FOOD AND DRUG ADMINISTRATION
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CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
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CELLULAR, TISSUE AND GENE
THERAPIES ADVISORY COMMITTEE
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FRIDAY,
APRIL 11, 2008
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This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service. Accordingly the Food and
Drug Administration makes no representation to its accuracy
The Committee convened at 8:00 a.m. in the Grand Ballroom
of the Hilton Washington DC North/Gaithersburg, 620 Perry Parkway,
Gaithersburg, Maryland, Walter J. Urba, M.D., Ph.D., Chair, presiding.
MEMBERS PRESENT:
WALTER J. URBA, M.D., Ph.D.,
Chair
MATTHEW J. ALLEN, Vet. M.B.,
Ph.D.
JEFFREY S. CHAMBERLAIN,
Ph.D.
RICHARD J. CHAPPELL, Ph.D.
KURT C. GUNTER, M.D.,
Industry Representative
LARRY W. KWAK, M.D., Ph.D.
DORIS A. TAYLOR, Ph.D.
SAVIO L.C. WOO, Ph.D.
CONSULTANTS PRESENT:
MICHELE P. CALOS, Ph.D.
WILLIAM TOMFORD, M.D.
MEMBERS NOT PRESENT:
FARSHID GUILAK, Ph.D.
CONSULTANTS NOT PRESENT:
SHARON TERRY, M.A., Consumer
Representative
FDA PARTICIPANTS PRESENT:
KIMBERLY BENTON, Ph.D.
SUZANNE EPSTEIN, Ph.D.
RICHARD McFARLAND, Ph.D.,
M.D.
KAREN MIDTHUN, M.D.
CAROLYN WILSON, Ph.D.
CELIA
EXECUTIVE SECRETARY PRESENT:
GAIL DAPOLITO
T-A-B-L-E O-F
C-O-N-T-E-N-T-S
Welcome and Introduction of Members 4
Walter Urba, M.D., Ph.D., Chair
Conflict of Interest Statement 4
Gail Dapolito, Executive Secretary
Recognition of Committee Service 7
Karen Midthun, M.D., Deputy Director
CBER, FDA
Update-Research Program, Office of 9
Cellular, Tissue and Gene Therapies
(Response to September 2005 Review of
OCTGT Research Program)
Carolyn Wilson, Ph.D.
Acting Associate Director of Research
CBER, FDA
Suzanne Epstein, Ph.D.
Associate Director for Research
OCTGT, CBER
Q&A 51
Update-FDA Somatic Cell Therapy Letter 85
Kimberly Benton, Ph.D.
Deputy Director, Division of Cellular
And Gene Therapies
OCTGT, CBER
Q&A 98
Update-OCTGT Guidance Development Prog. 101
Richard McFarland, Ph.D., M.D.
Associate Director for Policy
OCTGT, CBER
Q&A 121
Adjourn
P-R-O-C-E-E-D-I-N-G-S
8:02 a.m.
CHAIR URBA: My name is Walter Urba. I'm the Chair, and Gail Dapolito will read a
conflict of interest statement.
MS. DAPOLITO: Thank you, Dr. Urba. Good morning.
This brief announcement is in
addition to the conflict of interest statement read at the beginning of the
meeting on April 10th and will be part of the public record for the
Cellular Tissue and Gene Therapies Advisory Committee on April 11, 2008. This announcement addresses conflicts of
interest for topic 2 related to the Committee updates of the September 2005
review of the research programs in the Office of Cellular Tissue and Gene
Therapies, the FDA Somatic Cell Therapy letter, and recently released FDA
guidance documents.
Based on the agenda for this topic,
it has been determined that the Committee updates present no actual or
appearance of a conflict of interest for today's meeting. Thank you.
CHAIR URBA: What I would like to do is have the Committee
members introduce themselves.
DR. CHAPPELL: Rick Chappell, Department of Biostatistics at
the University of
DR. ALLEN: Matthew Allen, Associate Professor,
Orthopedic Surgery,
DR. CHAMBERLAIN: Jeff Chamberlain, Department of Neurology,
DR. KWAK: Larry Kwak, Chairman of Lymphoma and Myeloma
Department at M.D. Anderson.
DR. TOMFORD: Bill Tomford, Professor of Orthopedic
Surgery,
DR. CALOS: I'm Michele Calos, Professor of Genetics at
Stanford University School of Medicine.
MS. DAPOLITO: Gail Dapolito, Center for Biologics
Evaluation and Research.
CHAIR URBA: Walter Urba, Chiles Research Institute,
DR. GERSON: Stan Gerson,
DR. TAYLOR: Doris Taylor, Professor of Medicine and of
Physiology,
DR. GUNTER: Kurt Gunter from Hospira, and I'm the
Industry Representative.
DR. WOO: Savio Woo, Department of Gene and Cell
Medicine,
DR. WILSON: I'm Carolyn Wilson, Acting Associate Director
for Research, Center for Biologics.
DR. EPSTEIN: Suzanne Epstein, Associate Director for
Research, OCTGT.
DR BENTON: Kimberly Benton, Deputy Director, Division of
Cellular and Gene Therapy, CBER, FDA.
DR. McFARLAND: Richard McFarland, Associate Director for
Policy in OCTGT.
DR. WITTEN: Celia Witten, Office Director of the Office
of Cell Tissue and Gene Therapy at FDA.
CHAIR URBA: Thank you.
I'd like to start by asking Dr.
Karen Midthun to come up.
RECOGNITION OF COMMITTEE SERVICE
DR. MIDTHUN: Good morning.
I'd like to express my special thanks and appreciation on behalf of the
Center for Biologics to three of our members who are rotating off their term
and completing their term on the Committee today. These individuals are Dr. Calos, Dr. Tomford
and Ms. Terry. Ms. Terry unfortunately
can't be with us today, but nonetheless I just really want to express
appreciation for the invaluable advice and countless hours that they have given
to us in their efforts to advise us.
And as you all know, this advisory
committee deals with many complex issues, novel treatments that hold potential
for great good but also present very complex issues, and we really appreciate
your input as it really helps us advance and facilitate the development of
these products, and as a small token of our gratitude I have some plaques.
Let me read what it says. It says that "This Advisory Committee
Service Award is presented to Dr. Michelle Calos in recognition of
distinguished service to the people of the
(Applause.)
(Pause for picture.)
DR. MIDTHUN: Thank you so much. We appreciate what you've done for us.
Dr. Tomford.
(Applause.)
DR. TOMFORD: Thank you.
(Pause for picture.)
DR. MIDTHUN: Thank you so much.
DR. TOMFORD: Thank you.
DR. MIDTHUN: Again, thank you so much. We really do appreciate all you've done. It really does help us do our work better and
we're most grateful. Thank you.
CHAIR URBA: Okay.
We'll move on to the next point on the agenda and Dr. Wilson.
UPDATE - RESEARCH PROGRAM, OFFICE
OF CELLULAR, TISSUE AND GENE THERAPIES
RESPONSE TO SEPTEMBER 2005
REVIEW OF OCTGT
RESEARCH PROGRAM
DR. WILSON: Okay.
Good morning. Now that I'm fully
armed. Good morning. I'm going to try to review three major areas
in terms of CBER's research programs.
First, give you just a brief introduction to CBER's mission, areas of
products that we regulate, and how research fits into our regulatory mission
and then give you an overview of how CBER manages its research programs and
then finish with some themes that have come out from other reviews of Office
research programs that occurred during the years 2005-2006.
So to read the mission of CBER, it's
to "Ensure the safety, purity, potency, and effectiveness of biological
products including vaccines, blood, and blood products," and I've
highlighted for the purpose of today's conversation, "cells, tissues, and
gene therapies for the prevention, diagnosis, and treatment of human disease,
condition or injury."
Our vision is to protect and improve
public and individual health in the
As you can see, the products that we
regulate cover a wide range, everything from blood, whole blood, and
vaccines. This range of products, of
course, have huge impacts on public health and then the types of products that
this office regulates somatic cell and gene therapy, devices that are involved
in those products, xenotransplantation and tissues and also relevant devices to
either tissues or these blood products.
So these together I think that this combination of product portfolio
addresses key public health areas while also moving the field of medicine into the
21st century as we already are in terms of developing these very
novel approaches to treatment of disease.
