on an annual basis by management for
15 their alignment with their office-based
16 priorities as well as externally every four
17 years with the site visit. And that's a
18 critical component really of all these phases
19 which is that we always are engaged with the
20 outside to get external review and input on
21 the relevance of our research as well as the
22 quality and productivity.
Page 15
1 So our FY08 research priorities
2 which we're currently in the process of
3 revising for `09, but since the site visit was
4 done in `08 I think it's kosher to still show
5 these, is first, to improve or develop new
6 methods to measure and augment biological
7 product quality, safety and efficacy; second,
8 to evaluate, develop and integrate novel
9 scientific technologies to improve biologics
10 product regulatory pathways, availability and
11 quality; and third, to facilitate development
12 of new biological products for high-priority
13 public health threats, including pan-flu,
14 emerging infectious disease and agents of
15 bioterrorism.
16 And I won't read through the last
17 three. They're equally important, but they
18 aren't relevant to today's group that we're
19 reviewing. These are more related to
20 biostatistics and epidemiology.
21 So in the last half of my talk I
22 wanted to just review some of the definitions
Page 16
1 about our staff so that as you're discussing
2 each of the personnel and what kind of actions
3 you're recommending for them you understand
4 exactly what we're talking about when we use
5 certain terms.
6 So the first set of terms I'm
7 going to review are those that we considered
8 permanent staff members. And we use the lingo
9 "converted" or "permanent," but in academic
10 lingo it's the equivalent of tenured. The
11 first group is senior investigators. These
12 are independent research regulators with
13 assigned resources and support staff. The
14 second group are staff scientists. These are
15 support scientists who work under a senior
16 investigator and they don't have any
17 independent resources of their own. Both
18 groups of scientists are evaluated for cyclic
19 review for progress or in some cases for
20 promotion to the next grade level.
21 The second group are what we call
22 service fellows. These are non-permanent
Page 17
1 staff members, in other words not converted or
2 what in academia would be called tenure-track.
3 So there's one group which is what's called a
4 senior staff fellow or a visiting associate,
5 and these are up to 7-year appointments to
6 demonstrate the potential for conversion to a
7 senior investigator.
8 So these are people who are
9 independent scientists who are trying to
10 demonstrate their ability to work
11 independently and in an area that's of
12 relevance to CBER, and also to be doing high-
13 quality productive science. The staff fellow
14 or visiting associate is a 4-year support
15 position. It's equivalent more or less to a
16 postdoctoral fellow. They have the potential
17 to be extended up to an additional three years
18 and may be considered for conversion to a
19 staff scientist position.
20 So again, these are support
21 scientists who do not have their own
22 resources. And these individuals are
Page 18
1 evaluated through the site visits for final
2 review as a service fellow as well as in some
3 cases, depending on where in that 7-year cycle
4 the site visit hits, it may be a cyclical
5 review for progress.
6 This next slide is a summary of
7 sort of the career paths, and I want to thank
8 Kosta Chumakov, actually, for drafting this
9 very nice graphic because sometimes it is kind
10 of confusing, but the idea is that we kind of
11 have two parallel paths. One is a staff
12 fellow or visiting associate that once they've
13 had a successful site visit they go then for
14 an internal review by our Promotion,
15 Conversion and Evaluation committee, and if
16 favorable may be converted to a staff
17 scientist. And the other is senior staff
18 fellow or visiting scientist which again - who
19 needs to go through a successful - oops,
20 hello?
21 ACTING CHAIR MODLIN: Dr. Wilson,
22 are you still with us?
Page 19
1 DR. WILSON: Yes, can you hear me?
2 ACTING CHAIR MODLIN: Yes, please
3 continue.
4 DR. WILSON: Okay, sorry. So -
5 ACTING CHAIR MODLIN: Little
6 technical -
7 DR. WILSON: Okay, everybody's on
8 board now?
9 ACTING CHAIR MODLIN: Yes.
10 DR. WILSON: Okay. So after a
11 successful site visit and, again, internal
12 review by our Promotion, Conversion and
13 Evaluation Committee may be converted to a
14 senior investigator.
15 So the site visit team's
16 assignment is to evaluate these individual
17 principal investigators and service fellows in
18 a laboratory unit - apologies for that typo of
19 having "unit" twice. Their assignment is to
20 look at the research accomplishments since the
21 last review cycle as well as to evaluate the
22 research proposals that would cover the work
Page 20
1 for the next four years.
2 And in the context of looking at
3 this, we also ask the site visit to take into
4 account that because these research scientists
5 also have review work and assignments that
6 they need to take into account the amount of
7 time available to attend to the research. We
8 welcome administrative or management comments
9 in addition to scientific input if they are
10 relevant.
