UNITED STATES OF AMERICA
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FOOD AND DRUG ADMINISTRATION
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OFFICE OF THE COMMISSIONER
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SCIENCE BOARD
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MEETING
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FRIDAY,
APRIL 15, 2005
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The
meeting was held at 8:30 a.m. in Room 1066 of the Food and Drug Administration,
5630 Fishers Lane, Rockville, Maryland, Dr. Kenneth I. Shine, Chair, presiding.
MEMBERS PRESENT:
KENNETH
I. SHINE, M.D., Chair
GAIL
H. CASSELL, Ph.D., Member
SUSAN
KAY HARLANDER, Ph.D., Member
CATO
T. LAURENCIN, M.D., Ph.D., Member
F.
XAVIER PI‑SUNYER, M.D., M.P.H., Member
JIM E.
RIVIERE, D.V.M., Ph.D., Member
ALLEN
D. ROSES, M.D., Member
MEMBERS PRESENT (continued):
KATHERINE
M.J. SWANSON, Ph.D., Member
JOHN
A. THOMAS, Ph.D., Member
LESTER
M. CRAWFORD, D.V.M., Ph.D., Acting
Commissioner
NORRIS
E. ALDERSON, Ph.D., Associate
Commissioner
for Science
JAN N.
JOHANNESSEN, Ph.D., Executive Secretary
ALSO PRESENT:
RACHEL
E. BEHRMAN, M.D., M.P.H., Deputy
Director,
Office of Medical Policy, CDER
ROBERT
BRACKETT, Ph.D., Director, CFSAN
ROBERT
BUCHANAN, Ph.D., CFSAN
KATHRYN
M. CARBONE, MD., Associate Director for
Research,
CBER
STEVEN
GALSON, M.D., M.P.H., Acting Director,
CDER
JESSE
L. GOODWIN, M.D., M.P.H., Director, CBER
MARY
MALARKEY, B.S., Director, Office of
Compliance
and Biologics Quality, CBER
JOHN
R. MARZILLI, Deputy Associate Commissioner
for
Regulatory Affairs
ALSO PRESENT (continued):
THERESA
M. MULLIN, Ph.D., Assistant Commissioner
for
Planning
ARMANDO
OLIVA, M.D., Associate Director for
Policy,
Office of New Drugs
DANIEL
SCHULTZ, M.D., Director, CDRH
PAUL
J. SELIGMAN, M.D., M.P.H., Director, Office
of
Drug Safety, CDER
STEPHEN
SUNDLOF, D.V.M., Ph.D., Director, CVM
JANET
WOODCOCK, M.D., Acting Deputy Commissioner
for
Operations
PUBLIC HEARING PARTICIPANTS:
SADHANA
DHRUVAKUMAR, Senior Scientific Research
Specialist,
PETA
PAUL
DRZAIC, Ph.D., Vice President, Advanced
Development,
Alien Technology Corporation
JANELL
MAYO DUNCAN, Legislative and Regulatory
Counsel,
Consumers Union
G.
MICHAEL FITZPATRICK, Ph.D., Chief of Policy
and
Chief Operating Officer, America's
Blood
Centers
SANGTAE
KIM, Ph.D., Division Director, Shared
CyberInfrastructure,
National Science
Foundation
C O N T E N
T S
PAGE
Call to Order, Chairman Kenneth Shine........... 5
Welcome and Opening Remarks
Dr.
Lester Crawford....................... 8
Dr.
Janet Woodcock....................... 16
Introduction to Drug Safety, Dr. Steven Galson. 32
Pre-Market Drug Safety, Dr. Armando Oliva...... 42
Improvements in Drug Safety Information
Labeling
and Electronic Initiatives,
Dr.
Rachel Behrman....................... 62
Drug
Safety Initiative, Dr. Steven Galson 82
Post-Market Drug Safety, Dr. Paul Seligman.... 103
Drug Safety Resources, Dr. Theresa Mullin..... 113
Applying New Science to Drug Safety,.......... 141
Dr.
Janet Woodcock
Committee Questions and Discussion............ 154
Open Public Hearing
Ms.
Sadhanna Dhruvakumar ............... 192
People
for the Ethical Treatment of Animals
Ms.
Janell Mayo Duncan ................. 201
Consumers
Union
Dr.
Paul Drzaic ........................ 215
Alien
Technology Foundation
Dr. G.
Michael Fitzpatrick ............. 212
America's
Blood Centers
Dr.
Sangtae Kim ........................ 220
National
Science Foundation
Safety Systems to Vaccines, Blood and Tissue,. 227
Dr.
Jesse Goodman
cGMPs for Vaccines, Ms. Mary Malarkey......... 270
Committee Questions and Discussion............ 293
Adjourn
P-R-O-C-E-E-D-I-N-G-S
8:25
a.m.
CHAIRMAN
SHINE: Good morning. I'm Ken Shine, currently chair of the
Science Board Advisory Committee. And I
want to welcome you to this meeting.
We
will be shortly joined by Dr. Cassell who had another commitment but will be
with us shortly. I'm also pleased that
Professor Barbara McNeil at Harvard has agreed to join the committee. She couldn't be to this particular meeting
but she will be at our next meeting.
Before
we actually begin the program, it would be useful, I think, for us just to go
around the room and identify ourselves and our institutions for benefits of the
group. And perhaps we could start over
here with --
MEMBER
PI-SUNYER: Yes, my name is Xavier
Pi-Sunyer. I'm Professor of Medicine at
Columbia University and I'm Chief of the Division of Endocrinology and
Nutrition at St. Luke's Roosevelt Hospital in New York.
MEMBER
ROSES: I'm Allen Roses. I'm the Senior Vice President for Genetics
Research in GlaxoSmithKline.
MEMBER
HARLANDER: My name is Susan Harlander
and I have a consulting company called BIOrational Consultants.
MEMBER
SWANSON: I'm Katie Swanson, Vice
President of Food Safety with Ecolab.
MEMBER
THOMAS: I'm John Thomas, Vice President
and Professor Emeritus from the University of Texas Health Science Center at
San Antonio but now at Indiana University School of Medicine.
MEMBER
LAURENCIN: I'm Cato Laurencin. I'm a university professor and Professor of
Orthopedic Surgery and Chairman of the Department of Orthopedic Surgery at the
University of Virginia.
MEMBER
RIVIERE: I'm Jim Riviere. I'm a distinguished Professor of
Pharmacology at North Carolina State.
DR.
CRAWFORD: Les Crawford, FDA.
DR.
JOHANNESSEN: I'm Jan Johannessen. I'm the Executive Secretary of the Science
Board to the FDA.
DR.
WOODCOCK: Janet Woodcock, Acting Deputy
Commissioner for Operations, FDA.
DR.
ALDERSON: Norris Alderson, Associate
Commissioner for Science at FDA.
DR.
BRACKETT: Bob Brackett, Director for
the Center of Food Safety and Applied Nutrition, FDA.
DR.
SLIKKER: Bill Slikker, Deputy Director
for Research, National Center for Toxicological Research, FDA.
DR.
GALSON: Steve Galson, Acting Director,
Center for Drug Evaluation and Research, FDA.
DR.
CARBONE: Kathryn Carbone, Associate
Director for Research, Center for Biologics Evaluation and Research, FDA.
DR.
SUNDLOF: Steve Sundlof, Director of the
Center for Veterinary Medicine, FDA.
MR.
MARZILLI: Hi, I'm John Marzilli. I'm with the Office of Regulatory Affairs,
FDA.
DR.
SCHULTZ: Dan Schultz, Director CDRH,
FDA.
CHAIRMAN
SHINE: Good. I'm Ken Shine. I'm
sorry. Did I miss somebody? Yes.
Again,
I'm Ken Shine. I've Executive Vice
Chancellor for Health Affairs at the University of Texas. And I sit at the fulcrum between FDA and the
committee.
I
want to thank the staff of the FDA with regard to the creation of the agenda
for this meeting. A number of the
issues that we're going to deal with are important and challenging issues and
issues that the board is extremely interested in. And we look forward to a good overview of a number of these
issues and some important discussions.
But
I think it is appropriate to move quickly to hear from the Acting Commissioner
of the FDA, Lester Crawford, who, with Janet Woodcock, will be giving us some
opening remarks.
DR.
CRAWFORD: Thank you very much, Dr.
Shine. It's a pleasure for me to be
here. And welcome you all back again. Thank you for the commitment you've all made
to serving FDA in this way.
And
we're grateful for it and we're also grateful for the new organization, Dr.
Shine, that you have put forward on this board. And I think we're going to be able to do bigger and better things
as the result.
I'd
like to take this opportunity to briefly highlight some of the accomplishments
over the past year at FDA. By creating
innovative initiatives and improving existing processes, the FDA was able to
accomplish many goals that enhanced the lives of Americans in 2004.
We
introduced new initiatives to combat critical health threats such as obesity,
counterfeit drugs, and medical errors.
FDA's
Innovation Initiative has met some important milestones. First, a root cause analysis of multiple
cycle reviews, a pilot program to test the effectiveness of earlier
communication with product manufacturers, a cementing of our partnership with
the National Cancer Institute, and the establishment of an Oncology Office
within FDA to foster innovation in the treatment of cancer.
We
also launched the Critical Path Initiative, which we have presented to the
board on previous occasions. And Dr.
Woodcock is going to update you on that initiative a little later in the
program.
We
approved a substantially greater number of products, including an unprecedented
number of generic drugs.
We
strengthened the security of the nation's food supply against potential
bioterrorism attacks through the development of four important new regulations. We strengthened the food safety through measure initiatives and
actions and we streamlined paperwork processes to reduce areas, reform outdated
practices, and enhance new product innovation.
We're
extremely pleased with these accomplishments and we will continue to advance
these initiatives. But as you know, our
successes are continually challenged by emerging health threats, changes in
technology, and various global market forces.
FDA's
responsibilities are growing in scope and complexity and we're responding by
focusing on new and better ways to perform our core mission.
We
have the following strategic areas for 2005 that I would like to mention. First, enabling technology development and
innovation. Obviously we will be
continuing our efforts in the area of critical
path to pinpoint those areas of product development that could benefit
most from innovative approaches in emerging technologies.
Second,
protecting the homeland, counter-terrorism.
The past year has witnessed some of the most significant enhancements to
our Food Safety and Security Program in decades. Going forward, we will finalize implementation of our new food
security laboratories, intensified inspections, and closer interagency
collaboration.
Next
I'd like to talk about improving manufacturing practices. Good manufacturing practices are not only
vital to business success, they're also essential to FDA and they're essential
to the public health.
The
FDA's overhaul of the pharmaceutical cGMPs encourages manufacturers to
modernize methods, equipment, and facilities that will help eliminate both
production inefficiencies and undue risk for consumers. Our initiative also implements tougher
inspection rules to make them more targeted and effective.
We're
improving FDA's business practices also.
We're seeking to create a stronger and more unified agency. The increasing complexity of our regulatory
mission requires that we look for new ways to create efficiency, standardized
processes, enhanced infrastructure, and improved planning.
Some
highlights of our plan include full implementation of shared services,
including consolidation information technology infrastructure, development of a
common business process model.
And
finally the thing that I'm most pleased with and I think most FDAs are, the
continued development of the White Oak facility as we move forward with total
complete occupation in the year 2010.
By that time, we will have 8,000 FDA staffers in the White Oak facility
and we're very much looking forward to its completion.
Under
the area of patient and consumer protection, as you know the issue of drug
safety has received a lot of high profile media and Congressional attention
since we last met in November of 2004 which is why this session of the Science
Advisory Board is scheduled at a very opportune time.
There
has been a lot of public scrutiny over this issue with the recent concerns
associated with SSRIs last fall and the inclusion of a black box warning on the
label of Cox-2 inhibitors and the Merck withdrawal of Vioxx, the Pfizer
withdrawal of Bextra, the recent recommendations of our Drug Advisory Committee
on warning labels for over-the-counter NSAIDs as well as the prescription
NSAIDs.
Silicon
breast implants has just come up. And
we will be processing over the next 90 days the recommendations of that
Advisory Panel under the leadership of Dr. Schultz.
It
is important that these concerns do not distort the fact that drugs are safer
today than they have ever been before and that millions of Americans each day
benefit from them. But in order to
improve on current process, FDA has taken some bold steps to enhance the
internal deliberations and decisions regarding risk and benefit analyses.
FDA
also is developing new communication formats to better inform the public of the
Agency's deliberation process.
Next
I will discuss final risk minimization guidance. Just a few weeks ago, FDA issued three final guidances:
pre-marketing risk assessment, development and use of risk minimization action
plans, good pharmacovigilance practices, and pharmacoepidemiologic
assessment. These guidances are
evidence of FDA's commitment to transparency and risk management decision
making.
We
have announced. Secretary Leavitt and I along with Dr. Woodcock, the Drug
Safety Oversight Board in February. The
newly created Drug Safety Oversight Board will oversee the management of
important drug safety issues within our Center for Drug Evaluation and Research
under the leadership of Dr. Galson.
The
board will comprise members of the FDA and medical experts from other HHS agencies
and government departments as well as consultation with people from the outside
world.
We
have commissioned an Institute of Medicine study. In November of 2004, we asked the IOM to carry out a top to
bottom study of drug safety. We've
already transmitted two-thirds of the needed funding for this study to the IOM
and they're moving forward in initiating the study.
IOM
has assigned one of their most senior study directors to oversee the study and
have staffed up. The proposed committee
membership will be posted on the National Academy's website shortly, perhaps as
early as Monday, April 18th. We look
forward to their results and will act swiftly to improve standards for American
consumers.
The
second pillar of the Drug Safety Program is the Drug Watch webpage. FDA is proposing to set up a new Drug Watch
webpage for emerging data and risk information. This 21st century electronic evolution will bring the power of
information directly to consumers and increase the transparency of the Agency's
decision-making process. This site will
also enhance public knowledge and understanding of drug safety issues.
Now
I would also like to posit a brief overview of the day's agenda, Dr. Shine, if
I can.
Our
agenda today is devoted to these issues of pre- and post-market drug safety,
drug safety information for health professionals and consumers, and safety
issues related to blood products, vaccines, and vaccine manufacturing.
You
will be hearing detailed presentations on each of these topics throughout the
day. We're seeking your advice on
several issues today relative to our efforts to strengthen drug safety
monitoring and communication.
For
example, the Agency would value your input on the kinds of information needed
by healthcare providers and patients about the safety of a drug and how FDA can
best convey this information. More and
more we believe patients and consumers and general citizens look to FDA for
information, perhaps more than in the past.
We
also seek your input on how the reporting of adverse events could be
improved. Are there additional sources
of useful data that might help with post-market surveillance? If so, how can FDA partner with the
appropriate organizations to gain access to such data?
Perhaps
most importantly given FDA's resource situation, we seek your input as to the
appropriate areas of focus of these existing resources to most effectively
assure drug safety. We look forward to
your suggestions for improvement on this critical aspect of FDA's public health
mandate.
I
want to reaffirm that your independent views are important to FDA and to thank
you for your commitment to the Agency by participating as a member of this
board. I hope that your presentations
today will give you a good understanding of FDA's commitment to this important
issue of drug and biologic safety.
Now
it is my pleasure as always to introduce my distinguished colleague Dr. Janet
Woodcock.
DR.
WOODCOCK: Good morning.
In
the past, FDA and I have brought a number of initiatives before the Science
Board. The first one that I was
directly involved in was the GMP Initiative which has come to a satisfactory
conclusion and is ongoing.
Today
I'd like to update you on another initiative that we had gotten the input of
the Science Board on and that is our Critical Path Project. We, about a year ago, published the white
paper on the critical path.
And
in that white paper, we promised to publish a report on the various challenges
and opportunities, a project list almost of what had been identified as a work
that needed to be done under the critical path. We are working diligently on that report and expect to publish it
soon.
At
the same time, we're identifying projects that FDA within its current resources
can either carry out or lead in association with partners. And I would like to tell you that numerous
partners have emerged and although I can't go into detail about all those
offers that we've received and so forth, we're in the process of setting up how
to sort through and determine the priorities and which projects we actually can
work on with various partners.
And
so I'd like to just talk about some of the areas of great need that have been
identified and some of the things that we have done in the brief time that we
have this morning.
As
you know, we talked about one of the needs is to improve product
characterization and manufacturing scale-up issues. And that was particularly identified by Dr. Carbone in the area
of biologic, cellular, gene therapy, and so forth. We are continuing to explore ways in which to get some of that
work done and are hopeful that we can move forward in some areas.
In
the area of animal testing, the identification of the need for development of
new animal models. Particularly the
Device Center had some very innovative ideas about using in silico animal
models and computer modeling to eliminate some testing and keep up with the
rapid evolution of devices. And we are
seeking to find out how we can move forward with those sorts of projects.
Other
areas that we are still exploring but it looks like we will have partners
willing to work with us include toxicogenomics and various data mining
projects.
In
the area of other broad projects, biomarkers, of course, were identified as an
area that really needs to be developed and there has been considerable
discussion about this. We've had
numerous workshops and conferences run by the various centers or by outside
organizations to talk about this.
And
what we have identified is that the general conceptual development of how you
qualify a biomarker for regulatory use needs to be further evolved. There is a considerable amount of concern,
if you recall those of you who were here for Dr. Califf's presentation, based
on the experience in cardiology and the Cass trial in particular, there is
concern about the use of biomarkers as surrogate endpoints.
And
that has, in my mind, put a chill over the entire field of biomarker
development because it raises almost an insuperable barrier for the use of
those, those types of biomarkers in regulatory decision making. However, we have been able to tease this out
and I'm going to talk about that a little bit more. In addition, specific biomarkers need to be qualified further.
We
have kicked off the discussion of the conceptual framework for biomarker
development at an advisory committee that we held. And there is a general agreement that we should call this
something else other than validation.
Perhaps
we can call it qualifying biomarkers for various uses or evaluating biomarkers
for various regulatory uses. But the
term validation as always raises in people's minds some distinct barriers to
accomplishment.
So
we are putting together an initiative
in regulatory policy to try to figure out for the various regulatory
uses how you would describe and work up biomarkers. This is going to require public process and development of
various documents and so forth.
I
think FDA may have to lead this because it involves regulatory
decision-making. But we hope to involve
an academic partner or many partners.
And this may require discarding some of the current ideas or framework
about how -- the nature and use of these types of markers in development. And we hope it will encourage people to use
them more freely.
I
will say that there is a tremendous amount of enthusiasm now in the various
sectors as the ideas have permeated.
And there is a lot of interest in supporting these kinds of projects and
moving them forward including, you know, financial support. So we think we can get this type of work
done one way or another.
Now
we also though need to do some worked examples. We need to pick some biomarkers and move them forward for
regulatory decision-making because those concrete examples, I think, will be
more persuasive than just a conceptual framework.
We're
working on two efforts right now where we have identified good biomarkers that
we think are very close to having substantial regulatory use. And one is in the area of imaging and one is
the area of in vitro diagnostics of various types. And obviously the three medical product centers are going to have
to work very closely together on this because these involve devices, drugs, and
often biologicals together.
We
have identified partners to work with us on these and I can't go into any more
detail right now but we think what we will do, this would actually involve, at
the end of the day, doing clinical studies to generate more information on the
use of these biomarkers. And I can tell
you there is a tremendous amount of enthusiasm
in the relevant communities for getting this work done.
Now
the general process we think we need to go through is we need to identify this
type of opportunity for biomarker. We
need to analyze the current available data on the marker. And usually what we will find is there are
gaps in the data and how it correlates with clinical outcomes or how predictive
it is that prevent it from being used in various regulatory ways.
We're
going to identify those gaps in the marker performance -- in the understanding
of marker performance and then devise trials that would actually answer those
questions. And then have those trials
conducted or add the biomarker on to existing trials so that additional
information can be generated.
On
the flip side of this, in the safety side which is actually the, of course,
topic of much of the meeting today, there are many specific opportunities. And I love Dr. Roses' term. There are many forensic opportunities to use
biomarkers, especially genomic biomarkers.
We
are very interested in conducting research in clinical trials where the agent
is known to be toxic to a specific organ.
This is an opportunity to use new technologies such as genomics and
proteomics and so forth to see if we can either predict who is at risk for such
toxicities or pick up the evolution of the toxicity early.
We
also would like to go back and we're very interested in partners to go back and
identify and test people who have experienced severe adverse events and see if
genomic or other patterns can be identified that would identify people at risk
for these adverse events. We think,
obviously, this won't completely abrogate drug safety problems but this could
provide a great improvement.
Now
in specific biomarkers, we are working, as I said, with partners. We had a meeting on Monday and Tuesday on
pharmacogenomics drug development and in vitro diagnostic pharmacogenomic test
development. We had more than 500
people there. And I would like to thank
the Science Board.
We
brought this project to the Science Board, I think, about 18 months ago and
we've had over -- I think we've had 12 voluntary genomic data submissions where
we have in, you know, regulatory context, had extensive discussion of the
genomic tests and how they might theoretically be used in the development
program.
This
has also spilled over into the review side where these tests are then being
integrated into the actual drug development program and in review. And I think particularly in the cancer
field, we can see already this is an urgent need right now in the cancer field
to be able to link the diagnostic tests along with a drug. And the Device Center and the Drug Center
are working very closely together on this.
So
we have many more partners who have biomarkers than we have resources that will
be able to collaborate with them. So
this is kind of an embarrassment of riches.
But
in the safety area, we are going to focus, we're going to look at
padatoxicity. We have many partners
working with that, including NCTR is working with us on that. And we're also working on further evolution
of the QTC prolongation issue with drugs.
Now
in the clinical trial area, we're doing some worked examples of quantitative
disease modeling and simulation. And
this is a tremendous opportunity, which maybe we'll have an opportunity to
share with the Science Board later about a way to quantitate what we know about
a disease and what we know about how a disease responds to therapy in a way
that then the effect of new interventions can be modeled.
And
this can be used in the analysis of how you would conduct an additional
trial. This applies across the board to
vaccines, cell therapy, devices, and so on.
And the Device Center is particularly interested in this, as I said,
because of the rapid evolution of devices.
In
early clinical trials, this week we have just published the exploratory IND
draft guidance. This draft guidance is
out there for comment and it is a document that talks about getting into
people, not in the ordinary way of rapid dose, you know, escalation trials and
so forth, or IND safety trials, but earlier using imaging, using micro dose
techniques to look at metabolism, look at proof of mechanism for targeted
therapy and so forth.
So
we will be seeking from the drug development community and the academic
community, in particular, and put on this guidance.
We're
also doing a pilot on early meetings with sponsors that will allow us to talk
about some of the quantitative modeling and also early strategies in development.
We
had already talked, when we presented
to the Science Board last time about the projects that we wish to take
on in later clinical trials dealing with many of the analytic issues such as
Bayesian designs and so forth. And we
are working on those. We're moving
ahead and trying to set up those projects.
In
later clinical trials, there's also a regulatory modernization piece that we
found has to fit with any given modernization of the science. So we move the science along, we have to
move our mode of regulation along with it.
And so we have started what we call an analysis into how we do
bioresearch monitoring. We're moving
along on that.
And
we also recently had a Part 15 hearing, which is a way of perhaps initiating
regulatory changes on adverse event reporting to IRBs. This is something the IRB community has
brought up to us repeatedly as a problem.
We had a very good meeting on that.
And all of these efforts are intended to go along with trying to
streamline the process.
In
addition, and I'll hurry, we're working on -- we're continuing to work on the
automation and standardization of clinical trials. We have gone a long way with our partners CDISC and working with
HL7 on electronic data standards to be used in clinical trials.
We
are starting to work more on the content now.
Most of those standards have been worked on electronic interchange standards. Now we're starting to work on content standards. And this will be a Critical Path Initiative
that we will work on.
And
we're also partnering with the National Cancer Institute on electronic
reporting of -- a repository for CVs of investigators, something that kind of
plagues everyone who is involved in the clinical trial business, getting all
this information about all the investigators around to all the parties who need
it. And so the idea of an electronic
repository is something everyone agrees with basically.
The
final point I want to make is that training and infrastructure for this new
kind of science or this enhanced kind of science continues to be a
problem. We hear from the various
industries that they cannot hire and find the multidisciplinary scientists that
are needed for this kind of work. And
that's true for the FDA as well. These
folks are in very short supply.
These
issues overlap with things that were identified by the NIH in their Roadmap
Initiative. And so I think there are
opportunities here to make sure that programs are set up and people get
trained.
We
have raised these needs with the academic policy sector and hopefully, you
know, there will be a recognition of the need for more training. If we're actually going to move biomedical
science ideas into the clinic and get them to be commercial products available
to patients, we have to train people who are expert at that interface.
And
the final note I would like to add before I close is one of the things we've
all realized and we've learned throughout this year is the importance of
diagnostics to this whole enterprise.
We realize that better diagnosis is really the foundation of improved
therapy. And perhaps we were all
mistaken if we thought we could just determine better therapeutics without
further advancing the science of diagnostics.
We're
focusing on this issue with the Device Center and with our partners. And we hope this is something that can
really be moved along.
Now
the remaining barriers on this initiative, obviously we lack staffing at the
FDA to staff many of these projects.
And so that really slows down the rate of progress that we would have on
them.
Various
partners are still trying to work out how we could work together in
public/private partnerships. And what
the true, you know, arrangements would be.
There are ways to do this but they take time to make consortia.
And
we still, we're doing some analysis but we really need better incentive for
diagnostic development and we really aren't sure how that is going to get done.
So
the next steps are we are going to publish our critical path opportunities
list, hopefully very soon. Subsequently, we plan to publish a description of the projects
that we're actually able to be engaged upon at the FDA in the various centers.
We
hope to further develop these consortia.
In fact we will further develop these consortia, various types of
consortia to get this work done. And
the good news is there are people who are really willing to put resources into
this to make this happen. This general
recognition, this type of thing needs to be done. And we will try to gather some resources up internally to
continue to support these efforts.
So
the critical path concept has had a very positive response. We think publication of our list will
galvanize people to realize that there are huge gaps that need to be addressed
in their areas of interest.
We've
identified many projects. And within
our ability to do them have begun work on them. And right now the rate limiting steps are organizing these
collaborations and obtaining the resources to get them done.
CHAIRMAN
SHINE: Thank you very much, Dr.
Woodcock. Excellent. I call to the committee's attention the
large volume of guidance materials that we were provided in preparation for
this meeting.
And
one of them is the piece on pharmacogenetics, which this board discussed
extensively in April of last year. And,
Dr. Woodcock, I was very pleased to see the guidance that arose in terms of
that piece. We'll be talking about
other portions of that guidance as we go forward.
Are
there comments or questions for Dr. Woodcock at this time?
(No
response.)
CHAIRMAN
SHINE: The Commissioner has a
conference call and he will be back.
And we do have some questions for him but we'll give him a chance to get
some of his other business done.
Before
we proceed with formal presentations, Dr. Johannessen has a statement to make.
DR.
JOHANNESSEN: Good morning. The following announcement addresses
conflict of interest issues associated
with this meeting of the FDA Science Board on April 15th, 2005.
The
Food and Drug Administration has prepared general matters waivers for the
following special government employees: Dr. Kenneth Shine, Dr. Gail Cassell,
Dr. Susan Harlander, Dr. Cato Laurencin, Dr. Xavier Pi-Sunyer, Dr. Jim Riviere,
Dr. Allen Roses, Dr. Katherine Swanson, and Dr. John Thomas who are attending
today's meeting at the FDA Science Board for the discussion of drug safety,
safety systems for vaccines, blood, and tissue, and cGMPs for vaccine being
held by the Office of the Commissioner.
A
copy of the waiver statements may be obtained by submitting a written request
to our Freedom of Information Office.
Unlike issues before a committee in which a particular product is
discussed, issues of broader applicability such as the topic of today's meeting
involve many industrial sponsors and academic institutions.
The
committee members have been screened for their financial interests as they may
apply to the general topic at hand.
Because general topics impact so many institutions, it is not practical
to recite all potential conflicts of interest as they apply to each member.
The
FDA acknowledges that there may be potential conflicts of interest but because
of the general nature of the discussion before the committee, these potential
conflicts are mitigated.
And
I would just remind everyone to please turn their cell phones on vibrate and
for the Members at the table to push the button when you talk. Thank you.
CHAIRMAN
SHINE: Thank you very much, Dr.
Johannessen.