Now CBER's approach to regulation
is, of course -- our mission is to work within the legal framework provided by
the Food, Drug and Cosmetic and Public Health Service Acts combined with
regulations that we promulgate. But
under that umbrella, we use, as you heard, for example, yesterday, fora for
external discussion. Our own research
programs at CBER review of data that are submitted within INDs or BLAs or other
regulatory submissions and then obviously vigorous internal CBER discussion and
from that develop rational policy and decision making. So the point here also that I meant to
highlight is that active research is an integral component to our regulatory
process.
And to make sure the researchers are
relevant to the regulatory mission they are fully integrated in that they spend
approximately 50 percent of their time doing regulatory work in addition to
running their research labs, and the regulatory work covers the full spectrum
of work that would be done by full-time regulator reviewers, reviews of INDs,
BLAs, other regulatory submissions, actively engaging in policy and guidance
documents, meeting with sponsors and advisory committees, working on inspection
committees, looking at adverse drug reactions and risk assessment and then,
again, performing this research is an integral component to the regulatory
work. And also our research regulators
actively engage in outreach, going to scientific meetings of relevance to
communicate with stakeholders.
Our solutions, we use research to
both look at long-term programmatic needs as well as providing an ability to
respond to crises as they arise. It's
outcomes driven. We try to identify and
resolve specific high priority scientific challenges as we face them in the
review of new products. And we try to
focus on critical gaps in the scientific tools and knowledge for product
evaluation. So, for example, if there is
a vaccine that needed a better way to study the potency, that might be an area
of focus or a safety assay as well as other developing new preclinical models
to evaluate product safety or efficacy as well as a range of other activities.
We try to support product
development for critical unmet public health needs, and, where feasible, we use
multi-disciplinary, coordinated team research to face these regulatory
challenges. Some of these teams are
internal within CBER across various offices, and oftentimes we leverage
extensively externally collaborating with other government agencies, academia,
and so on.
So the guiding principles for how
CBER manages its research program are that it should encompass the scientific
basis of manufacturing, preclinical, and clinical studies. Outcomes should be taken into account in regulatory
decisions, inspections, post marketing surveillance, and guidances. So again, the point here is that the research
is really a critical component to how we do our regulatory work. We aim for high quality, efficient, and
directed research, managed to provide outcomes addressing scientific and
regulatory challenges in product development and safety, efficacy, and quality,
and, where feasible, the research should be highly collaborative including not
just the laboratory but also epidemiologic, statistical, and clinical sciences.
So this cycle here gives you an
overview of our approach to research, and, in fact, actually it's somewhat
trivial that we've -- I've numbered this number one but you have to start
somewhere. But this truly is cyclical
with each of these steps feeding into the other.
The other component I wanted to
emphasize is that external review and input is an integral component to each
and every one of these steps. I'm going
to, in the next few slides, try to break down each of these four areas in more
detail so that you can understand how we do each of these steps.
So, first, to identify regulatory
and public health needs, we look at what does our regulatory work load look
like, what are the key areas where we have policy needs, and what are public
health and emerging issues, often referred to as horizon scanning. To identify these areas, we solicit the input
of our own staff, research regulators, full-time review regulators, management
and heavily rely on external input by participation in scientific meetings and
workshops, input from advisory committees, and input from external site visit
review committees.
This information then, once this
list is generated, feeds into the development of our research priorities. These are first generated at the center
level, and these are taking into account what are some areas that can impact
facilitating product development in areas of product quality, safety, and
efficacy, and we also take into account what are the ways we can leverage our
unique CBER expertise, meaning our ability to look across broad product areas
to identify the gaps in scientific knowledge that are needed to facilitate
product development.
To give you an idea of our research
priorities for this fiscal year, and this is a list that was developed from
CBER's Research Leadership Council. This
is a council of representatives from each of the four product offices that
includes both full-time review staff as well as researcher reviewers and the
associate directors for research from each office. First, to improve or develop new methods to
measure and augment biological product safety and efficacy; to evaluate,
develop, integrate novel scientific technologies to improve biologics product
regulatory pathways, availability, quality; facilitate the development of new
biological products for high priority public health threats, including pandemic
influenza, emerging infectious diseases and agents of bioterrorism; improve
clinical trial design and evaluation, including adaptive design approaches;
develop formal risk management and risk assessment approaches; and enhance
safety surveillance by developing improved analytical tools and accessing large
databases.
Some examples of CBER research
programs that were identified as high priority in the form of receiving
Critical Path funding for fiscal year `08, I wanted to give you these, one
example from each office just to give you a flavor of the types of research
that would address these priorities
In the Office of Biostatistics and
Epidemiology, one of the areas is to analyze healthcare databases for
biological safety and effectiveness evaluation.
The idea here is that by looking at a much larger database than just
that which we have access to within FDA in the form of adverse event reporting,
we can identify trends in terms of post marketing issues.
Office of Blood is doing a program
to use proteomics to identify biomarkers that may be predictive of efficacy for
stored red blood cell and platelet products.
Office of Cell, Tissues and Gene
Therapies has a program to look at safety and efficacy of adenovirus vectors
for gene therapy.
And Office of Vaccines is developing
an in vitro method to predict the in vivo toxicities of novel vaccine
adjuvants, the idea being that this would be a faster and less expensive way to
screen novel adjuvants.
So then from our CBER research
priorities, this feeds into development of CBER research plans and -- office
research plans and priorities. Again the
same three major areas are examined except this time at the office level, and,
in addition to those areas, there's also an annual as well as cyclical review
of research programs.
I wanted to just emphasize this for
a moment to mention that this includes both an annual review by offices for
scientific relevance, quality, and productivity as well as a four-year research
program evaluation in the form of an external site visit review which many of
you may have participated in at various times for some of the programs within
OCTGT as well as an internal peer review through the Promotion, Conversion,
Evaluation Committee which involves cyclical review.
The annual review is a web-based
research reporting where we collect scientific achievements in the form of
publications, relevant guidance documents, presentations as well as an
explanation of future plans, and then this is reviewed by office leadership.
The programs are rated on the
achievements based on the return of research resources expended, looking at the
impact on regulatory challenges, what is the quality of the scientific
publications and where are they presenting their scientific results, how does
the work contribute to development of new policy, impact internationally, and
they also are reviewed for their review workload and quality as well. And then the future research plans are also
evaluated, and these include both short and long term, and, again, they should
be relevant to the regulatory challenges facing that office or division.
The four-year cycle of the external
site visits involves a site visit team comprised of -- usually chaired and
co-chaired by two advisory committee members and then supplemented with
appropriate expertise so that we can have relevant scientific input and their
reviews -- based on the laboratory unit so that it's not just a research
reviewer. But it's in the context of
their research program. And this
includes a very detailed submission by the PI as well as a day-long interaction
through formal presentations as well as informal opportunities to interview
each principal investigator. They then
draft a site visit report which is presented to the full advisory committee.
The interval review through the
Promotions and Conversion Evaluation Committee, all researcher regulatory staff
are evaluated for conversion to permanent staff after an up-to-seven year
period where they're in the conversion track, promotions, and every four years
for progress. And the Review Committee
is comprised of senior research regulators as well as full-time review
scientists, and the review includes not just the research but also a very
detailed assessment of their regulatory work and the quality of that work.
And the committee provides
recommendations to the Center ADR and then also just to mention that there are
formal SOP and procedures for this committee.
So then to finish a review of the
research management, as you can see, at that output of the research programs,
this information then can drive and inform the development of the next cycle of
regulatory and public health needs.
Again, as you can see, the external review is really a critical
component.
I wanted to just finish in the last
few slides with some themes. In 2005 and
2006, each of the offices were reviewed by their parent advisory committee
supplemented with appropriate expertise to look programmatically at the office
research programs which is the focus of today's discussion in terms of the
OCTGT review. But I thought it would be
informative to share with you some of the themes that came out of the reports
from the other office reviews.
So, first, committee members who
have been familiar with the research programs over a period of years note that
there has been a striking improvement over time in terms of focus and
relevance. The research prevented had
direct relevance to the critical pathway of biologics product development
availability as well as the quality of research has improved. Many of the ongoing studies are equal in
quality to those of the NIH and of sufficient caliber to compete for R01 and
other NIH grants.
The advisory committee strongly
supports the FDA's continued emphasis on the importance of having a strong
intramural research program to support its Critical Pathway program for
effective and efficient regulatory activities and if we are to maintain our lead
in health care development in the U.S. regulatory science needs to be given the
priority it deserves, independent of the short-term political and economic
flurries that can derail progress.
Several strengths that were
identified, the productivity, the scientific merit, and the mission
relevance. Scientists were well
recognized for outreach efforts, complementary cross-office expertise, success
at recruitment and retention, development of core facilities within CBER to
provide some technology to support the science, and the leveraging and
collaboration that goes on with a variety of different academic and government
agencies.