11 Okay, and the regulatory tab for
12 these and regulatory work, while presented to
13 provide a context for the scientific
14 activities is not assessed per se by the site
15 visit team, but the quality of regulatory work
16 is assessed when these individual scientists
17 are reviewed by the Promotion, Conversion and
18 Evaluation committee.
19 So we ask the site visit team to
20 provide suggestions about whether or not an
21 individual is on the right track, if not how
22 would they get to the right track. We want
Page 21
1 them to comment on the quality of the science,
2 what research directions and approaches should
3 be considered if they're not already, if
4 there's additional laboratory expertise that's
5 lacking to address the scientific problems and
6 whether or not there are changes in laboratory
7 organization or new collaborations that should
8 be suggested.
9 The draft report which is the
10 subject of today's conversation is distributed
11 to the full advisory committee by Dr. Freas'
12 staff, and it's your task today to review that
13 report and either approve it or send it back
14 to the site visit team for revision. Once it
15 is finalized, the center uses these reports in
16 many ways.
17 As I mentioned, it becomes a part
18 of the package that goes for Promotion,
19 Conversion and - for evaluation by the PCE
20 committee for these personnel actions, the PIs
21 read these reports very carefully and take
22 into consideration the scientific suggestions,
Page 22
1 and by management these are also used for
2 making decisions about resources pending
3 resource availability.
4 So to just finish up then, when we
5 do get to the point if a person has a
6 favorable site visit and we want to put them
7 forward for conversion or promotion, just so
8 you understand that part of the process, they
9 can be nominated by the division director or
10 self-nominated, and a very detailed package
11 goes for review by the PCE committee who then
12 makes a recommendation to the center director.
13 And I just wanted to finish with a
14 quote from the FDA Science Board Subcommittee
15 on Science and Technology that was submitted
16 in November of last year that CBER has a
17 rigorous process for establishing priorities
18 and the impact of center research on
19 regulation, and in addition that leadership
20 insists upon integration of laboratory
21 scientists both in the review and
22 manufacturing site inspection process. And
Page 23
1 the most important component here relevant to
2 today is the external peer review of research
3 programs is the norm rather than the
4 exception. And so we really thank you for
5 your time and effort and your input into this
6 important process. Are there any questions?
7 Okay, thank you.
8 ACTING CHAIR MODLIN: Okay. No
9 questions for Dr. Wilson? If not, we'll move
10 on to the overview of the Office of Vaccines
11 Research. Kosta Chumakov, you're up.
12 DR. CHUMAKOV: All right, thank
13 you John. All right, so I'll give the
14 overview of the Office of Vaccines Research
15 and Review, and the way research programs are
16 managed here. So the mission of the office is
17 to regulate protective vaccines and we do it
18 by review of regulatory submissions as well as
19 conducting intramural research here in our
20 office.
21 So the next slide shows you a
22 structure of the office, and I must say that
Page 24
1 there are several mistakes here because the
2 structure is undergoing changes, especially in
3 the Division of Vaccines and Related Products
4 Applications. So there are two product
5 offices that conduct intramural research. The
6 first one is the Division of Bacterial,
7 Parasitic and Neurogenic Products and the
8 second one is Division of Viral Products which
9 is the subject of today's review. They also
10 have two offices, Division of Vaccines and
11 Related Products Applications that deal
12 exclusively with regulatory review of
13 submissions as well as the recently
14 established Division of Product Quality the
15 goal of which is to ensure quality and quality
16 assurance and quality control of vaccines.
17 So the goal of your research
18 program is to - next slide, Number 3 - is to
19 develop approaches for evaluation and
20 improvement of safety and efficacy of
21 vaccines. We'll also do development and
22 validate reference materials needed for
Page 25
1 assessment of vaccine quality. Important part
2 of our research mission is identifying new
3 pathways for regulatory evaluation of vaccine
4 product, especially new, innovative vaccines
5 that are coming on the market. And the
6 overarching goal, it is last but not the
7 least, is to maintain scientific expertise of
8 the office staff. So next slide.
9 As Dr. Wilson already described,
10 CBER uses what we call researcher reviewer
11 model which means that scientists performing
12 initiate - investigator-initiated research are
13 also personally involved in review of
14 regulatory submissions which provides them
15 with the unique outlook on the issues that
16 they address in their research programs.
17 So the unit of our research
18 program - and next slide please, Number 5 - is
19 the research group which is led by a principal
20 investigator. It's a senior scientist that
21 leads a group of support staff and fellows
22 that conduct research, and this is -
Page 26
1 ACTING CHAIR MODLIN: I'm sorry,
2 John, there's something interfering
3 periodically with your presentation. It
4 sounds like someone's rustling papers or
5 something, but I'd just encourage everybody to
6 put their phones on mute unless they have
7 something to say and then we'll continue on.
8 Thanks.
9 DR. CHUMAKOV: All right. So our
10 principal investigators are selected after a
11 nationwide search and they undergo tenure-
12 track evaluation and then put on permanent
13 staff. So together with the principal
14 investigator there are often scientists who
15 are not independent which means that they work
16 on assignments given by their principal
17 investigator. So there are also technicians
18 who are either biologists, microbiologists, or
19 chemists and our junior research staff which
20 is hired through our contract mechanism which
21 we call ORISE Fellows. So as of the end of
22 last fiscal year OVRR had about 30 principal
Page 27
1 investigators, 10 staff scientists, there was
2 also five senior staff fellows who were on
3 track to become principal investigators, 39
4 staff fellows and visiting associates who
5 potentially then can be considered for
6 conversion into staff scientist position as
7 well as 82 ORISE Fellows working together with
8 their PIs. So slide Number 7.