I
think we will now move directly to the first presentation, which is an introduction
to drug safety by Steve Galson, Acting Director of the Center for Drug
Evaluation and Research.
Dr.
Galson?
DR.
GALSON: Thank you. Okay.
Let me see if I can make this thing work. Good.
I'm
very happy to be here and to see all of you today. And we have a number of very, very interesting presentations
about drug safety. I'm going to give a
brief introduction just to set the stage.
Don't have a lot of time in just ten minutes for much detail.
But
I think you don't have to be working with the drug industry to be aware that
the drug safety policy environment has become more contentious. This has been all over the news, as you
know. Among other things, there's been
a lot of fuss about the risks of the SSRI class of antidepressants, the
withdrawals of the Cox-2 analgesics that Dr. Crawford already talked about a
little bit.
There
have been a lot of allegations thrown around, among them that the FDA doesn't
care about drug safety, something that hits all of us very hard. There are numerous, in fact a record number
of Congressional oversight investigations and hearings that we're trying to
slog through.
Most
recently, last month, Drs. Woodcock and Kweder engaged in a real testimonial
tour de force in front of the Senate talking about our drug safety efforts and
the history there.
And
what's been going on in the press that all of you are aware of has been very,
very interesting. It started out with a
lot of very accusatory, very sharp articles and it has evolved somewhat. And those of you who are students of the
press probably recognize this sort of pendulum effect.
Just
last week, there was this article that came out in the Congressional
Quarterly, which is a kind of low circulation, high impact periodical
circulated on Capitol Hill. The thrust
of this is that a lot of the effort that has gone on to nail down what the
problem is that FDA ignores the fact the drugs benefit patients and, in fact,
ignores the fact that Congress has been very involved in the last decade at
trying to help FDA get more resources to speed up approval of new and
innovative products.
And
that when this is all over and the dust settles, Congress is realizing that
they really set the stage for how the FDA is working today. And they're going to accept responsibility
for that and probably not make that much change although, you know, I'm not
making an editorial comment on that.
Just noting that it has been very interesting to see how the changes
have occurred.
And
then just this week, perfect timing for you all, there was an editorial, an op
ed in the Washington Post by Ann Applebaum, who has been closely
following drug safety and who many of us have talked to to try to educate her
about the realities at FDA.
And
the interesting thing about this is it really describes the pendulum effect,
how back and forth throughout the history of the last few decades at FDA, drug
safety has come up and the pendulum is swinging now towards more concern about
drug safety and expressing the real concern which is out there.
We
know from patient groups and from the industry as well that if the FDA becomes
more strict and more careful about safety, there's going to be a real impact
for patients. So this side of the story
is coming out as well.
I
think all of you know, and this addresses one of the major misconceptions
that's been out there in the press about drug safety that it is, in fact, a top
priority across the regulatory programs at the FDA. It's not just an issue that we look at in post-marketing
surveillance.
It
crosses all of our work from our new drug program to the manufacturing,
regulation of drug quality, to our generic drug program, to the regulation of
clinical trials, promotional activities, and all the other things we do. Many of the resource decisions, the time
that people spend on these problems are because of concerns about drug safety
in various different realms.
So
I wanted to very, very quickly talk about where this all comes from and it
really is derived from the Food, Drug, and Cosmetic Act which very vaguely but
at the same time very clearly says that we're allowed to require all tests
reasonably applicable to safety.
And
the way that we implement that is through our regulations, as you all know and
among the millions of pages of those regulations that we have to assure that
the product is safe for recommended use.
And that's the way that we decide what data gets sent to us from
companies.
And
then after the regulations, we've issued a series of FDA and then worked very
closely with the international community, as you know, on international
guidance documents that specifically lay out in many, many different realms the
level of evidence needed for safety evaluation.
But
one of the issues that I think is very, very relevant for you all on the
Science Board, we talk about it a lot, but is sometimes lost in the public or
lost to the public is that even though we are scientists and we have hundreds
of scientists in the FDA, many of the judgments having to do with risk benefit
and regulation involve more than science.
They involve judgment and they involve policy.
And
so when people say, you know, the science is broken or we're not following
science, what that really avoids is the fact that a lot of the decisions that
FDA makes have to consider non-scientific societal factors.
And
those of you that have been involved in regulation or involved in risk-benefit
decision-making, which I know is a lot of the people in the room, already know
this. That you can't just go back to
your biochemistry book and figure out how to answer questions of
risk-benefit. There is invariably
judgment, invariably policy in there.
So,
of course, this means there is a huge amount of room for disagreement. The most basic level of disagreement is how
safe is safe? How safe does a product
have to be demonstrated to be before we decide that it is safe enough to be
approved?
I
don't have to tell this audience that safety doesn't mean no risk. The risk-benefit for an individual drug or
class has to be done separately because of different severity of clinical
conditions, different situations, different availability of data for drugs as
they go through the pipeline.
And
so there is no formula that can be plugged in to say bingo, green light, safe
enough, effective enough. There are
always going to be individual decision-making and this is why there is always
room for disagreement.
And
then the fundamental double-edged sword, which Dr. Woodcock focused on very,
very well at her testimony from the Health Committee, which is that if we are
going to require more information be submitted to the Agency on safety, if we
want to be more sure about safety, there are inevitable consequences.
It
would drive up the cost of drug development.
Or drive up post-market costs for companies and for the healthcare
community as a whole. And this has --
can have adverse consequences for innovation and availability of new products.
So
this zero sum game, double-edged sword concept is very, very important for you
all and everyone to understand as we move forward. And it is very much behind the efforts that are underway in the
Agency.
A
lot of the questions that have been raised have been about whether the User Fee
Program has changed how we balance benefit and risk in making drug approval
decisions. And I don't have time to go
into the detail of this but we have done a very careful examination of the rate
of drug withdrawals and how frequently we use black boxes in warning about
drugs.
And
there is really no evidence of actual change in our risk threshold over time
because of the User Fee Program. Of
course, there are lots of people that claim this and they throw data
around. But at least the careful
evaluations that we have done, we haven't really been able to demonstrate that.
And
this is just a list -- I hope you can -- yes, you can read it there -- of the
drugs that have withdrawn -- withdrawing drugs from the market is something
that has happened since the beginning of FDA's regulations. And as I mentioned, we've looked at, in what
we think is the fairest way possible, the proportion of drugs that have been
withdrawn as opposed to marketed before and after the User Fee Program was
instituted. And there really isn't any
difference in the proportion. And you
can see throughout time it's been happening since way before the Drug User Fee
Program.
But
have our data requirements changed with science? Yes, they have. We are
now able to avoid some well-known safety problems that plagued earlier drugs. We're far from perfect. We're going to talk about that a little bit
later as is Dr. Woodcock again.
We
have more data submitted to support applications than ever before and we do
feel that the drug supply, because of this, is safer than it ever has
been. But there will continue to be, as
I've already pointed out, many issues.
And
I'll just point out a few of these before moving on. The first is that the bulk of the studies that are conducted
really have as their main focus efficacy.
Science has moved ahead more with how to determine efficacy than it has
with safety analysis. And many of you
involved in drug development know very well that, for example, with toxicology,
we're doing almost exactly the same toxicology tests we were doing probably
when I was born for drugs. They haven't
changed very much.
The
size of the pre-market safety database is usually determined by the size for
what's needed for the efficacy studies.
Rare or time-dependent effects are not known at approval. They're just -- with the number of people
participating in the studies for the period of time that we require the drugs
to be studied, we are not going to be able to see those rare or time-dependent
effects.
And
we can't require additional safety studies after approval according to our
regs. Our only tool, which is somewhat
like hitting an ant with a mallet, is that we can take a drug off the market. And we can use that authority to get
companies to do things. We do it. But we do have limits on our regulations.
As
I mentioned already, major additions to preapproval safety database would have
potentially adverse consequences. And
then in the post-market area we don't, even as much as some other countries in
the developing world, have an organized national pharmacovigilance system that
automatically gets us information about drugs that run into trouble.
We
have a system of looking at spontaneous adverse events reports but that's very,
very different from an organized national sort of certainly required
pharmacovigilance system.
So
what we're going to do this morning is take you through a quick run through of
our program. Of course not enough
detail but you guys already know a lot about our programs. And then give you some time to look at the
questions that you've heard about.
Very,
very quickly, Dr. Oliva is going to go through Pre-Market Drug Safety. Rachel Behrman is going to talk about some
of our very, very exciting initiatives on labeling and communicating with the
public about drug safety which we think is one of the key issues for us.
I'm
going to come back and talk a little bit more about the drug safety initiatives
that you heard about from Dr. Crawford this morning. Dr. Seligman is going to talk about what we do in the post-market
arena.
Theresa
Mullin, Dr. Mullin, from our Planning Office is going to talk about some very
careful work that she and her staff have done to really document the resources
that we spend on drug safety. And then
Janet will be back again to talk about critical path applications and
applications of new science to drug safety.
So
with that, I'll let Dr. Oliva kick it off.
Thanks very much.
DR.
OLIVA: Well, it's both a pleasure and
an honor to address the committee this morning on the issue of pre-marketing
drug safety. As a former clinical
reviewer, it's no exaggeration for me to say that the FDA spends a tremendous
amount of time and effort on the evaluation of pre-marketing drug safety.
And
what I would like to do this morning is inform you on the contents of a new
guidance that came out just last month on the review of pre-marketing drug
safety.
This
is a guidance that represents the good review practices for the clinical
reviewer on evaluating drug safety. And
it really represents the collective knowledge through many years of doing this
in the Center. And it was a
collaborative effort across many offices within CDER, including Office of New
Drugs, Office of Drug Safety, and Office of Medical Policy. And I'm sure there are others that didn't
get on this slide.
Now
the guidance says very specific purposes and first of all, it's meant to assist
reviewers in how to conduct the clinical safety review of an NDA or BLA. It does document good review practices, as I
mentioned.
And
we think it's important in order to provide standardization and consistency
across all our review divisions on what constitute an adequate evaluation of
drug safety as well as provides instruction on the format actual review -- of
the written review of drug safety. It
ensures that critical analyses and presentations of the data are included in
the review.
This
guidance also dovetails very nicely with the clinical review template that we
issued last July. The two are
completely harmonized so that a reviewer, once they're ready to document their
review, has all of the headings of the drug safety guidance are included.
And
the guidance, what it does is it expands the headings of the clinical review
template so it serves as a very nice reference to reviewers on each heading,
which I'll go into.
One
of the important points that the guidance stresses is the need for
collaboration. Although this is a
document geared towards the clinical reviewer, we do recognize the need for
additional skill sets such as analysis of event rates and so forth. And, therefore, it stresses the need for
collaboration with biostatistical colleagues and other experts when necessary
to get a complete picture of safety.
So
what exactly is in the guidance? Well,
there's advice on how to conduct and organize the review, of course. And there's also an annotated outline of
what the safety review should look like.
The
guidance identifies four important tasks for the reviewer when they evaluate a
drug's pre-marketing safety risks.
First and foremost is to identify serious adverse events that might do
these three things: might prevent use altogether, in which case we would not
approve the application, that could limit use, and that may require special
risk-management efforts.
Secondly,
the safety reviewer will estimate the frequency of commonly occurring adverse
events, which will need to be communicated to the public.
Third,
the reviewer evaluates the adequacy of the data in the application. For example, was exposures adequate and did
they occur at relevant doses?
And
finally, it's important that the reviewer identify any unresolved safety
concerns that may need further attention either pre-marketing or
post-marketing.
These
are additional tasks for the safety review.
We need to identify factors that predict the occurrence of AEs, both
intrinsic and as extrinsic factors, ways to avoid adverse events through
monitoring or other techniques, and ways to manage them when they occur. And finally we need to provide a
comprehensive evaluation of risk information in support of labeling. And Dr. Behrman will get into that in more
detail.
The
guidance outlines the key sources of safety information. Now I'm not going to go through all this
long list, but I put it up there to emphasize that there are a lot of areas
that we ask reviewers to look at when looking at safety in an application.
We
talk about causality determination which is heavily dependent on a comparison
of event rates between treatment groups.
And it's also heavily dependent on proper coding of the adverse events. And we ask reviewers to look very carefully
at how adverse events are coded because this is the only way that we can get
accurate numerators for event rate comparisons.
And
there's also an emphasis on the individual case reviews of deaths, serious
adverse events, and drop-outs due to adverse events or adverse drop-outs.
As
far as the organization of the safety review, it's basically broken down into
four broad areas that I show here. And
I'll walk you through to each one. But
this is what constitutes the documentation of the pre-marketing safety review.
The
first one is the methods and findings.
This is where the reviewer assesses the safety of the drug, describes
what were the findings. And they
describe the relevant data sources that went into this determination, what
safety assessments were conducted along with the major safety findings. And it emphasizes the use of a very
systematic approach.
This
section of the safety review, 7.1, is quite detailed. And again, I won't go through each one of these. But I put it up again to emphasize the fact
that reviewers systematically go through each of these domains with each
application and documents the findings in these areas.
Section
7.2 is where the reviewer will assess the adequacy of the safety database. Was patient exposure adequate? Were sufficient numbers of subjects exposed
for long enough duration at the appropriate levels? Were specific subgroups analyzed for safety? And what were those findings?
We
look at the quality and completeness of the safety evaluation, including what
animal testing of safety occurred, what in vitro tests showed, what long-term
safety can provide, as well as any specific assessments that were performed. And we ask ourselves are additional safety
testing needed either pre- or post-approval.
The
third section of the safety review is the summary section where we provide a
brief summary of the critical findings of the safety review. And this section also contains the adverse
events that the reviewer considers are important and drug related that may need
to be communicated post-approval. And
here is where we document any important limitations of the safety database
along with our conclusions.
The
final section of the safety review is a general methodology section. It's sort of an appendix. This is where we get to describe the
analytical methods that the reviewer used in reviewing the data along with a
general discussion of any other methodological issues that were not discussed
elsewhere, discuss the general idea of pooling, why was it done, how was it
done, as well as how we explored the data for predictive factors and how we
assessed and determined causality.
So
in summary, I want to leave you with the notion that this final guidance is
really a culmination of many, many years of collective effort throughout the
Agency in how to conduct a pre-marketing safety review. It promotes good review practices. We believe it will lead to increased
standardization and consistency of format and content of the pre-marketing
safety review.
And
it ensures the critical presentations of the safety data and the analyses are
not omitted. And it's entirely
harmonized with the Clinical Review Templates so that our reports that are
posted on the web all have the same look and feel and are consistent and
complete.
So
with that, I'll end my talk and turn it over to our next speaker, Dr. Behrman.
CHAIRMAN
SHINE: Yes, before we go further, we
have a couple of minutes. And I would
like an opportunity -- if any members, this is a very important document. If any members of the committee want to ask
specific questions --
DR.
OLIVA: Sure --
CHAIRMAN
SHINE: -- about the document. One thing you might help me with is a number
of these documents are headed, "Contains non-binding
recommendations." And I wonder if
you would -- or Janet or whatever -- help me with that. Given that this seems to me to be a rather
important set of criteria by which our reviewers operate, why do we use this
kind of language that kind of implies that they may or may not do this?
DR.
OLIVA: Sure. Since this is a guidance and we abide by the good guidance
practices by regulation, this is standard language. And that unless it is something that is mandated by a statue or
regulation, then it's by definition non-binding.
And
Dr. Woodcock, you may be able to elaborate further.
DR.
WOODCOCK: Yes, that's true. That provides the flexibility,
obviously. But we have -- the purpose
of the supervisors here in the supervisory chain, if a reviewer decides that a
different type of analysis is better, that's fine. And they should do that.
But
then their supervisor has the right to say well, that analysis really wasn't --
doesn't get to the question that you were supposed to get to. So that is part of the purpose of having various
experts look at these reviews and so forth.
But
yes, we don't require in this guidance or any guidance that people do things a
certain way. If there is a satisfactory
scientific way or superior way to get to the same result of the analysis in
this case, then it can be done that way.
CHAIRMAN
SHINE: But doesn't that increase the
ambiguity for people who are developing drugs and so forth to understand, in
fact, how that particular product is going to be evaluated since there would be apparently this --
DR.
OLIVA: Well, one of the principals in
good guidance practices is that if someone is going to deviate from a guidance,
that it has to be well justified and it has to be justified in writing.
So
the assumption is that reviewers will do it this way unless there is a very
good reason that has been fully vetted internally to do it a different way or a
better way because we realize that guidances are living documents and that they
-- and through knowledge and experience can change. And this allows the opportunity to improve on it.
CHAIRMAN
SHINE: At what point in the process
will the folks who are involved with the new product be notified that you're
going to use a different methodology?
DR.
GALSON: As -- I would say as early as
possible, right?
DR.
OLIVA: Sure.
DR.
GALSON: I mean what we're trying to
encourage is more intense early interaction between our reviewers and people
from the companies, very early in the development. And as soon as we would detect that there was going to be something
different that we were interested in seeing, we would say that. You know it's not a perfect system. But that's what we try to do.
CHAIRMAN
SHINE: Dr. Pi-Sunyer?
MEMBER
PI-SUNYER: Yes, I wanted to ask you a
question with regard to time-dependent adverse events. You made the point that you cannot require
additional safety studies after the approval of a drug so you don't have a way
to do that after you've approved it.
But
if it is possible that you're really getting safety data mostly two years, at
the most, and say something in a drug makes you think that there might be a
time-dependent adverse event, can you add some kind of qualifier that will
allow you to continue to survey that drug?
DR.
OLIVA: Well, let me elaborate a little
bit because I, you know, somewhat used shorthand. We don't have the statutory ability to require something after
approval. But we can ask and we do ask
and we get things done that way all the time.
When
there is an important safety question that has to be answered, we try to get it
answered either by asking the company to do a study or working with other
groups. And so I don't want to convey
that we have no tools at our disposal.
But it's not a you will do this and if you don't, X will happen kind of
authority.
DR.
WOODCOCK: Can I add to that?
DR.
OLIVA: Yes.
DR.
WOODCOCK: Can I add to that?
CHAIRMAN
SHINE: Yes, absolutely.
DR.
WOODCOCK: Yes, in addition, at the time
of approval, if -- you know one of the important parts of the safety review is
to identify the unanswered questions.
Not just to review whatever has been sent in but to think about what
don't we know about this drug? That's
as important as what we do know about a drug.
And
at the time of approval if there is a very burning question that hasn't been
answered but might require much additional work and we feel the benefit-risk is
satisfactory for the drug, we can ask that either registry or study be done as
a post-marketing commitment.
DR.
OLIVA: Another useful tool that we have
to get that information post-marketing is the label itself. For example, if we have insufficient
information to assess the risk of the drug in a special population such as
hepatic or renal impairment, prior to approval we may contraindicate the drug
in labeling in that population until that data are collected and submitted and
reviewed.
CHAIRMAN
SHINE: A key element, just to follow
up, is the question that the reviewer is asked, namely is additional safety
testing needed either pre-approval or post-marketing.
DR.
OLIVA: Yes.
CHAIRMAN
SHINE: My question is from a procedural
point of view, who looks at that recommendation? What's the process by which we are sure that a recommendation of
that kind gets evaluated at a fairly high level in terms of the follow up?
DR.
OLIVA: Yes, once the safety review is
written, then it is reviewed internally at several layers. There's usually a secondary reviewer as well
as the division director and for a new molecular entity, the office director
will evaluate those recommendations and look at the reasons for those
recommendations and then act upon them and make a decision whether the
uncertainty is great enough, whether additional work pre-marketing is needed.
DR.
WOODCOCK: And whatever that decision
is, it will be documented in writing.
CHAIRMAN
SHINE: Yes, I just -- my concern is
that we are very sure that those kinds of recommendations are evaluated at a
high enough level in the organization so that we're quite comfortable that
other kinds of interactions are put in the proper perspective in terms of doing
that.
One
of the interesting things, as I read the material, was you point out the
problem with the definition of symptoms, complications, and so forth. I think one of the examples you use are the
SSRI business, emotional disturbances versus suicidal ideation.
To
what extent could you, in fact, have a glossary of terms explicit enough so
that investigators would, in fact, have a minimum opportunity to categorize
items in ways that don't truly display the nature of the problem?
DR.
OLIVA: Well, this is an ongoing
challenge. I mean there are numerous
dictionaries and thesauruses available that will allow the mapping of
investigator terms to standardized terms.
And those are readily available to the reviewers and they're routinely
used in the evaluation of the coding of the adverse events.
And
if we see a problem, if we see that certain terms are being mis-categorized,
then that would be a cause to have them re-categorized, if necessary either by
an independent panel or --
CHAIRMAN
SHINE: But the key is that the
investigators are in the same thesaurus as you are, right? In other words -- yes?
DR.
WOODCOCK: This gets to the issue of
standardizing the case report form and the reporting of adverse events out of
clinical trials. And as you probably
well know, that hasn't -- but as I said in my introductory remarks, we are
starting down that path.
The
use, for example, of electronic case reporting forms with pick lists and so
forth will help with this. But I think
what Armando is reflecting is often we get, you know, like a company gets a
narrative and an investigator has sort of decided what terms they're going to
use for that particular adverse event or whatever.
And
we need to -- you're right. We need to
work on further standardization. But
we're not quite --
CHAIRMAN
SHINE: Yes.
DR.
WOODCOCK: -- the field isn't there
yet. Is that fair?
DR.
OLIVA: Yes, no, exactly. I mean in an ideal world, the investigator
when they were ready to enter the adverse event onto the case report form, they
would have the pick list, the standardized terminology readily available to
them so they could make that call.
CHAIRMAN
SHINE: Exactly. And I think that's important.
Dr.
Cassell?
MEMBER
CASSELL: Yes, I think Ken, following up
on what you said, to me in terms of pre-approval, the collection of adverse
events and the investigators is one thing because you have selected
investigators very knowledgeable, hopefully, in the area and so forth. But post-marketing when you're collecting
adverse events, who is responsible for training of individuals, in
communicating to individuals on the appropriate methods, terminology, et
cetera, for collecting adverse event data?
And
I guess, Janet, I was thinking back to your comment about the need for training
and where in the medical school curriculum as tight as it has gotten today, we
all know in terms of pharmacology period, it has shrunk considerably as
pathology and molecular biology have expanded.
What
are we thinking looking towards the future now as far as collection of adverse
event data and the practicing physician?
Who will be responsible for the education?
And
again, just to add one more piece to that that I worry a lot about with all the
changes and the way companies now are able to interact with the practicing
physicians in educating in terms of drug use, again it just poses more
limitations, I think, on getting to those individuals that are going to be
collecting the data.
DR.
OLIVA: Well, this is my own personal
opinion, but I think standardization is the key. I think that we're now moving to the area where we have standard
variables for different types of adverse events. And now, as Dr. Woodcock pointed out, standard terms for the
actual adverse events themselves.
And
the next step is encouraging collection of the adverse events in clinical
trials using these terms. The next
logical step will be the use of the very same terms in clinical practices and
use in the electronic health record so that it is just one continuum from the
doctor's office to -- every step along the way.
CHAIRMAN
SHINE: Amen.
Quick
comments from Dr. Thomas.
MEMBER
THOMAS: I was just curious how and what
process you used for pooling data.
Whether it's at the pre- or post-surveillance stage?
DR.
OLIVA: Well, my comments about pooling
data were strictly relating to the pooling of safety data across clinical
trials in pre-marketing -- during the pre-marketing review. That's the easiest place to do that type of
work simply because there is a certain amount of consistency already built in
in the way they are collected. And so
they lend themselves readily for pooling.
In
the post-marketing world, I'll have to let Dr. Seligman weigh in on that and
others. But it's obviously much more
challenging.
MEMBER
THOMAS: There's probably a great
adherence at the safety level --
DR.
OLIVA: Yes.
MEMBER
THOMAS: -- from the standpoint of
protocol.
DR.
OLIVA: Exactly.
MEMBER
THOMAS: Than later.
DR.
OLIVA: Yes.
CHAIRMAN
SHINE: Dr. Laurencin?
MEMBER
LAURENCIN: The guidance document that
you put together appears comprehensive.
But every page says non-binding recommendations. And so the two questions are number one, how
much will it be utilized by the reviewers?
And what are the plans to monitor to what the extent the reviewers
actually utilize this? Because it is
important for industry and for others who are looking to bring products
through.
DR.
OLIVA: Sure.
MEMBER
LAURENCIN: That's the first question. What are your thoughts?
DR.
OLIVA: Well, you know why it says
that. Because it is a guidance. And we have to say that if it's a guidance.
But
the nice thing about it, because it is a guidance to reviewers and it is an
internal guidance, that we have other policy tools internally to make sure that
reviewers adhere to it. You know, the
supervisors and team leaders and division directors all can expect, and as part
of internal policy, can say this is the way that it will be done.
And
part of the secondary and teriary reviews will include a check -- does include
a check to make sure that the reviews adhere to this document.
MEMBER
LAURENCIN: Just as a follow up, what is
the mechanism by which the changes in the guidance document will be relayed to
all? Because so many times it is a
draft guidance document. The phrase
living document comes up and everyone smiles.
But how will these changes be relayed to the greater community?
DR.
OLIVA: Well, guidances are
updated. A guidance can be modified and
then that goes through the -- again, posted for public comment before it gets
rewritten. So there is a mechanism in
place to update guidance. And this one
would go through that.
CHAIRMAN
SHINE: We're going to have to move
on. I think -- at least my sense is
that the committee -- the board is quite impressed with the document. It really does show a good comprehensive
kind of guidance with regard to it.
Our
hope is that it will be applied fairly consistently. Dr. Woodcock has indicated there may be rare examples where a
different methodology is involved which would require explicit kind of
language.
But
I think this is a good step forward.
And I congratulate you on the accomplishment.
Why
don't we move forward?
DR.
OLIVA: Thank you.
CHAIRMAN
SHINE: We're going to hear from Dr.
Behrman.
DR.
BEHRMAN: Good morning. Let me just make sure -- okay, thanks.
Good
morning. I have actually the distinct
pleasure this morning, unlike some others who have to discuss things that are in
their infancy, to describe for you two initiatives that are nearing the end of
development and will be rolled out shortly.
And that's the Physician Labeling Rule and structured product labeling.
And
just since we've had a discussion of standards, I'd just like to point out that
Dr. Oliva and I, as members of the SPL team, have sacrificed our personal
preferences and we present from a standard format. Not required but we do it.
(Laughter.)
DR.
BEHRMAN: In terms of today's topic,
which is primarily focused on safety, one needs to think about
information. And FDA -- one can think
about this in this way, FDA regulates information in two primary ways. We regulate the development of information
through clinical trials and that is not the topic today.
And
then we also regulate, to a certain extent, the dissemination of
information. And over the years, we've
probably focused on that -- or we have focused on that substantially less. And gradually have come to realize that this
is clearly part of our mission and responsibility.
We
have statutory authority to do this.
The Federal Food and Drug Cosmetic Act clearly states that we regulate,
we have authority over the content of labeling the way we speak.
So
a drug or device shall be deemed to be misbranded if its labeling is false or
misleading in any particular. And the
Secretary cannot approve an application, can refuse to approve an application
if the labeling is not adequate.
Similarly,
we have implementing regulations, specific requirements on the content and
format of labeling for human prescription drugs, 21 CFR 201.57. Those regulations were promulgated -- draft
in `75 and the final in `79. Clinical
trials, drug information looked very different in the mid-70s than it does now
and clearly it's time for those regulations to be updated.
So
the first topic that I'd like to cover for you is the Physician Labeling Rule,
which I said is nearing completion.
Now
anyone who has thumbed through a PDR recently may be surprised to learn that in
fact there is a very specific order to the information. That's not obvious because there is no same
look and feel and there's no application of the basic principals of
communication in terms of white space and bolding and other means of
emphasis. But there is a very specific
order.
Unfortunately,
the order is not one we would today say makes tremendous sense. Generally the principal is you put the most
important things either first or last.
Well, first is the description.
That tends to be the chemical structure. Last is references. That,
again, tends not to be the first thing one might turn to.
The
safety information, as you can see, is sandwiched in the middle as is dosage
and administration, for example. So the
information that one wants most quickly is difficult to find.
So
going back a number of years, the intent was to develop a tool that is more
informative, that's more accessible, that's a better risk communication
management tool.
And
the development process was quite lengthy and quite comprehensive. It included focus groups. It included a national physician survey,
physicians being the primary user of drug labels although the public meetings
that followed included pharmacists, nurses, et cetera, and the public, others
who use the drug label.