Concerns included the increased
regulatory workload without decreasing support and the impact that may have on
the research, how to best balance the mission of having research that's
relevant without micromanaging the research programs, how to cover many
research areas while still focusing on quality in a few areas, and how to
develop an explicit strategic plan for the next two to five years getting --
how best to get regulatory and stakeholder input.
Additional concerns involved needs
for improved mentoring, recruitment, and retention, increased research program
visibility -- I'm sure many of you before you were tasked with serving on the
Advisory Committee didn't even realize FDA had research programs -- continuing
education support for scientists, collaboration within and outside of FDA,
increased FDA base funding support for research, how to identify new creative
leveraging support, and actually on this last bullet, we now do have -- we're
getting established a Reagan-Udall Foundation many of you may have heard of
which may answer some of these concerns, and, then again, a public relations
campaign and system of reward for successful research.
I want to finish with a quote from
the report in November of 2007 from the Subcommittee on Science Technology that
was prepared for the FDA Science Board.
Commissioner von Eschenbach asked the Science Board Subcommittee to
review the science at the agency level, and the outcome of that was a series of
very detailed recommendations.
But I wanted to note one quote from
there that indicated that "CBER has a rigorous process for establishing
priorities and the impact of Center research on regulation. In addition, the leadership of CBER insists
upon integration of laboratory science both in the review and manufacturing
site inspection process." And then
again to emphasize, "External peer review of research program is the norm
rather than the exception."
So, finally, I wanted to thank you
for your time, expertise, and input into our research programs, and, as you'll
hear from Sue in the next talk, I think that the input that OCTGT received was
very valuable, and they've considered it very carefully. And I think we're going to take questions
after Sue's talk. But I thank you for
your attention.
(Applause.)
CHAIR URBA: Dr. Epstein.
DR. EPSTEIN: Okay.
Before I start the presentation, I want to first say a few words about
Eda Bloom. As many of you know, Dr.
Bloom passed away unexpectedly in January, and we have lost a dear colleague
and friend. She contributed in many ways
to CBER and to the public health community.
Her research career of almost 40
years included work on topics including natural killer cells, regulation of
immune responses to xenotransplants and, most recently, immune responses to
allogeneic stem cell derived cell populations.
She was an insightful regulatory reviewer, an outstanding mentor of new
reviewers as well as research fellows, and a leader in policy development in
the area of xenotransplantation.
She was my branch chief in the Gene
Therapy and Immunogenicity branch of DCGT and a leader at CBER in many other
capacities. We greatly miss her presence
and contributions.
So I'll now be talking about the
same topic Carolyn Wilson discussed but specific to OCTGT.
The Office-wide site visit was held
in 2005 as part of the CBER research management initiative, and the purpose of
today's session is to respond to the recommendations, to indicate to those who
review our programs that their input has an impact, and to provide information
in an open public setting about our research programs and reviews of them. This can provide transparency and
accountability.
I'll be discussing first an
introduction to OCTGT and its products and programs, then the site visit
process and report. I'll then describe
our research management and progress we feel we are making responsive to the
recommendations in the report and then give a few examples of the research
initiatives.
The mission of OCTGT is to
facilitate development of, approval of, and access to safe and effective
medical products in the areas we review.
The structure of the Office is shown
here. In addition to leadership and a
regulatory management group, there is a Division of Cellular and Gene Therapies
where the laboratory programs reside, a Division of Clinical and Pharmacology
Toxicology Evaluation, and a Division of Human Tissues. So all the research programs I will be
describing are -- well, they're mainly within DCTG with interactions with the
Clinical and Human Tissue groups.
Here is the structure of the
Division of Cellular and Gene Therapies.
There are review branches dealing with gene therapies and cell therapies
and then the three branches that include laboratory research as well as
regulation are Gene Transfer and Immunogenicity Branch, Tumor, Vaccines, and
Biotechnology Branch, and then the Cellular and Tissue Therapy Branch. There are currently ten principal
investigators.
This slide lists the products
regulated in this office. As Dr. Wilson
mentioned, cellular therapies and gene therapies are included. Tumor vaccines and immunotherapy can overlap
both of those other areas. Then tissue
and tissue-based products, xenotransplantation products, a variety of combined
products, and then devices that are related to the cellular and tissue
products.
The regulatory activities include a
large number of INDs and amendments, one licensed product, and a growing number
of products in Phase 3, a variety of devices.
Tissue regulations are established in this office. We do a lot of pre-IND meetings and
pre-pre-IND consults as you heard about yesterday as well as advisory committee
meetings, inspections and then considerable effort has gone into enforcement
actions on occasion.
Our research strategies cannot
include work on every type of product because the products are too
diverse. So we review new types of
products. To facilitate their progress
towards delivering public health benefit, we have to work at the cutting
edge. In fact, we have to help define
the cutting edge. So our role is to stay
ahead of the curve to prepare the way for anticipated products which can be
complex, as you know, to perform studies relevant to entire product classes
rather than one individual product. A
sponsor might study their product, but we try to look at the foundations for
all the products. And then to make the
results public and thus accessible to all sponsors to advance the entire field.
The main research areas are
indicated here that support work on all these product categories. We have virology research, immunology, cell
biology and differentiation including stem cell biology, cancer biology, biotechnology
approaches including microarray analysis, flow cytometry, and proteomics, and
then in addition to the laboratory-based programs, we have some work in the
area of clinical trial design.
I'll now describe the office site
visit process that led to the report we are responding to. The office site visit was held to obtain
suggestions concerning OCTGT research from experts in appropriate scientific
and clinical fields. The reviewers were
11 experts from academia, government, and industry who formed the CTGTAC Research
Review Subcommittee. We provided to them
an extensive briefing package about our regulatory roles, our research programs
and accomplishments, research management approaches, publications, and then on
the
The benefits of this were we
received their insights and suggestions.
The process provided transparency and accountability, and this is an
opportunity to inform stakeholders about what we do.
They drafted the report that went to
this present advisory committee, and at a public meeting in 2006 the report was
approved by the full advisory committee meeting. Follow-up to the report has included our
internal discussions leading to today's meeting. We provided a briefing package for this meeting
that contains more details than I will have time to present now about their
comments, our responses, and our progress.
There have been other CBER site
visits as mentioned by Carolyn. There
have been office site visits to review the programs in the Office of Blood and Vaccines, and the
reports have been received. The Office
of Blood has already responded in this same way at a public advisory committee
meeting, and the vaccine response is pending.
In their report, the site visitors
commented about our research management approaches. They had comments in the areas of
recommending explicit research priorities obtained by horizon scanning and they
had recommendations about annual reporting and assessment, about internal
resources and outside funding, recruitment and retention practices including
mentoring and professional development, communication and collaboration, and
they emphasized it was important that the research management process should
stimulate innovation and creative problem solving, not become micromanagement.
They also divided their report into
areas referring to the particular product areas on which they had expertise,
gene therapy, cell therapy, combination products, xeno, counter-terrorism,
tumor vaccines, and bioinformatics.
I'm now going to summarize briefly a
variety of our management initiatives that are responsive to the
recommendations in the report and in which we feel we are making some
progress. I'll be discussing a little
bit about the Research Leadership Council, communication, collaboration, some
examples of activities, then how do we do our horizon scanning, what are the
actual priorities of OCTGT, and a little about ongoing recruitments and
funding.
Carolyn described the Research
Leadership Council which includes both researcher reviewers and regulatory
scientists from each office, plus Center management. The goal is to have transparent procedures
that are shared across offices and explicit priorities so that we aren't just each
doing things differently.
So the CBER priorities have now been
identified and announced, and she showed them to you. We then identified office research priorities
from workload analysis as well as horizon scanning, and our research programs
are now expected to address these priorities.
Evaluation of the research programs is linked to their budgets. So there are consequences. And we have initial development of an
automated regulatory workload system.
We're working on that. It's not
yet available. We're also working
towards a scientific expertise database.
Some of the communication tools
within the Office include work-in-progress talks. The frequency was increased in response to
the report. The website includes annual
reporting and brief summaries. We get
input from all the staff regarding priorities and recruitments. And then an OCTGT leadership meeting or
go-away within the building was held in November 2007 to discuss our research
priorities.