9 As you know, two years ago OVRR
10 was reviewed by a site visit and one of the
11 recommendations was that the office should
12 develop a more comprehensive strategic plan of
13 research management and identification of
14 important issues to address in the intramural
15 program.
16 So in response to this suggestion,
17 office established a research management
18 committee that consists of the Associate
19 Director for Research, Management and
20 Scientific Affairs as well as division
21 directors and their deputies from two product
22 offices, bacterial and viral products, and
Page 28
1 also directors of regulatory offices in
2 regulatory division and Division of Product
3 Quality. And there are also representatives
4 from each of the divisions that are either
5 principal investigators or staff scientists
6 who kind of do have a representation from all
7 levels of research management.
8 And the goal of this management
9 committee - next slide, please - is first to
10 set office research priorities and to ensure
11 that investigator-initiated research addresses
12 these priorities which is very important
13 because of course there are issues that are
14 coming from our regulatory work, but on the
15 other hand we still maintain the time-tested
16 investigator-initiated research model, and to
17 ensure that these two concepts work well
18 together we need to devise special mechanisms
19 of communication within the office.
20 Of course, it's important also to
21 maintain uniformity because the research is
22 conducted in different offices and we must
Page 29
1 make sure that all the procedures are
2 equitable across the office. And of course,
3 it's very important to make sure that those in
4 OVRR staff that do not perform their own
5 research on the bench should also be able to
6 communicate priorities and ideas that they can
7 gather from regulatory work to those who can
8 implement these ideas in the laboratory
9 research.
10 So here is a next slide, I think
11 it's next to the last at least for OVRR
12 research priorities that were based on the
13 wider CBER priorities. So the first addresses
14 development of new methods and concepts that
15 enhance safety of vaccines and related
16 products. The second one addresses the issues
17 of efficacy of vaccines. The third priority
18 is special emphasis of new biological products
19 that are addressing high-priority public
20 health threats, including counter-terrorism
21 activities as well as emerging diseases and
22 pandemic influenza issues. And finally, we
Page 30
1 also consider work on the new technologies
2 that open new regulatory pathways also a very
3 high priority.
4 So, finally on the last slide
5 there is a chart that illustrates the research
6 management process. As I already mentioned,
7 we have this research management committee
8 that serves as a hub for communications
9 between PIs on the bench and the regulatory
10 scientists in the review divisions.
11 So first we identify priorities
12 and they are being communicated to principal
13 investigators who also synthesize all this
14 information based on the current regulatory
15 issues that they identify themselves in the
16 course of their review activity, also site
17 visit recommendations, advisory committee
18 recommendations, interactions with their peers
19 in academia, et cetera, et cetera. So after
20 our principal investigator digests all this
21 information, he or she proposes a plan for the
22 next year research plan. And this is
Page 31
1 communicated through a lab chief and there is
2 a feedback, there is a discussion between each
3 principal investigator and lab chief, and the
4 opportunity to adjust the next year plans.
5 And then the same process continues from the
6 level of division director and lab chief.
7 So, finally division directors
8 collate all this information and combine all
9 the proposals coming from principal
10 investigators and their division-wide research
11 plan, and this portfolio is submitted back to
12 a research management committee that meets for
13 the second time during the fiscal year cycle
14 and reviews all the proposals from both
15 divisions and also has an opportunity to
16 provide feedback to principal investigators
17 and everybody else involved and submit the
18 overall annual office research plan to the
19 senior management in the office and later it
20 goes to the center level for budget
21 allocation. So this is basically how research
22 is managed in the office and this concludes my
Page 32
1 presentation. I'm ready to take any
2 questions.
3 ACTING CHAIR MODLIN: Kosta,
4 thanks very much. Are there questions for Dr.
5 Chumakov?
6 DR. DEBOLD: I have one question.
7 This is Vicky Debold.
8 DR. CHUMAKOV: Yes.
9 DR. DEBOLD: Can you tell me where
10 the work is done? I'm looking at that second
11 slide of yours where you said that there were
12 some updates that needed to be made to it. Is
13 there a particular place in the organization
14 where research on adjuvants is done, or is
15 that handled with specific vaccines as opposed
16 to adjuvants as a group?
17 DR. CHUMAKOV: No, we don't have
18 an organizational unit that addresses the
19 adjuvants. Research on adjuvants is conducted
20 in different labs. And no organizational
21 structure can capture the complexity, you
22 know, multi-layer issues that we address. So
Page 33
1 I mean, it's a continued work in progress. As
2 the research evolves, I mean, some of the
3 laboratories are combined and often
4 laboratories emerge based on the emerging
5 issues.