And
finally, initiated a formal notice and comment rulemaking process with the
review of, I believe, 93 written comments.
So
what will -- in the proposed rule, what did we propose that the drug will look
like -- and because the rule has not been finalized, I'm going to stumble a
little bit and keep referring to the proposed rule. But it does give you the flavor of what we're thinking and
certainly what was reflected in the comments.
Well,
the first is to start with the most important information. And what is the absolutely most important
information? A box warning if there is,
what the drug is used for, and then the dosage and administration.
You'll
notice that the safety information in terms of contraindications, warnings,
precautions, adverse reactions, is consolidated. It's worth noting also that in the current label, there is a
warning section and there is a precaution section. The distinction is not really clear to anyone.
And
precautions, which sounds like it might be safety information, includes many
other things including use in special populations such as patients with renal
impairment, et cetera. So it's a
mish-mosh or a potpourri. And that's
been separated out with new sections having their own -- let's see -- for
example, use in specific populations would be separate, clinical pharmacology
has been pulled out, et cetera.
And
then at the end, again putting something important last, patient counseling
information. There's clear information
that prescribers should be communicating to the user of the drug and we want
that highlighted so it is easy to pull out, easy to access for both the
prescriber and for the patient.
But
perhaps the most novel and -- from the focus groups and from our point of view
important notion would be of highlights, that a very quick summary of the most
critical drug information up front where it can be easily accessed. And the limitation statement is -- we'll
just be describing the fact that it is not the entire label.
But
notice what one could see very quickly.
That -- well, first of all, what product it is. But obviously if there have been any major
changes since the last label. Or not
since the last label but any major changes.
Indications, dosage, contraindications, everything very important right
up front. And I'll show you an example
of that in a moment.
In
addition, we feel it is important to establish minimum font requirements. The one -- my favorite comment to the
proposed rule came from an eye care company that said that under the proposed
eight point minimum font, they would no longer be able to publish their label
in a 4.5 font. This is an eye care
company.
(Laughter.)
DR.
BEHRMAN: So we believe that no one
should be asked to read such a label.
And, in addition, that standardized bolding and white space, all of us
-- I mean there are, I'm sure, many in the room who try to use labels to
prescribe drugs, the information is there.
It's very hard to scan it and find it.
With standardized bolding and white space, that would be changed.
And
as I mentioned, frequently referenced sections would be moved forward. And, in particular, safety information
should be consolidated.
We
heard pretty clearly that highlights not only being critical had to be limited
to about a half page. And that we
should bullet the information, again, making it easy to scan.
Moreover,
that we should create some form of index.
This will be particularly important in the electronic era so that you
can hyperlink. But even if not, to get
a quick, easy view of, in fact, what is the label, although what was proposed
in the rule and what was discussed in the comments, in fact, is not an
index. It's a content but that's
another point.
And
that we provide greater clarity in our requirements. Again, if you go back to `75 and `79 and read these proposed
rules, they were appropriate to the state of information in the mid-70s but not
in 2005.
So
this is, we think, a thing of beauty.
But this is an example of a highlight --
(Laughter.)
DR.
BEHRMAN: No, quite seriously.
(Laughter.)
DR.
BEHRMAN: I mean can you imagine, those
of you that have been in emergency rooms in the middle of the night being able
to just scan down a drug with which you are not familiar or for an indication
that you don't know or a dose that you don't know or just to make sure that
nothing has changed since you used the drug a year ago or what the most
important warning is because you're using it in a population you've never used
it before.
We
think that in terms of importance of clear communication, safe prescribing,
reducing medical errors, et cetera, that this will make a major contribution.
Similarly,
the index I described to you -- and this would give you a feeling of, again,
not only what the sections look like and how the more important information is
reordered forward, but also give you a sense of electronically how you would
link, how you would just jump to the section that you wanted if you were, in
fact, not in paper, which you probably won't be pretty soon.
We're
going to roll out, when this does roll out, a number of things with it. One thing is companion guidance. I know we've just had a bit of discussion
about what guidance means but this is going to be a very new label for us, a
very new label for industry. We're
going to have to help people learn how to write them. It's not easy. Those of
us that spent some time doing it, it takes some getting used to.
More
detail, more clarity on what should be in the adverse reaction section and how
it should be organized. Clinical
studies, again, an important place for information about how to use the drug
safely. And then warnings and
precautions, contraindications, and boxed warnings, a section which we have
never provided guidance and for which there is a lot of confusion about what
the contents should be.
And
then switching gears slightly, clearly to move forward into the 21st century,
into the electronic era, the way I've been thinking about it lately is think
about everyone who is walking around with an iPod and what they can tell you
about their music but they can't tell you that about their drug information.
We
want to support and are supporting the health information technology
initiatives because the Physician Labeling Rule will be concise. It will be clear. And it will be easy to hyperlink.
So
the other major initiative that I want to describe in that vein is Structured
Product Labeling. And what is
Structured Product Labeling? Probably
most people don't know. But this is
something that is going to roll out this fall so it's here.
It's
the content of labeling in standardized electronic file format. So the blocks of text are tagged. There we go. So in pdf, you just have a lump of text. But in SPL, you have a tagged section. And, therefore, that means you can link it,
you can move it. If you want to
standardize it, you can do that. It's
manipulatable.
This
is crucial to support a very important and exciting initiative called DailyMed
which will be an electronic repository of current labeling. It will be managed by NLM but it will be
populated by FDA. So it will be the
most current labeling, vetted, approved, the gold standard of drug information.
And
I just wanted to add also it's responsive to the Medicare Modernization Act,
which requires uniform standards.
So
what else do we need to do in order to be able to spit this labeling out on a
daily basis to NLM? Well, we need
something called ELIPS, Electronic Labeling Information Processing System. And the primarily important thing to you is
the last bullet which is that we will be transmitting SPL with one business day
lag.
So
this is really in real time. We're
giving ourselves one business day so that we -- the oops phenomenon, the not
sending something out to the public that we later regret, but we'll be able to
receive SPL. We'll be able to reject it
if it is missing something. We will be
able to review it, manipulate it, and then we will be able to shoot it out.
And
this is just portrayed graphically there for those of you that like that. So the applicant will send us their
SPL. They will be required to do this
starting in the fall. Right now they're
just required to send us an electronic copy but it will have to be structured
starting in the fall to our document room.
We
will do what we need to do in terms of review and manipulation. When it is ready to go out, it will be
released by a labeling authority. There
will be a single labeling authority for each product. And then it will go to the NLM.
And it will be accessible to whomever needs current labeling.
And
anyone who has tried to look for current labeling on the weekends, for example,
not at FDA, it's extremely difficult to find.
This
is the most exciting part of this slide.
We will meet our October `05 target date. We had our first demonstration.
What's the right word? We had
the first -- saw the first prototype this week. And we are on schedule.
And
we will roll it out -- it will take a year to populate. Companies have a year to get their current
labeling in to us. So by October of `06
-- and we may cut off at the end of the year just for convenience, the
population -- the SPL ELIPS will be populated with current labeling for every
product.
In
one sense this is a pilot in that we're starting only with prescription
drugs. And it's a pilot-approved
concept. But in the other sense, it is,
in fact, it is the beginning because we will have one -- at least one center
up. And then we will expand to the
other medical products.
Phase
Two will include unapproved prescription and OTC drugs. That will -- the target date is August
`06. It will require a number of other
things to happen, ELIPS to be up and running, which will be on time, Substance
Registration System, which will require that someone assign a unique code to
each ingredient so that then they can be linked and tracked. And then we will need the Drug Listing
System in place in August of `06.
So
in sum, we are poised to provide and can provide up-to-date labeling
information. We have, over the years,
recognized that to support many of the things we do, some of the initiatives in
providing information to consumers and to practitioners that Dr. Galson will
discuss, initiatives such as providing the information with advertisements.
Right
now, the "brief summary", which you often see, is just -- well, it's
not readable and it's not intelligible.
A year and a half ago, we promulgated draft guidance suggesting the
companies might want to think about even before the Physician Labeling Rule was
finalized, mocking up brief summaries that looked like highlights because
ultimately highlights will exist. It
will be vetted information.
We
will have already decided it's the most crucial information. And why not make sure that's what consumers
see with a drug ad as opposed to something that can't read?
So
we're increasingly trying to educate ourselves in how to communicate. We sit on the gold standard of
information. And we need to get a
little bit better about, in fact, sharing it.
So the Physician Labeling Rule will ensure that the actual label, be it
printed or electronic, will be readable and will be accessible.
And
that electronically, this will be available to anyone through NLM from any
computer. And it will be accurate and
up to date. And that will support,
obviously, electronic prescribing, electronic health record, and decision
supportware, really bring FDA in concert with others, into the 21st century.
CHAIRMAN
SHINE: Thank you very much. We have time for a question or two.
Dr.
Pi-Sunyer?
MEMBER
PI-SUNYER: Will this be accessible to
Palm Pilots? You know the average
physician --
DR.
BEHRMAN: Right.
MEMBER
PI-SUNYER: -- now doesn't use a big
computer.
DR.
BEHRMAN: Exactly.
MEMBER
PI-SUNYER: He uses a Palm Pilot.
DR.
BEHRMAN: This will be -- we will take
it -- we will send it to NLM. It will
be available and accessible to anyone.
So whomever makes either your Palm Pilot or your Palm Pilot software can
access that. And then develop decision
supportware or whatever search engine, if you will, that is appropriate for
you.
For
example, if you're an infectious disease practitioner, you may have very
specific sets of queries that you want.
And if you're a clinical pharmacologist, it may be very different.
CHAIRMAN
SHINE: Dr. Thomas?
MEMBER
THOMAS: I was going to ask you if the
SPL would in any way replicate what we now know as the package insert with
respect to information.
DR.
BEHRMAN: Well, let me -- in case I
didn't make it clear, let me walk through that. Package insert, that's the printed piece of paper that comes with
your bottle. It will ultimately, if you
will, replace that perhaps likely. The
package insert is required -- every drug is required to have the package insert
go with it. That's very expensive and
it is not very accessible.
So
we believe that once the information -- it's the exact same information just
delivered in a different way -- is available either electronically or some
other way, the package insert will no longer be that useful. But it will be the same. The content will not change.
So
if you read the package insert or you
read it off the computer, it will be the same information. Just how you choose to access it or how you
able to access it.
MEMBER
THOMAS: A follow-up question with
regard to safety information, I didn't see quite as much safety information on
your SPL. Is that going to be --
DR.
BEHRMAN: Should be go back?
MEMBER
THOMAS: -- accommodated by a hyperlink?
DR.
BEHRMAN: Can we go back?
MEMBER
THOMAS: No, maybe I just missed it.
DR.
BEHRMAN: No, it's all there.
MEMBER
THOMAS: It's all there?
DR.
BEHRMAN: In fact, it's -- the really
exciting part, I think, is that it is consolidated. And I probably didn't --
MEMBER
THOMAS: Maybe that's why I missed it.
DR.
BEHRMAN: Yes. Well, we heard that it should be together. So thinking about -- looking down, your box
warning will likely to be short.
Indications and usage, dosage administration. Then you get into what we consider the core safety
information. Contraindications, warnings,
precautions, adverse reactions, all together right up front.
So
-- and if you go to the -- now remember this is just the highlights. So this is not going to be the whole
thing. But you'll get your box warning. Any major changes which typically are safety
related. And then you have all the
safety information together.
Contraindications, warnings, precautions, adverse reactions.
CHAIRMAN
SHINE: Dr. Laurencin?
MEMBER
LAURENCIN: Thank you.
I
still have some concerns about the information being provided.
DR.
BEHRMAN: Yes?
MEMBER
LAURENCIN: And just as a preface, we've
expressed this to the FDA. I'm Speaker
of the House of the National Medical Association in one of my roles. And the NMA has expressed this that this
information provides no information in terms of effects of drugs in the
minority communities, specifically African-Americans --
DR.
BEHRMAN: Well --
MEMBER
LAURENCIN: -- in terms of one, degree
of testing in the African-American and other minority populations, number two,
adverse effects of drugs in minority populations. It doesn't present the information. Even trends, et cetera.
And
the concern is with so many drugs that may be utilized by minority populations,
to a great extent there is no information really describing, at least what I
see here, describing possible effects in minority populations especially.
DR.
BEHRMAN: Well, you are correct that
this does not address clinical trials.
So this will only address how to present the information that is
developed in the clinical trial.
Although
the guidance documents do talk about what the importance, in fact stress the
importance of special specific populations, but in fact it is highlight. It will be easier to find information about
specific populations.
MEMBER
LAURENCIN: I mean my feeling is that --
DR.
BEHRMAN: Yes?
MEMBER
LAURENCIN: -- use in minority
populations is so important that if it is not there, it should be specified
that it is not there, it's not present, or it has not been studied.
DR.
BEHRMAN: Right. So in other words, you would want to
highlight the absence of information as well.
And I'm just going back to the guidance documents that we're developing
to -- I'm not getting there very quickly --
CHAIRMAN
SHINE: But it would be appropriate in
that section a use in special populations for that description to take place.
DR.
BEHRMAN: Well --
MEMBER
LAURENCIN: Agreed.
DR.
BEHRMAN: -- but I wonder if you're
saying should -- it was definitely not proposed to require the absence of
information. It's to require a
description -- and again, I'm talking about the proposal -- would require a
description of the information and discussion of what is missing.
But
I think that when you -- you have to think about the final rule plus the
companion guidance documents. And as we
have discussed publicly a number of times, there is much greater emphasis on
describing different populations and how drugs behave and the safety profile.
CHAIRMAN
SHINE: Well, this would seem to me to
be an appropriate thing to follow up on in terms of Dr. Laurencin's concerns.
DR.
BEHRMAN: Okay.
CHAIRMAN
SHINE: Perhaps you can discuss that
with him a little further.
DR.
BEHRMAN: Sure.
CHAIRMAN
SHINE: One final question I have is are
you -- you've gotten lots of guidance and input into this. Are you doing marketing studies with the
final product?
DR.
BEHRMAN: Once the rule finalizes? Or for --
CHAIRMAN
SHINE: I mean are you --
DR.
BEHRMAN: -- for the labeling rule for
SPL or for --
CHAIRMAN
SHINE: For the labeling rule, have you
got focus groups where other --
DR.
BEHRMAN: There have been tremendous --
the research that supported this, which was --
CHAIRMAN
SHINE: I'm not talking about the
research. I'm talking about the final
document being exposed to a variety of audiences in terms of whether it meets
their needs.
DR.
BEHRMAN: Our hope -- there is no plan
to test the final Physician Labeling Rule in focus groups. Our hope is that as we develop different
types of consumer information and practitioner information, that will clearly
have to be tested, for example, the new kinds of information that we are
putting up on our website because that is something that has not yet been
subject to focus groups and other kinds of testing.
CHAIRMAN
SHINE: Okay. All I was saying is that you go through an iterative process.
DR.
BEHRMAN: Right.
CHAIRMAN
SHINE: The question is is the final
product carefully tested by consumers with a variety of backgrounds, age
levels, things of this sort --
DR.
BEHRMAN: Right.
CHAIRMAN
SHINE: -- so we know that it works.
DR.
WOODCOCK: I would just like to say it
would be very nice to do this but under -- the rulemaking process takes about
five years, okay, and so we try to do a lot more of this in guidance, which is
more amenable to such an iterative process.
DR.
BEHRMAN: And I just did want to add
that we made use, in addition to our focus group testing and other testing, the
work that CFSAN had done. They had done
tremendous work. And also that the OTC
regulations.
CHAIRMAN
SHINE: I agree, Janet. There are lots of ways to do rulemaking.
Thank
you very much, Dr. Behrman.
Dr.
Galson is coming back and talking to us about this drug safety initiative.
DR.
GALSON: Okay. I'm happy to be back here again.
And what I wanted to do now is take you through some of the recent drug
safety initiatives that have been announced.
The
first is Dr. Crawford's announcement back last year in November and then our
Secretary's announcement in February and a little bit more detail on those.
First
of all, the announcement from November, and Dr. Crawford went through some of
this quickly, is first the Institute of Medicine study, and I want to just
emphasize that again because we think it is so very important. There are a lot of groups out there making
comments about our drug safety system and investigations, GAO, Congressional
committees, et cetera.
But
there really is no peer to the Institute of Medicine, as you all know, in terms
of getting neutral experts involved in a very deliberative fashion. And although the studies do take some time
and require some investment of funds, we think this is going to be very, very
important in the long run for helping us design a permanent system to improve,
if improvements are needed in how we evaluate safety and what FDA's place is in
the drug safety system.
The
second component of this announcement was a program for adjudicating
differences of professional opinion, very, very important within the Center for
Drugs. As you all know, there are
differences of opinion. We've talked
about this before a little bit.
And
two people looking at the same information can come to different
conclusions. And historically, there
have been flare ups every once in a while in the Center for Drugs when there
are these differences and reviewers don't think that their opinion or their
analyses are being adequately considered in a final regulatory decision.
So
what we've done with this new policy, which was very, very carefully vetted
internally, is create an organized way for a reviewer who has a difference of
opinion to get that opinion examined and reviewed and moved up the hierarchy
all the way to the Center Director so that if they really have a professional
disagreement, it can be considered by others who can peer review it and look at
the opposing views and help make a decision.
And
it is very, very organized and lays out in a step-wise way what those reviewers
can do. And we think this will help the
sense among some reviewers that they have trouble getting their voice heard. And I'm looking forward to getting involved
in the first one of those adjudications.
The
third point here was that we've had a vacancy in the leadership of our Office of
Drug Safety for some time with Acting Directors in place.
And
we've sort of taken a huge step in involving the federal government's Office of
Personnel Management in helping us design a really state-of-the-art search
nationally, which involves getting a group of experts in to figure out what the
ideal components would be for a director, attributes for a director. And that's moving along. And hopefully we'll be able to get somebody
in place there within the next few months.
The
fourth component of this was the acknowledgment that we need to do more in
terms of getting input from outside experts in specific drug safety and risk
management decisions. And so we'll be
planning more outside meetings similar to advisory committees but there are
other sort of fora that we can use such as Part 15 hearings that you've heard
about.
And
then the last part of this, the risk management guidances that Dr. Crawford
talked about. We've already published
so I won't spend any time on that.
And
then a couple months ago, Secretary Leavitt, along with others, announced our
Drug Safety Plan, which is very comprehensive and has as its overall goal the
promotion of more of a culture of openness and enhanced oversight for drug
safety within the FDA. And involves
several different areas of change.
The
first is more outside expert consultations feeding on to what I already
mentioned.
The
second is improving the management of drug safety within the Center for Drug
Evaluation and Research.
The
third is to change how we communicate about emerging drug safety risks to
improve transparency. And this is very,
very important for patients, for practitioners, for those in academia and other
places.
And
the fourth is to continue our work to improve scientific methods of improving
adverse events.
So
the initiative will give patients, healthcare professional, and other consumers
better access to information about medicine.
And this is all tied in as well to what you heard about from Dr.
Behrman.
And
second, to make FDA's drug review approval and monitoring programs as
transparent as we can make them under our statutes.
We've
got some new information outlets that we're putting together. And these are going to be implemented
immediately as opposed to some of the rules that take a long time and the
systems that Dr. Behrman was talking about which, although will be implemented
fairly quickly, are not going to be implemented immediately. So these are things that we can roll out
quite quickly.
The
first is a proposed Drug Watch Program.
I'll get into that a little bit more.
And
the second are patient information and healthcare professional information
sheets. These sheets are already being
produced by the Center.
They're
already on the internet for some high profile drugs that you've heard about in
the news recently: Celebrex, other drugs that have been the subject of
Congressional scrutiny in other areas.
You can go on our website and see these sheets. And I have some examples to show you in a
minute.
And
the second big part of this is the creation of the Drug Safety Oversight
Board. I'm going to give you more
detail about that. The Drug Safety
Oversight Board is going to provide independent oversight and advice to the
Center for Drug Evaluation and Research Director on management of drug safety
issues and policies. And dissemination
of certain safety information through our website on an emerging basis.
So
the oversight board will help select which drugs and which drug safety issues
are important enough to be conveyed to the public on an emerging basis. They need to go up right away even before we
can change the drug labels so that practitioners and patients are aware of this
information.
And
the second is when there are policy issues such as what is the threshold for
putting a black box warning on a drug or other sorts of drug safety policy
issues, this board will be convened and will help give important advice to the
Center on it.
It
will be chaired by the Deputy Center Director of the Drug Center. I don't know if Doug -- Dr. Throckmorton is
here. He's the Acting Deputy Director
and he'll be hopefully, without too much delay, chairing the first meeting of
this board.
The
Executive Director is going to be Susan Cummins, who I know is here. Susan, if you would stand up a minute so
everybody can see you. She's agreed to
take on these very, very important responsibilities. And we're excited to have her get in place starting next week.
The
membership is going to include representatives from a number of different CDER
offices, not just the people who were involved in looking at the drug. In fact the people who have made decisions
about the drugs that are coming from the board won't be able to vote on
decisions having to do with that particular drug.
What's
really new about this, in addition to getting other offices across CDER
involved, is that we're bringing in representatives from outside of CDER,
membership from CBER, from CDRH, and even more significantly from outside FDA,
from NIH and VA in the board. We'll
also have consumer and patient representatives and we'll have consultants from
our advisory board also helping the Drug Safety Oversight Board.
We
do have restrictions having to do with the Federal Advisory Committee Act,
which you are all aware of. We've
received some criticism on this. Why
aren't we having really completely outside people involved. And this would turn the board more into an
advisory committee and really make it very difficult to do the work as facilely
and quickly as we'd like the oversight board to be able to do.
We're
going to be making our operating procedures available hopefully very, very soon
so that all the questions that many people have about how we're going to
operate in detail will be available to all of you.
A
little bit more detail on our proposed Drug Watch web page, again, this would
be a section of our web page designed somewhat differently than what we
currently have up there about drugs that we think, again, that the information
that is coming out, that's emerging, is important enough that we need to make
the public, both patients and healthcare providers, aware of it immediately.
And
I've got some examples here. Again,
there are already examples up on our website but just to highlight some of the
features, you can see it is designed to be very clear and crisp, to just have a
very limited amount of information, specifically some alert language that
really is the crux of what we want the public or healthcare practitioners to
know about, whether there are any specific recommendations.
There
may or may not be recommendations based on some of our dry runs with
drugs. The details of data,
particularly changes, and then links to more information if people want to get
specific information on their links to our MedWatch and how to call in and get
additional information. Again, this is
the patient version of it.
Again,
like the drug information initiatives that Dr. Behrman talked about, this is
really an enormous step forward in making information about our products really
available at people's fingertips so they can get them very, very quickly and
find out key facts about emerging drug safety changes.
And
this is just a proposal. This isn't
what our website is definitely going to look like. But this is a proposal about how we would highlight, we could
highlight specific and new drug safety information on our website.
So,
again, you can go to our website now.
It won't look quite like that but you can find some of this information
very quickly. What we'd like to do is
highlight it even more.
So
in summary, we feel that we're being very responsive to the concerns that we've
heard from all over about drug safety, decision-making, and communication on
drug safety within the Agency and within CDER.
While
comprehensive review is underway at IOM, we are going ahead and implementing
what we see as very, very important changes to improve public knowledge, how we
manage drug safety, and how we involve the outside world in our
decision-making.
As
you already know, and those of you who work for drug companies who are in the
audience or on the board know, these changes are not free of controversy. They have, perhaps, unexpected adverse
consequences that we may have to deal with -- we will have to deal with.
They
certainly raise important policy issues in drug regulation. We're here to talk about them and we know
that we will be having to deal with them over the next period of time. And we look forward to it.
So
thanks a lot. I don't know, Dr. Shine,
if you want me to stay up here for questions.
CHAIRMAN
SHINE: Yes, please. Yes, we do have some questions.
Dr.
Cassell?
MEMBER
CASSELL: What criteria will you use to
establish something as an emerging issue before it is posted? And then I guess along those same lines, how
much will be done to try to validate the events that someone is reporting as
adverse events?
DR.
GALSON: Yes, both of those are very
complex questions.
I
think first of all, the board hasn't met yet.
And when the board meets, that's going to be the first issue that it on
its table is to really establish policies.
In the meantime, we have, within the management structure of the Center
for Drugs and in consultation with the Commissioner's Office, we have been
making case by case decisions.
And
just like our normal risk-benefit decisions about individual drugs, there isn't
a formula. But in general, what we've
-- the criteria that we've been using is when there is something that is
emerging -- first of all, we think it has a very high likelihood of being real,
it's not a specious kind of finding or something we think has another
explanation.
So
first if it is something real. And then
if we think that patients and practitioners are going to use this information
to perhaps change their risk-benefit analysis in using a product, that's when
we have decided that this information would be available.
So
that's -- it's not mathematical. But it
is -- if this information can be used to perhaps change a decision, we think it
goes out.
MEMBER
CASSELL: And will biologics and
vaccines also be taken into account by this --
DR.
GALSON: Right.
MEMBER
CASSELL: -- oversight body? And, I guess, thinking about that, if they
were, one of the things that was striking about the membership of your
committee was the absence of a representative from the Centers for Disease
Control, particularly, obviously, with respect to vaccines.
DR.
GALSON: Right.
MEMBER
CASSELL: And I wondered if that might
not be a valuable addition to the committee.
DR. GALSON: Right. As you know and
you're going to hear more from Dr. Goodman, I think is going to be here this
afternoon, the whole vaccine safety system which I know you are very familiar
with is really very different from the one that is set up for drugs. So initially we have not sought to include
vaccines in this board.
I
can't say what's going to happen down the road. But we felt like we were biting off a huge chunk here and really
representing a very, very significant change with drugs. So we haven't included -- the biological
products that are regulated by the Center for Drugs will be included but not
the other products that are in CBER.
CHAIRMAN
SHINE: Dr. Thomas?
MEMBER
THOMAS: Yes, I think one of the
operative words in your presentation was threshold. And I'm referring to Drug Watch.
And that, in part, has been elaborated on by our colleague. My question, however, is once a drug does
get on the Drug Watch and suppose this is some idiosyncracy and can't be
re-documented, how does one get their drug off this drug alert?
DR.
GALSON: Sure. There is no question that a drug can both go on and go off the
watch. As a communications tool, it's
not going to be very useful if it just grows and grows and grows and
grows. It won't be really -- people
won't be able to highlight and prioritize the information.
So
as -- the board will have to set criteria and policies for putting drugs
on. We'll have to also set policies for
taking drugs off.
DR.
WOODCOCK: Can I make a comment, too?
CHAIRMAN
SHINE: Dr. Woodcock?
DR.
WOODCOCK: Yes, there will be a public
document published, okay, for public comment on both of these issues that have
been raised, the threshold for posting as well as the procedures and so forth
for moving off.
DR.
GALSON: Yes. And also public meetings, I'm sure, to accompany the comments.
DR.
WOODCOCK: Right. So there will be a sense of discussion of
this point.
CHAIRMAN
SHINE: Dr. Galson, two questions.
One
is one of the concerns has been the resources available to FDA --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- for working on safety.
DR.
GALSON: Right.
CHAIRMAN
SHINE: Will the IOM Committee be asked
to look at the resource issue?
DR.
GALSON: Yes. That's part of their charge.
CHAIRMAN
SHINE: Thank you.
The
second is you made reference to outside consultants from an advisory board --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- with regard to this.
DR.
GALSON: Right.
CHAIRMAN
SHINE: What's that mean?
DR.
GALSON: As you know, the chairs and
members of our advisory committees are special government employees. And we can bring them on, as we do already
in the Center for Drugs in some circumstances, to give us advice outside of
their work with an advisory committee.
So
if there is a specific drug safety issue that's coming from the board, we could
ask either a chair or a member of the committee to come in and write a position
paper or look at some data, prepare some materials that would then be presented
to the board.
CHAIRMAN
SHINE: I understand.
DR.
GALSON: Yes.
CHAIRMAN
SHINE: I understand that the
organization of this board is designed to be operational, to have players and
people who know about it to make decisions in a timely way. I applaud the inclusion of some patient or consumer representatives. But this is still very much an inside board.
DR.
GALSON: Yes, right.