To communicate beyond our office, we
used briefings of the Center and Agency leadership. The FDA Science Board review was an
opportunity to discuss research broadly with others. There is a new FDA website that includes our
programs. For communication with
stakeholders outside the Agency in fiscal `07, there were 32 research
publications that came out of this office as well as contributing to regulatory
publications and guidances. And then we
give talks at scientific conferences, workshops, and meetings as another way to
communicate with stakeholders.
The site visit report mentioned collaborations.
So I have just listed here a brief summary of the collaborations. I won't read them all, but the point is there
are extensive collaborations of OCTGT investigators with other laboratories in
the government. These are many
institutes of the NIH as well as The National Institute for Standards and
Technology, CDC, and The National Toxicology Program, and then there are
collaborations with a variety of academic centers throughout the country and in
other countries.
To give just a few examples of the
other activities in the Office that provide the context for the research and
that draw upon the research, in October of 2007, a Tissue Processing Workshop
was held, also a Workshop on Clinical Use of Biomarkers. In December, FDA collaborated with the
National Institute for Standards and Technology on a Cell Scaffold
Workshop. We participate in the
Interdisciplinary Pharmacogenomic Review Group, and here are some ongoing
partnerships in which OCTGT participates: the NCI Interagency Oncology Task Force,
the Multi-Agency Tissue Engineering Science or MATES working group and a
Biomarker Consortium which involves a variety of Federal agencies plus other
sectors including the private sector.
This is a very brief listing of
examples. There could be a whole
separate presentation on the activities and outreach activities of the Office.
In terms of our horizon scanning,
product trends are noted from submissions as well as pre-submission inquiries,
scientific conferences, and the general literature. We try to anticipate areas of major product
activity that are related to Critical Path issues, and then we monitor for gaps
and weaknesses or redundancies in our own staff expertise and address them.
I'll now show you the priorities
that were announced for this year. These
will be an evolving set.
First, the development and
evaluation of methods and standards for improved product characterization,
including definition of product biomarkers predictive of safe, effective, and
consistent product performance.
Secondly,
development and evaluation of non-clinical methods informative about the safety
and efficacy of our products. This
includes both preclinical animal studies as well as in vitro studies, so thus,
non-clinical.
Thirdly, participation in CBER, FDA,
and Department-wide initiatives including risk assessment, clinical trial
design and monitoring, development of biomarkers, counter-terrorism, pandemic
influenza preparedness, and HIV/AIDS programs as well as Office-specific
initiatives in these areas.
And fourth, improvement of the
microbial safety of human tissue products by development and evaluation of
methods for better processing conditions, pathogen inactivation and/or pathogen
detection.
This last one is a new area, and
I'll return to this. So these are very
broad priorities. We are not trying to
micromanage the programs.
I'll now discuss the recruitments of
the recent past and then the ones that are currently ongoing. Since the year 2000, we've had several
recruitments. In each case, a scientific
gap was identified and the field of expertise endorsed by the Center. Then an open public recruitment with a search
committee was conducted. The last five
PIs recruited were all from outside the government. They were in fields of development and cell
fate, adeno and herpes viral vectors, organ development, and proteomics, and
they came from these institutions.
We have a recruitment ongoing now in
the tissue area. I referred to that new
priority. The history here is that in
2005 the tissue industry was required to begin submitting adverse events. This is work of our Division of Human Tissues
that's developing new regulatory paradigms.
In 2006, 147 adverse reactions were
reported, although not all of those are necessarily due to the tissue. In 2006, the Human Tissue Task Force was also
established and again planning additional regulatory activities.
In 2007, the public health issues
that had been highlighted by these events showed us that we had scientific gaps
in our programs. This led to planning a
laboratory program in DCGT to work on human tissue safety. This is in coordination with the Division of
Human Tissues and the Office of Compliance and Biologics Quality, and our
recruitment of a first principal investigator is now in progress.
There are two other recruitments
currently in progress. Sorry, one has
been completed. In Virology, an
investigator has just been recruited to start a new program in DCGT. He has experience in lentiviral vector
research and as the director of a core facility producing adenoviral, AAV and
lentiviral vectors.
In Immunology, immune regulation and
tolerance has been identified as a gap in expertise that is needed for
regulation of gene therapy, cell therapy, and xeno products, and a search is in
progress. So these are staff
replacements.
There were recommendations
concerning funding sources and since CBER scientists are not eligible for many
major grants, we seek other sources. The
mechanisms we use are interagency agreements and cooperative research and
development agreements to avoid conflict of interest. Several of the sources currently being used
are the Interagency Oncology Task Force with NCI through a training program,
the FDA Critical Path Initiative, Pandemic Influenza Initiatives, and, in the
counter-terrorism area, various grant programs that address infectious agents
and emerging threats and then chemical, biological, radiological, and nuclear
emergencies.
I'll now give you just a few
examples of our current research initiatives.
There were more examples described and in greater detail in the
materials on which these various reviews were based. That is the briefing material for the office
site visit and for the FDA Science Board.
One project is addressing gene
therapy risks and is in collaboration with the National Toxicology Program
through NIEHS and some academic partners.
We recognize the need for new pharm-tox models for the unique risks in
gene therapy, and Dr. Wilson has coordinated this program establishing a
preclinical model for assessing the risk of retroviral vector-mediated
insertional tumorigenesis. This will
permit comparing modified vectors and new types of vectors to see if they
provide reduced risk.
The animal studies involved use
large sample sizes and are very long-term studies. So it would not be possible to carry them out
at CBER alone, and it would not be possible for single sponsors to carry them
out. So this consortium approach is
leveraging the answer to an important public health question.
Another project is addressing
adenoviral vector issues. Why are
adenoviral vectors cleared so quickly?
Intravenous use of gene therapy vectors to target disseminated cancer
cells might be a valuable approach. But
with adeno, the pharmacokinetics are very unfavorable. They disappear quickly.
The CBER research finding is that
adenoviral vectors are rapidly recognized by scavenger receptors and are
cleared by Kupffer cells in the liver, thus removing them from the system and
preventing them from reaching their targets.
This has implications that might be
useful. If you could block the scavenger
receptors, you might have an ability to reach the targets more
efficiently. This problem is a hurdle in
the path to effective therapy which then could use lower doses and thus would
be safer.
Another example is a collaboration
with NIST looking at improved characterization of human mesenchymal stem cell
based products. The goal is a simple and
robust measure that can predict the differentiation capacity of these cells. NIST provides computerized, high throughput
cell measurements of size, morphology, proliferation rate, and biomarker
detection. DCGT provides quantitative
bioassays for the frequency of progenitors.
These mesenchymal stem cells
differentiate into three lineages. They
have progenitors for fat, cartilage, and
bone, but those assays take a very long time.
Those would not be good product testing assays. So the approach is to find out whether NIST
measurements that can be made rapidly and quantitatively correlate with
progenitor frequencies in the mesenchymal stem cell population.
We also have research programs
related to CBER, FDA, and Department initiatives as I mentioned in one of the
priorities. These are related to
emergency responses, counter-terrorism, and pandemic flu. So we have projects on blocking of Ebola
virus infection, on new approaches to control of pandemic influenza, and to
cell therapy for radiation exposure.
There are also laboratories that
have established cutting edge technology which will be valuable in product
characterization. We're using gene
expression microarray and proteomics to provide high throughput screening and
detailed information. These can be used
to characterize cellular products or cell substrates for manufacturing other
biological products. These could be gene
therapy vectors or vaccines and they can also be used for characterization of
patient samples.
OCTGT has also contributed to
development of reference materials that are important in moving our product areas
forward. A retrovirus reference material
was developed. Carolyn Wilson led that
effort. It was developed by CBER and is
now available from ATCC to investigators throughout the world.
An adenovirus reference material was
developed by a consortium which included multiple members of OCTGT staff as
well as other partners. That reference
for adenovirus standardization is now available also from ATCC.
External RNA spike-in controls are
being prepared and will be valuable for standardizing PCR and microarray
analyses.
In the area of quantitative flow,
CBER has collaborated with NIST to develop standards. These are now available for distribution from
NIST. They include a fluorescent
standard solution and fluorescent microbead standard. The value here is if flow cytometry is
standardized from one site to another and one day to another, different
clinical sites and different patient evaluations can be directly compared
quantitatively.
So to summarize, our research deals
with new products that present novel scientific and regulatory challenges and
opportunities. We identify questions of
regulatory importance and address them.
The solutions to key problems can contribute to patient safety and
product development and can inform our regulatory decisions and policy.
To quote just one bit from the
office site visit report, they felt that "new treatment modalities like
cell and gene therapy will never move from effective laboratory reagents to
products for patients with disease unless the FDA maintains a strong cadre of
researcher-reviewers," and "an active research component within the
FDA is essential."