6 And since the issues with
7 adjuvants are coming to the forefront, I mean
8 it is possible that there will be some
9 adjustment in the future. So the structure is
10 in the flux and - but no, to specifically
11 answer your question, there is no single
12 organizational unit that deals with adjuvants.
13 It's spread in different labs.
14 ACTING CHAIR MODLIN: Thank you,
15 and maybe I could follow up is, it's certainly
16 fair to say that in the process of
17 responsibilities with the entire office for
18 conducting regulatory reviews is that both the
19 safety and the intergenicity of the other
20 issues regarding effectiveness of each
21 individual product are examined in explicit
22 detail. I just wanted to emphasize that for
Page 34
1 the record. Are there any other questions for
2 Dr. Chumakov?
3 MS. WALSH: This is Christine. I
4 just wanted to remind all the members, if you
5 do have a question if you could please
6 identify yourselves in the beginning. We do
7 have a transcriber in the room who needs to
8 know who is speaking. So thank you very much
9 for that.
10 ACTING CHAIR MODLIN: That was
11 John Modlin. Pardon the oversight. Our next
12 speaker is Dr. Jerry Weir who is going to give
13 us an overview of the Division of Viral
14 Products. Jerry?
15 DR. WEIR: Thanks, good afternoon.
16 I thank everyone for coming. I'm going to
17 give a brief overview. A lot of you have
18 probably heard some version of my presentation
19 of this in the past so I'll try to be brief as
20 well. If you flip to the second slide it
21 gives the organizational structure of the
22 Division of Viral Products.
Page 35
1 There's seven laboratories roughly
2 arranged along product lines. I'm the
3 director, Phil Krause is the deputy director.
4 The seven labs are named the Laboratory of
5 Hepatitis Viruses, the Laboratory of DNA
6 Viruses, Laboratory of Respiratory Viral
7 Diseases, the Laboratory of Immunoregulation,
8 the Laboratory of Vector-borne Viral Diseases,
9 the Laboratory of Retrovirus Research, and the
10 Laboratory of Method Development.
11 Since we had this site visit in
12 April we've had a few changes. Andy Lewis,
13 the lab chief of DNA Viruses, asked to be
14 relieved of his administrative and managerial
15 responsibilities and we've accommodated that
16 request for the time being with Phil Krause
17 taking over those responsibilities in the
18 laboratory. Andy of course remains principal
19 investigator in his lab. You've also heard
20 Konstantin Chumakov give the overview for the
21 Office of Vaccines. He's now acting as the
22 Associate Director for Research. So we're all
Page 36
1 sort of wearing several hats for the time
2 being.
3 The next slide shows a very brief
4 statement of our mission and functions in the
5 Division of Viral Products. It's pretty
6 simple. We regulate viral vaccines and
7 related biological products and ensure their
8 safety and efficacy for human use and we try
9 to facilitate the development, evaluation and
10 licensure of new viral vaccines that
11 positively impact the public health. To do
12 that we're engaged in many different
13 activities.
14 As you see on the next slide, I've
15 listed some of these here. We are involved in
16 investigational new drug application review,
17 biologics license application or BLA and
18 supplement review. We're involved in lot
19 release review and actually no longer involved
20 in lot release testing. That's actually
21 something I need to update on the slide, but
22 we do still participate in lot release review
Page 37
1 and sign-off. We're involved in different
2 post-marketing activities, for example
3 biological product deviations. The division
4 participates extensively in manufacturing
5 inspections and we have an extensive role in
6 consultation with other public health agencies
7 such as WHO, CDC and NIBSC in the UK.
8 Last but not least, in the next
9 slide we conduct a research program to support
10 our regulatory mission. The type of research
11 activities can span the spectrum from the very
12 basic to the very applied. They cover
13 different things throughout the division
14 including viral pathogenesis, vaccine safety
15 and efficacy, including cell substrates,
16 vaccine and viral vector evaluation.
17 We have studies on correlates to
18 identify correlates of protection. We're also
19 still involved with reagent preparation
20 exercises, particularly for influenza vaccines
21 and pandemic flu vaccines. We have studies on
22 methods development and evaluation and of
Page 38
1 course we're responsible for addressing
2 emergent issues. Some of the ones in the last
3 few years that we've addressed include BSE,
4 counter-terrorism and of course pandemic
5 influenza. The next slide shows a brief
6 summary in a graph form of the staff of the
7 Division of Viral Products.
8 We've been fairly static over the
9 years. We're hovering around 70 full-time
10 equivalents now. That's the full-time
11 equivalents that we have. We also in addition
12 have probably more like 50 contract employees,
13 mainly administer to the OIs program. A lot
14 of these are postdocs and other technicians
15 that are hired through this program. At any
16 time the total staff of the division is
17 somewhere around 120 individuals.
18 The next slide shows a graph of
19 some of our - just a brief snapshot of our
20 budget situation. I haven't updated it for
21 2008. You can see that at this point in time
22 the external funds that we bring in to support
Page 39
1 our research sort of dwarf the amount of
2 internal funds, and in the past year including
3 in 2008 the division has brought in over $5
4 million in outside contracts and grants. The
5 internal budget which supports of course most
6 of our basic operating work and the things
7 that go on throughout the division has
8 actually increased in the last year or two.