CHAIRMAN
SHINE: And the question I would raise
is whether in view of the importance of these issues, there ought to be some
mechanism for some little more distance oversight of this process --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- whether it is in the form of
a separate advisory panel, whether it is in the form of a subcommittee of this
board which interacts or oversees it, whether it's a liaison member from this
board, or whatever.
DR.
GALSON: Yes.
CHAIRMAN
SHINE: What I'm concerned about is that
we, as you use the word openness on many occasions, is that we have a process
by which this board is scrutinized --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- regularly from a bit of
distance --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- in terms of the issues. And I would just encourage you and the
Commission to look very carefully at how we can structure. I don't consider the consultation from a
chair of one -- that's a science --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- input.
DR.
GALSON: Yes, yes.
CHAIRMAN
SHINE: What I'm thinking about is some
mechanism whereby we can assure that there is a real kind of oversight that
goes beyond -- and, in fact, is designed specifically so that it doesn't
involve people who have ever had anything to do --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- with approving of a drug --
DR.
GALSON: Right, right.
CHAIRMAN
SHINE: -- at any time.
DR.
GALSON: Sure, sure.
CHAIRMAN
SHINE: But who can represent --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- the public interest.
DR.
GALSON: Yes, I think that is a very,
very important concept. As you know,
we're just in the very early part of birthing this board. It hasn't met yet. We haven't put the guidance document on the web yet. We will hopefully shortly.
And
I think that's a very important issue that we're going to have to address. And there are lots of different
options. And I look forward to
discussing with you --
CHAIRMAN
SHINE: I would --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- suggest that that is
something that you folks ought to look at --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- in preparation of a board
because I don't know what their interests are and our interests are in terms of
the public --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- oversight of this kind of
activity.
DR.
WOODCOCK: I will point out there is an
existing advisory committee --
DR.
GALSON: Right.
DR.
WOODCOCK: -- on risk management and
safety, drug safety.
DR.
GALSON: Right.
DR.
WOODCOCK: An established advisory
committee or subcommittee, I'm not really sure.
DR.
GALSON: Yes, no, it's a full advisory
committee.
DR.
WOODCOCK: Full advisory committee.
DR. GALSON: Yes. And, in fact, people
have sometimes used too much shorthand because I'm so used to these
issues. We've been asked multiple times
by members of Congress and from the outside as well. Nothing that we're doing here in setting up the board is meant to
diminish the role of our advisory committees.
In
fact, I expect that we will have more advisory committee meetings on specific
drug safety issues over the next few years as the board gets going. It's not meant to supplant the activities of
our expert advisors on the outside.
CHAIRMAN
SHINE: Well, there's a nice balance
here --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- because on the one hand, you
don't want to supplant those functions.
On the other hand, you want at least the oversight of this to be such
that it does not include people who have had a vested interest in prior --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- drug approvals --
DR.
GALSON: Right.
CHAIRMAN
SHINE: -- which might in any way
influence their decisions about what the policies are to be in terms of
thresholds.
DR.
GALSON: Yes.
CHAIRMAN
SHINE: So I really would like to see a
very close look at this even before the board organizes itself --
DR.
GALSON: Yes.
CHAIRMAN
SHINE: -- because you're going to see
their philosophy reflected in whatever those recommendations are.
DR.
GALSON: Right.
CHAIRMAN
SHINE: Any other comments? Gail?
MEMBER
CASSELL: With respect to the board,
what do you include of your definition of consumers? In other words, what will that group be representing? What types of --
DR.
GALSON: Right. We have an established a group of consumer
representatives that are the same group that are members of our specific
advisory committee. I'm sure you've
worked with them if you've been on advisory committees.
And
they represent all of the patient groups, the cancer groups, the arthritis
groups. And they've all been gone
through the SGE process and are vetted.
So we'll choose from those -- that group.
CHAIRMAN
SHINE: Any other questions?
(No
response.)
DR.
GALSON: Thanks.
CHAIRMAN
SHINE: Very important activity, Dr.
Galson. Thank you.
Let's
take a ten-minute break. And we'll
promptly reconvene in ten minutes.
(Whereupon,
the foregoing matter went off the record at 10:23 a.m. and went back on the
record at 10:38 a.m.)
CHAIRMAN
SHINE: Thank you very much. We are now going to go to post-market drug
safety and Paul Seligman is going to take us through his presentation. Paul, thank you.
DR.
SELIGMAN: Yes, Dr. Shine, good morning
members of the board. I have a slight
case of laryngitis this morning so I'm not going to be my usual mellifluous
self. Maybe I'll try to speak in a
lower register.
But
my objectives this morning are twofold.
First of all to describe how we monitor drug safety -- how we monitor
the safety of drugs marketed in the United States and second to talk about some
of the challenges we face in implementing this Post-marketing Drug Safety
Program as well as the challenges we face as a society in the ongoing
assessment of the benefits and risks of drugs as information and science
continuously evolves.
There
are basically three pillars to pour Post-marketing Risk Assessment
Program. The first is the analysis and
interpretation of case reports of adverse drug events and medication errors
generated by healthcare professionals or by consumers and submitted to the FDA
either directly or via the drug manufacturer or drug sponsor.
The
second pillar is the monitoring of how drugs are used or utilized in the
marketplace. And third is a program to
conduct population-based observational studies either in collaboration with
outside researchers or directly by FDA staff.
What
I will not be focusing on this morning in this short time is the full breadth
of safety activities undertaken by the staff in the Office of Drug Safety.
These
include participation in pre-marketing safety assessments of drugs,
particularly for those products with notable safety concerns that may require
additional efforts in the post-marketing arena, whether it comes to risk
minimization or risk management or whether it requires additional
post-marketing surveillance.
I
believe all of you in your packages for today's meeting received the three
guidance documents that we recently published on pre-marketing risk assessment,
risk management as well as post-marketing pharmacovigilance. And though I won't be discussing these in my
presentation, we're clearly here and happy to answer any questions about those
documents.
Finally,
as noted on my slide here, the Office of Drug Safety is also home of the
MedWatch Program, which receives direct adverse event reports from consumers,
healthcare providers.
But
it's also responsible for the regular communication of safety information to
over 45,000 members of our listserv as well as 130 partner organizations I
think in a vital, important risk communication vehicle that we have within the
Agency.
And
finally as also noted in this slide, we play a major role in the prevention of
medication errors by reviewing all of the proposed trade names to screen for
look-alike and sound-alike names and for confusing packaging, which are a major
sources of medication errors in the marketplace.
Our
Adverse Event Reporting System, or our AERS System, is an Oracle database. It's a repository, an electronic repository
that now contains over three million adverse event reports. As you'll see in the next slide, there's
been a steady increase in the number of reports every year. In calendar year `04, we have now over
400,000 reports submitted.
This
is a publicly-available database. You
can access actually the last quarter of 2004's data on our website now. It was previously available, and is still
actually available through the National Technical Information Service. We now provide the AERS data, redacted, of
course, of personal identifier information, now directly on our website.
This
slide just basically shows the trends in adverse event reporting over the last
decade and a half. There are three
important points, I think, here to note.
First the line in the center of the graph shows the point where we moved
from what we called the spontaneous reporting system to our AERS System when it
became an electronic system.
And
as you can see, there has been steady increase in reports but -- and I
apologize. Although you can't read the
little teeny box up there on the left, I think you might note at least by the
colors that some of the colored bars are changing.
And
one of the most important changes in the colored bars is the increasing
proportion of serious adverse event case reports that we are receiving
consistent with our emphasis with industry as well as in the medical community
with reporting those serious reports.
In
response to a question that was asked earlier by one of the panelists, all of
the coding of adverse event reports is done via the MedDRA system, which is an
internationally-agreed to coding language for all adverse event reports.
All
the drug sponsors who code these reports and submit them to us use the MEDDRA
system. We quality control them and
assess this coding on a regular basis as well as those reports that are
submitted to us.
One
last point is that we employ via contract a staff that basically codes and
enters these data 24 hours a day, six days a week. And then eight hours on Sunday.
It's a huge expense for the Agency.
And we are moving increasingly towards electronic reporting of these
data. In fact, this year now over 50
percent of the serious reports are now sent to us electronically rather than in
paper form.
The
second pillar of our program is the tracking of how drugs are utilized in the
market. This slide just simply points
out that we use a variety of data sources, both to assess inpatient as well as
outpatient use, looking not only at dispensed prescriptions, the sales, but
data over time. And we use a variety of
different kinds of databases that are either based on pharmacy benefit
management systems or surveys in both the in and outpatient realm.
We
use these data -- these drug utilization data in a variety of ways. First they permit us the opportunity to
create a crude rate or a reporting rate, using the case reports that we receive
in AERS as the numerator.
Second,
these data in and of themselves give us a view of prescribing patterns by
doctor, by patient, by diagnosis, by concomitant use medicine that provide us
very important insights on how drugs are used both on and off label in the
United States.
And
finally for those drugs for which there are risk management plans that may call
either for limited or restricted use of a product, these kinds of databases
allow us to track the utilization of these products that can provide
information on whether or not the prescribing practices that are recommended in
the risk management guidances are being adhered to.
Finally,
in the area of ongoing population-based studies, it's important to note that
many of these studies are done by drug sponsors either at the behest of the
FDA, as part of a Phase 4 commitment, and I'm sure you are all well familiar
with that terminology, or are conducted on their own initiative, even sometimes
without even the knowledge of the FDA being aware that such studies are being
done.
We
at the FDA have a modest research program, the Cooperative Agreement Program,
that we're conducting with three groups.
We have recently obtained access to the British General Practice
Research Database or the GPRD.
And
are working with the Center for Medicare and Medicaid Services, CMS, as they
implement the Medicare drug prescription benefit to utilize their national
database as it is developed and comes online for the implementation of that
program.
We've
also, to the degree that we can, have been opportunistic as the need arises in
working with other groups such as the Veterans Administration, Kaiser
Permanente of California, to conduct studies to clarify the relationship
between drugs and adverse outcomes.
Now
I just show this slide simply to point out that the size of the populations
covered by these various databases, the Cooperative Agreement Program, covers
the Harvard Pilgrim HMO Network in the Northeast. We use the Tennessee Medicaid Database and the UnitedHealth Group
in the Midwest.
But
also to emphasize that, you know, the way our healthcare system is currently
configured in this country, we have to rely on a variety of different kinds of
databases to answer questions and these are, depending on your point of view,
have fairly limited populations and often make it, you know, on occasion,
difficult to project the national populations.
Despite
the limitations of adverse or spontaneous reporting as noted here, voluntary
case reporting of adverse events still provides the bulk of information that
results in label changes, warnings, safety alerts, and, on occasion, the
withdrawal of a product.
Although
it is difficult to rigorously test, we rely on the eyes and the intellect of
physicians, pharmacists, nurses, dentists, other healthcare providers to make
the connection between a drug adverse event -- or drug and an adverse event and
to file a report.
But
as we move into an age of bigger databases, linked databases, tools that can
rapidly sift through huge volumes of data and records that are increasingly
maintained on electronic media, I think we're all looking for ways in which to
tap into these trends to improve both the thoroughness, efficiency, and
timeliness of our ability to identify safety problems.
If
you believe, and I certainly believe that the learned intermediary still needs
to make the call, then we need to figure out ways to facilitate and make
reporting either a more valued part of every healthcare practitioner's daily
life and figure out ways that we can facilitate reporting such as, for example,
using the electronic medical record and figuring out ways that one might be
able to push a report button and populate certain fields of our MedWatch form
and then submit it directly to the FDA.
But
we also, you know, are very interested in the notion of being able to extract
critical information directly from the medical record, key diagnostic,
laboratory, drug use information, that may define an adverse event and then
build the kind of algorithms to electronically scan databases and search for
suspected cases essentially bypassing the role of the healthcare practitioner.
Clearly
what we do is critically dependent on the type and the nature of the
information that is available to us, both in our ability to conduct timely
surveillance as well as in our ability to study the relationship between the
drug and its toxicity.
What
for me in my tenure at the FDA has been the most challenging is how to
appropriately weigh evidence from different sources each of which has its own
strengths and limitations.
There
is certainly no easy formula for how to continuously weigh, assess, and
reassess the benefits and risks of products as we try to translate data from
randomized clinical trials, adverse event reports, case reports, observational
studies into actionable information.
And to me that synthesis can be, and I think will always continue to be,
the greatest challenge for all of us.
Nevertheless,
we do act. We act with label
changes. We act with warnings. We act with alerts, medication guides for
patients. And all of these with an eye
towards limiting the risks of these products.
And
what we sorely lack is a consistently applied regular program to evaluate the
public health impact of our actions.
There is some good data in studies that, you know, our organization has
conducted looking at whether people read their healthcare provider letters or
the impact of various alerts.
Think
we're at least comfortable with the notion that while these efforts have
influence, we really haven't carefully assessed how these products are received
and what impact they have.
And
finally, our assessment of safety in my mind will always be
circumstantial. Until the science of
drug-induced injury has advanced sufficiently for us to understand the
mechanisms of injury, to identify markers for these mechanisms, and to help us
identify which populations and even which individuals within these populations
are at risk for drug-induced injury.
I
suspect, Dr. Woodcock, you'll probably
have more to say about this later.
And
with that, I'm happy to answer any questions, Dr. Shine, from you and the
members of the committee.
CHAIRMAN
SHINE: Thank you very much, Dr.
Seligman. I have to say that since the
issue of packaging and names and drugs and so forth was one of the featured
recommendations of To Err is Human, I'm delighted to see you taking a very
close look at that and following it carefully.
Is industry responsive to concerns about similarities in names and
packaging? And have you had a
reasonable response in terms of making sure that one can tell one Cephalothin
from another Cephalothin?
DR.
SELIGMAN: Well, you know, industry
invests huge resources in choosing names.
They know that we carefully scrutinize these. In fact, at present, we reject about a third of the names that
are proposed to us because of sound-alike or look-alike or potential confusion
issues.
We
have held public workshops on these matters.
We have, at present, a draft guidance in the works on good naming
practices.
But
there again, in many ways somewhat dependent on the size of the company -- or
actually definitely depending on the size of the company, lots of resources
being invested particularly in the larger manufacturers on carefully screening
and doing the kinds of either analyses or focus groups that we -- the techniques
that we employ to try to determine whether or not there might be a drug name
that would cause that kind of confusion.
CHAIRMAN
SHINE: Questions from the
committee? Dr. Laurencin?
MEMBER
LAURENCIN: How many people are working
in the Post-market Drug Safety Risk Assessment Program?
DR.
SELIGMAN: In the Office of Drug Safety,
we have about 100 employees.
MEMBER
LAURENCIN: And in terms of the adverse
--
CHAIRMAN
SHINE: They work on issues across the
board in Safety. Not just in
Post-marketing --
DR.
SELIGMAN: Well, no, just pretty much
focused on the post-marketing arena.
CHAIRMAN
SHINE: Just post-marketing?
DR.
SELIGMAN: You'll see in --
CHAIRMAN
SHINE: Okay.
DR.
SELIGMAN: -- Theresa Mullin's next
presentation sort of the breadth of how, you know, safety work is done
throughout the Center. But the 100
people that I described basically work on the adverse event, drug utilization,
medication errors, sort of the limited activities that I just described in my
presentation.
MEMBER
LAURENCIN: Just as a follow up to that,
400,000 adverse events, fiscal year `04, how many drug label changes took place
from those 400,000 adverse events that were reported?
DR.
SELIGMAN: Oh, I don't -- someone else
have -- I don't -- I know that there are lots of them. But I don't know the degree to which -- I
don't have that information right at hand.
Does anybody?
Theresa,
does anybody have the information on how many label changes there were in this
last year?
DR.
MULLIN: I don't know how many label
changes there were.
DR.
SELIGMAN: All right. So what Theresa says, we currently have a
study going on which is looking at black box warnings, in particular, and how
many of those were done. But I don't
know to my knowledge whether we have data on the total number of label changes
that occurred --
CHAIRMAN
SHINE: It would be interesting to know
that.
DR.
SELIGMAN: -- in answer to your
question.
CHAIRMAN
SHINE: Dr. Roses?
DR.
ROSES: You mentioned the timeliness,
efficiency, and thoroughness of those issues with the AERS database. What and if ever has anybody done to look at
the accuracy and validity of the self-placed complaints?
DR.
SELIGMAN: We look, particularly when
we're looking at a case report, we look, you know, we often ask for hospital
records, sometimes pathologic specimens, other data to help, you know, validate
a particular report. I mean it's,
although I don't have any specific data, I can tell you that there's lots of
missing information in these reports.
And missing information makes it difficult to interpret lots of these
cases.
These
are often cases which are complex, individuals with complex medical histories,
on medical regimens with lots of different, you know, products that, you know,
could be responsible for the adverse event observed.
Is
that kind of what you were getting at?
DR.
ROSES: Well, what I'm getting at is you
said you act and I was wondering what you act upon. And whether or not we could design a much better database that
would get prospective data in a standardized form from patients taking new
drugs.
DR.
SELIGMAN: Well, I think that's why I
mentioned in my presentation, you know, the possibilities that, you know,
electronic medical records or others might offer us or, you know, databases
where we could actually query directly then get that kind of information which
would fill in many of the gaps that we get currently -- many of the gaps that
currently do exist in our voluntary reporting system.
CHAIRMAN
SHINE: Dr. Pi-Sunyer?
MEMBER
PI-SUNYER: Yes, I have two
questions. The first is are there other
countries that are doing this better that you can get information from? Or not?
DR.
SELIGMAN: Better. That's one of those words.
CHAIRMAN
SHINE: Yes, let me -- I was going to
ask you a very similar question.
DR.
SELIGMAN: Yes.
CHAIRMAN
SHINE: Reference was made that we do
not have a national pharmacovigilance program.
DR.
SELIGMAN: Yes.
CHAIRMAN
SHINE: And the question is what would
be the ingredients of such a program?
And does such a program exist somewhere else?
DR.
SELIGMAN: Well, to my knowledge,
practically all countries, at least in Western Europe, rely in voluntary
reporting. France, for example, has a
series of pharmacovigilance centers that are responsible for, you know, regions
throughout France that are more active and aggressive in getting physicians and
other healthcare providers to report to their center.
You
know the British carry on a regular standard survey for new products that are
introduced into the British market.
But
many of these systems -- many of the Western European countries, because they
have nationalized healthcare systems, have access to, you know, a national
database, if you will, that allows them to do the kinds of things that we can't
do in this country because we lack such a national database.
That's
why that slide of, you know, a little bit here with Tennessee Medicare and a
little bit with, you know, Kaiser Permanente, and the Veterans Administration
and all of these various pieces to try to assemble sort of the picture of the
elephant.
But,
you know, I think many of the initiatives that are occurring elsewhere within
the Department of Health and Human Services within the nation to try to, you
know, standardize healthcare fields, data, electronic reporting, all of which,
I think, will ultimately filter down to our benefit an be able to kind of
access in a standard way the kind of information that will allow us to pick up
on early signals.
Absent
that, we have to do sort of purposeful kinds of things in a variety of
different environments to get that kind of information.
CHAIRMAN
SHINE: And you had a second question?
MEMBER
LAURENCIN: My second question is --
it's a follow up to Dr. Roses. As
you're trying to get information on reports, are you finding that HIPAA is a
problem?
DR.
SELIGMAN: No. I mean well I shouldn't say that. HIPAA -- there is, you know, an exemption or exception within
HIPAA for, you know, public health activities and public health surveillance. And we can assure the providers who give us
information about our ability to protect the confidentiality of that
information within the current privacy statutes.
Nonetheless,
you know, HIPAA has, you know, created a whole new level of, you know, concern
and caution that we have to overcome on occasion. But I'm not aware that it has, in any meaningful way, impacted
our ability to gather and gain information.
CHAIRMAN
SHINE: Thank you very much. And your mellifluous tones --
DR.
SELIGMAN: Okay.
CHAIRMAN
SHINE: -- were well heard.
DR.
SELIGMAN: Okay. Thank you.
CHAIRMAN
SHINE: All right. Let's move on to Dr. Mullin.
DR.
MULLIN: Good morning.
CHAIRMAN
SHINE: Good morning.
DR.
MULLIN: Let me know if you can't hear
me using this. I'm going to present
today the results of an internal study that we did last winter to try to
provide an estimate of the total resources devoted to drug safety within the
Center for Drugs.
We
felt there was the need to do a study like this, because of the ongoing public
discussion, and policy options being considered for dealing with and improving
the drug safety approach within the agency.
But the information that was publicly available was incomplete and providing
an incomplete picture, and the perception of an imbalance ‑‑ a
pretty severe imbalance ‑‑ in the resources currently being devoted
to drug safety.
Well,
what was available to inform those discussions? The most readily available resource numbers that we could provide
in response to questions from the press, for example, were budget figures for,
say, components within the FDA Center for Drug budget. Prescription Drug User Fee Program ‑‑
we have to report those numbers, so there were PDUFP numbers that could be
provided.
We've
had special additional needs requests we've had over the years for the Office
of Drug Safety, so we could provide a number for that office. But these often were not tracking safety
activities.
They
were components within the organization, and, as a result, it would lead to
statements sort of like this one I have here as an example. This year, the Safety Office received less
than $24 million of CDER's budget of almost $500 million.
In
addition, the reports in the media suggested that there was a limited
understanding of the rather complex process of assuring drug safety within
CDER, including the process of pre-market review. And here are some quotes that illustrate, we think, that limited
understanding that was being conveyed.
FDA
and industry have gotten very successful at getting drugs to market based on
their efficacy. Safety has become a
stepchild to the ‑‑ of the agency in the process.
Currently,
drug review divisions generally oversee labeling and other decisions, even
after medicines go on the market, with the Drug Safety Office in an advisory
role. And these statements on the face
are true, but you're missing all of the other background and effort around
that, and so it ‑‑ we are ‑‑ it tends to convey a
partial picture.
And
so we wanted to do a study to try to provide a more complete account of the
safety work and the resources devoted to that safety work throughout FDA, and
answer questions like these. What
activities are considered part of the drug safety effort? What level of effort does FDA devote to drug
safety? And how much drug safety effort
is spent on pre-market versus post-market?
Again,
there was this notion being conveyed that safety was sort of a post-market
concern for FDA, and mainly a post-market concern as opposed to pre-market and
post-market. So we wanted to understand
better how that worked out across the different components within the Center
for Drugs.
The
challenges that we faced in doing this included that the analysis of doing
safety ‑‑ safety is integral to many of the functions within the
Center for Drugs. There is no easy
pullout of that information.
We
had time reporting data that we wanted to use, but that was organized by stages
in the life cycle of the drug, if you will, from pre-IND all the way through to
special activities that we'd use to report.
And
safety, again, is an integral part across those, and so we had to do something
to get into ‑‑ dig deeper into that set of activities to pull out
what was explicitly safety versus something else like assessment of efficacy
and other issues. We wanted to really
drill down to the safety questions.
So
our overall approach included selecting a sample of experts. We wanted to take expert judgments from
within those offices within the Center for Drugs, technical expert judgments,
and combine that with the time report data that we had to try to make an
estimate of this.
So
we elicited those expert judgments on the percentage of the time they spent
doing safety-related activities. And we
used the time reporting data to extrapolate from those individual assessments
where ‑‑ I'll tell you in a minute how we used the sampling of
experts that we involved. And we used
the time report data to weight the averages of that time across activities
within each office and build up an estimate from that.
I'd
like to add at this point that we ‑‑ this was a two-month
effort. We wanted to get it done
because of the urgency of the discussion.
We wanted to try to come up with an estimate that would account for the
bigger picture of safety work, and we couldn't have done that without the help
of the Office of Management in the Center for Drugs.
They
were able to provide us the time report data, break it down into the levels at
the office level that we needed it, and by job series, and so forth, and the
work of the Office of Policy and Planning.
And,
in particular, in the CDER I'd like to mention that Richard Allen, Dong Kim,
and Bob Linkous were pretty critical to our effort. And in the Office of Policy and Planning, Kara Morgan and Corrina
Sorensen worked a lot on developing the methodology and the protocol, and
Malcolm Bertoni was leading the effort on developing the methodology and the
modeling, which was utterly essential to producing the numbers I'm going to
share with you today.
Okay. Here you see the offices that we involved in
this study. We had to look at the
office level, because the percentage of time spent on safety work and what
these offices did varied substantially.
The scientific expertise, you see over in the right-hand column,
populated many of the offices, but what they were involved in was very
different.
And
so here we've got offices ‑‑ new drugs, pharmaceutical science, the
pharmacoepidemiology and statistical science, clinical pharmacology and
biopharmaceutics, the Office of Compliance Medical Policy, the Office of
Counterterrorism and Pediatric Drug Development, and executive programs ‑‑
have somewhat specialized functions within the Center for Drugs.
We
took advantage of that, if you will, because there's a fair amount of
homogeneity within those offices. So
you can go to a medical officer doing drug reviews and, by and large, the way ‑‑
the way they're spending their time in one division was rather similar to the
kinds of questions and the way they'd spend their time in another
division.
So
we were able to use the sort of homogeneity within offices to extrapolate from
experienced reviewers and scientists within those offices. And that's really the approach we took on
this.
So
we developed a multi-attribute model using the time report data. Now, the time report data in the Center for
Drugs has 400 categories ‑‑ pre-market and post-market
distinctions. To do specialized
studies, we often want to go down to that level. We didn't want to do that in this case, thought that would not be
helpful.
But
we used the most recent four-week time reporting data, which was from
mid-October to mid-November of 2004. So
that was ‑‑ people had just finished doing that time report cycle,
and the technical staff do 100 percent reporting. So basically we had a very good snapshot of where people were
spending their time.
We
then, in order not to use the 400 categories, we had some of the experts in the
Center for Drugs who are used to using that time reporting system, and
performing the work within those offices, help us aggregate up to a smaller set
that was still meaningful, and that the people using it could still connect
what they're doing to those smaller number of bins, and we could still maintain
that pre- versus post-market distinction which we wanted to keep as we got the
estimates.
We
also wanted to pull out overhead activity, and so we didn't include that in the
estimate because we're trying to drill down to safety work. We conducted formal interviews. We developed an elicitation protocol using
the principles of the Stanford/SRI approach, which is a motivation of ‑‑
to try to be sure that people are willing to participate in the effort and
understand and not going to produce a biased estimate.
And
that they ‑‑ in fact, we would ask a particular person that we
interviewed, "Do you feel you are able to speak and represent the typical
work of somebody performing this function in your office?" If they didn't think so, then they wouldn't
be a good person to involve in this.
So
we needed people who had some experience and who were very familiar with that
function within their office, and we used that within our motivation phase.
Structuring
‑‑ we used the time report categories to help structure their
thinking about activities that involved safety, so we would take a particular
activity ‑‑ and I'll show you in a minute the list of activities
that we used, and it's in your presentation, if you have the handout.
Within
that category, what kinds of activities do you engage in? What would be ‑‑ if anything,
would be explicitly safety? Not
efficacy, not something else. This is
directly related to product safety.
We'd have them define that, identify what those items were.
Now,
when you're reporting time to that category, on average, what percentage of it
would be devoted to the things you just mentioned, you just described to
me? And we did that systematically in
each of these categories.
We
conducted 51 of these interviews spread across those offices and those job
functions that I showed you a minute ago.
We used the 2004 time reporting data and budget actual data, which is
the number of FTEs spread across the organization to apply our time reporting ‑‑
to apply those percentages that we got from the interviews.
And
just quickly, although it's so small in your handout ‑‑ you may be
not that quick to see this ‑‑ on the left you see the super
categories that were used. And this is
what we have given to people, and it's a brief description of the activities
that that included, which again track to things that they had been reporting in
a more detailed time reporting format.
So
this is ‑‑ these are familiar terms to the people who we're working
with. And it's important, of course, to
have something that they can relate to and is familiar to them, in order to get
a reliable estimate.
So
we have a pre-IND category. You can see
the meetings, of course, that may occur and the things before an IND is
submitted. Here is the kind of
activities you'd expect to see under the IND review, you know.
First,
the review of it in the first 30 calendar days, and then beyond that, meetings
on that application, and so forth, around the IND submission, and actually
interactions that there might be that are of a more informal type throughout
the development process would fall into that category.
The
pre-IND category focuses more on the formal meetings prior to the NDA. So this would include the end of Phase II
meetings and pre-NDA meetings ‑‑ time spent doing that, how much of
that, what kind of safety questions come up, typically what part of that
discussion and that interaction is explicitly on safety. That's the kind of question we ask people.
