Food and Drug Administration
Center for Biologics
Evaluation and Research
SUMMARY MINUTES
VACCINES AND RELATED
BIOLOGICAL PRODUCTS ADVISORY COMMITTEE
Meeting # 88 November 28-29, 2001
Holiday Inn, Bethesda
Bethesda, Maryland
Members
Present
Dr.
Robert Daum, Chair
Dr.
Michael Decker
Dr.
Walter Faggett
Ms.
Barbara Loe Fisher
Dr.
Judith Goldberg
Dr.
Diane Griffin
Dr.
Sam Katz
Dr.
Steve Kohl
Dr.
Kwang Sik Kim
Dr.
Peter Palese
Dr.
Dixie Snider
Dr.
David Stephens (Nov. 28 only)
Members
Absent
Dr.
Pamela Diaz
Dr.
Audrey Manley
Dr.
Julie Parsonnet
Dr.
Rich Whitley
Dr.
Thomas Fleming
Dr.
Ralph Freedman
Dr.
Michael Greene
Dr.
Pamela McInnes
Dr.
Martin Myers
Dr.
Dennis O’Connor
Dr.
Sonia Pagliusi
Dr.
William Reeves
Dr.
Ellen Sheets
Dr.
Elizabeth Unger
Dr.
Edward Wilkinson
Executive
Secretary
Ms.
Nancy Cherry
These
summary minutes for the November 28-29, 2001 meeting of the Vaccines and
Related Biological Products Advisory Committee were approved on ______________________
.
I
certify that I attended the November 28-29, 2001 meeting of the Vaccines and
Related Biological Products Advisory Committee and that these minutes
accurately reflect what transpired.
_____________________________ ______________________________
Nancy
Cherry Robert S. Daum, M.D.
Executive
Secretary Chair
The
88th meeting of the Vaccines
and Related Biological Products Advisory Committee was called to order in
closed session at 8:30 AM on Thursday,
November 28, 2001 by the Chair, Dr. Robert Daum. The first open session, which started at 1:54 PM on Thursday,
spanned two days and addressed a single topic:
Efficacy trial endpoints for vaccines for the prevention of Human
Papilloma Virus (HPV). Open and closed
sessions pertaining to review of CBER laboratories were also held.
The
Conflict of Interest statement was read.
Based on the agenda and on the financial interests reported by meeting
participants, the members and consultants may be granted full, limited or
restricted waivers, appearance documents permitting full participation, or the
opportunity to recuse themselves from the discussions. The following chart summarizes the actions
taken for the open session on HPV clinical trials.
SGE |
Action |
|
Palese |
Full
Waiver under 208(b)(3) |
|
Fleming |
Full
Waiver under 208(b)(3) |
|
Freedman |
Full
Waiver under 208(b)(3) |
|
Daum |
Disclosure |
|
Griffin |
Disclosure |
|
Stephens |
Disclosure |
|
Fleming |
Disclosure |
|
Freedman |
Disclosure |
|
O’Connor |
Disclosure |
|
Sheets |
Disclosure |
|
Unger |
Disclosure |
Although
no votes on the HPV session were expected, Drs. Fleming, McInnes, Myers,
O’Connor, Reeves, Sheets, Unger and Wilkinson were granted Temporary Voting
privileges by the Director of the Office of Vaccines Evaluation and Research for
the session on HPV.
An
Open Public Hearing session was announced.
Three individuals from the audience came forward to address the
committee. Ms. Cindy Pearson, Executive
Director of the National Women’s Health Network, spoke on the choice of
endpoints for HPV trials; Ms. Karen Vanderhoof-Forschner from the Lyme Disease
Foundation, and Mr. Stephen Sheller of the law firm of Sheller, Ludwig and
Beatty, called for the removal of LYMErix vaccine from the market.
Following
is a summary of the discussion. A copy
of the agenda is attached Additional
information and specific details may be obtained from the transcript of the
meeting, http://www.fda.gov/ohrms/dockets/ac/cber01.htm.
Proceedings
were adjourned at 2:12 p.m. on Thursday, November 29, 2001 at the end of closed
session 6.