9 This past year and in 2007 we had an internal
10 budget of over $2 million.
11 Numbers like these have actually
12 not been seen - it's not on your graph, but
13 have actually not been seen since 1995 or
14 1996. So the last couple of years have been
15 a little better for us in terms of operating
16 monies than some of the early part of this
17 decade were. But in any case, the take-home
18 message here is that the staff and the
19 division bring in a lot of outside funds and
20 I think this is a good example of their
21 competitiveness and the quality of their
22 research programs.
Page 40
1 Okay. So today of course you're
2 here to get the site visit report for the
3 Laboratory of DNA Viruses. I'm not going to
4 belabor this. Phil's going to give you a
5 little overview of the lab itself. I've
6 listed in this slide the actual teams. There
7 are four principal investigators in this
8 laboratory. One is - and the titles of their
9 programs are listed on this slide. Andrew
10 Lewis is a principal investigator and team
11 leader and works in the development of assays
12 that define sensitivity for the regulatory
13 management of novel cell substrate. Phil
14 Krause has his laboratory in this laboratory
15 and the title - his research - getting
16 feedback somewhere. Okay, can everyone still
17 hear me?
18 (Whereupon, the foregoing matter
19 went off the record at 1:41 p.m. and went back
20 on the record at 1:44 p.m.)
21 MS. WALSH: Okay. We apologize
22 for the interruption. Dr. Weir will continue.
Page 41
1 DR. WEIR: I was winding down
2 anyway, but the - with the description of the
3 four teams. As I said, one is run by -
4 directed by Andy Lewis, the second one by Phil
5 Krause concerning with DNA virus vaccine
6 safety issues. Michael Merchlinsky is a team
7 leader and his work concerns the development
8 and evaluation of new generation smallpox
9 vaccines. And my laboratory is also in this
10 lab. It's concerned with DNA virus vaccines
11 and vectors. The - next slide.
12 The type of regulatory
13 responsibilities that are addressed by this
14 laboratory include smallpox vaccines, herpes
15 virus vaccines, cell substrate issues, and
16 like many other laboratories in the division
17 now we've split up influenza virus vaccine
18 regulatory work because of the workload that's
19 involved in that subject matter now.
20 The areas of research that are
21 covered by the laboratory include the
22 development and evaluation of new generation
Page 42
1 smallpox vaccines, safety concerns associated
2 with cell substrates including detection of
3 adventitious agents, the use of neoplastic
4 cells, the development and evaluation of
5 herpes virus vaccines and the development of
6 methods to detect extraneous agents in
7 vaccines.
8 And the last slide just summarizes
9 the site visit evaluation of April 3. The
10 committee reviewed the research programs in
11 this laboratory, they evaluated the progress
12 of individuals in each research team and
13 assessed the future directions of each
14 research program. And that's all I have.
15 Thank you for your time.
16 MS. WALSH: Is everyone still
17 there? This is Christine.
18 DR. HETHERINGTON: Yes. Everybody
19 is still here.
20 DR. DEBOLD: Did we lose Dr.
21 Modlin?
22 MS. WALSH: Dr. Modlin?
Page 43
1 ACTING CHAIR MODLIN: How about
2 that.
3 MS. WALSH: Dr. Modlin, are you
4 there?
5 ACTING CHAIR MODLIN: Yes, I am.
6 MS. WALSH: Okay.
7 ACTING CHAIR MODLIN: I'm sorry, I
8 think I had my button on mute. I apologize.
9 MS. WALSH: Okay, that's all
10 right.
11 ACTING CHAIR MODLIN: But are
12 there - again, are there any questions for Dr.
13 Weir?
14 DR. DEBOLD: This is Vicky Debold
15 again. I just have a general question. I
16 wasn't aware that the FDA staff was receiving
17 grants external to the agency. Can you give
18 me some idea of the funding mechanisms for
19 their external grants?
20 DR. WEIR: Can you hear me?
21 DR. DEBOLD: Yes.
22 DR. WEIR: Okay. Sure, I can give
Page 44
1 you a little bit and I think Carolyn Wilson
2 could give you an even better overview. We
3 have several mechanisms, but they don't for
4 all practical purposes include R01s from NIH.
5 We have other places like the Department of
6 Defense, the National Vaccine Program Office
7 and there are private organizations that will
8 support research here. I don't know, Carolyn,
9 you want to elaborate any more?
10 DR. WILSON: So in terms of the
11 exact mechanisms. If the sources of funding
12 is coming from another government agency then
13 that would be typically transferred through an
14 interagency agreement, and in those cases
15 where we are receiving funds from private
16 granting organizations we use the
17 Collaborative Research and Development
18 Agreement in order to review those for
19 conflict of interest and that's the mechanism
20 by which we receive those funds.