The
NDA primary review ‑‑ and those activities, which are familiar to
you all, the generics review process ‑‑ we included generics, of
course, because generic drug review and generic drugs are just as important in
this whole safety discussion.
Continuing,
here are the other categories. We call out
activities related to antimicrobial resistance, so that's in there as
well. NDA supplement reviews, of
course, pharmacovigilance and epidemiology work, and then general
post-marketing activities.
And
this would include a variety of things, as you can see ‑‑ Phase IV
activities, promotional material review, compliance activities; the Office of
Compliance, including inspections, to make sure the product is safe; as it's
being manufactured, the ingredients are safe; and then pediatric studies, which
include, you know, the written requests, and so forth, you know, the range of
things there.
The
result of this analysis, as we took the estimates ‑‑ and let me
explain for a minute ‑‑ we talked to people in different
disciplines and functions, and I'd like everybody ‑‑ now, there's a
typo in the handout. So if you can take
your pen right now and correct your handout, because the numbers got
flipped. I don't know how, but it
should be 32 percent in the pre-market and 18 percent post-market, adding up to
50 percent.
Well,
what we did with these 50 interviews spread through those functions and those
offices is take those estimates and apply them to the hours and other people
who are ‑‑ who reported their time across those time report
categories and the percentage of safety that, say, you know, a pharmacologist
will spend within that category to the pharmacologists in that office, and
build up those hours office by office, because the percentages differed and the
hours differed by the office that they were in.
So
each office built up and we aggregated up through the organization. You can imagine an org chart where we're
aggregating up through the org chart to get the total effort for the whole
Center for Drugs. And that total came
to 50 percent.
And
here's the ‑‑ a breakout for you to show you how that looked across
the different offices. And what you can
see is that the percentages varied, but, of course, the size of these offices
varies, so the number of FTEs as a result reflects that. So in the Office of New Drugs, aggregating
up 51 percent of the effort that they engage in over the course of their
activities they considered to be explicitly safety.
And
that translates into 352 full-time equivalent staff. That's what those hours translate into.
Office
of Pharmaceutical Science ‑‑ 51 percent is what the workup, the
buildup number, was for them for their safety-related work, and that translates
into 252 FTEs. The Office of
Pharmaceutical and Statistical Science as a whole, across all of the offices
within that ‑‑ within that super office, 60 percent of the overall
effort and 126 ‑‑ Office of Drug Safety, 100 percent of their
time. So you get 96, as Paul said,
about ‑‑ about 100 people there.
And
you can just see the rest of the breakout there of how the percentage of time
spent and what that translated into in terms of numbers of people, or FTEs is
really a more accurate way to describe the level of effort.
How
does that fit in the context of the whole agency staffing? This just shows you a summary of that, so
the drugs ‑‑ you see it's about half of their folks, and here we
have the FTEs on board for 2004 for the other components or the other centers
within the agency. And so it's about ‑‑
it's 50 percent of drugs, it's about 10 percent of our overall FDA effort, our
overall FDA resources.
So,
in quick conclusion, ensuring safety involves the work of a lot of different
offices and different disciplines, and they're doing different things, although
it all is critical to safety.
So
it begins at the earliest stages of drug development before early tests in
humans, and it continues through the oversight of clinical trials and the
marketing of applications, marketing application reviews, continuing through to
post-market surveillance, risk management, epidemiological research, and it
also involves oversight of commercial manufacturing to be sure that the product
itself physically is safe, and proper labeling and monitoring of product
promotion that assure that it's safely used, and overall about 50 percent of
estimated staff effort.
CHAIRMAN
SHINE: Thank you very much, Dr. Mullin.
Dr.
Cassell?
DR.
CASSELL: Thank you. Very interesting and very good to know,
comforting. I have two questions, and
one of them is related to the antimicrobial resistance. First of all, could you say a little bit
more about the rationale for collecting that data? In this particular survey ‑‑ and then, I'd be real
interested to know what the actual percentage was.
DR.
MULLIN: We could probably ‑‑
I could ‑‑ the second question I'm probably better able to
answer. The first one, we felt that any
category where people have been reporting their time we wanted to explore.
And
since there was enough time being reported there, we didn't assume that it was
efficacy, just safety, either/or, it was just another way to frame our
discussion systematically with the people that we were talking to throughout
the organization. And it would be, we thought, an omission to not have it in
there, and so we probably can pull that out.
DR.
GALSON: You may be wondering, why do we
even collect this? Is that part of what
‑‑
DR.
CASSELL: Well, kind of. I mean, I'm really pleased to see it. I've not ever seen that data, but I ‑‑
it would be enlightening I think to know ‑‑
DR.
GALSON: Yes.
DR.
CASSELL: ‑‑ in terms of
what we know is going on on the outside ‑‑
DR.
GALSON: Right.
DR.
CASSELL: ‑‑ how much time
you're actually spending on the issues internally.
DR.
GALSON: Right. The reason is very pragmatic. When Congress gives us specialized funds for
a certain topic, we need to track and make sure that we can justify that we're
spending that money. We have had
targeted funds for antimicrobial resistance, not right now, but a few years in
the past.
DR.
CASSELL: But the percent you don't
remember right off hand?
DR.
MULLIN: I don't have it off the top of
my head, but we have such vast and detailed spreadsheets that I suspect we
could pull it out for you.
DR.
CASSELL: The other question was with
respect to the generics and the ‑‑ I guess the frequency with which
you might have adverse events associated with the generic product versus the
product still under patent life. And in
the event that you do have problems, in terms of safety issues with generics,
do you go back to those companies, then, also, and ask for additional studies
to be done?
And
excuse my ignorance, I should probably know this, but ‑‑
DR.
MULLIN: No, no, no. Well, I'm going to have to say excuse my
ignorance, because I'm the economist and I work with the data. I pull everything about the substance from
those people over there, so I'm going to ask Dr. Woodcock ‑‑
DR.
WOODCOCK: Yes. There is a therapeutic inequivalence
process. The adverse events would be
put through the same process that other adverse events and part of an analysis
might be if, in fact, we found out whether it was a generic or not that was
prescribed ‑‑ I mean, if we get the generic name, we may not
know.
But
we get reports of therapeutic inequivalence where people raise the issue, they
believe a generic is not performing in the same fashion, and we have a whole
process to deal with that.
CHAIRMAN
SHINE: This appears to be a very
careful, well-done study. It roughly
shows that about two-thirds of the effort is in pre-market safety activities
and one-third in post-market safety.
As
an economist, what kind of methodology would be worth developing to decide
whether that ratio is the right ratio?
DR.
MULLIN: I think you can look at how
many different ‑‑ the relative contribution to safety or preventing
problems of different activities, and I think you wouldn't want to remove
anything that's going on now.
I
think there are areas which we have sort of chronically underresourced and
maybe need to do a better job to catch up with the fact that ‑‑
well, we still ‑‑ we need better tools, I think, and this is what I
hear from the scientists at FDA, to be able to predict safety in the pre-market
period, and that's something that's I think in the works and of interest.
But
the new systems that we need to keep up with the utilization in the marketplace
and the multiple prescriptions people use at the same time are creating a more
complex environment, so I think maybe that's the area we need more ‑‑
CHAIRMAN
SHINE: Yes. It would be interesting to try to not necessarily ‑‑
it may not be about shifting resources.
It may be about the necessity for additional resources; it may not
be. But it might be interesting to
develop some models which look at the overall rate of adverse events or new
adverse problems that are identified in the post-market period, in comparison
to what happens in the pre-market period.
There
are a variety of ways that ‑‑ none of them perfect, but it would be
worthwhile, it seems to me, to try to ‑‑ to get a better handle on
what would be an optimum distribution of resources over time.
Do
you have some ideas about that, Dr. Woodcock?
DR.
WOODCOCK: Definitely. I will point out that some of the safety
activities that are done in the pre-market period are overseeing the human
experimentation, and that is a big effort.
And a lot of safety problems are caught during clinical trials, and it's
in the best interest of everyone to make sure that enterprise remains safe and
trusted by the public.
So
that's a chunk of resources. It is also
well known that one of the main causes of late failures of products to be
marketed is safety issues that arise late, or maybe the FDA turns a product
down because the benefit-risk analysis is not viewed to be adequately toward
benefit.
So
I kind of agree with Theresa. I'm not
sure that ‑‑ I think there are analyses that could be done that
would be very interesting. It might
relate to a question that was raised by the Board earlier about, actually, the
rate of ‑‑ and magnitude of label change is very high in the
post-market period.
There
are large numbers of labeling changes that occur, and that accounts for a lot
of the activity that goes on in the post-market period from those 400,000
reports that we get each year.
CHAIRMAN
SHINE: When the fundamental rubric is
balancing efficacy against safety, safety has to be, obviously, a major feature
of everything that goes on pre-market.
I would be interested in seeing if we can't use some rubric, which over
a period of time could help us with the idea of what would be the incremental
resources that would be required to do the post-market surveillance if we did
it, as well as the pre-market surveillance.
DR.
WOODCOCK: We agree.
DR.
MULLIN: Absolutely right. And with better data we might even be able
to have some marginal - you know, the marginal contribution estimate, and we
can certainly be looking at cost effectiveness of interventions and new things
that we try. And we are looking at an
evaluation component on the new initiatives that we're talking about, to see
that we do get the most for the money that we spend on this.
CHAIRMAN
SHINE: Thank you, Dr. Mullin.
Oh,
Dr. Roses I think has ‑‑ go ahead.
DR.
ROSES: I was just going to comment on
what you said. One of the
characteristics of the pre-market component is that people are being studied by
protocols, and they're being looked at regularly. The post-market component is a different system. It's haphazard. Medical care is haphazard.
And it's not being studied by the same protocols in the reports, and
that was by my question about accuracy.
It can be very variable.
CHAIRMAN
SHINE: Sure. But that doesn't mean we shouldn't be looking closely at whether,
in fact, we're adequately resourced to, for example, determine the accuracy of
those reports.
Let's
move on. I think Dr. Woodcock has a
presentation before the discussion period.
DR.
WOODCOCK: All right. I'm going to talk about ‑‑ sort
of pull all of this together and talk about sort of some of the ways we need to
move forward I think.
What
we've heard about the current drug safety system today is there is an extensive
pre-market testing that is done of products and on protocol, and so forth, with
frequent observations. And then,
there's a rigorous FDA review, which includes an evaluation of what are the
remaining uncertainties after that clinical evaluation and testing has been
done.
Then,
we have proposed implementing user-friendly communication with the drug label,
a modified drug label. It will be
compatible with e-prescribing and the electronic decision support that we all
hope will come very soon.
We
have implemented over the past five years a proactive risk management system
whereby the risks that are identified ‑‑ and you heard this from
Armando ‑‑ they have to be called out by the reviewers and then in
the risk management plans around approval overt strategies for managing those
risks need to be put into place.
And
then, we have post-market, we have what Paul described a voluntary adverse
event reporting system, and with the FDA having limited capacity to do
additional population-based studies to gain additional information.
Now,
the capacity of this system is it will generate a profile pre-market of common
adverse events in the tested populations during the drug development
process. We also nowadays ‑‑
and this is new over the past decade ‑‑ understand drug metabolism
and the common metabolism-based drug interactions, many of which caused severe
harm in the past.
We
are able to develop plans for managing and evaluating these anticipated risks
after marketing, and we can identify in the system the rare serious adverse
events after marketing. And despite all
the flaws of the voluntary reporting system, it's actually quite efficient in
identifying many of these rare adverse events.
The problem is determining whether or not they were linked to the drug.
Now,
what the current system does not elucidate, as we've heard over the past
several months with regard to the NSAIDs and the COX-2s, it increases
infrequency of events that occur commonly to uncommonly in the population that
is not taking the drug. In other words,
if there is a background in the population that is not necessarily rare but not
real common, it may not pick up that increase in frequency.
Time-dependent
events, as we've talked about earlier, it may take a much longer time to evolve
and occur. Events occurring more
frequently in populations that are not tested in the trials, particularly the
people who are very sick who weren't entered into trials, people who are in
polypharmacy, for example, people with multiple medical problems, these we may
not be able to extrapolate fully from the pre-market experience.
And
events ‑‑ and this is very common ‑‑ that occur much
more frequently with off-label uses, and we ‑‑ although we have an
extensive program, we don't always pick up products that are implicated in
medical errors post-market. We also
don't always pick up products that people may abuse post-market, and this ‑‑
that's hard to predict in humans. So
the current system does have safety limitations.
And
as we've heard, we can utilize the emerging electronic medical records system
better for surveillance, and that poses a great opportunity for finding
things. Also, doing randomized trials
or registry ‑‑ registries in practice settings after
marketing. And, again, that also will
be facilitated once we have a more coherent health care system in place.
We
also need ‑‑ and I think Paul Seligman's people are putting in
place or making plans for doing more surveillance in specialized settings, such
as from the ER. The ER is a place you
would expect to pick up a lot of adverse events, because that's where you go
when you have one. Or in nursing homes,
where a tremendous amount of adverse drug problems occur. So that's a very positive outcome.
And
all of these approaches should be implemented, and probably whatever the
Institute of Medicine comes up will be a very comprehensive list of
opportunities. But the traditional
focus here, I would like to remind you, is on detection, and then it's on
communicating these problems through warnings, precautions, or whatever, and
trying to manage the ‑‑ knowing the prediction, okay, knowing that
these could occur with the drug.
But
we need to add, where possible, really being able to predict who is going to
get these adverse events. We need to
move to a different level of management of adverse events. We need to try and prevent them rather than
simply describe their occurrence in the label.
We also need better measures ‑‑ and Paul mentioned this ‑‑
to monitor their emergence before they have fully occurred, and to mitigate
them.
The
goal of the new science, I think, would be to avoid treatment of individuals at
high risk for an event, because serious side effects, even in drugs that are
withdrawn from the market, are usually only occurring in an extremely small
number of patients.
And
when these withdrawn drugs occur, we hear from many people who have benefitted
from those drugs who are very bitter that it has been removed from the
market. And we need, as I said, to
develop new ways of monitoring for emerging toxicity before it becomes severe.
Now,
I'd like to go over very briefly ‑‑ I won't take much time on this ‑‑
why we do have to make these changes as a society. Right now, as Steven alluded to, drug development, including
animal and human testing, is largely empirical in nature. And this tradition focuses on the outcomes
and population means, and then the observation of outliers.
And
if you look at the guidance that Armando presented, that's basically what it's
going to talk about to a great extent.
This
empirical approach directly translates into the trial and error approach used
in clinical medicine, which I think Dr. Roses just said was haphazard. Something like that. And that's because clinicians don't have,
really, any better information right now.
And the way this is done creates, I think, a major loss of information
that can be gained in the clinical development program and translated into
clinical practice.
But
‑‑ and this has led to many calls, as you all know, for many more
clinical trials and significant more work pre-market, larger clinical trials,
trials in many more populations, and so forth, specific trials. But we all have to recognize there are
significant limitations and a number of questions that can be answered via
empirical testing.
There
just aren't enough people in the world or money in the world to answer all of
the kinds of questions you might want to answer about any given drug, much less
the whole panoply of drugs. And these
limitations are imposed by the availability of people, by the practices
evolving, even when you're trying to do these trials, by cost, and so forth.
And
the clear fact is despite the fact that any drug development program will cost
hundreds of millions of dollars, we often lack information and approval of that
drug that is important for prescribing.
We do know that the drug is effective in a defined population, and we
can describe its common side effects in that population that was tested in the
trials.
But
we know that many of the people who are subsequently exposed to the drug will
not benefit from the treatment, and we know for any drug we approve that some
people who are exposed to the drug will be harmed by the drug.
Now,
let's switch to another imperative.
Right now, the current data says that for drugs that enter into Phase I
trials, they have already gone through perhaps five or more years of
development work preclinically, and a huge investment of time and effort, their
success rate of actually becoming marketed products is lower than 15 percent.
And
there's no other real part of our technological infrastructure, say building
bridges or designing airplanes, or whatever, that operates at nearly this level
of risk. This is just an astounding
level of risk ‑‑ of failure.
The
same evaluative tools that will ‑‑ I would like to explain ‑‑
or tell you or argue that the same evaluative tools that will improve
predictability will also support markedly improved decisionmaking in clinical
medicine, and, therefore, will impact significantly on the drug safety problems
that we are currently experiencing, and much of this information can be
developed.
Now,
I'm going to give you some examples to make this real. Drug metabolism is a good example. For example, there is a hepatic enzyme,
which I have listed there ‑‑ and don't pay attention to all of the
words and numbers and everything ‑‑ but this is an enzyme that is
responsible for ‑‑ in many drugs for metabolizing it within the
body, using it up.
And
this is ‑‑ there's a typo in here.
Drugs that are substrates of this enzyme may have up to 10-fold higher
blood levels if you're a poor metabolizer.
So there are probably a person or people in this room who is a poor
metabolizer of these drugs.
It's
a very bad choice of words. The
clinical pharmacologists made up the poor metabolizer. But what it means is your enzyme uses a drug
‑‑ uses a drug up very slowly.
And if you took the normal dose of the drug ‑‑ and we don't
know who in this room is this person, that's the problem ‑‑ if you
took the drug, you would have 10 times the blood level of most of the other
people in this room from that drug.
And
the distribution of alleles ‑‑ in other words, the distribution of
really fast metabolizers, very slow metabolizers ‑‑ varies with
ethnicity. And this gets to some of the
points that were raised earlier about the different profiles in different
ethnic groups.
The
drugs that are substrate of this enzyme are frequently implicated and
unavoidable ‑‑ they are called unavoidable right now ‑‑
side effects. And we think that the
exposure ‑‑ in other words, the fact that these perhaps 1 in 300 people
walking around are getting extremely high exposure to this drug ‑‑
is probably a very large contributor to this ‑‑ to the problem of
these drugs causing adverse events.
Now,
the Center for Devices recently approved a commercial test to determine ‑‑
you can determine your status, your enzyme status, and determine what kind of
metabolizer you are. All right? But, of course, it's not being widely used
clinically yet.
Now,
drug development, though, recognized this some time ago. It used to be that these drugs were put on
the market, drugs that were the substrate, and they got into a lot of trouble
post-marketing. What happened was FDA
worked with industry to develop tools that could use human cells and other
models, but mainly human cells, to predict the human metabolism of candidate
drugs before they got into people and before they began to be developed.
This
caused the manufacturer to start eliminating candidates that were substrates of
this enzyme system and not putting them into clinical development. Okay?
Fifteen years ago, problems with metabolism was the number one ‑‑
and availability, and so forth, was the number one cause of late failures of
drugs, if you can believe that.
In
other words, drugs late in clinical development, they had already gone through
many of the clinical trials and they had to be pulled from development, it was
because of drug metabolism problems.
Since this screening has started, that has dropped down to an extremely
minor cause of late failures in development, because those drugs are eliminated
early from the pipeline.
Now,
this just shows the power of an evaluative, predictive tool that can be used
early to remove this ‑‑ these problematic drugs from the pipeline
and, thus, markedly improve the safety of marketed drugs.
Now,
I'll tell you the critical path initiative is a great example. It's focused on development of additional
tools that would actually do this.
Unfortunately, the clinical test, a test just approved recently by the
device center, for this metabolism has come much later.
All
of the drugs that are on the market that are a substrate of this enzyme, the
clinicians are not used to using this test and adjusting the dose of these
products. So safety problems continue
to arise related ‑‑ because of variable metabolism. One of the things we'd like to do is do some
studies looking at can ‑‑ can metabolic testing like this decrease
the frequency of adverse events of these marketed drugs.
But,
in general, these new technologies, including genomics, proteomics,
metabolomics, and so forth, can really help us predict both in drug development
and in clinical medicine, and that's really my point. The drug safety problem is, to a great extent, related to the fact
that so much of therapy is still empiric.
We
could go and do these tests in patients who have had serious side effects and
study them versus patients who haven't.
And I would defer to Dr. Roses who has done a lot of this work. We can study this both in prospective trials
and in patients who have had serious events that are reported under MedWatch.
We
need to develop the ability to predict and avoid treatment of high-risk
patients or monitor people for development of side effects before overt
toxicity occurs. And while we need to
do all of this other safety surveillance, because we'll never be able to
predict all adverse drug event problems prospectively, this is where we need to
move ‑‑ toward prevention, targeting individualization of therapy
overtly, to really deal with the safety issues.
In
addition, as we develop targeted therapeutics ‑‑ and this is
beginning to happen in oncology ‑‑ we can identify subgroups of
patients who have high response rates.
This means we avoid treatment of people who have very low probability of
benefitting. This is equally important.
Right
now, we just don't know for many therapies, because they're empiric, who is
going to benefit. This can help drug
development, because it will remarkably decrease the needed power, how many
patients you need to test, okay, before you find a positive result.
But
on the other hand, out in the marketplace, it can significantly improve the
benefit-risk of a therapy, because at least the people who are getting the
toxicity had some chance of benefitting from the drug.
So
for the future of drug safety, we really do need to continue to improve the
current system, and we look forward to the committee discussion, but we also
have to start really focusing on delivering the right dose to the right
patient, and to monitor those people for emergence of side effects, and to
really focus on preventing serious side effects by predictive measures. And that's one, as you know, of the very big
focuses of the critical path initiative.
The
issues for this ‑‑ how would we get this applied science done? Well, if you've heard some of this message
before, it's because we're telling people this again and again to make sure
that people really understand this is really part of drug safety. Unfortunately, there has been no entity
really charged with this task. It has
not really been seen as a job of the FDA, or any group really.
Public-private
partnerships, as I alluded to earlier, may be an ideal way to get some of this
work done. We need some venues to pull
and itemize data from various trials, and so forth, and we need the ability to
conduct studies or add-on modules to existing trials to develop some of these
safety biomarkers. But we are very
optimistic that we can get this work going and remarkably improve drug safety,
as I hope the drug metabolism example has ‑‑ has shown.
Thank
you.
CHAIRMAN
SHINE: Thank you very much, Dr.
Woodcock.
Why
don't we begin the discussion period, with specific questions for Dr. Woodcock
you might start with, but I would raise any questions that you would like to.
Dr.
Riviere?
DR.
RIVIERE: Yes. I've had one general comment and one general question, and your
last slide pretty much nailed the comment.
I think a lot of what has happened is that we have not got the resources
and the base knowledge as to how to predict these side effects coming out that
pick up in post-surveillance studies.
It
needs to be really underlined somewhere in here, either as a charge to the IOM
Committee looking at this, that ‑‑ how do we actually direct
research to start determining what are the signals that we're looking for?
DR.
WOODCOCK: Right.
DR.
RIVIERE: Your very clear example on the
drug metabolism ‑‑ and this has happened with other areas ‑‑
when we actually had mechanistic information, we find it.
DR.
WOODCOCK: Right.
DR.
RIVIERE: The other ‑‑ the
other question is is that we develop these preclinical toxicology
databases. I was a little bit disturbed
in Dr. Galson's statement saying that the science of efficacy has advanced, but
the science of toxicology has like sort of just been stuck and did not advance.
(Laughter.)
That's
really not true. What I'm not sure of
is how much of some of these areas ‑‑ and I know why it's not
applied to preclinical studies. Because
it might generate false positive signals, nothing ever goes forward ‑‑
DR.
WOODCOCK: Right.
DR.
RIVIERE: ‑‑ and, you know,
in that constant pendulum battle.
Has
anyone looked at these post-marketing adverse drug reaction databases, and then
done studies to go back to the full preclinical data, not necessarily the
univariate detection of a signal that we know cause and effect, but basically
could we have come up with something to detect this earlier? And I think that's an area that the data is
there.
We
have a lot of information on both approved drugs and non-approved drugs.
DR.
WOODCOCK: Right.
DR.
RIVIERE: You could pick it up right
now. If you knew this was a metabolizer
of this specific enzyme, you'd know there was a problem. But is there ‑‑ any attention
been focused to basically let's go ad hoc ‑‑ post hoc go back now
and look and see if we could have done better.
DR.
WOODCOCK: These are the data mining
efforts I alluded to earlier, and we do have some folks who have come forward
and are interested in partnering with us to conduct these studies, or
retrospective data mining efforts.
Part
of the problem is a lot of the data are not electronic, and so there's this
huge data entry problem that occurs every time we have to go back and data mine
the prior results. But you're right,
FDA is sitting on this huge repository of animal and human studies, and then
have ultimate human outcome data to follow that.
CHAIRMAN
SHINE: Dr. Roses?
DR.
ROSES: I can add something to
that. I took the Lotronex database, the
entire database, hired an outside firm, for privacy reasons, to track down
every patient in that database to find out as much as we could about the
adverse events that were happening.
I'll just make three quick remarks.
The
patients either came through self-referral, they came through physician
referral, or they came through lawyer referral. In no case of a lawyer referral were we ever able to gain the
identity or a DNA sample anonymously from any patient.
About
half the patients were lost to followup in the physician referral. In the self-referral database, out of 186 ‑‑
I think the number was ‑‑ 168, one of those two ‑‑ we
got about 30 patients that we actually got to.
And of those 30 patients, three had never gotten a prescription for
Lotronex, nor ever taken Lotronex.
That's
why I'm concerned about the quality of the data that we get. And you can't go back. It's not just the information to do this
genetically, to do it ‑‑ just even a SIP-2D, you have to have a
sample, even if it's an anonymous sample.
DR.
WOODCOCK: Well, one of the thoughts we
have, if I may partly respond to that, is it's possible that if FDA asked for
some of these and conducted ‑‑ partnered and conducted some studies
like this, we may get more willingness by patients to give us the samples.
CHAIRMAN
SHINE: Other questions for Dr.
Woodcock? Oh, Jesse. Dr. Goodman?
DR.
GOODMAN: I was just going to amplify a
little on the comments several people and Janet made. And I'm not sure I completely got your original question, but I
think part of the intent in some of FDA's pharmacogenomics initiatives, and the
voluntary submissions, is to increase our power to do these kinds of things.
And
even in some of our products like the vaccines, etcetera, or gene therapies,
you know, we're encouraging archiving during ‑‑ during studies of ‑‑
of information. And, after all, DNA and
genomics and results of microrays are just another form of information. But it's one that already is pretty
automated and accessible.
A
lot of the kind of concerns that somebody mentioned that you get all of these ‑‑
you get ‑‑ 2,000 genes go up, and some of them have ominous
names. What does that mean? But the ability to then go back to them
retrospectively, if a problem is discovered in a much larger population base
and identified predictive tools, I think that's the kind of thing that can
really move our ability to prevent some of these adverse events forward, much
the same way it was done with metabolism.
DR.
RIVIERE: And that's what I was really
aiming at is ‑‑ is that it's not the real noise in the 80-odd
databases. It's these really serious
ones that we now know as this class effects, and maybe subclass effects, to go
back to that original data ‑‑ I mean, which there probably were
samples even collected some of these analyses ‑‑ this is the animal
database and the preclinical database ‑‑ to see if we could have
looked at that differently to actually pick that up.
CHAIRMAN
SHINE: Allen, go ahead. Do you want to ‑‑
DR.
ROSES: Yes. In predictive tox experiments that have been done, and they're in
the process of being reported, written ‑‑ they have been reported,
the experiment ‑‑ it's done in a number of companies. The experiment that we did was to ask the
question: if we have chemicals that
pass four-day animal tox, then fail at 28 days, can we predict which ones they
were?
And
some are using genetic-genomic kinds of techniques. The answer is we found 10 markers that would predict, with 98
percent accuracy, that a drug that passed four-day tox, looked pretty good,
would fail. It's another way of asking
the question: can we make
predictions? The answer is, yes, we can,
but now we have to get the database.
DR.
WOODCOCK: Right. But that's a tremendous opportunity. Even there, it shows that you detected
emerging toxicity before it became overt, and that's really one of the goals
that we want to do in patients as well.
Sorry
to interject.
CHAIRMAN
SHINE: Absolutely.
Dr.
Laurencin?
DR.
LAURENCIN: I'm going to reflect back on
some ‑‑ on the old science again.
I mean, to what extent does FDA, in examining the clinical trials,
examine the study population and the population to which the drug is going to
be administered to? Because clearly,
obviously, if the populations are different, then one would expect to have
different adverse events. And that may
be what we're seeing.
DR.
WOODCOCK: The indication that is given
to the drug relates to what was tested ‑‑ what population was
tested in the clinical trials. So, yes,
we look at that very closely. We do a
lot of subgroup analysis and cut the data many ways for the pre-market
database.