So I want to join Carolyn in
thanking you for your attention to CBER research programs, and I want to thank
many OCTGT colleagues for contributing to this presentation and to Gail
Dapolito and the Advisory Committee staff for organizing the meeting. Thank you.
(Applause.)
QUESTIONS AND ANSWERS
CHAIR URBA: Thank you, Dr. Epstein.
Questions from the Committee? Dr. Taylor.
DR. TAYLOR: You showed us an organizational development
chart in one of your slides, and I guess my question is who within that
organizational structure sets these research priorities?
DR. EPSTEIN: The office leadership does it in
consultation. I'm the Associate Director
for Research and working with Celia Witten, our Office Director.
(Off the record comment.)
DR. EPSTEIN: So Celia Witten and all the office
leadership. Stephanie Simek is the
Deputy Director. I'm the Associate
Director for Research. Richard McFarland. Then the division directors, Raj Putri, Ashok
Batra, and Ruth Solomon, form a management group and as in my role, it's my
responsibility to seek them out, communicate with them, bring issues to their
attention. They bring issues to my
attention as well.
For example, the area of Human
Tissues was a collaborative development between the public health team working
on tissues and making us aware of those issues and then with Dr. Puri and Dr.
Witten, the idea was developed that there should be a laboratory program. They took that to CBER leadership.
So the list of priorities I showed
you was drafted by myself and with input from a lot of people and then went
through many iterations with first the management team and then the entire
office for input.
DR. TAYLOR: So you said there is some sort of leadership
council or research leadership group or some -- I didn't fully understand
that. What is that and how does that --
DR. EPSTEIN: I'm sorry about one semantic thing I may have
made confusing. The Research Leadership
Council is CBER-wide. I should use a
different term here. But within OCTGT
the leaders listed on this slide. It's basically
the Office director, deputy director and the division directors and the
associate directors form a group that discusses priorities. They don't discuss each research project or
the budgets and the evaluations and all that.
But they discuss the priorities and they attended this Go-Away that was
a half day meeting last November to examine the priorities proposed by myself
and the research staff and the other people who had contributed and see if it
addressed the proper public health priorities.
They had contributed some of those themselves in earlier rounds.
There are meetings held periodically
both at NIH and at Woodmont which is the site of our full-time review offices
to accept input from horizon scanning.
So it's a two-way interactive process.
This is the leadership.
DR. TAYLOR: And one final kind of follow-up to that to
try to put it all together for me.
You've talked about the research priorities. You all were -- it was suggested that you
create a two-year and five-year plan and who -- is this the group that does
that? Are you the person who does that
and who then, if that's true, who then checks to see if scientists within your
program are fitting within that two- to five-year plan?
DR. EPSTEIN: Okay.
Very good. The two- to five-year
plan is reflected in the priorities which will be evaluated every year. But similar to the research programs, there
will be an even more intensive four-year cycle approximately of going more
deeply into whether changes are needed.
The evaluation of whether the
principal investigations are addressing the priorities appropriately is
conducted once a year and then more intensively every four years. The annual evaluation is by the division
director, associate director for research and then with input from the office
director. The in-depth, every four years
evaluation includes external peer review.
And in the future -- this is the
first time we've had such explicit priorities.
A laboratory-based site visit in the future will have a copy of the
current version of the "priorities" and in the past what we did was
to say what products were regulated in that area and how this person's work was
relevant. But it will now be all
explicit and so we will have both internal and external review.
Carolyn, did you want to comment?
DR. WILSON: I wanted to just add one additional point to
what Sue said which is this year we're actually doing a new process within the
Center which is each of the product offices are developing research program
plans which do provide a broad framework programmatically for the direction of
their research programs incorporating into that what is their regulatory
portfolio. From that, are there critical
gaps in scientific knowledge, areas of future direction that they would want to
pursue if resources were available, and then also a section that will sort of link
the research priorities to the previous year's scientific accomplishments and
how those are linked. And this is sort
of a pilot this year, but we hope that every year after that. And that's reviewed at the Center level.
DR. GERSON: I wonder if I could comment after having
observed and watched and reviewed for a short period of time about to me the
remarkable accomplishments of this effort and of the strategic response, if you
will. It is not easy to move an
organization and to move a scientific group.
I think I see an incredibly reaction
to the rapidly moving field and your desire and capabilities sort of keep up
both at the cutting edge in terms of the research efforts and the issues that
the field is raising.
And, if you will, it's astonishing
to me that you have on your shoulders the need to engage with every type of
this broad base of product development and have expertise in it both of the
research and of the review process. So I
really am humbled by the accomplishments that I see and the rapidity of the
response and the creativeness that you've taken in organizing the office around
the issues that came up during the review.
DR. WOO: I would add my support to that comment just
made by Dr. Gerson. I think it's very
important for the FDA to continue with this research program so that you can
talk the same common language with the stakeholders when they come to you and
you understand what the issues are and what are the problems they face and so
this interaction is critically important and many of us on the outside
appreciate this very much.
My question to you is that you have
mentioned that you have a priority setting mechanism in-house, whatever the
name of that is, to identify new areas that are important for public health and
so on and so forth, and that's wonderful.
My question to you is that with the limited budget it's one thing to
identify new areas to focus your research efforts on. What that means is also that you have to
discontinue some of those other less important areas. So I was wondering. Do you have a mechanism of doing that as well
so that it would facilitate your ability to continue with this wonderful
process?
DR. EPSTEIN: You're aware of something that's certainly a
reality. We do seek new sources of funds
and have had some success. So not everything
is a replacement. But I mentioned some
of our recruitments happen to be replacements for departures. Then Tissues is a new initiative that is
additional that if there's a new public health problem of magnitude that gets
the attention of the Center and agency level it can be possible to launch a new
initiative.
But then a lot of it otherwise is
the gradual shifting of investigators if they've finished answering a question
and they themselves perceive a new area
rising in importance, our staff are fairly nimble, and we have had staff
members not change their whole field, it would be within virology or within
immunology, but they move on to tackle that issue that they see. There have been some very productive shifts.
DR. KWAK: I have two comments. Actually, the first is a comment and the
second is a question. First is to simply
congratulate you on the recruitments, and second is a question just of
clarification. How does this site visit
that you've described differ from the every four year laboratory site visits
that we participate in?
DR. EPSTEIN: Okay.
Good question. The every four
year laboratory site visits are at the individual investigator level. They involve very detailed presentation of
data both in the briefing package and in the presentations on the day of the
site visit, and those are for evaluation of individuals for productivity and
relevance, and that feeds into their conversion which is the equivalent of
tenure or promotion.
The office site visit was much
broader because it covered all the laboratories. So it could not drill down to the level and
was not intended to drill down to the individual performance issues and the
individual projects. It was intended to
look very broadly at the portfolio, the research priorities, the procedures and
management practices of the office and make recommendations very broadly about
how we conduct the research programs.
So the every four year laboratory
site visits will continue. That's simply
how we have outside peer review of our staff.
The office site visit was a unique event which may be performed again at
some future time, but it's more like a blue ribbon panel evaluation of the
whole FDA but at the office level.
CHAIR URBA: Dr. Chappell.
DR. CHAPPELL: I echo others' congratulations of your
programs and also ask that you mentioned the existence of a biostatistics
office which does important analyses of data sets and also yesterday the issue
of design arose, and so I was wondering if -- and I think this is a relatively
new area in which new designs may be needed or at least considered for Phase 1
and higher level trials. So is that a
priority? I mean I would hate to add
anything to your list and tell you what to delete.
DR. WILSON: Those may or may not overlap with the office
priorities, but at the Center level, I probably went through it pretty fast,
but we actually had three Center level priorities that were related to
biostatistics related to clinical trial design as well as surveillance issues
for post marketing. But there is a very
active effort right now to improve clinical trial design methodologies,
incorporate Bayesian statistics and that kind of thing. So our Office of Biostatistics and
Epidemiology is actively engaged in thinking about those new paradigms for
clinical trial design.
Does that answer your question?
DR. CHAPPELL: Sure.
Who is the head of that now? I
think it changed recently.
DR. WILSON: Right.
The new Office director is Robert Ball, and Steve Anderson is remaining
as the deputy Office director.
DR. CHAPPELL: Thank you.
DR. TOMFORD: Thank you.
That was a good presentation.