21 DR. BAYLOR: This is Norman
22 Baylor. I just want to add here that we don't
Page 45
1 receive funds from the regulated industry. We
2 cannot. We're prohibited from receiving funds
3 from the regulated industry.
4 DR. DEBOLD: I'm sorry, I'm having
5 trouble hearing that. Norm, you need to speak
6 up a little bit.
7 DR. BAYLOR: Okay, I'm right over
8 the mic. How about now?
9 DR. DEBOLD: Better.
10 DR. BAYLOR: Okay. I was just
11 adding that we don't receive funds nor are we
12 allowed to receive funds from the regulated
13 industry. I just wanted to make sure that was
14 clear.
15 ACTING CHAIR MODLIN: Thanks. Dr.
16 Debold, any other questions? Does anyone have
17 any further questions?
18 DR. DEBOLD: No, thank you.
19 ACTING CHAIR MODLIN: Okay. If
20 not, why don't we move on to Dr. Krause's
21 presentation, and this will be the overview of
22 the Laboratory of DNA Viruses, Dr. Philip
Page 46
1 Krause.
2 DR. KRAUSE: I'm Phil Krause. I'm
3 the Acting Lab Chief of DNA Viruses. At the
4 time of the site visit back in April Andy
5 Lewis was the lab chief and so I'm going to
6 present the slides that he actually presented
7 in large part to the site visit committee when
8 the site visit actually occurred. The Lab of
9 DNA Viruses, as Dr. Weir told you, has four
10 organizational units, a unit on cell
11 substrates and adventitious agents with Andy
12 Lewis as the principal investigator, a unit on
13 viral gene expression with Jerry Weir as the
14 principal investigator, a unit on pox virus
15 biology with Mike Merchlinsky as the principal
16 investigator and a unit on viral latency which
17 I am the principal investigator.
18 The Laboratory of DNA Viruses has
19 a number of important regulatory
20 responsibilities. The kinds of things that
21 fall to our members include management and
22 consultation on regulatory issues associated
Page 47
1 with DNA virus vaccines that are under
2 development. We now have a large number of
3 licensed DNA virus vaccines including the
4 varicella vaccine for chickenpox, a zoster
5 vaccine that was licensed in 2005, MMRV which
6 is a combination vaccine that includes a
7 varicella component, a smallpox vaccine and a
8 papilloma virus vaccine.
9 And then also because of the
10 involvement of DNA viruses in many of these
11 issues we ended up taking the lead on cell
12 substrate and adventitious agent issues. And,
13 as Dr. Weir pointed out, the influenza
14 regulatory burden has been spread fairly
15 uniformly across the division because there
16 has been a lot of work there, and so some of
17 that has fallen to our laboratory as well.
18 And then, of course it's important then to
19 maintain flexibility to accommodate these
20 changing vaccine safety and efficacy
21 priorities in DVP and that includes also the
22 cell substrate-related issues associated with
Page 48
1 the shift in influenza vaccine manufacture
2 from embryonated eggs to cell culture.
3 The next slide summarizes the
4 Laboratory of DNA Virus staff as it existed
5 both at the time of the previous site visit in
6 2004 and the site visit in 2008 and you can
7 see the division there. As is perhaps not
8 that surprising based on the data that Dr.
9 Weir showed you, all of the laboratories
10 contain combinations of FTE staff and non-FTE
11 staff. In most cases the non-FTE staff is
12 supported by outside funds. And then along
13 the same lines if you go to the next slide you
14 can look at the Laboratory of DNA Virus
15 funding picture in Fiscal Year 2007 where in
16 fact a large proportion of the funding for
17 research into the Laboratory of DNA Viruses
18 came from the outside.
19 And you can see the sources of
20 funding for the DNA virus lab was mostly the
21 National Institute for Allergy and Infectious
22 Diseases, with some money coming from BARDA
Page 49
1 and from the National Vaccine Program Office.
2 This next slide just gives a few
3 examples of Laboratory of DNA Virus
4 accomplishments since the previous site visit,
5 and this is not an exhaustive list, but that
6 includes review of a very large number of
7 INDS, IND amendments, master files and master
8 file amendments. It actually also includes
9 the review of a large number of manufacturing
10 supplements which aren't even listed here. We
11 participated in the licensure of the next-
12 generation smallpox vaccine which is ACAM2000.
13 We also participated in the zoster vaccine and
14 in the MMRV pro-quad vaccine which we also
15 licensed through this period. We presided
16 over the first revision of the OVRR CBER cell
17 substrate guidance document since 1993, and a
18 draft version of that was put out in 2006, and
19 the final version we hope will be issued soon.