So
whatever the company is granted reflects the patients who were studied. However, the clinical usage of the drug will
always or inevitably be much broader than whatever narrow indications are put
on the label. That's just how the
practice is.
CHAIRMAN
SHINE: Which leads to lots of questions
about what, in fact, should have to happen in the post-approval state.
Dr.
Thomas?
DR.
THOMAS: I was going to ask about your
remarks with regard to polypharmacy in this geriatric generation that we now
have and multiple drug use. Do you have
any way to specifically identify, say, drug-drug interactions or drug-nutrient
interactions? Or is this mostly in the
post-surveillance phase?
DR.
WOODCOCK: No. First of all, we identify the drug metabolism prior to
approval. So those interactions that
can be predicted based on metabolic knowledge and what we know about all the
drugs on the market, that is already identified.
In
addition, companies are often asked to do specific drug-drug interaction
studies with drugs that would commonly be used in that condition. Okay?
But if you did a factorial design of all the drugs that are out there,
and then added a new drug on, we cannot do ‑‑ or no one could do an
empirical test of the interactions of all those drugs together and the
pre-market period would never get done.
So that is not done, and that has to be picked up, and often is, in
post-marketing.
CHAIRMAN
SHINE: Cato, did you have another
comment?
DR.
LAURENCIN: A followup question. NIH requires an assessment of numbers of ‑‑
contributions of women and minorities to clinical studies. And, in fact, when we study a section, we
actually grade the ‑‑ grade it unacceptable ‑‑ either
give it a U or an A, unacceptable or acceptable.
And
it could actually mean that the clinical trial won't even be funded if it's got
unacceptable numbers of women and minorities in the study. Does FDA do that? If FDA doesn't, why not?
And what's the plan?
DR.
WOODCOCK: Well, there is reporting of
enrollment, and so forth, and that was done in regulations and guidance
sometime ago. But since we do not fund
clinical trials, we don't have the authority to tell people they can't do
clinical trials, at the time of filing, then those subgroups are reported as
part ‑‑ overtly as part of the NDA database, the representation of
each subgroup.
DR.
LAURENCIN: But you don't fund it if you
‑‑ if these ‑‑ if a guidance document states that these
numbers are going to be important, and that they're going to be looked at, and
that they will ‑‑ they will reflect whether a drug may be approved,
then I think that ‑‑ that there may be a response corporately.
DR.
WOODCOCK: Yes. We've done everything we can to encourage
enrollment. As you know, we've worked
with the National Medical Association, for example, in training investigators,
and so forth, to try and increase enrollment of certain groups.
CHAIRMAN
SHINE: Dr. Roses?
DR.
ROSES: Yes. I think this is being addressed also in a different way. So if you take the SIP-2D case, just as
itself, there's a very simple genetic trait that if you have one form you ‑‑
and you can measure the allele frequency of that trait in any population that
you have 3,000 people. So you can get
that kind of information of who is at risk.
You
turn that around, and there have now been adverse events that have been found ‑‑
for instance, in the caucasian population ‑‑ with a very, very high
degree of sensitivity and specificity that have not been found in other
populations, and, in particular, black populations where the recombination rate
is much higher than in later populations, so that the differences between
Japanese, Chinese, and African-American, or different African populations are
quite different.
But,
fundamentally, when you're talking about adverse events, you're talking about
the person who gets it. The N is 1, and
that's what we're aiming at.
CHAIRMAN
SHINE: Dr. Woodcock, there are kind of
two kinds of problems with the post-marketing issue. One is the impact of time, and the other is the impact of ‑‑
of both the numbers and the nature of the population. To what extent, on the time issue, is there any systematic
attempt to follow at least some portion of a population involved in a
short-term clinical trial for longer periods of time in order to begin to get
more insight into the time dimension?
And
to what extent, given that, as you pointed out, invariably the population exposed
is substantially larger and often quite different than the population ‑‑
or sometimes quite different than the population that is tested ‑‑
to, in fact, seriously require post-marketing clinical trials in a real
population?
DR.
WOODCOCK: Well, the first question was,
is there a secular trend on hazard rates, or the hazard rate for some adverse
event might increase the longer a patient is exposed to the drug.
And
unfortunately ‑‑ I think Bob O'Neill was here before ‑‑
I think, you know, the problem is that usually requires randomized trial data
very frequently to determine that. You
know, it's not the kind of thing that you would pick up in a ‑‑ you
know, just post-marketing surveillance.
So
that would require ‑‑ I think this is something that obviously has
come more to the forefront, say, with the COX-2 inhibitors, and so forth, that
require longer randomized observation.
For
many populations that we have, it's ‑‑ people with symptomatic
disease or serious disease, we can't keep them on placebo. So then you have to do an active controlled
trial, and then you have to know what the background rate is in that other
group to calculate how you would set up the trial. We often don't know that.
We are inheriting the uncertainties of the past, which create a great
amount of problem in setting up trials of the future.
The
second is: to what extent do diversity
in the population ‑‑ how can you extrapolate from the clinical
trials to this very diverse use of ‑‑ types of uses that are going
to occur in the clinical situations?
Yes,
sometimes we can require clinical trials ‑‑ as a post-marketing
commitment that a company do post-marketing trials. As Armando said, sometimes they would be done in people with
liver failure, renal failure, some predicable group.
But,
Steven or Armando, do you have other comments on that?
DR.
GALSON: We can require more studies;
there's no question about it. But,
again, it's a balancing act.
DR.
WOODCOCK: And it's hard for us to
predict always how the clinical community is going to use that drug. That's part of the issue ‑‑ that
drug is introduced. Sometimes it has to
do with the way it's promoted.
Sometimes it simply has to do with somebody publishes and an article,
and they say it's great for this, or in this group of patients, and then the
use really takes off. And we wouldn't
have predicted that necessarily.
CHAIRMAN
SHINE: Yes. Dr. Thomas?
DR.
THOMAS: Yes. That strikes at the heart of off-labeled use, and probably you
get more abuse of that in children and perhaps in the field of oncology. What sort of proportion or percentages do
you see with respect to off-label use of a drug and the incidence of AEs?
DR.
WOODCOCK: You know, I think one of the
things that ‑‑ based on many of the questions the committee has
asked us this morning, one of the things it would be nice to have is for
Theresa to have some staff to do studies of all these ‑‑
(Laughter.)
‑‑
all these things, because we don't really know ‑‑ we don't perform
as much, you know, step back and look at the big picture analysis we should of
all these things. We know that in the
pediatric world that the percentage of off-label use is extremely ‑‑
you know, is the majority of uses, basically, leaving aside antibiotics.
And
I don't know to what extent ‑‑ that we know to what extent that
impacts adverse events. But in the
pediatric trials that have been done to date, we have had some very startling
information on the need for dose adjustment, up or down, things that we would
not have predicted a priori.
CHAIRMAN
SHINE: The committee has been asked
about a number of questions, and let me remind you of some of those.
Thanks,
Janet.
And
let me ask you to think about and make some comments about them. The first is: what kind of information do health care providers and patients
need about a drug's safety? And how can
FDA best get that information across?
You've heard about some labeling proposals. You've heard about the role of electronic communications in the
National Library of Medicine.
Other
thoughts with regard to that issue, with regard to information?
Dr.
Harlander?
DR.
HARLANDER: I'd like personally to see
more information available electronically.
But I also assist with health care with some elderly former in-laws that
don't have access to any of that ‑‑ that information. And what I found in working with them, that
it ‑‑ that their primary source of information is through their
pharmacist. And I know that's kind of
lumped into the health care professional category probably, but I am wondering
if there isn't a way to leverage that as a communication tool. We all have to see a pharmacist when we pick
up these prescriptions.
The
other issue that I've run into in dealing with these elderly relatives is the
drug-drug interaction, and, you know, they will give me a list of the 11 drugs
that they're taking, some of them picked up at different pharmacies and from
different doctors.
And,
you know, I know there's no way to force people to go to the same pharmacist,
but I think there is an educational avenue there that ‑‑ that could
really be exploited very much more, even in taking out that ‑‑ that
drug insert and helping people walk through it, even the first time, would give
you, you know ‑‑ especially if the format is going to become more
consistent, which I think would be excellent, to help consumers take more
responsibility to look at ‑‑ at those kinds of drug inserts.
And
if there's any way to make ‑‑ because I took those lists of 11
drugs, and I tried to do some drug-drug interaction investigation myself, and
it's like hopeless. I mean, I can't
find it. If it was on FDA's website,
I'm not even sure I could get to it.
You know, and I ‑‑ and I know a little bit about it and have
gone to the website a lot.
So
‑‑ so I guess using ‑‑ the message would be using the
pharmacists more, if we can, or find avenues directly to consumers and to
provide more of that drug-drug interaction kind of information in a
user-friendly way would ‑‑ I would encourage.
CHAIRMAN
SHINE: Is there a website in which you
could, in fact, put in the names of 11 drugs and have the computer tell you
what interactions might take place?
DR.
GALSON: Yes. The PDR has a website that ‑‑ and a software that
does that, and there are some software tools.
They're not from FDA, and I can't, you know ‑‑ I don't think
‑‑
CHAIRMAN
SHINE: I just wonder how user-friendly
those are.
MR.
GALSON: They're pretty
user-friendly. I don't think they're ‑‑
you have to know a lot to use them effectively. You can't count on them.
But there are some tools.
DR.
WOODCOCK: Yes, the problem is ‑‑
and we would ‑‑ we would like to, if you don't mind ‑‑
I'm sorry ‑‑
CHAIRMAN
SHINE: No. Go ahead.
DR.
WOODCOCK: ‑‑ we'd like to
step into this realm ‑‑ this is another realm. There are many interactions of drugs. If you're taking more than five drugs,
you're having interactions.
The
question is: which ones are clinically
significant? And, unfortunately, the
practice that FDA has had even is just to list all of the interactions, figure
out ‑‑ let the professional figure out ‑‑ I can tell
probably even a pharmacist could not figure out, without going to the
literature, whether those 11 drugs were going to result in clinically
significant ‑‑ I don't even know whether a pharmacologist could
figure that out.
It's
very, very difficult, and we need to do a better job, and we know, of pulling
out the really big ticket items and really highlighting those, so those people
know, okay, well, you might ‑‑ every time you take more than five
drugs, you're going to have some shifts.
But these you really have to be careful about. That's the kind of message we need to get out.
CHAIRMAN
SHINE: And are you working on that in
terms of the actual project?
DR.
WOODCOCK: Yes. We have been discussing it, but we aren't
very far along. It's difficult for
scientists to do. They don't like ‑‑
CHAIRMAN
SHINE: They don't like to ‑‑
DR.
WOODCOCK: ‑‑ making ‑‑
CHAIRMAN
SHINE: ‑‑ discuss the big
ones.
DR.
WOODCOCK: No.
CHAIRMAN
SHINE: Right. Dr. Thomas?
DR.
THOMAS: Having written several articles
over the years on drug interactions or drug-nutrient interactions, you always
come to the situation where you've got a case study that's reported, one
patient. And now, what do you do with
that?
It
gets in the literature and it gets carried along for the next 20 years as a
drug interaction, and it probably ‑‑ it may or may not have any
clinical significance. And that's the
sort of dilemma that you're dealing with when you get into that arena of
drug-drug or drug-nutrient interactions.
CHAIRMAN
SHINE: Yes. The question is whether you're going to ‑‑ whether ‑‑
the perfect test to paralyze you in terms of being able to give people some
reasonable guidance. I think we've got
to think that out in terms of ‑‑
DR.
THOMAS: Well, if you listen to the
evening news, and all of the side effects with respect to drugs, you get the
feeling that that's one way that the public is being convinced of how dangerous
drugs are, because they're all citing the worst AEs that you can possibly
imagine, including death.
CHAIRMAN
SHINE: Any other comments on this issue
of getting information out? Dr.
Cassell?
DR.
CASSELL: I don't know that it really
has to do with getting information out, but in some respects it does. And I may be off limits to Janet to ask this
question, but would certainly value your thoughts on the role you think that
clinical trial registries might play in overall drug development, but
particularly as it might have bearings on the safety issue. And what kinds of information do you think
are absolutely crucial at the inception and completion of studies in such
registries to really be impactful as far as public health is concerned?
DR.
WOODCOCK: Well, I know registries have
been advocated as perhaps dealing with a lot of these issues. But registries, in my experience, are most
helpful when you know the question you are asking as you go into the
registry. So you have a specific
question or hypothesis you're trying to deal with, and you're able to design
the registry very parsimoniously, you know, with very few data element
collection to answer that specific question.
But,
in those circumstances, for certain especially safety questions, it may be
extremely useful, because it can deliver to Dr. Seligman and his colleagues the
denominator, a numerator and denominator, something we are very sorely lacking
in many drug safety occurrences often.
CHAIRMAN
SHINE: Any other comments? One of the things I've wondered about, Dr.
Woodcock, is whether some kind of ‑‑ you have the black warning
with regard to the drug and its medical uses.
But
in terms of drug-drug interactions, whether you could resolve some of the
problems that Dr. Thomas is talking about by indicating there's a category of,
if you will, red interactions, yellow interactions, whatever, which ‑‑
DR.
GALSON: Like Homeland Security?
(Laughter.)
CHAIRMAN
SHINE: ‑‑ purple
interactions, magenta. But, in other
words, something that, in fact, gives the consumer an idea that this is a big
one but doesn't necessarily mean you drop everything off. But, clearly, there would be a hierarchy of
things to worry about.
DR.
GALSON: I think that's a good
idea. There is no question we're way in
the last century somewhere in our communications tools. And we're ‑‑ you know, we're
playing catch up. But there's ‑‑
I think there are some real hopes there.
CHAIRMAN
SHINE: How can the reporting of adverse
events be improved? Question ‑‑
the cooperative agreements you have with Kaiser and VA, and so forth, what's
the nature of that system? What's
happening in those cooperative agreements?
DR.
WOODCOCK: Well, the cooperative
agreements we have are ‑‑ you know, we provide money, and then they
agree to do certain studies based on questions that arise.
CHAIRMAN
SHINE: But these are research studies
as opposed to ‑‑ I mean, VA has a very good electronic medical
record.
DR.
WOODCOCK: Right.
CHAIRMAN
SHINE: Does this involve linking with
their medical record?
DR.
GALSON: They're not all ‑‑
DR.
SELIGMAN: As Janet described, they are ‑‑
where we currently use them is actually to ask specific questions. On occasion, we have used them to amplify
certain signals that we've gotten from adverse event reportings. We haven't used them in the way I think
you're suggesting, which is to sort of systematically use their data in ways to
‑‑ you know, as an alternative to sort of voluntary or spontaneous
reporting.
CHAIRMAN
SHINE: Yes. I was thinking in terms of a number of these representing
opportunities to develop model reporting systems.
DR.
CASSELL: Or couldn't you look at them
as a ‑‑ somewhere like single sites as you would if you were doing
infectious disease surveillance.
DR.
GALSON: Yes. We've certainly heard that suggestion, and we've done some
explorations of that. It would require
substantially more resources than we have available. But this ‑‑ it certainly is an option to do that as ‑‑
particularly as the health information infrastructure becomes more
sophisticated, we'll be more able to do that specifically with certain kinds of
adverse events.
DR.
SELIGMAN: Right. Just one quick comment. This past week we announced in the Federal
Register a request for information on pilot initiatives for active
surveillance. We're asking groups to
sort of come to us with, you know, ideas and thoughts on how we might indeed,
you know, work with existing databases or health care systems to do just that kind
of work.
CHAIRMAN
SHINE: Yes. One of the thoughts that occurred to me is that, as Gail and
others know, an awful lot of money is being spent on syndromic surveillance for
infectious disease, including, for example, the network that ‑‑ in
Pennsylvania on emergency room reporting.
And
it would seem to me that trying to develop collaborations with those networks,
so that you can do syndromic surveillance on drug interactions from those same
sites with the same terminals, I don't know how much incremental cost it would
add to it, but there you've got it. And
there are a number of those now around the country in terms of syndromic
surveillance.
It
does emphasize again what we talked about before, and that's the need for
standardization, so that you know that you're talking about the same things.
Please.
DR.
RIVIERE: Shouldn't the pharmacy
professionals be involved in this, too?
I know U.S. Pharmacopeia used to really be up on keeping track of
adverse drug reactions, because of the same thing. The person may call the pharmacist with an interaction.
DR.
GALSON: And Gail asked about the
pharmacist before, too, or you asked.
The pharmacy community is very, very interested in this. The major problem, which no one has really
come up with a workable solution, is that there is no funding model for
pharmacists to get involved in this.
And
you all know what pharmacists are ‑‑ pharmacies are like. There's a long line of people. There really isn't much privacy. They don't have extra time. And if they are going to have extra time,
there has to be some model that compensates them for that. And we'd love to see them involved. They are very highly trained, as you know,
to detect, to counsel, and it needs some good brains working on that one.
CHAIRMAN
SHINE: Dr. Thomas?
DR.
THOMAS: I was just going to add with a
somewhat cynical note one way to identify side effects is to threaten a class
action, and all of a sudden you find out where all the side effects are across
the United States.
DR.
GALSON: As you've heard from Dr. Roses,
you may hear about them, but that doesn't mean that they're actually
legitimate.
CHAIRMAN
SHINE: Thank you, Dr. Thomas.
Dr.
Cassell?
DR.
CASSELL: So, Ken, it seems to me that
it boils down to two things ‑‑ one, our resources, both the human
capital, but the financial capital to do this and do it right, and the other
thing is the implementation of the electronic medical records, or you can't
really do it and do it efficiently. So
regardless of adding additional resources, it won't be as good as it could
be.
So,
in your opinion, what can this Board do to try to emphasize this, bring it to
the attention of those that can do something about that.
CHAIRMAN
SHINE: About which part of it, the
resource issue and ‑‑
DR.
CASSELL: The resource issue, both from
the human capital standpoint as far as training is concerned, the funding issue
as it relates to the pharmacy model, and then also just the resources here
within FDA to actually get it done, or to bring the groups together like we
were talking last night, so you can be sure that we can synergize and
capitalize on the investment being made in IT resources and other federal
agencies, including the CDC, including DHS, and why not also including NSF and
FDA? Like I hope we might hear about in
the public comment period this afternoon.
CHAIRMAN
SHINE: Yes. Just a couple of thoughts.
I mean, obviously, this is a very difficult area. A) I think clearly on the electronic health
records side we're beginning to actually make some progress. And a recent survey showed that some 24
percent of academic health centers in the country now have a working electronic
medical record, and almost every other one is actively pursuing it.
Working
with NIH, in terms of both language and connectivity ‑‑ I'm sorry,
HHS, and with Baylor and his office with regard to language, and the concept
that the health information super highway should provide this kind of
information, would be I think a very cost-effective and synergistic way to do
it. And I suspect some of those
conversations are going on.
As
you know, the Congress did not provide the $50 million for that office that was
requested, but I believe that money is going to get restored by another
mechanism. So I think that's going to
happen.
Secondly,
you are seeing the proliferation of ‑‑ in using electronic medical
records, of error reporting in institutions, where the institutions themselves
are looking for ways that they can identify errors. The question is: can you
link that? Can you integrate that with
the drug problem, whether it's an interaction, formally an error or not?
And
I think there are some very interesting opportunities, both in academic health
centers and with a couple ‑‑ you know, this is a conversation that
would be very worthwhile having with Reed Tuckson at United Healthcare, given
the power of that electronic system.
DR.
CASSELL: Well, could I suggest that
maybe an interesting followup to our Board meeting today, which is all focused
on safety, that there could be a followup meeting with an emphasis on the IT
issue, the critical nature and urgency of that, and the resource issue, and to
try to help identify opportunities for synergism amongst the agencies and other
groups as you have just mentioned.
Should
we consider that and maybe think about the fact that it might take more than
just a day or part of day to really do it justice?
CHAIRMAN
SHINE: Yes. Well, I think your point is well taken. I would also argue that this is clearly a public health problem,
and so identifying it with some CDC's efforts, with regard to what they're
doing in terms of monitoring, is another way to do that. And I think there is some activity there.
I
mentioned syndromic surveillance, and DHS has some very interesting programs
trying to move that agenda. So I think
the most likely way to get substantial additional resources is to show that by
bringing a number of resources to the table that they could be leveraged
ultimately into a national pharmacovigilance program. I mean, that's really what you want, and you want to have it in a
‑‑ it seems to me, in a ‑‑ in a serious that would
protect privacy.
Incidentally,
I strongly recommend to you Bernie Love's article in JAMA this last week on all
of the misconceptions about HIPAA, and the notion that HIPAA prevents us from
doing a lot. It doesn't. I mean, a lot of what we're talking about,
HIPAA would be quite consistent with.
But
my thought, Gail, is that creating ‑‑ you know, clearly, the FDA
needs more resources in this area, and that's one of the reasons I'm probing
for a rationale in terms of the way in which you can articulate the need in
some kind of formal way.
But
at the same time, I think to the extent that you can mobilize multiple agencies
with a program, which shows that you're building on things that are of interest
to a number of constituencies, we've got a better chance of making a
significant investment.
Other
thoughts? Dr. Goodman?
DR.
GOODMAN: I'd just like to ‑‑
I concur with all of that. I'd like to
add a dimension which you probably have in mind, but it isn't always made
explicit, which is we're in this situation of not having access to health care
information, and there not being a health care information system. So, rightfully, we say you really need that,
and that's the most efficient system for looking at medical products and their
adverse events. That's all correct.
But
I think you also have to envision what will happen when that information
becomes available. And I think the
issue ‑‑ one of the first issues there is going to be how to
analyze it and interpret it. And I
would suggest that as we're seeking the information ‑‑ and maybe
this is where also FDA can contribute ‑‑ we also examine, you know,
what are going to be the tools ‑‑ the analytic tools and approaches
to that information, not just getting the information.
You
and I know from rounds and things like that that even when we're seeing that
very patient, and have been seeing them for two weeks, interpreting events in a
medical chart, or some day an electronic medical record, when you have
absolutely every bit of data, plus first-hand observation, is very difficult.
And
to do that with quantum increases in the amount of data, and number of data
points, and patients, I think is something we need to look at. And syndromic surveillance in a way is the
analogy of why that ‑‑ that illustrates some of the problems. There is something very simple. You're just looking for infectious diseases,
not even what they are.
And
we have a lot of ‑‑ I think those who are trying to do that are
seeing a lot of challenges with the data that gets generated.
CHAIRMAN
SHINE: I agree with you entirely,
Jesse, but that's one of the reasons why I asked about doing the
collaborations, whether it's with the VA or with some other organization that
has a functioning EHR, so that you can begin to develop the methodologies as
you generalize that. And so I ‑‑
I'm pleased to hear about the inquiry that has gone out.
But
I would also think that there are some other places where there are ‑‑
this kind of information is available and we need to develop the methodologies
that you're talking about. Absolutely.
DR.
GOODMAN: Yes.
CHAIRMAN
SHINE: Other comments about reporting
issues? I think, Allen, your concern
about the validity and the value of the data is extremely relevant. Do you have any additional suggestions as to
how in the world, given the current system, we can help with regard to the
accuracy of the data?
DR.
ROSES: Here I'm going to put my
individual hat on, or my hat from 27 years at Duke, rather than eight years in
industry. Where I've been impressed ‑‑
and I didn't know about when I went into industry ‑‑ was some of
these risk management programs that currently exist.
And
I think we would be remiss if we didn't say that there are risk management
programs in place that have provided valuable medicines for sometimes very
severe illnesses that have side effects, and that there are ways that went
ahead to keep the drug out there for the people who needed it, and to mitigate
side effects. That exists.
If
it exists in a risk management program, why can't it exist for the general
population? And one of the things that
we ‑‑ that I've proposed within my company, and which I think is
going to happen, is that we're going to take one of the drugs that we put out
that has to be in a risk management program anyway, and we're going to get DNA
and clinical followup on the first X-100,000 people who would take that
particular medication.
And
what we would hope to be able to do would be to identify time-related or rare
or even common side effects that may occur in one population and not occur in
another population, and be able to have, in an anonymous way, so that the ‑‑
it's banked anonymously, but the bank gets contacted and we get the DNA
anonymously, and by the time the FDA could call an Advisory Committee together
to look at it, we would have the answer as to what it is that is a predictive
classifier that says these people, no matter what ethnic group they come from,
if they have these characteristics genetically, they shouldn't take the drug.
Now,
if we can do it on a drug-by-drug basis, one of the things that might actually
happen in the future is that we could do this for everybody. And the technology isn't quite there yet. We can do it; but it's expensive.
But
at some time in the very near future ‑‑ we all know what happened
with the ‑‑ with sequencing the genome. Costs came down when demand went up. That the measurement ‑‑ standardized measurement of
500,000 variants across the genome could allow us to start to get at these
answers.
That's
not in the context of public health, and it's not in the context of what we
should be doing. We should put in
place, for planning a system, not to deal with the problems that we have today,
but to deal with the opportunities that we have in the next 5 to 10 years.
CHAIRMAN
SHINE: Well, we will follow with great
interest, because that's exactly the kind of approach that I think Janet and
others are ‑‑ have been promoting.
And the question is: can you
eventually do it, as you say, at a cost that makes it something that can be
generalized? So we will be very
interested in the followup of that.
We're
going to break for lunch in three minutes.
One other element of all of this, as it relates to information, still is
the fundamental problem we have in the United States with communicating risk ‑‑
what it is, what it means, what it means to individuals, what it means to
populations.
We
still, as a society, believe that there should be zero risk associated with
essentially every aspect of our lives.
And I was struck by the fact that after 9/11 people wouldn't fly planes
but did drive very extensively, where the risk, and, in fact, the reality of
death was substantially greater than if they had been flying.
The
thing that's remarkable in terms of the development of agents in the 20th and
21st century is that, in fact, they work.
They are potent. And it's their
very potency which in many ways confers a certain kind of risk on them, to
which is added all of the other issues of accessibility and the fact that more
people in the population have access to them, and, therefore, more likelihood
that there's going to be problems, both with people in general and with special
populations.
So
somehow communicating the notion of the benefit of these agents, the constant
balancing act that's made between efficacy and "safety," it seems to
me has to be one of our major challenges as we try to provide this information.
And
we need, I think to find some rubrics, if you will, to do that. You know, one of my favorite metrics is an
LBU. An LBU is a lightning bolt unit.
(Laughter.)
I
don't know, what is the probability in the United States of being killed by
lightning? Anybody want to tell me what
that ratio is off the top of their head?
Hmm? One in 750,000. And yet people don't ‑‑ you
know, they know to get off the golf course during a lightning storm, but they
don't realize that something that was ‑‑ that is one in a million
is actually less likely than being struck by lightning.
So
I ‑‑ I just emphasize, I think what we're doing ‑‑ what
you're doing in terms of providing easier access, easily readable information,
whether it's the internet, whether it's the pharmacist, and so forth, extremely
important.
But
the background to all of this is somehow those of us in health have to be able
to help people understand that, if it works, it's likely to have some
risk. And the question is: what's an acceptable risk? And that's not just a hypothetical
question. I believe the Drug Safety
Board is going to have to address that when it makes decisions as to what it
says in terms of how do you decide what is an acceptable risk when you put
something out.
We're
going to take a break for lunch. We
will convene precisely at 1:30, because we have five public presentations, and
we're going to need to have them occur in a timely way.
Thank
you very much.
(Whereupon, at 12:26
p.m., the proceedings in the foregoing matter went off the record for a lunch
break.)
CHAIRMAN
SHINE: Ladies and gentlemen, if we could reconvene. We're now about to have an open public
hearing. Both the Food and Drug
Administration, the FDA, and the public believe in a transparent process for
information gathering and decision making.
To ensure such transparency at the open public hearing session of the
advisory committee meeting, FDA believes that it is important to understand the
context of an individual's presentation.
For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement to advise the committee of any
financial relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting.
For
example, the financial information may include a company's or a group's payment
of your travel lodging, or other expenses in connection with your attendance at
the meeting. Likewise, FDA encourages
you at the beginning of your statement to advise the committee if you do not
have any such financial relationships.
If you choose not to address this issue of financial relationships at
the beginning of your statement, it will not preclude you from speaking.