I'm intrigued by the idea of horizon
scanning so that hopefully you pick up problems or potential problems. How do you interact with the private
sector? You know, there are about 1.5
million tissues transplanted annually now.
Let's say you see a potential area of problems or a few problems that
have occurred. What is the -- do you
have interaction with this non-governmental sector? How does that occur, or do you do basic
research yourself?
DR. EPSTEIN: There could be several parts to the answer,
but I want to mention how it works for other products as well as tissues. We have pre-IND contacts and pre-pre-IND contacts. In the tissue area it would be other communications. But the fact that people talk with us at
meetings and on the phone and to ask us questions gives us some sense of what's
going on.
Then in terms of if a problem
develops, our response can be multiple.
There will be people in the Human Tissues Division who are engaged in
regulating that industry who may be talking with those centers and working out
the response to the problems. The
research program will support that by addressing underlying scientific questions. For example, is there a way of processing
that could get rid of new organisms? Say
there is some cutting edge technology that people aren't even aware of yet or
can be developed that could either get rid of organisms, could detect more
sensitively than just taking a swab from the outside, could be more
representative than a snip.
So the research program will be
interactive with the Division of Human Tissues and the Office of Product
Compliance. I never get the name of that
office right. It was on the slide. Those groups are involved in the tissue
inspections and so on.
The new Tissue Research Program will
interact with them and talk with them.
Information will flow in both directions, and then we would hope the
research will lead to some solutions to some of these problems or at least
ideas about how to better define and measure the problem. That's often a step forward in itself.
DR. WITTEN: I'll just add. We do have also the regulatory component that
has regular discussions with AATB, EBAA and other organizations that are involved
on the outside with tissues across the board, cord blood programs, and, as Dr.
Epstein just said, when we have the research program up and going then I think
it will be sort of a three-way dialogue, the research and regulators together,
and there will be some discussion with the outside groups like AATB.
DR. TOMFORD: I think that's good because a lot of these
groups don't do a lot of research as you probably know. So I think the office can function at least
in promulgation of research efforts or ideas in that area.
DR. WITTEN: Yes, I think that's exactly part of the goal
of that program is to do research but also stimulate some work on the outside
in some of these challenging problems.
DR. GUNTER: I guess my question is for Dr. Wilson, and it
has to do with the promotion and conversion activities, and I think you said
that the scientists in the office are looked at both on their research and
regulatory activities. But how is that
weighted? Are they 50/50? Is research more important?
And then I have a second part. Can you give me a sense or give us a sense as
to how the regulatory burden is trending over the last few years for the
individual reviewers in the office? Are
they having to do more regulatory work at the expense of research, for example?
DR. WILSON: Okay.
I will answer the first part which is that when the committee reviews
each individual investigator it really is a 50/50 balance in that the review
process involves an assignment of four individuals to each package that comes
before the PCE, and those four individuals are two research review scientists
as well as two full-time review scientists.
So each is tasked with -- obviously, the research reviewers are looking
very carefully at their research outcomes and productivity and quality taking
into account the site visits, external recommendation letters that are required
in addition to a recommending memo from the division director that gives a
narrative of their research accomplishments and the relevance to the regulatory
program.
And then the full-time reviewers are
looking -- they are given specific examples of review memos, a portfolio of
their review workload. They do detailed
interviews with their branch chiefs and division directors to assess the
quality of their review work.
So really it's very important that
both of these are weighted carefully because you may have the most stellar
scientist in the world, but if they're a complete disaster or ignoring their
review work, then obviously that's not the type of individual we would want to
retain. So it's very important and very
different for CBER in that respect that our research scientists are competent
and dedicated to both aspects of the their work.
In terms of the regulatory workload,
that's a more difficult question to answer partly because as Sue can attest to
because she's tried really hard to do these analyses, it is sometimes very
challenging to get an accurate picture of what the regulatory workload looks
like, and this is confounded because, for example, one IND may have 200
amendments in a given year. But those
amendments may be very trivial and take five minutes of a reviewer's time. So counting 200 amendments versus maybe one
amendment that took two weeks to review, it's just really apples and oranges.
So these are really challenging
issues. It's something that both the
Offices and the Center are trying to address to get a better metric on how do
we measure the regulatory workload. So I
can't really address that as well as I can.
I can say that the Center this year
has been fortunate, and we've received an additional 84 FTEs. Many of those are, I think almost all of them
are, going into review positions and so this should help alleviate the review
workload in coming years. Obviously,
right now, we're in the process of recruiting and filling those positions.
DR. EPSTEIN: We have tried a system of putting INDs into
three tiers, very active and original submissions and controversial ones, ones
getting a few amendments and ones where it's just the annual report. So it is possible to try this form of
analysis and, Stephanie, you may want to comment. I think there's no question the workload has
gone up.
DR. WOO: Having participated in one of these reviews
recently and appreciating the importance of these researchers and reviewers,
the dual function, I would urge the Agency to protect these researcher
reviewers in terms of their research time.
I understand the importance of
review. Obviously, this is the FDA, and
I understand that. But if you are going
to do research with less than 50 percent time or when you're in the middle of
your very exciting research program and you get pulled away to do an IND for
months, this is not conducive to productivity in research, and if we are
demanding that your researcher-reviewers to be competitive with the outside
review groups and to publish in quality scientific journals, then I think you
are really asking too much of your researcher-reviewers.
So it's critically important in my
mind for the Agency to protect these folks, to have at least 50 percent review
time and -- otherwise, you're putting these people's careers at risk.
CHAIR URBA: Dr. Puri had a comment and then Dr. Taylor.
DR. PURI: I also wanted to comment on the question from
Dr. Gunter that we do have 50/50 workload for 50 percent research, 50 percent
review. But most of how our staff does
actually not do only 40 hours a week.
They work a lot more than they are required to, and actually it's a
balancing act, and as you heard from Dr. Wilson that you can't actually tell
when you're going to get too many, you know, one particular amendment have a
lot more work than the others. But I
must say that most of our staff spends more time in doing regulatory work than
the research. But they balance it by
adding on additional hours like you folks in the academic institutions and
others as well.
And I appreciate Dr. Woo's comment
about protecting our research which is a -- provides underpinning to regulatory
research as well as regulations.
DR. TAYLOR: I actually want to follow up on that if I
could and then also ask the original question I wanted to ask. In terms of having participated in two of
these site reviews now, the issue that seems to emerge over and over and over
is that there are some incredibly productive, great scientists doing fabulous
work at the FDA, and they seem to have increasing regulatory workloads that
limit their ability to do their work. So
I echo Dr. Woo's concern in that regard and that's come up at every site visit
in which I participated.
But the other thing that's come up
is there are unfortunately some scientists who aren't as productive as they
could be in terms of peer reviewed publications and top tier publications, and
when we've tried to dig deeper into that, one of the issues that seems to come
up is they don't feel they get the guidance they need or the mentoring they
need. And
so I know that's been an issue of conversation, and I'd like to know what you
have put in place to help these scientists who aren't perhaps right on track
going forward.
DR. WILSON: CBER-wide in the past year, we've instituted
a formal mentoring program which involves actual deliberate pairing of
individuals with a mentor and then the individuals who elect to participate in
this program receive specific training about mentoring. What are the expectations of a mentor? What are the expectations of a mentee? What are the responsibilities of both and so
on?
But in terms of research scientists,
they can choose to participate in this formal mentoring program, but it's
certainly not required, and so I think your point is well taken that the way
process works now is that the mentoring is really the responsibility of the
individual scientist branch chief to make sure that that individual
investigator is on track and is maintaining product of quality research. But I certainly take your point that that
type of mentoring may be uneven across the Center, but it is something that we
are trying to address, and Sue may have some additional points to add.
DR. EPSTEIN: I was going to mention both of those and then
just the fact that if there isn't progress, the individual scientist is brought
to discussions with the leaders. That
would be noticed before, say, a four year laboratory site visit. It's not a perfect world, and there's a
spectrum of the outcomes, but the effort to advise people about how they can
become more on track, say, where on track includes both relevance and
productivity, those efforts like the other efforts to announce priorities are
becoming more explicit.
They used to be implicit. In response to the recent office site visit
report, all of these activities are more forefront and more explicit. The outcomes will still be a spectrum, and
that is part of -- the consequences
include budget and tenure decisions, for example, and not everyone
achieves tenure at CBER.
DR. TAYLOR: I had my original question, but if you have a
follow-up.