20 Members of the laboratory published or
21 contributed to the publication of 39
22 published, peer-reviewed papers, delivered a
Page 50
1 large number of talks, Dr. Lewis came up with
2 27, but I think the actual number is quite a
3 bit greater, at least five of which were as
4 consultants to the WHO. Received grants and
5 contracts as you've seen from NVPO, NIAID and
6 BARDA which I think serves as an additional
7 reminder of the quality of the work and the
8 value of the work not only to CBER, but also
9 to other government entities. And then
10 members of the laboratory such as ad hoc
11 members of various study sections as well for
12 NIH.
13 I'm just going to go through the
14 four units briefly here and tell you a little
15 bit about the main aims in their research
16 programs. So the cell substrate and
17 adventitious agent program, the aims - so the
18 major project is actually called "Development
19 of assays to define sensitivity for the
20 regulatory management of novel cell
21 substrates." So this program focuses really
22 on cell substrate issues. And the three aims
Page 51
1 that Dr. Lewis' lab focuses on are assessing
2 the potential risk of oncogenic activity of
3 residual cell substrate DNA, polyomaviruses as
4 adventitious agents, and the evolution of the
5 neoplastic phenotype with a focus on Vero and
6 MDCK cells. And you don't have to go very far
7 back, in fact just to the very last advisory
8 committee meeting to see the immediate
9 relevance of this kind of work because in fact
10 a lot of the scientific data that were
11 presented to help the committee get through
12 its deliberations in thinking about what to do
13 about the use of MDCK cells in the manufacture
14 of next-generation influenza vaccines in fact
15 came from Dr. Lewis' lab. At the time of the
16 site visit there had been nine publications
17 since the previous site visit and of the
18 laboratory members, Dr. Lewis, who is a
19 principal investigator and at that time was
20 the lab chief, was being reviewed for
21 progress.
22 The second unit that I'll describe
Page 52
1 is a unit on viral gene expression. Jerry
2 Weir is the principal investigator and the
3 project title there is "DNA virus vaccines in
4 vectors." And the major aims there have been
5 to evaluate the immune response to vaccination
6 with smallpox vaccines, to evaluate immune
7 response to HSV-2 antigens and immunization
8 strategies to enhance response and to
9 facilitate preparation and development of
10 pandemic influenza vaccines, a project that
11 Dr. Lewis' lab took on in 2006. This has also
12 been a highly productive enterprise with 11
13 publications since the previous site visit.
14 Dr. Weir, who as you know is both a member of
15 the laboratory and the division director, was
16 being reviewed for progress. In addition, two
17 members of the laboratory who had been staff
18 fellows were being reviewed for conversion to
19 staff scientists at some point in the next
20 couple of years. Those are Clement Meseda and
21 Falko Schmeisser.
22 The third unit I'll describe is a
Page 53
1 unit on pox virus biology where Michael
2 Merchlinsky is the principal investigator.
3 The title of his laboratory research program
4 is, "Development and evaluation of new
5 generation smallpox vaccines," and the aims
6 are to study and develop assays for appraisal
7 of preclinical and clinical efficacy of
8 smallpox vaccines, to study bioassay systems
9 to evaluate the role of genes in protective
10 immune response to smallpox vaccines, and to
11 study viral genes that participate in the
12 resolution of viral DNA replication
13 intermediates. This has also been a highly
14 productive endeavor and the research has
15 contributed directly to the regulatory work on
16 smallpox vaccines with 11 publications since
17 2004. Dr. Merchlinsky was being reviewed for
18 progress and Alonzo Garcia, a member of the
19 laboratory, was being reviewed for potential
20 conversion to staff scientist.
21 And finally, the unit on viral
22 latency is the unit that I direct. The title
Page 54
1 of the project is, "DNA virus vaccine safety
2 issues, contamination and viral latency," and
3 in our lab we focus really on two major
4 issues, although we've done a few other things
5 as well: herpes simplex virus latency and
6 molecular methods for virus detection. And it
7 was interesting to hear again at the most
8 recent advisory committee presentations and
9 discussion the recommendation of the advisory
10 committee that we look into novel molecular
11 schemes, including high-throughput sequencing
12 for detecting viruses in contamination and to
13 assure the safety of cell substrates. That in
14 fact is exactly what we're doing, so I think,
15 as is the case with all of the projects in all
16 of these units, they're really very focused on
17 where we see the regulatory work not only
18 being, but also where it's going. We had
19 eight publications since 2004 and have had a
20 few more since. And I'm the principal
21 investigator and also the deputy director of
22 the division and was being reviewed for
Page 55
1 progress.
2 So to summarize really is the
3 Laboratory of DNA Viruses is very proud of
4 what we've been able to accomplish over the
5 past four years. We certainly look forward to
6 the challenges of the next four years and
7 really are very grateful to the advisory
8 committee for its feedback and suggestions
9 which we hope are going to help us to meet
10 those challenges. So thank you very much.
11 ACTING CHAIR MODLIN: Dr. Krause,
12 thank you. Let me ask if there are specific
13 questions for Dr. Krause. Maybe I could ask
14 one. John Modlin. Dr. Krause, how much of
15 the external funding that's coming through
16 NIAID is actually bioterrorism-related
17 compared to the rest of the external funding?
18 And I guess correlated to that, or add-on
19 would be what's your view of the future of
20 bioterrorism funding for the laboratory going
21 forward?
22 DR. KRAUSE: So it's a mix. Some
Page 56
1 of this money has been bioterrorism-related.