We
have five presenters in the course of a one-hour open public hearing. Each has been asked to limit their comments
to ten minutes, and we will have to be quite strict in terms of limiting to ten
minutes. At nine minutes for the
speakers, I will try to give you a little signal that you're one minute from
the end. And then at the end of ten
minutes, you'll have to conclude your remarks.
I apologize for having to abbreviate it in such ways, but we think this
is important so that we can fairly hear from all of the speakers, and still
maintain our schedule.
The
first speaker is Sadhana Dhruvakumar, who is from the People for the Ethical
Treatment of Animals, and we'd ask Sadhana to come forward to make the
presentation.
MS.
DHRUVAKUMAR: I want to say that I appreciate this opportunity to address
the science board, and also that I don't have any financial relationships of
the type that you were mentioning.
I
just wanted to start by briefly telling you a little bit about PETA. PETA is celebrating its 25th
anniversary this year, and we're a non-profit.
We've been growing very quickly to 800,000 members now globally, and so
far our work in animals used in experimentation has been with the EPA in terms
of government work, but we have been developing a relationship with the FDA
over the last few months. So when it
comes to animal experimentation, I'm going to be talking with a little bit of a
focus on drug safety, since that's the topic.
The
scientific issues that we see with it, is that most of the animal tests that
we're using for drug safety are decades old tests that may not be able to be
validated today. As Dr. Galson was
saying, many of them are from before when he was born, and many of those are
animal tests. They're not reliably
predictive of human responses, not that they can ever be predictive, but when
you do an animal test, you don't know until you do the human test which species
and what is actually going to be predictive.
Extrapolating
from different species results is always guesswork. When you get disease models, the animal disease is an animal
disease, and may not have the same ideology as the human disease that you're
looking to study. Of course, you have
animals that are held in labs, in cages in labs. They're fed lab chow of your choosing. They have stress from being handled, and that type of thing
really affects their physiology and the results that you're going to get. And, of course, in terms of repeatability
and reproducibility because of some of those factors, there's some problems.
They
also take a lot of resources, and basically I'm trying to convey that the whole
paradigm that we have been having of using animals as surrogates - we work out
something entirely in animals, and then we try to translate that to humans was
something that we did in the past, because when there weren't as many tools as
we have today for studying humans directly, and there really needs to be a
transition from that paradigm to a more human-based paradigm.
So
what would that involve when it comes to medical products? So in terms of target discovery, we've had
pharmaceutical companies tell us that some of them have switched almost
entirely to using human tissues, disease versus normal, early versus
late-staged disease tissues, and doing genomics and proteomics profiles, and
that kind of thing in order to map out human-specific disease pathways.
We
also, in terms of safety and efficacy testing, there's in vitro technologies,
such as tissue cultures especially that based on humans, different
physicochemical technologies. When it
comes to studying humans directly in terms of experimental medicine trials,
microdosing, that's all being enabled, as Dr. Woodcock was speaking about in
her speech, by some of these genomics, proteomics, different imaging
technologies looking at biomarkers. We
can now go much more quickly and directly into humans without compromising
their safety. And a lot of
pharmaceutical companies are doing that, just because they don't want to fail
in clinical trials. They want an
earlier indication of human relevance.
And then, of course, bioinformatics, predictive
toxicology in silicone modeling, which was also mentioned earlier. So these are some of the alternatives, the
way that things could go in the future.
The
advantages of these in vitro technologies are numerous. Basically, they should be very attractive to
pharmaceutical and vaccine, and all kinds of medical products companies, or any
kind of company because they're usually cheaper, quicker, and more consistent
than the corresponding animal test.
Making a transition is hard, but in theory they're more attractive.
The
main problem with these in vitro technologies that people always raise is that
they're not a whole animal test. That's
the main disadvantage that they have, but when you look at a whole animal, that
isn't a human, you're not really sure of what you're getting anyway, so the
value of this whole animal test is suspect.
It's more of an empirical test.
It's a little bit more of a black box, and you don't see what happens,
but the way to get away from this is to move from the empirical to the
mechanistic understanding that we're striving for. And once we have that, we will be able to design in vitro
technologies that test specifically for what we're looking for, and we won't
necessarily need to do something in a whole animal, except for the human-based
experimental medicine-type things, which we still will be able to do.
So
when you look at the price that we've paid by doing this animal research, of
course animal research, if it predicts wrongly; one way it might predict
wrongly is that it might say that a drug that would have been great for humans,
might be bad in an animal, and we might never use it. For example, penicillin is toxic to guinea pigs, has no effect
whatsoever on rabbits because it's excreted too quickly, and is one of the
biggest booms to human medicine.
You
might also miss problems when the animal tests do not -- when the drug doesn't
have a deleterious effect on animals, but does have it on humans. For example, with the COX-2 inhibitors that
have obviously been so much in the news, and the animal studies actually found
that COX-2 inhibitors had a protective effect on cardiovascular health. So that's a missed opportunity to spot
something in the preclinical stage and stop it right then, or at least
understand that type of problem before you go forward to the clinical stage,
where it would be a lot more expensive.
And also, Dr. Woodcock mentioned the whole example of the P450 enzymes,
and the fact that so many more drugs used to fail because of metabolism
issues. I thought that was actually a
perfect example, as well, because people are probably aware that animals have
very different P450 enzymes. That's
some of the greatest areas of species divergence, and so for liver metabolism
toxicity, animal models are not very good.
It was switching to human enzymes and human-based human cell tests that
enabled that progress to be made which stopped so many of those studies that
would have failed in late stage.
The
last quote I just always like, "We have cured mice of cancer for decades,
and it simply didn't work in humans."
That's Dr. Rick Klausner of the NCI just pointing out the fact that if
we devote our resources to studying animals, it may not pan out for humans, and
that's where we spend a lot of resources.
So quickly, this is the type of data that someone might look at when
they're trying to interpret what animal results mean for humans. And as you can see, for any given chemical
there's no consistency; even between mouse and rat, you don't even get a lot of
concordance.
And
so I think all of these issues have caused a lot of debate to be going on in
the recent years scientifically. People
are trying to validate the previous animal tests; for example, human skin patch
testing for irritation was found to be only -- the rabbit test was only 45
percent predictive, which isn't very good.
People are trying to look at and validate these animal tests, and
they're finding that they're lacking.
And there was a paper in BMJ last year that I hope you'll look up
because it was a really good paper, and it concluded that clinicians and the
public often consider it axiomatic that animal research has contributed to the
treatment of human disease; yet, little evidence is available to support this
view. They did some systematic reviews,
so we really need to look at yes, we conduct these animal tests, but do they
really make a difference to the end result, are they really utilized in that
way?
I
wanted to quickly touch on animals in the critical path. I was just speaking with Dr. Woodcock
earlier about how this really fits with the concept of the critical path, which
is about modernizing old technologies, and transitioning to the newer
technologies, most of which are human-based or in vitro. And if you look at the Critical Path
Report, there's actually statements in
there about animal toxicology being laborious, time-consuming, and not
predicting safety problems, and problems with currently available disease
animal models, and things like that.
CHAIRMAN
SHINE: One minute, Sadhana.
MS.
DHRUVAKUMAR: Okay. I'm trying to
rush. I know I had a lot on these
pages. That's why I'm not touching on
all of it, but I'm trying to kind of cover all of it.
I
just wanted to raise the issue of international harmonization, obviously very
important in medical products, and the
fact that our groups have been trying to work on that level, as well. And the fact that there's an upcoming issue
based on the fact that the EU does not accept animal tests when a validated
alternative exists. If that's every
industry, so that when these alternatives exist in EU, if the FDA and other
regions don't keep up, there's going to be harmonization issues with companies.
And
lastly, what can the FDA do next?
Basically, the regulations need to change. The regulations have not been keeping up with the regulations,
the guidances, and kind of a review processes with these validated non-animal
technologies, things that have been validated by other countries and things
like that.
We
need to put a little more effort into getting some of these new technologies
developed here. I think a workshop
would be great, because the European government has held many workshops. The USDA has held workshops at the Center
for Veterinarian Biologics specifically on alternatives, and the FDA could
definitely get that dialogue going.
And
lastly, just the fact that the animal protection community is getting
involved. And I think that what we can
bring is the experience from working with these other groups, highlighting some
of the tests that are valuable, that are validated, and kind of helping this
transition where transition is really hard.
And
the last few pages I'm not going to go over, but there are ways to move from
the generalized idea of validated alternatives to specific examples that we can
bring forward and highlight, different campaigns that we have, and information
that we can bring forward to help guide that process. Thank you very much.
CHAIRMAN
SHINE: Thank you very much.
Fortunately, we have copies of your Powerpoint so the Committee can look
in more detail at a number of those slides.
We appreciate your presentation.
Thank you.
MS.
DHRUVAKUMAR: Thank you.
CHAIRMAN
SHINE: Our next presenter will be Janell Mayo Duncan, the Consumers
Union. Janell.
MS.
DUNCAN: Well, no slides, but I wanted to thank you for the opportunity to
come and speak to you all today. I'm
Janell Mayo Duncan. I'm the Legislative and Regulatory Counsel at Consumers
Union. We publish Consumer Reports magazine, and we offer the following comments on
pre and post marketing safety programs with a focus on broader safety
issues. And I ask that you take a look
at our longer statement for a better look into our views.
The
recent controversies related to NSAIDs and anti-depressants have generated a
lot of public concern. And rather than
outliers in an otherwise sound regulatory system, we're concerned that the
recent drug safety failures might indicate serious structural and regulatory
shortcomings here at FDA. And we think
that any attempt to improve the system must ensure that the agency is equipped
to strike an appropriate balance between a drug's risks and benefits at the
time of approval, conduct proactive post-market safety surveillance, and take
timely action to mitigate unreasonable risks when they arise.
And
while FDA might make changes that could mitigate some of these problems, we
very, very strongly urge the agency to work with Congress to develop
fundamental reforms and ensure that it has the authority to address the
problems, the tools, and the resources necessary to do its job, a lot of which
resources is money. And our
recommendations are as follows.
Relating
to pre-approval safety improvements, first, we recommend that FDA routinely
require post-market clinical trial commitments. And we are concerned at the limited availability of pre-market
clinical trials to identify safety issues because of their limited duration,
small size, and enrollment by often healthier and younger subjects in patients
likely to take the drug are of a concern.
And these shortcomings strongly argue for more post-marketing safety and
study commitments as a condition of approval for new drugs, or at the very
least, for drugs likely to have widespread public use, be prescribed off-label,
or where pre-market trials raise unresolved safety concerns.
We
suggest that comparative trials be required, because comparison to more
existing treatments would better allow the FDA to make comparative risk-benefit
determinations at the time of approval, not years later after patients may have
been put at risk.
We
recommend improved risk management at the time of approval. We recommend that FDA manage risk more
carefully at the time of approval, particularly for new drugs for which safety
concerns are still unanswered. With
more active risk management at the time of approval, FDA would be in a better
position to lift risk management restrictions
when safety concerns have been addressed, rather than imposing them after the
patient population has already been at risk.
To
address post-market safety concerns, we recommend that FDA create a more - as
I've heard a lot about today - a more active adverse event reporting
system. The weaknesses of a largely
passive post-market safety surveillance system have been widely noted, and are
of great concern.
Among
other shortcomings, adverse event reporting, though better equipped to identify
rare side effects, is far less able to detect common adverse events, such as
cardiovascular events. And we are
recommending an increase in resources and authority for the Office of Drug
Safety. With a staff of what we
understand to be just over 100, the Office
of Drug Safety was responsible for this huge job of safety
surveillance. And the lack of personnel
and funding, which we had understood to be $30 million annually, limit its
ability to identify the safety risks that adverse event reports may not
detect. And with greater resources,
independence, and authority we think that ODS could play a more effective and
active role in ensuring the safety of prescription drugs.
And
we recommend the elimination of internal conflicts of interest. Last year's reports of ODS drug reviewers,
pressured to down-play safety recommendations, raised troubling questions about
the power imbalance between ODS and the Office of New Drugs. We recommend that these conflicts of
interest be addressed and eliminated.
And
we think that FDA should seek the authority to mandate Phase 4 studies once a
drug is approved, and to ensure compliance with all the post-marketing study
commitments made at the time of approval, to impose civil monetary penalties
for non-compliance, and the ability to mandate label changes, boxed warnings,
medication guides, and other risk mitigation measures. And finally, we believe that there should be
an independent Office of Drug Safety, with sufficient authority and autonomy to
ensure post-market safety.
In
conclusion, thank you for the opportunity to share our views.
CHAIRMAN
SHINE: Thank you very much, Ms.
Duncan. Our next presenter will
Dr. Paul Drzaic of the Alien Technology Corporation. I probably should comment that because of the time constraints,
we're not going to be able to discuss each of these at the time of the presentation,
but I do hope that we're going to get back to a number of these issues in the
course of our discussion at the end of the day, so please don't think that
we're not listening carefully to your comments. Dr. Drzaic.
DR.
DRZAIC: Great. Thank you, Dr.
Shine. My name is Paul Drzaic. I'm Vice-President with Alien Technology
Corporation in Morgan Hill, California.
I have no financial conflicts as outlined in the introductory talk.
I
am here not to discuss use of RFID within pharma. I think the FDA has examined this on numerous occasions, and is
taking very sensible steps to help protect the nation's drug supply. And certainly, in nine more minutes I won't
have time to review that.
Reading
through the FDA report, though, it appears that there could be a very rapid
move towards adoption of RFID, and I have not seen, however, what I believe is
an adequate description of the various technology platforms for RFID that you
may move to implement. So basically,
why I'm here is to provide an update on the RFID industry, just some general
trends that are happening in other areas outside of pharmaceuticals, and urge
for some additional study before adoption is mandated. So I have the summary up front.
So
RFID should provide tremendous benefits to the U.S. pharma supply. There was a report that the FDA did last
year, and again it outlined this in great, and I think good detail, providing
electronic pedigree, enable improved track-and-trace for recalls or freshness,
and efficiencies in the supply chain, which would make the pharmaceutical
companies happy.
Beyond
that, though, there are a couple of different platforms that you might consider
to adopt. One is called HF or
High-Frequency RFID. This is a mature
technology that's available today, if any of you have card access badges that
has HF RFID inside of it. However,
there is tremendous investment occurring in what I'll call EPC UHF RFID, UHF
for short, promising lower cost with equivalent or even better performance
compared to HF RFID.
Additionally,
I believe there are layers of protection that the FDA perhaps has not
considered, that just due to the ubiquitous nature of the UHF RFID that's going
to be appearing in consumer goods in the U.S. could provide some additional
layers of protections to consumers. So
again, the bottom line is additional study is warranted before one type of RFID
is selected for widespread adoption within pharma.
Okay. Just very briefly to remind you how RFID
works. It's a passive device in that
there is a reader that sounds out an electromagnetic signal, a radio wave, that
wakes the chip up. There's no battery
on the chip or on the tag. And then by
modulating that radio wave, it communicates a signal back to the reader. And then that information then gets sent up
to the network.
So
the two different types of RFID tags, the
High-Frequency tends to have a metallic coil antenna. Also, and because of the coil, if you think
about the geometry, you have to have a crossover so that the metals don't touch
as you make the connection. And while
that's sort of an obscure point, it's an important one, because in terms of
fabrication, it adds a tremendous amount of cost, or extra cost in terms of
fabricating the devices.
In
comparison, the UHF RFID, they can be about the same size, but they can be a
very simple construction called a dipole construction, where you basically have
two planes of metal. So I have some
examples I'm happy to leave behind for you to play with, if you'd like. But you can also do some innovative things
with the UHF RFID, so this is something we just pulled out of the lab very
quickly before I left. By cutting a
slot in the blister pack here, and connecting the chip across it, we turned
this blister pack into an RFID tag. And
in terms of thinking about low cost deployment on lots and lots of items, there
are tricks like this that you can play with the UHF RFID that you can't
necessarily do with the High-Frequency version.
Okay. There is a strong market pull for the UHF
RFID led by Wal-Mart, the U.S. Department of Defense. Again, I have this here basically for reference, but there's a
very large infrastructure being built up to support the UHF RFID, primarily in
consumer packaged goods right now, but other industries are looking at that, as
well as pharmaceuticals, transportation.
One
outcome of this is that readers are likely to become ubiquitous, and perhaps
even available to consumers, because these tags are going to be
everywhere. You can readily build the
reader into a cell phone, and it's possible that you could actually push the
reading of these RFID tags for safety purposes onto both retailers and also
consumers, as well, which is something worth considering.
Global
availability - again, this is primarily for reference. The UHF is going to be available worldwide,
so there's no problems with shipment of drugs across borders. I have, again, primarily for reference
purposes, this table. I think one of
the issues that I want to point out is that the UHF tags typically start off
with five or six times the range of the HF tags. And while they are both degraded by metal, being close to metal
if you don't deal with it properly, and the UHF tags are sensitive to water,
the start-off with so much better performance and range that typically even a
degraded performance of the UHF tag can out-perform the High-Frequency tag.
The
other thing I'll point is the HF tags are pretty mature. Four hundred million tags have been shipped
in the last ten years. The UHF tags are
still relatively new, but 50 million have been shipped in the last two
years. And Alien is constructing a
plant in North Dakota right now which will be able to crank out 20 billion tags
per year. So again, there's the
expectation that these tags are going to be everywhere. Other details regarding the size, and
regrade and the like that I don't have time to go into.
I
did pull this quote out of the FDA report from last September, that pointed out
that "Regulatory or policy determinations should be made after experience
in the marketplace". And my point
is that the HF technology, since it's been around for a while, does have
pharmaceutical-specific products in the market. So if you wanted to go out and buy an HF tag for pharma, you can
probably find one or more products to do so.
For the UHF, because it's still relatively new, you can buy functional
tags and readers, but not necessarily those aimed at pharma. So again, I think that there is a strong
interest. I know within Alien, for
example, there's a strong interest in the pharmaceutical marketplace, so again,
these products will be coming. And
again, I'm here simply to caution against perhaps a rush to judgment on what's
available today for your particular needs.
Okay. So the UHF RFID is going to become
established. Again, it's the choice of
Wal-mart and the U.S. Department of Defense, among others. These organizations, by the way, did examine
the High-Frequency technology because it has been available for a number of
years, and rejected it in favor of the developing UHF technology. The UHF RFID is mature, but again it's going
to be difficult to innovate further because they're pretty much done everything
they're going to do with it. And there's
going to be a massive infrastructure deployed to read the UHF RFID tags.
Again,
this infrastructure can be used to improve the visibility of pharmaceutical,
the electronic pedigree for pharma and perhaps far more places outside simply
the factories of the manufacturers and distributors of the manufacturers.
So
my recommendation, while the HF RFID technology is mature, we believe that the
UHF RFID promises at least equivalent performance at lower tag cost. Now I realize I zipped passed that part in
the table. Today, UHF tags cost about
30 cents in high volume. We are selling
UHF tags at 20 cents, and the expectation is that they'll be driven down to
about a nickel. And if you could do
things like integrate them into the blister pack, they can come down to
pennies. So again, if you think about
making these technologies affordable for widespread deployment, the UHF has a
much better trajectory than the HF does.
The
reader infrastructure, again, is going to allow more visibility for UHF tags
than you can with High-Frequency tags.
And simply, the relative benefits and difficulties of the High-Frequency
versus the UHF RFID have not been established.
So I would urge you to give this some study before mandating any
particular adoption mechanisms, so that we can have the best effect and usage
of RFID in protecting the nation's pharmaceutical supply. And then I have a little blurb about
Alien.
CHAIRMAN
SHINE: Thank you very much. Our
next presenter will be G. Michael Fitzpatrick, who is ABC Chief Policy and
Chief Operating Officer for America's Blood Centers. Dr. Fitzpatrick.
DR.
FITZPATRICK: Thank you. I've got
a copy of our written statement for the committee. There are also extra copies outside. There were some rapid changes this afternoon from the President
of our association, so that will be a brief departure from the written
statement, but we'll have that for the reporter, too.
America's
Blood Centers is an association of 76 U.S.-based not-for-profit community blood
centers that collect nearly half the U.S. blood supply from volunteer donors,
and we have two Canadian members responsible for all blood collection in
Canada. And I thank you for the
opportunity to be here to address the Board.
In
anticipation of Dr. Goodman's talk, we want to emphasize that the critical need
for scientific research to support the development of new knowledge and
technologies that results in increased blood availability and improves
transfusion safety is extremely important, but what is urgently needed are
major changes in FDA's processes and infrastructure, and a focus on the path
ahead.
We
believe that CBER, the center that regulates blood and blood products, needs to
enhance substantially the infrastructure for basic research and evaluation of
currently licensed blood components. We
believe as a regulator and a compliance agency, they need to be able to
evaluate these products.
We
have confronted in recent years a number of incidents that raise serious
questions and safety concerns about the availability of blood and blood
components to patients in need. Recent
examples are the discovery of white particulate matter in red cells, and the
appearance of hemolysis in a large number of red cell products subjected to
leukofiltration using filters from one particular manufacturer.
What
became evident during those investigations was that CBER lacks the
infrastructure for basic research and evaluation of those blood components and
those devices. They had to rely on the
industry and on the device manufacturers to generate the data required for
science-based decision-making.
Similar
deficiencies in laboratory support can be seen in other regulated areas, such
as the quality of life live plasma products, and products such as
anticoagulants and collection bags or devices.
FDA does not have the ability to characterize these products as far as
their basic chemical and molecular content.
Lot-to-lot variability has contributed to both the white particulate
matter, and the hemolysis incident with the filters. Yet, the very agency charged with the release of these lots lacks
the capability to detect significant changes in the product itself.
Quality
of donor screening tests, particularly when new concerns are raised, as in the
case of specificity for Hepatitis-B Surface Antigen, and new variants of HIV,
HTLV, or the need for individual donor testing for West Nile virus have all
been accentuated by this lack of infrastructure.
The
closure of most research departments by the American Red Cross at the Holland
Laboratories, reduced capabilities of the Army Blood Research Laboratory, and
the closure of an independent laboratory run at the University of Boston by Dr.
Bob Valeri under the auspices of the Naval Blood Research Laboratory, and the
aging of primary investigators in our field should be sending signals to the
FDA in this country that future regulatory decisions, and the available data
about collection devices, blood components and modifications to current
components will rely solely on data from manufacturers and institutions
supported by the manufacturers.
To
prevent this, either the government-based or independent laboratories must be
supported, and be available for rapid analysis of devices and transfusable
components, and be unimpaired by contractual obligations from revealing that
analysis, and free from apparent conflicts of interest.
We
recommend that FDA adequately fund its own laboratories based on priorities and
recommendations from an advisory panel.
FDA should have its own extramural granting mechanism, or NHLBI be
directed to support research required to evaluate and characterize blood
products and the devices and soft goods used in the collection, manufacture,
and storage of blood products for regulatory compliance and safety. If these were multi-year funds, a grant
cycle could be developed that would guarantee funds are not wasted, and would
always be available.
The
most difficult aspect of administering a compliance and regulatory program for
a research program that is focused on blood products is recruiting, supporting,
and retaining accomplished scientists that are capable of merging their
scientific investigative capability with the evaluation of the clinical impact
of a slight lot-to-lot deviation or change in a manufacturer's specification or
raw material.
We
would all like to believe that the collection of the right data in an
appropriate scientific model based on a valid hypothesis will provide the
information to tell us whether or not a product is safe for clinical use. Unfortunately, the biological information
organisms that receive the product are more diverse than any of us like to
admit. And the range of reactions
induced in a patient is sometimes just as diverse as the patient population
itself.
The
ability to interpret data from a small subset of patients and apply it to the
entire patient population is a unique blend of scientific and clinical
skills. It is essential that the FDA
and CBER be able to attract individuals with those skills, and have fellowship
programs designed to mentor and train the next generation of regulators, will
be facing far more complex sets of data and specialty products. We believe that a well-funded, focused
research program is the best way to attract, train, and retain such individuals.
We're
aware that CBER needs funding and resources to accomplish this. However, the issues are bigger than just
money. FDA needs improved and more
frequent dialogue with industry on guidances, regulations, and memoranda. We are aware that a number of rules restrict
FDA's ability to engage with industry after the internal decision is made to
develop a guidance document, but we need a mechanism that allows open dialogue.
We
suggest that CBER hold an annual meeting or workshop to discuss guidance
regulations that it intends to publish during the upcoming year. This might eventually evolve into a review
of priorities and an open discussion with stakeholders about what is needed to
meet patient needs first, industry needs second, and regulatory and compliance
needs, as required.
We
also recommend that the Blood Product Advisory Committee have at least one
meeting per year devoted to strategic planning and advising FDA on the needs of
both patients and the regulated industry.
Ultimately,
we are looking for far greater communication, and the use of a scientific
approach to investigate threats to the blood supply. FDA and CBER need to have the ability to rapidly investigate
threats to the blood supply, such as white particulate matter, emerging
diseases and incidents of hemolysis.
ABC believes that CBER does not have the necessary resources to perform
its core functions.
Of
course, industry needs to be inspected and be responsible with the compliance
arm for meeting regulation. AT the same
time, the agency must respond rapidly to changes and advances in technology
without tying the hands of industry.
FDA must have the qualified personnel in laboratories to make
science-based decisions, and the scientists must understand blood and blood
components in depth.
We
need to redefine the relationship and provide a framework that enhances patient
care, product advancement, availability, and patient safety. We could legitimately claim that the U.S.
patients are at risk because clear safety enhancements that have been put in
place outside of the United States; that is, the use of a product called PRISM,
to test and evaluate blood products for infectious diseases, pre-pooled
platelets which are used to provide a product that can be bacterially tested,
and even frozen platelets that are available in some countries where inventories
are not as short as they are here, are unavailable here because of what
manufacturers see as an insurmountable roadblock at FDA.
Innovation
in the United States is being stifled.
We need to work together to find a way to meet our patients' needs, improve
the blood products we use to treat those patients.
I
want to thank you for the opportunity to make these comments to you.
CHAIRMAN
SHINE: Thank you very much, Dr. Fitzpatrick. Our last presenter is Sangtae Kim of the National Science
Foundation. Dr. Kim.
DR.
KIM: I'm here representing the National Science Foundation. I am currently at NSF on loan from Perdue
University, and I do not have any conflicts of interest as indicated at the
beginning.
In
the brief time that I have here today, and especially since I'm just across the
river, I'm sure if some of the officials at the FDA are interested in the
linkages between the cyber infrastructure and IT granting activities of the
National Science Foundation, and some of the critical IT issues in FDA's
critical path, I'm certainly available for a subsequent meeting. So in the brief time I have today, I'd like
to convey to the Science Advisory Board the linkages between NSF activities and
IT issues in the Critical Path Initiative, give a brief overview of the most
salient points to set the stage for potential inter-agency collaborations,
additional background materials for the record, including current activities of
two large centers that are supported by the National Science Foundation. And in terms of the highlights, I'd like to
briefly describe the National Science Foundation's track record in setting the
information technology infrastructure that we have today. It's so ubiquitous that we almost take it
for granted. And also, highlight some
of the emerging trends of potential interest to the FDA.
I
just FDA RFID mandate as an example of a driver for some of the significant
investments that we're currently making at the National Science Foundation in
supporting research and development in middleware technologies. Another example that I'll highlight is
digital archiving. With digital age
less than three or four decades old, we face a new challenge of data
permanence.
Many
records from civilizations that last millennia, we take for granted that
artifacts will be there for centuries and millennia to come. No one has really thought hard about how do
we take the most important artifacts that are produced in the digital age and
guarantee that there are business processes and technologies to guarantee that
digital records will be available not only for years and decades, but centuries
and millennia. So these are some of the
fundamental issues that we are exploring at the National Science
Foundation.
The
track of NSF activities and cyber infrastructure, this chart shows just the
past 20 years. The National Science
Foundation actually has made significant investments going back to the 1960s
that largely fostered the creation of computer science departments in the
universities today, including much of the campus computing infrastructure prior
to 1985.
In
the mid-1980s, the National Science Foundation created both the networking, as
well as the Supercomputer Centers, and
to just illustrate some of the impact of that, if you look at the past, just
give you two examples of things that are important in modern society. The NSF networking, otherwise known as
NSFnet, in partnership with the ARPAnet, became the internet that we have
today. In fact, the original name of
the internet was actually Inter-Net, indicating there was a linkage between
NSFnet and ARPAnet.