DR. SIMEK: I just want to make a point that as Carolyn
mentioned we do understand the issue of our researchers. It's a very difficult position to be in, and
they really need to be credited with what they do. They spend a tremendous amount of time doing
both regulatory and research. What we
have been lucky this year as Carolyn has mentioned is we have received a number
of positions that are for full-time reviewers.
Now this in no way -- our review load increases every year and so we are
hoping that with this increase in full-time reviewers this will be able to help
our researchers. I mean, they still do
their considerable load of regulatory work, but it will allow them to do the
research that's extremely essential to be able to help with the mission of the
FDA.
So this in answer to, Dr. Woo, one
of your questions is this is one way that we have been fortunate to be able to
handle this situation.
DR. TAYLOR: Can I ask my original question? When you were discussing research, you used
mesenchymal stem cells as an example of an interaction with the FDA and NIST, a
collaborative effort to look at -- to try to develop some high throughput
assays for predicting differentiation.
So mesenchymal stem cells are one kind of cell and the differentiation
markers you're looking at are very specific for even subpopulations.
And I guess in terms of relevance,
my question is how do you generalize these kinds of findings and obviously
you're asking one very specific research question which we all have to ask to
move science forward. But it seems to me
that the goal of the Agency is to develop broader, more generally applicable
assays. And so are these kinds of
questions viewed as frameworks and models and proofs of concept so that you can
go forward and develop more broadly applicable programs? Help me here.
DR. EPSTEIN: I'll give you an analogy. If we want to study viral vectors we have to
study a particular viral vector, and suppose we solve the problem of
standardization of retroviral vector assays with reference material and RCR
testing, but then the whole field moves on and those vectors are no good anyway
and gene therapy starts to use AAV, by horizon scanning we would realize that
and move on.
We always have to pick a particular
example, and it may not always even be the example of the broadest product use
at that moment. But it's partly what you
said about proof of concept. It's partly
that stimulating interest in the whole field in this case in a more
quantitative approach and in assays that can be carried out more quickly, for
cell therapy in general we want to stimulate use of biomarkers or other
parameters that can be measured before the cells all die and that won't consume
all the cells in the process of measuring it.
So, yes, we do like everyone have to
pick out examples to work on, and we may not always be able to move on to a particular
example that solves the whole field, but we will be much better informed in
viewing other assays for having this experience.
CHAIR URBA: Dr. Witten, it looked like you were going to
make a comment.
DR. WITTEN: I think Suzanne made it which is primarily
one of the goals is to stimulate
interest in the field in this type of method.
If it proves to be useful, I don't think the goal would necessarily be
that FDA develops or FDA and NIST develop this method for every type of cell
marker but that we would show that this method was possible, could be useful,
and hopefully if it was something useful to the field would get developed
further in the specific cases where it's needed.
DR. GERSON: Implicit in our discussion about how you've
redirected the research orientation of the Agency and some of the priorities of
interest and investment, is a dissemination of this effort through all of the
resources you directly control and perhaps even more through the collaborations
that you've very effectively showed us?
But you didn't describe terribly well for us actually how it gets to the
troops, if you would pardon the expression, folks who are in the laboratories
whether they be principal investigators or the associates or technicians who
would be involved in some of the shifting of research efforts or the
encouragement of these collaborations that you want to be strategically
prioritized.
DR. EPSTEIN: So you're saying how do we communicate with
our own staff the need for the shifts.
You don't mean how do we communicate our research results to the outside
world.
Okay. Within the division or the office, the
principal investigator is the nidus of this kind of decision making. I work a lot with the PIs to advise them
about being more clear and explicit in explaining their research. They have to be able to explicitly connect
what they're doing to the priorities or to the products we regulate.
In terms of the post doctoral
fellows or technicians, it's less important that they be fluent in this kind of
dialogue, but their research will be directed into a reasonable area by the PI
and as they mature and may become part of the CBER staff, they also will attend
meetings where they hear all of this.
But the most important level to
communicate it to is the PIs because they have to both make good decision about
what to do, and they have to become communicative about why that work addresses
that priority. That latter part is
something where I feel many of our past problems lay. People might be doing projects that were of
reasonable public health value, but they were not explaining it explicitly
enough, and someone not in the field might not realize the value of why are you
doing that. So we are working hard.
This is true of science in
general. If scientists won't speak in a
manner that others can understand, we won't be funded. It's critically important, and Dr. Gooden has
now hired a communications expert who is a very good writer who used to be at
St. Jude's, and we're working with him.
He may be able to assist us in getting the word out about some of these
projects.
CHAIR URBA: Other comments? Questions?
DR. GUNTER: Well, this is just a very specific question,
I guess, for Dr. Epstein and has to do with the discussion yesterday on
embryonic stem cells. In part of your
horizon scanning process, where do you see that, and do you have the expertise
in-house now to review those kind of products and, if not, what are the plans
to obtain the expertise?
DR. EPSTEIN: Okay.
We have expertise in-house based on reviewing other kinds of cellular
products, work on other kinds of stem cells.
I do -- as I mentioned very briefly, Dr. Bloom was actually working on
embryonic stem cell lines and looking at immune responses to them. So this is a bit early for me to try and --
it's a sad loss for us that we did have that very specific expertise.
But we still have in-house expertise
on laboratory use of other types of stem cells and from yesterday's discussion
it's not clear the problems will be always different. There will be perhaps different awareness of
certain risks. Whether it calls for a
new laboratory program, I think that's a matter for future discussion. It's not clear.
If anyone else wants to comment, but
we do have a very active program in cell biology and work on cell-based
therapies.
CHAIR URBA: Thank you.
We set aside a few minutes for open public hearing. It's scheduled for 9:45 a.m. after the break. But I thought we might open the floor at this
time for any comments from the public.
If not, I guess it's probably good
to take a break now then. Is that
okay? Yes, we'll take the break now, 15
minutes. We'll meet back here at 9:40
a.m. and hear from Dr. Benton.
(Whereupon, at 9:23 a.m., the
above-entitled matter recessed and reconvened at 9:42 a.m. the same day.)
CHAIR URBA: Okay.
It looks like we're about ready.
Before I introduce Dr. Benton, Dr. Taylor had one additional comment she
wanted to make about this morning.
DR. TAYLOR: I appreciate it. I just wanted to make one more comment about
mentoring that I would like to strongly urge for the record that scientists who
are viewed, either by their peers or by their supervisors as to not be on track
that maybe the mentoring program should not be an optional event, but that it
might be something that should be at least required for a year.
CHAIR URBA: Thank you.
Okay. Dr. Benton?
UPDATE-FDA SOMATIC CELL THERAPY LETTER
DR BENTON: Good morning.
This presentation will provide to the Committee and the stakeholders an
update on the somatic cell therapy letter.
Although we don't have a question to pose to the Committee on this
topic, we appreciate the opportunity to use this public forum to respond to the
question that they raised at our 2005 office-wide site visit regarding our
progress and the outcome of our review of the somatic cell therapy letter
responses. So I'm going to summarize our
experience and discuss our plan to discontinue both issuing the somatic cell
therapy letter to new INDs and requesting submission of yearly updates from
sponsors in this particular format.
The somatic cell therapy letter was
a request for information issued by our office to all sponsors of somatic cell
therapy INDs. The letter was issued
since June of 2002. So throughout my
slides, you'll see I've abbreviated somatic cell therapy letters as SCTL, but
for ease of pronunciation, I'm going to refer to it in my talk today as the
letter.
So the letter requested the
submission of information by IND sponsors on topics of product manufacturing,
quality control procedures, product testing and clinical trial oversight and
monitoring.
We issued the letter to address the
recurring deficiencies that we had noticed in our review of INDs and master
files and also through inspections of cell manufacturing facilities and
clinical sites. We determined that the
letter would be a beneficial activity, based on our experience with a similar
letter that was issued to the gene therapy field.
As many of you know, in March 2000,
we issued a Dear Gene Therapy Sponsor letter, following the death of a subject
in an adenoviral vector clinical trial.
Although there was not a specific safety concern in the cell therapy
field that prompted us to issue the letter to cell therapy sponsors, we felt
there was a need to request updated information because the field was very
diverse and constantly evolving and also for some IND sponsors, we have very
frequent communications in the initial period of IND review and then
significantly less communications.
Sometimes just brief annual reports are submitted.
So our goals in issuing the letter
were to ensure that all cell therapy products in ongoing clinical trials met
our current expectations for safe conduct of the trial, to identify lapses in
product testing with potential safety implications, to obtain information on
the status of product characterization and manufacturing practices, and to
encourage the development of clinical trial monitoring programs that would
adhere to good clinical practice and to encourage the submission of final study
reports. Additional goals were to gather
information on the need for additional guidance or other regulatory documents
and other forms of outreach that we could provide to the somatic cell therapy
field. All of these fed into our larger
overall goal of enhancing the safety of somatic cell therapy products and
facilitating product development.