Session 1, 2, and 3
– Closed Sessions
Session 4 – Open Session
Efficacy endpoints for preventive HPV (human papillomavirus) vaccines were the main topic at the November 28-29, 2001, meeting of the Vaccines and Related Biological Products Advisory Committee held in Bethesda, MD. There were 12 Committee members (including the chairperson) and 12 invited consultants who were also present at the table. Several sponsors and FDA, as well as several guest speakers gave presentations. Most of the discussion centered around the use of persistent HPV infection (only) or CIN (cervical intraepithelial neoplasia) 2/3 with virology as the primary efficacy endpoint.
Most committee members/consultants voiced a preference for use of CIN
2/3 (with virology to determine the associated HPV type) as a primary endpoint,
either in the context of “traditional” approval or as a confirmatory endpoint
in an accelerated approval. Preference
was also expressed for having one large trial that would assess both CIN 2/3
and virology in a definitive manner. It
was recognized that CIN 2/3 itself is a “surrogate” for cervical cancer, but
the data were thought to be adequate to accept CIN 2/3 as a “validated” surrogate
for cervical cancer. In addition, it is
standard of care in the U.S. to always treat CIN 2/3, e.g., with LEEP (Loop
Electrosurgical Excision Procedure).
There
was agreement that CIN 2/3 histology, rather than HSIL cytology, should be used
for any definitive endpoint case definition. Cervical
cancer was not viewed as a feasible efficacy trial endpoint, although observational data for cervical cancer rates in a
post-licensure setting would be of interest.
With
regard to accelerated approval, two endpoints were discussed as possible surrogate
endpoints to support the initial approval: 1) an
“early” look at CIN 2/3 (with virology), and 2) persistent
HPV infection. Incident HPV infection
was not considered a useful surrogate due to the transient nature of most
infections. There
was considerable discussion on possible meaningful definitions for persistent
infection; limitations were recognized, with a preference voiced for a duration
of > 1 year. Concern was
expressed that accelerated approval should not be used if this would preclude
obtaining a definitive efficacy outcome for CIN 2/3. In this regard, concern was voiced that
it would not be feasible to continue any randomized confirmation trial once
licensure occurs. Thus, the timing of
obtaining adequate data for the “confirmatory” endpoint (CIN 2/3) was viewed as
critical. Also, it was viewed as
critical that accelerated approval not preclude having adequate prelicensure
safety data, either with regard to number of subjects or quality of data, at
the time of initial approval.
One participant indicated that persistent HPV infection alone
would be a sufficient efficacy endpoint for an approval without other
data. Another participant thought that
persistent HPV infection with a spectrum of cytologic and histologic findings
(including ones less advanced than CIN 2/3) would be adequate.
The committee members/consultants requested that virological and
cytologic data be obtained at frequent intervals during any trial. There was also interest in identifying an immune
response correlate(s) of protection for HPV infection (any), persistent HPV
infection and CIN 2/3. Assessing durability of protection was viewed as an
important clinical development goal.
In a post-licensure setting, it is unlikely that vaccinees will be screened for HPV status prior to vaccination. Thus, the committee members/consultants recommended obtaining some pre-licensure vaccine safety data in people who are HPV seropositive or HPV DNA positive (for vaccine HPV types) at baseline.
This
session was called to order at 1:54 PM on Wednesday, was adjourned for the
evening at 5:08 PM on Wednesday, reconvened at 8:33 on Thursday, and concluded
at 12:24 PM on Thursday. No votes were
taken.
Session 5 – Open Session
The committee heard short talks on the organizational structure of the laboratory and on the work by Drs. Willie Vann and Michael Schmitt. Dr. Vann described his research activities on the biosynthesis of capsular polysaccharides, specifically polysialic acid and the binding of tetanus toxoid C fragment to gagliosides. He also spoke of the laboratory’s work on anthrax. Dr. Schmitt described his research characterizing the iron transport systems in the corneybacterium diphtheria.
Session 6 –
Closed Session
The committee met in closed session to review the report prepared by the site visit team which visited the Laboratories of Bacterial Toxins on July 19.
By unanimous vote the committee accepted the report as written. The report, with its recommendations, will be submitted to the Center Director.