2 Some of the money actually was also more
3 specifically related to cell substrate issues
4 because NIAID recognized some years ago also
5 the need to make sure that data were available
6 to support changes in cell substrates for
7 vaccines. And so they created a request for
8 proposals and members of our division,
9 including our lab, Dr. Lewis and myself as
10 well as other investigators were able to
11 compete successfully for some of that money.
12 And as you correctly point out, a lot of those
13 sources of external funding are dwindling as
14 NIAID looks more closely at its budget. So in
15 fact the funding for the cell substrates, last
16 year was the final year and so Dr. Lewis and
17 I are looking for other sources of external
18 funding to continue that work. And some of
19 the bioterrorism funding still exists, but
20 it's been supporting some of the work from Dr.
21 Weir and Dr. Merchlinsky's laboratory, but as
22 you point out also with the increasing
Page 57
1 pressure on the entire federal budget, it's
2 always a question of how long that will last.
3 ACTING CHAIR MODLIN: Other
4 questions or comments? Let me open this up
5 and ask if there are questions of any of the
6 presenters or anyone else that's present at
7 OVRR. Hearing none, let me thank each of the
8 speakers for both brevity and clarity. It's
9 been an interesting hour. I guess the next
10 thing, Christine, is to ask if there is anyone
11 who wants to make a presentation during the
12 open public hearing session of the meeting, is
13 that correct?
14 MS. WALSH: That's correct. Is
15 there anyone in the room who would like to
16 make a public comment? Dr. Modlin, I see no
17 one.
18 ACTING CHAIR MODLIN: So that
19 means we can dispense with the boilerplate,
20 right?
21 MS. WALSH: Yes.
22 ACTING CHAIR MODLIN: If that's
Page 58
1 the case, then I think that we will go into
2 closed session at this point. Again, I'd like
3 to thank all of the speakers and I take it
4 that we here on the phone are just expected to
5 stay on the line and wait for the room to be
6 cleared and that you'll let us know when it
7 is, is that correct Christine?
8 MS. WALSH: Yes. If everyone
9 could stay on the line and it'll just be a few
10 moments until the room clears, and then once
11 it does we'll go into closed session. I'll
12 let you know who remains in the room with us
13 so it'll just be a minute and we'll be right
14 back.
15 ACTING CHAIR MODLIN: Thank you.
16 DR. GILBERT: This is Peter
17 Gilbert. The window is closing to ask
18 questions, but is Dr. Krause still there?
19 ACTING CHAIR MODLIN: Please, go
20 ahead Peter. Go ahead and get it in, yes.
21 MS. WALSH: We'll bring him right
22 back.
Page 59
1 DR. GILBERT: Okay. That window
2 closed so quickly.
3 MS. WALSH: Dr. Krause is back.
4 DR. KRAUSE: I'm back. Sorry.
5 DR. GILBERT: Okay. Yes, I
6 thought I'd better ask this before we go into
7 closed session. It's, you know, I don't know
8 much about your lab, but when you have studies
9 that take a relatively advanced, maybe it's a
10 physical input of design or analysis, do you
11 have statisticians as part of the LDV, or do
12 you collaborate with statisticians?
13 DR. KRAUSE: So in fact the -
14 obviously CBER has a fairly large Office of
15 Statistics and Epidemiology, and in fact one
16 of the nice features that we've been able to
17 set up here in the Office of Vaccines is one
18 of those statisticians comes down here and
19 sits in our main office one day a week and is
20 available for consultation, has actually
21 helped some of us out quite a bit in solving
22 various statistical problems. Sometimes
Page 60
1 statistical issues can be solved in other ways
2 too because a lot of our work is collaborative
3 with other institutions and so sometimes
4 statisticians in other institutions also play
5 some role in helping us analyze our data. But
6 we're very fortunate to have Lev Sirarda as
7 the statistician who ends up really focusing
8 on laboratory issues. I think it's a very
9 nice synergy because he then also then - he
10 also will do some review work on laboratory-
11 related issues as well, and so he sees that
12 not only from the perspective then of what the
13 manufacturers do, but also from the
14 perspective of some of the research work
15 that's going on in the office.
16 DR. GILBERT: Thank you.
17 ACTING CHAIR MODLIN: Thanks very
18 much. Any other questions? Okay, if not we
19 will go into closed session, and I'd just ask
20 the members of the advisory committee to hang
21 on for just a minute or two, please.
22 MS. WALSH: It'll just be a
Page 61
1 minute. We're just clearing the room. This
2 is Christine. Okay, Dr. Hetherington, are you
3 still with us?
4 DR. HETHERINGTON: I think, yes.
5 I think the last time I signed off during the
6 closed session.
7 MS. WALSH: That's correct, yes.
8 DR. HETHERINGTON: Okay, well
9 thanks very much everybody.
10 MS. WALSH: Okay, thank you so
11 much Dr. Hetherington.
12 (Whereupon, the foregoing matter
13 went off the record at 2:04 p.m.)
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