The letter consisted of eight
multi-part Chemistry, Manufacturing and Controls -- which is commonly referred
to CMC questions -- and three multi-part
Clinical questions. The requested date
for response or to submit their response was 60 days from the anniversary date
of their IND file. Lack of response was
not considered a cause for placing the file on clinical hold.
I've simplified the content of the
CMC questions to the topics that are listed on this slide and the following
slide: quality control and quality assurance program; providing an overall
description of the procedures; the personnel that are involved in the program
and their responsibilities; and the conduct of audits; qualification of the
starting cells, reagents used in manufacturing and equipment; product tracking
and segregation and container labeling; cleaning and sanitization of the
manufacturing facility and equipment; and control of contamination;
additionally, the timeline of product manufacturing process and when tests were
conducted; a description of the test methods, both those used in-process to
test intermediates in the manufacturing process and testing of the final
product for lot release; sterility validation and aseptic processing; product
characterization activities; stability program; and cross-referenced files.
The clinical questions requested an
update of the following information: a complete description of the clinical
trial monitoring program, including a description of the personnel responsible
for the monitoring activities and a summary of the procedures for clinical
study conduct and monitoring; and, additionally, provided a request that final
study reports be submitted for all studies.
Responses that we received to the
letter were reviewed by the specific IND review team that was assigned to that
IND. The focus of the review was to
ensure ongoing clinical trials met our current expectations and to identify any
lapses in product safety testing. We
identified safety issues in a small number of INDs, but these were not
generalizable across the field and these issues that we identified for a
specific file were addressed between the IND review team and the sponsor and
the issues were resolved by communication through a teleconference and
submission of additional information.
One generalization we could make is
that we observed very broad differences in the status of product
characterization. And the major outcome
of our review activity was identification of the need for additional CMC
guidances and other forms of outreach to the somatic cell therapy field.
In response, since the time that we
began to issue the letter in 2002, our office has developed multiple CMC
guidances, and I'm going to give a very brief description of those most
relevant to the somatic cell therapy letter activity today, and I'd also note
that in the talk following mine, Dr. McFarland will give a more thorough
overview of guidance development in our office.
So a few years ago, we published the
draft guidance which is blacked out, faded out, on the left and this was a
draft guidance for FDA reviewers for instructions on a template for completing
their CMC review of INDs. Just this
week, I think it was Wednesday, we have published the finalized guidance of
this document, which is Guidance for FDA Reviewers and Sponsors; Content and
Review of Chemistry, Manufacturing and
Controls Information for Somatic Cell Therapy INDs.
So this finalized guidance provides
information on the data and information that sponsors should provide in their
IND submissions and that CMC reviewers should document in their review of
IND. There is a template that is appended
to this guidance and our CMC reviewers use this template to ensure consistency
in the documentation in their CMC review activity and we also note that
sponsors may use this template as a format for formatting their CMC section for
their IND submissions.
Additionally, our office was the lead
in developing guidance shown here, Validation for Growth-Based Methods for
Sterility Testing of Cell and Gene Therapy Products and this was in response to
the broad interest in alternatives to traditional sterility test methods.
Our office also contributed to
agency wide or multi-center guidances that have sections on special
considerations for somatic cell therapy products. Most notably of these are INDs: Approaches to
Complying with Current Good Manufacturing Practice During Phase 1, and Sterile
Drug Products Produced by Aseptic Processing: Current Good Manufacturing
Practice. So these four CMC
guidances which I've shown on the past few slides contain information and
guidance to sponsors on the topics that were the subject of our CMC questions
in the Somatic Cell Therapy Letter.
In the clinical area, guidance
relevant to the topic of the clinical questions is provided in good clinical
practice guidances, provided in the International Conference with
Harmonization, document E6, Good Clinical Practice: Consolidated Guidance.
In addition, our office has a number
of guidance documents in development. An
example that I'm showing you today from the CMC area is a guidance that's under
development for potency measurements, which was the topic of the February 2006
meeting of this advisory committee.
In addition to guidance documents,
we have increased and improved our outreach activities to the cell therapy
field. We regularly give presentations
at numerous conferences each year which reach broad audiences in the field, and
we regularly hold liaison meetings with several groups in the field and the
focus of our CMC talks commonly includes a discussion of product
characterization and potency measurements.
And again, I'll remind you that these were areas that we found were
ongoing challenges to cell therapy sponsors.
And CMC talks also commonly address the regulations in 21 CFR Part 1271
which are commonly referred to as the tissue rules.
Just to give a brief expansion on
this point, when we released the somatic cell therapy letter in 2002, the
tissue rules were still proposed rules and in subsequent years these have been
finalized and went into effect in May 2005.
The tissue rules focus on the prevention of the transmission of
infectious disease and donor testing and screening and design of manufacturing
practices to control contamination and cross-contamination are critical safety
issues in the production of cell therapy products. The sponsors may refer to the Guidance for
Industry Eligibility Determination for Donors of Human Cells, Tissues and
Cellular-and Tissue-Based Products for more information on donor testing and
screening.
In addition to eight sponsors in
locating resources such as our guidance in other documents, our office has
consolidated relevant information on our website. Specifically the link is References for the
Regulatory Process for the Office of Cellular, Tissue and Gene Therapies and
the link is shown here. And we intend to
update this site periodically as new information is available.
So in summary, our experience in
reviewing the data that was submitted to the somatic cell therapy letter
responses contributed to multiple guidance documents, some have already been
issued and others are in preparation, and also to numerous ongoing outreach
activities that are broadly applicable to the field of cell therapies.
And so we've concluded that there
are now guidances available which address our expectations for IND submissions
and clinical trial conduct and, therefore, it is not necessary to convey these
expectations and request responses from sponsors in the separate format of the
somatic cell therapy letter. Our office
will therefore discontinue issuing the somatic cell therapy letter to new INDs
and no longer request that sponsors provide updates in the format of the
somatic cell therapy letter questions.
So IND sponsors may submit updates and information to their INDs in
amendments and in their annual reports, as appropriate.
We would like to thank the sponsors
of somatic cell therapy INDs who provided the responses and the data that led
to our experience and also to thank the Committee members for their interest in
this topic, both at the 2005 site visit and for your attention today. Thank you.
(Applause.)
CHAIR URBA: Thank you, Dr. Benton.
QUESTIONS AND ANSWERS
CHAIR URBA: Any questions or comments from Committee
members. Dr. Chamberlain.
DR. CHAMBERLAIN: I was struck by your comment that individuals
that didn't respond to the letter were not placed on clinical hold, and are
there still any groups that have not responded or how did you deal with that
situation?
DR BENTON: Well, this letter, unlike the gene therapy
letter, there wasn't a specific safety issue that prompted us to issue the
letter. Our goal was to bring existing
INDs up to the current expectations and consider it as a tool to the way we
could communicate to all the IND sponsors.
But since there wasn't a specific
safety issue that we were seeking information on, we determined it wouldn't be
appropriate to place someone on hold for lack of response. We do have other mechanisms people are
required to submit yearly, annual reports, and if that isn't done we send
reminder letters and that sort of thing.
So we probably received about a 50
percent response rate and some of the responses -- factoring into that, let me
also say -- some of the responses are trials inactive. You've reminded me to reactivate my file and
therefore, if I decide to initiate a new clinical study and reactivate, I'll
respond to the letter then.
CHAIR URBA: Any other comments from the Committee? Questions?
DR. TAYLOR: Is there any -- you may have given us this
and I don't recall it. Is there a time
line for the guidance document that's in preparation on --
DR BENTON: I mentioned that a guidance document for
potency measurements is in preparation.
DR. TAYLOR: Yes.
The potency measurements.
DR BENTON: We definitely have an early draft
prepared. We considered the comments
that we received at the advisory committee and also, as with any other CBER
guidance it's very difficult for us to give an exact issue date. But we've already put some time into it and
we certainly hope it will be published soon.
DR. TAYLOR: And are any of these -- these are all documents for somatic cell
therapy. Given our conversation
yesterday, are there guidance documents being generated for non-somatic cell
therapy?
DR BENTON: Our cell therapy guidances are really broadly applicable to all the cell products that we regulate as biologics. The distinction would be, these don't apply to cell-based products that are regulated as tissues in general.