Just
another example of impact of the National Science Foundation Supercomputer
Centers, the NCSA Mosaic project created the worldwide web browser, which then
went on to become Netscape. And even to
this day, if you click on the Internet Explorer help button, it will
acknowledge the NCSA Mosaic Project as the source of the web browser. And some of the more technical details of
the web services and the worldwide web today, everything that is so-called
web-enabled, the actual technology on the server sites, the so-called Apache
web server, which to this day is the dominant architecture, was also created by
the Supercomputer Centers.
If
you look at the trends of the future, worldwide adoption of NSF Grind Engines -
you may have heard the term "utility computing" or "grid
computing". What is not widely
appreciated is that almost all scientific grid computing that is done worldwide
today is done on computational grid middleware that has been developed and
supported by the National Science Foundation.
And
as I mentioned earlier, things like the RFID mandate of the FDA - the RFID tag
itself is a relatively simple piece of hardware, as the previous speaker
pointed out, that they're going now to literally just a few pennies in the
future. Now one of the reasons why they
cost so little is they're a relatively simple device. All the intelligence is on the software site, and one of the
things to highlight is that the middleware to actually enable these
technologies, much of that has yet to be done in terms of creating the right
capabilities, and to fully utilize the potential of all these exciting
possibilities. So with regard to things
like the FDA mandate, it's extremely important that we continue to make
progress in research and development, and deployment of middleware software.
And
one of the things I did after coming to the National Science Foundation is
double the annual budget of the NSF Middleware Initiative from approximately
$10 million a year, to about $20 million.
Another example that I'll highlight, again in the interest of time I'll
just touch upon it, is the San Diego Supercomputer Center is working with NSF,
the National Archives, the Library of Congress, and I believe there's also some
FDA involvement, as well, to create these new technologies for data permanence
of digital archiving, looking at processes that can preserve data not just for
years and decades, but into processes that will scale into centuries.
The
other thing to point out about the National Science Foundation is that the NSF
doesn't do the work directly itself. It
is a funding or foundation agency. In
the area of IT and cyber infrastructure, the annual NSF grants budget is about
$500 million a year, and it covers a very broad landscape of enabling cyber
infrastructure over the entire science and engineering landscape.
One
of the things to think about in terms of the cyber infrastructure is we take
the internet for granted, but right in front of our eyes, the internet is
actually undergoing an information flow reversal. The historical internet, until very recently, is a radio or
broadcast model; that is, there are central stores of information - for
example, at eBay, Amazon.com, university centers and so forth, that have
information that everyone wants to access.
And then that information is broadcast to the peripheries.
RFID
is just one example of the paradigm shift.
There are other technologies, like sensor nets, environmental monitoring
and so on, and there's an information flow reversal where in the next wave the
data at the peripheries, the massive generation of data at the peripheries, so
the peripheries are no longer passive absorbers of information, but actually
generators of information. And so the
information architecture of the internet has to be redone to recognize the fact
that information is now going to be flowing mostly in the opposite direction,
and RFID is just one example of that.
And so in my division at the National Science Foundation, an important
strategic element of our funding strategy is to get the societal transformation
and enabling role of cyber infrastructure to get ready for this information
flow reversal.
So
the big picture at the National Science Foundation today is we understand and
appreciate that in addition to the actual science and engineering research,
that there's an enabling role of cyber infrastructure, not just for science and
engineering research, but it has a parallel paradigm for a transformative power
in the next wave of the "e" revolution, and there's immediate
economic and societal impact. So we
feel very good about the fact that an otherwise very difficult federal
budgetary climate, that we are prepared to spend a half a billion dollars a
year.
The
drivers are massive data generation at the periphery, as I said; high-end
computers at the core, and a new architecture, including middleware, to link
the core to the periphery. And just an
example of what this looks like, as we transition to the next generation of
cyber infrastructure, for example in like RFID technologies, that we continue
the tradition of U.S. leadership in deployed cyber infrastructure, that there
is a fundamental strategic advantage of the cyber infrastructure that's used
worldwide to come from U.S. architecture and designs. In the same way that the nation has an advantage in that the
dollar is a worldwide currency, we believe that to the extent that the
worldwide deployed cyber infrastructure comes out of our creations and efforts
in this country, it actually creates a fundamental competitive advantage for
the nation.
So
thank you very much for your time, and I'll leave the rest of the reading
materials.
CHAIRMAN
SHINE: Thank you very much. I
want to thank all of our presenters for being extraordinarily efficient in
their presentation. Is there anyone
else who wishes to make any kind of public statement in the course of our
public hearing? Is there any question
that any member of the board wants to direct?
We will be coming back to a couple of the issues that were raised, but
any specific question you have of any of the presenters before we go back to
our agenda?
If
not, thank you very much for your presentations, and we'll move on to our
agenda with the next presentation by Jesse Goodman on safety systems for
vaccines, blood, and tissue.
DR.
GOODMAN: Okay. Well, good
afternoon, and I do appreciate the chance to be here with the Science Board,
and to get both their input and public input on this important issue of safety. I'm going to give an overview of what I was
asked to do about some of the patient safety and safety-related activities we
do to assure that a really unique group of products, blood, vaccines, and
tissues are, indeed, as safe as we can make them, and that we continue moving
things in that direction.
I'm
going to discuss some of the unique issues about these products, and how we, as
a center regulating them, deal with this organizationally, and from a systems
point of view. And then provide at
least a couple of examples of how this plays out in practice.
Now
I think you'll see some of the differences in our products which I'll
highlight, but I think you'll also see some of this will resonate with some of
the common challenges in getting the right information in a timely manner, et
cetera. So with that note, I'll get
started.
Okay. Actually, the history of biologic safety
precedes in many ways the history of drug safety. I'm not saying in absolute history, but certainly the regulatory
mandate and the steps that led the American people to say we want an agency
which protects the safety of our products.
And it all started with a horse named Jim, thirteen children in St.
Louis, who during an age where serum therapies were regarded as miraculous,
they were saving children with fatal diseases, but it was an unregulated
industry with dozens, I think, of local manufacturers producing things pretty
much in their - well, could be in their garage or whatever on their farms - and
thirteen children in St. Louis died from tetanus after receiving diphtheria
antitoxin from a horse that had tetanus.
And Margaret Pittman stated, "This tragedy convinced Congress and
the public that producing antitoxin or vaccine was not a simple matter like
weighing out a dose of a drug."
Now
we all see from this morning that weighing out a dose of a drug is not a simple
matter. This led to the Biologics
Control Act of 1902, and just a couple of years ago, the Center for Biologics
celebrated what is a centennial of a long organizational history in various
forms. And it said, "Although the
preventive and curative powers of viruses, serums, toxins, et cetera, has
long-since been established, certain unfortunate incidents have tended to
discredit their use." And I think
that "discredit their use", talking about that even then is a very
interesting comment. History is always
there in terms of confidence in products.
And, "The extreme value of the preparations in preventing and
curing disease renders it of prime importance, therefore, that action be taken
to preserve the confidence of the medical profession and the community
generally in them." So I think
very telling words for them, and certainly for posterity, probably, because
we're always going to face these challenges.
Now
particularly in biologics, we have this parallel, but you see it in drugs, too,
between miraculous therapies, tragic events, regulation, and all of this
informing product development. These
are just an example, but going back to Jenner, prevented Smallpox, but spread
Syphilis with Smallpox vaccines. The
famous Cutter incident where inactivated polio vaccine was not properly
inactivated, and a number of children died, and the product developer actually
then committed suicide in this case, because he was so unhappy with what had
happened. Transmission of tetanus and
other infectious diseases through serum, like I mentioned. A more modern one, particularly HIV
transmission through blood; a more recent one leading to an enhanced FDA role
in tissue safety - some tissue contamination episodes; and then much more out
there in new technology, successful gene therapy, and adverse events related to
that. So we live in a world of this
kind of risk. There are many things
flying at us. The actual predictive
abilities are what we struggle with.
Some
of the big themes and cultural issues particularly for our products, but many
of them apply in various degrees to other products, complex products and
production, inherent risks, and I'll get to those a little more; but an example
is the source material. And some of
these risks are predictable, but some of them are unpredictable. All that is predictable is that there is
risk, but what that risk will be, Mad Cow Disease, for an example, would have
been unpredictable before that pathogen was discovered.
These
products, particularly vaccines, but also blood and tissues often given to
healthy individuals in large numbers, and their safety is taken for
granted. On the other hand, there is a
conflicting need for access and supply.
The markets here are particularly fragile, so they are sensitive to
development cost. But I'd like to point
out, they're also sensitive to problems, so that if confidence or risk of
products is perceived as a business liability, people will be less likely to
make products. On the other hand, if
the cost of developing them is so much, due to over-regulation or undue
demands, that may also affect supply.
The
confidence in the public health system is almost always at stake in our daily
work in these products, and so there is a need to build safety into the
products and production for many of these characteristics. And there's a need to be a bit ahead of the
curve here, and that's part of the culture; identify emerging safety issues,
and respond before or as they evolve.
And
these are just an example of why we have very little business as usual in our
center, vaccine safety concerns one minute, availability concerns the next,
serious on both ends - blood safety and availability, same thing. Emerging infectious diseases affect many of
these products, and may not be predictable.
Increasing use of exciting new technologies ranging from tissues, to
cells, to gene therapy, and then the external need for products to deal with
counter-terrorism, many of which are developed in abbreviated, urgent manners,
and sometimes which cannot be evaluated adequately in clinical trials before a
possibility of use occurs.
So
all of these present both long-term and day-to-day safety and risk assessment
issues. So what's been our overall
approach? I think I would say
prevention first, and that includes guidance and extensive pre-marketing
interactions with sponsors around their products; labor-intensive,
resource-intensive, a wise investment.
Manufacturing
process controls and oversight - Mary Malarkey will talk about this a little
with vaccines, but we need to not do this in an uniformed way. We want to do this in a continually updated
manner, and that's part of what the agency's initiatives are about.
We
do have to find post-marketing safety responsibility in CBER in the Office of
Prior Statistics and Epidemiology which does report to me, and it is
responsible for the routine adverse event surveillance analysis and related
research. But they don't work in
isolation, and we take a systems approach to this. There is routine evaluation of serious adverse events for
important wide-use products, such as blood, vaccines, and tissues. And we are doing a periodic assessment and
update of our current SOPs and approaches, so that's why again I look forward
to being informed by what we're learning here by the IOM, et cetera, even if
it's about a different class of products.
AS I said, there are some common challenges.
Collaboration
and communication is very important in how we do this. These are complex products where our product
experts, let's say, in vaccines and blood, have one whole universe of
knowledge. They must consider the
epidemiological statistical aspects of the pre and post marketing information,
so they need that communication. And
it's bidirectional - our expert epidemiologists, most of whom are physicians,
may not be expert in specific vaccine, preventable disease, or a specific
product, so they need that bidirectional collaborative approach. So the data is generally shared and
evaluated collaboratively, ultimately; even though post marketing data comes in
for adverse event reporting, has a primary responsibility within this office.
There
is also collaborative work planning in safety studies, and this we're trying
more and more to direct along the lines that Mike, I think, mentioned. Our limited resources in terms of
understanding or investigating new problems, whether they're laboratory
science-based, or population-based in an agenda-driven manner.
One
of the important things we do is we do rely on our advisory committees a
tremendous amount, and most significant adverse event issues or let's say
safety threats, such as emerging threats to the blood supply, or safety
allegations, are brought to our advisory committees. And we do a lot of public discussion of these things. And in addition, we have inter-agency
partners who have important roles here, as well as resources, and ways they can
contribute, and their own advisory committees which we also bring this
information to. And that includes CDC,
NIH, and the Office of the Secretary, which for example, our of the Secretary's
office, we have very public and open broad constituency advisory committees in
the vaccine and blood area.
We
get a lot of advice, whether we want it or not. We get a lot of advice, so I think incorporation - and actually that advice, and the
diversity of it, is very, very important.
And also, it encourages on the part of the federal agencies,
transparency and information sharing.
The
other thing we've done particularly in the last couple of years is recognize
that a lot of what we do falls into the risk management, risk assessment
paradigm. And again, this is reflected
to some degree at the agency, as well with the promulgation of guidances for
new products, risk management programs, in effect.
We've
also tried to incorporate a basal level of risk science training and modeling,
training into our center so that modeling, regulatory mitigation and public
health actions are seen in an analytic framework, and I'll say a little more
about that. And that let's us more
objectively balance risks and benefits in the context of things like the
intended use of the product, the alternatives to the product, et cetera.
And
I think a very important feature of how we as FDA, and especially on some of
these products respond, is that we do need to continue to seek to recognize
deficiencies of our information and data, and to keep an open mind. Seek new data, pay attention to it, and reassess
what we do as things go along, because I think in public policies, the biggest
mistakes were made when somebody picks a course. They've usually made the best decision they can, but then when
they construct a construct where changing course and getting new information is
difficult, and we try very hard not to do that, and I'll give some examples.
So
what are some unique attributes here?
Biological sources - you can get human and animal diseases; the
mechanisms of action are very often quite complex; the predictors of toxicity
are even more poorly established than for small molecules where there are still
challenges. The manufacturing processes
for many biological -- well, some are becoming better characterized, still for
others they're still poorly characterized.
And then there are some uncertainties in terms of emerging infectious
disease threats, cutting edge technology.
And one important point is how people react to these things, that these
are all products, particularly in cutting
edge technologies, but blood and vaccine have their own emotional
dimensions, so there are emotional dimensions to how people view products. And I don't, at all, discount those. I think
how people feel about things is something very important, and you have to
evaluate it in that framework; but it's often based on knowledge that maybe is
harder to scientifically quantify, but often turns out to have value, but we
need to consider it, at least.
Other
things is we have products that are often needed for public health and
individual health, so if you are preventing spread of measles in a community,
or polio by vaccine, obviously not having that vaccine impacts not just a
patient, but a community. And this gets
to this issue of distributive risk and benefit. And, for example, parents who may never have seen many of these
vaccine preventable diseases and what they do to people, may see absolutely no
reason to vaccinate their child, particularly if they've heard about a concern
about the product. And we have to deal
with that, and recognize that. And that
requires multiple partners, medical care community and the public health
community, industry, and our partners in government.
There's
often no substitute product. And again
in drugs, there are situations where this is true. And you heard even with the COX inhibitors, that there are
certain people for whom certain drugs
were viewed by them as lifesaving, or whatever; but we often have that
very globally. You saw what happened
with the flu vaccine this last year. We
often have products where there's one or two manufacturers. There's not a substitute for blood, if
there's a blood shortage in the United States at this time.
Everything
seems to have a worse case scenario in these products, and it does keep me up
at night. It's not just that other
people worry about it, we worry about it too.
There's a lot of interest. And
then often, as there is in these very charged situations, there's a perceived
need or a real need for immediate action at a time when you may not have the
data. So how do we get it, do the best
job we can under those circumstances, and what things could we use to improve
it?
One
thing I mentioned, we put in a program of risk training. We have a small risk assessment unit with an
expert scientist, Steve Anderson leading it, and have worked collaboratively
with a university to put together risk training. This mentions courses we put on in management, risk assessment,
risk communication and message techniques using biologic case studies. And the idea here is to create a common
understanding, and begin to create a common use of these tools across our
organization. We also want people to
recognize the limitations of these tools.
It's something that I always give people a hard time about; the
uncertainty around our estimates, and how to communicate those honestly.
Okay. Now I'll just, since I was asked to go into
some of the activities in each of the product areas. Blood safety, we
traditionally say there are five layers of blood safety. There's really a lot more, but we determine
is the donor eligible by taking a history, and by doing then testing if they're
still eligible. If they're not, they
wind up on a list which is really a registry that says you can't donate
blood. As I said, they're tested for
communicable diseases. Blood that is
found to be from a unsuitable donor is quarantined and taken out of the system,
and may be recalled if it's been issued.
There
is a system, and this fits most with the paradigm of some of the questions that
are coming up about drug safety, of investigation of problems and adverse
events, and I'll get into that. And all
of these are also connected with anticipating and tracking emerging infectious
disease problems. And people don't
realize the complexity, for example, of blood.
Mike mentioned it involves bags, involves filters, a whole host of
things that we evaluate in the context of blood safety, as well.
So
what are we doing to try to find improvements in these areas? In donor eligibility, the questions you ask
are a safety issue, so we're working with the blood community to try to improve
how we do that, developing a uniform donor history that's used across the
industry to improve science-based results, and to improve the sensitivity and
efficiency of that. These things have
been successful, so we should celebrate and appreciate our successes. And I feel this is true in other product
areas, too. There are challenges, but
there are also successes.
Look
at this dramatic reduction in the risk of viral disease transmission from blood
in the last 20 years, to the point where those numbers are now more like one in
two million for Hepatitis-C and HIV, the two most serious blood borne
transmissible diseases. So new
technology, regulation, cooperation between the regulated industries,
cooperation with FDA and the product developers have led to this.
I
could get my Powerpoint to do it, but I wanted to draw West Nile virus on here
also to give an idea, but essentially West Nile virus in 2003 was kind of up in
here, and that became the most common viral, and now it is down in here thanks
to what has been accomplished, and I'll give those examples.
Another
thing, we cannot do all of this ourselves.
I realize the expectations are high.
This is not an industry which has tons of money and resources. They would like us to do more. We try to do what we can, but a lot of what
we do is also in partnership. And this
is not exactly a classic safety thing, but as I said, blood isn't a classic
drug substance.
Here
we have worked with the American Association of Blood Banks, which basically
represents the United States blood banks and supplies, and put together a task
force on domestic disasters and terrorism.
And essentially, this integrates the public and private sectors, the
Secretary's office, to be prepared and respond to emergencies, and not just
things like what happened at the World Trade Center where we found ourselves
all scrambling, but managed to coordinate.
But also, things like Mike mentioned, the white particle problem, so
when we see a problem, we bring this right away to the blood community, and
they help us collect information, and we work together to identify how to
answer the scientific questions. And
try to respond in a calm and rational manner.
A
couple of examples. A big concern is
Mad Cow disease or Variant CJD, and the potential risk to the blood
supply. And this gives an example of
how risk assessment and management can change over time, and how no matter what
we do, we can always learn from it.
So
in 1999, we initiated donor deferral policies for people who have spent a
certain amount of time in the United Kingdom.
And we got push-back on this.
There had been no transmission of classical CJD or Jakob-Creutzfeldt
disease through the blood supply, but we got push-back on this. And it was going to affect some of the
supply, but there were scientific concerns.
As opposed to classical CJD, the prions or the presumed infectious
particle, and perhaps their symptoms are seen in lymphoid tissue, the scope of
the epidemic at the time was unclear.
It appeared to be increasing, and this was a precautionary measure, and
it was taken to a level where modeling versus effects on supplies indicated that
this could be done in a way to substantially reduce potential risk, while not
creating new risk from supply disruption.
Not that this was easy for anyone, including the blood community,
because blood is always in short supply.
At
the same time, we said the science does support that this isn't spread by
classical CJD, so we removed for that previous agent of concern recall
requirements, et cetera. And we said
again, this point of continuing assessment, we will re-evaluate this twice
yearly, new scientific data; and the thought was the data would show we didn't
have anything to worry about, probably, and you might scale these back.
However,
in 2001-2 the scope of the epidemic was increasing, and animal studies showed
that blood could, in an animal at least, animal model, transmit the disease. So we actually found ourselves in the
position of extending these deferrals to reduce risk further, and to include
other geographic areas where the epidemic had spread. And then in the last year or so, there have been two human
transfusion-related cases occurring in the U.K. And again, we're re-assessing risk for a variety of products, and
trying to say what can we do from a more upstream version to reduce use of
animal proteins, for example, in recombinant products, et cetera.
Okay. And then we're doing a bunch of other
things. As I said, we're going to
periodically continue to re-review risk.
We are doing risk assessments for other products we're concerned about,
including plasma derivatives. But what
could we do to really prevent this problem, rather than just pull donors
out? And this gets to areas, again,
where there are technologies where judicious investments could have significant
public health payoffs. There are
filters that may be able to remove prions from blood products, but we need to
know how to evaluate them. And there's
going to need to be an honest evaluation of those products, and it's not
cheap. There's like two labs in the
world that can handle these agents, two or three labs, and there's very limited
capacity.
Same
for putting together reference panels.
There's possible blood screening tests out there. It would be wonderful to be able to screen
the blood, very important especially for plasma recipients who get frequent
transfusions. And then there are
manufacturing issues. We know that
certain manufacturing processes, for example, plasma derivatives, may remove
prions and may do so effectively. And
we're working with the industry to identify what those are, and share that
information.
Here's
another one I think that's been a success story, and most of you know about,
the West Nile in summer of 2002, CDS and us identified that the epidemic was
evolving, that there was asymptomatic viremia in patients, and issued an alert
to the transfusion centers, and within weeks, the first cases were detected.
Then
we worked with our partners and challenged ourselves in industry to develop and
implement screening. We had a workshop
to define pathways. We tried to provide
standards and shared samples, and guidances for donor deferral. And this was a very successful
approach. Two very capable companies
jumped in, used their platform technologies already being used for nucleic acid
screening for HIV, et cetera, and filed INDs, and now recently have filed
license applications. But the result
is, from 2003 on we were ready the next summer, and over a thousand infected
units of blood have been removed since then and not transfused. And I think this has been a model of both
inter-agency and public/private cooperation in getting out ahead of the curve.
Now
I will say again, when we first started getting excited about this, people said
why are you so excited about this?
Well, I was excited about it because I knew if it went the way it was
going, the next year we were going -- if the epidemic continued, we'd have a
major problem. And that if we didn't
get excited, we weren't going to get this accomplished by then. This typically is a process that takes years.
Now
because of these successes, the risks from transfusion are changing. So another thing in addition to always
revisiting our risk mitigation or our regulatory decisions is revisiting our
scientific agenda. And again, this
pertains to a couple of comments Mike Fitzpatrick made. But you could see here that the risk from things
like HIV all the way on the left are in the one in a million now, and now these
more mundane, less seemingly dread, but just as bad risks are more common. It's a rare problem, but mis-transfusion,
getting the wrong unit, classic medical error or sometimes lung injury, cardiac
injury, et cetera, bacterial contamination is a big one, and these are things
that we have to work on.
And
just as an example to face these changing risks - and again, I would say
industry was ahead of us on this one - was developing methods to try to detect
and work on bacterial contamination. I won't say ahead of us, but they took the
ball and moved it, and we had to scramble to find some regulatory ways of doing
this. But this is an example of a
win-win regulatory approach, where people were developing rapid methods to
detect bacterial contamination of blood.
This occurs mostly because when you take blood from a person and the
skin isn't sterile, although some patients are just infected. And we combined that with the need to have
platelets that last longer, something you heard alluded to. So in 1984, platelets had been allowed to be
used seven days after they were collected but there were a lot of disease
transmissions occurring and bacterial contamination. So the ability to have more rapid testing for bacterial
contamination, along with validated blood bags that have been shown to store
platelets and keep their functionality for a longer time period allowed us to,
in a sense, do what's almost a linked approval for use that will allow the
duration of blood storage to be increased of platelet storage, but maintain
product safety.
Okay. Now more to the analogies, more to the drug
situation or post-marketing surveillance.
It's not necessarily the same, but what happens to these products when
they're transfused? One thing we do
look at is the performance of the devices used in testing the blood. Are they performing the way the blood banks
expect them to? That is also a public
health issue. But for blood plasma and
the rest of transfusion, we have two major areas, biological product deviation
reporting, or BPDRs and required fatalacy and serious event reporting, and I'll
tell you a little bit about that.
Biological
product deviation reports are almost analogous to reports of manufacturing
problems. They are required, if it's a
deviation or event that could affect the safety, purity, or potency of the
product, they have to be reported within 45-days of the discovery. And there are similar provisions in our new
framework for human cells and tissues that I'll get to.
Why
do we do this? Well, this kind of can
serve as an early warning system for manufacturing problems. This could be as simple as they did bad
typing and released a unit that wasn't properly typed, to other things; such
as, we notice clumps of platelets in product.
There wasn't the amount of red cells that there's supposed to be. These things could indicate problems in a
blood bank or in the manufacturing. And
they could lead to serious investigations, and even recalls.
Surveillances
can be trended. If we normally see that
well, 3 percent of stuff has this problem, the hematocrit is below whatever,
and then we suddenly start seeing a change, it may tell us that some component
in the system is broken. For example,
in 2004, there were about 38,000 such reports; and again, like you heard for
the AERS, the medical AERS system, we've been able to make these electronically
reportable, which helps everyone, I think.
And we post these. So this helps
direct training, outreach, and guidance, so we can look at what are the
problems people are having, are they real problems, how can we prevent them?
Fatality
reports, this is inherently obvious. If
people die after a transfusion and it might be related, we really need to know
about it. And we do preliminary and
seven-day follow-up information on all blood-related fatalities, whether it's
believe caused or not. We may send
investigators to the site in many of these cases to be sure we're hearing the
events properly, particularly if there were any issues raised by the
reports. And again, this is data very
important to look at for trends and priorities. And I've just given you an example of what are the related
fatalities we see.
Non-fatal
adverse, serious adverse events are handled a little differently. They're reviewed during establishment
inspections at least every two years, but we have proposed a rule where they
would be required to be reported in real time to provide us more
information. So that's an example of
one of the enhancements we're talking about.
But as I said, we don't want to make it too burdensome either.
Current
priorities then are based on what I showed you, the changing epidemiology,
which only our surveillance can tell us; so donor mismatch, bacterial
contamination, TRALI which is a lung injury associated with transfusion, the
emerging infectious disease issues, and I think some very good kind of critical
path issues, areas where there's tremendous benefits that could occur, where
our scientific infrastructure or others are collaboration supported,
inactivation technologies, and particularly candidate tests and evaluation for
TSEs.
Now
I'll have to pick up the pace. Now on
vaccines, this is done as a safety group collaboration between the Office of
Vaccines, that's OVRR reviewers that exists already at the time of licensing
with the post-marketing surveillance group.
What are the studies that are needed, what should be the pharmico
vigilance plans?
The
adverse events come in through a system like AERS, called VAERS, Vaccine
Adverse Event Reporting Systems. It's
co-managed by FDA and CDC, so again we have a big partner here. It adds some resources, it adds some
complexity, but we work very well together with them on vaccine issues. Cases are reviewed, case series can be
constructed. This is electronic
reporting.
More
modern systems are being increasingly used.
That is a passive reporting system, but there's a lot of reports. Vaccine to safety data link is sort of like
Paul and Steve were describing with some of the healthcare database
systems. We can ask specific questions
in large managed care plans to look at hypotheses. None of these are yet at the point of providing real time active
surveillance data, but they're examples where people said although a vaccine
causes arthritis, measles causes autoimmune disease, vaccines cause diabetes,
and where controlled studies using these databases were able to examine those
issues and were negative. And there's
an ongoing study about thimerosal in neurodevelopment.
CDC
has the lead with the vaccine safety database but we worked closely with them
there. And CDC has clinical
immunization assessment centers, and we also have pilots with CMS and with
other healthcare databases on a variety of issues; for example, influenza
vaccine and Guillain-Barre syndrome.
We
review these reports. All licensed
vaccines are assigned to a specific reviewer in the Division of Epidemiology
Vaccine Safety Branch. Fifteen-day and
direct reports are forwarded by a contractor within a business day. They are reviewed daily for unexpected
events. They're followed up, if needed,
with the reporters, and there's a weekly meeting of this team to discuss the
events, and periodic summaries of safety information are constructed.
Qualitatively,
this is to look for, detect signals and unexpected adverse events. Of course, signals detected through this
kind of passive reporting almost always require confirmation through a
controlled study.
More
quantitative methods are applied to these databases, reporting rates versus
background rates. Data mining is now
being routinely applied to our VAERS system to identify events that appear to
be reported more commonly for one product than another, for example. And there have been some things
retrospectively, we could detect rotavirus into susception in this manner, and
prospectively, we've detected allergic reactions with the typhoid vaccine.
Of course, these don't account for a variety of
things, and medical judgment and follow-up is needed. And based on time, I'll leave the obvious alone there.
There
are some challenges here. Very low
incidence of most serious vaccine adverse events and very few unvaccinated
children to serve as controls. Poor
understanding - again, this is a recurrent theme from drugs, with the normal
population incidences of diseases - did something cause, is two cases of lupus
in a million vaccinated people out of line?
Reliance on passive surveillance.
And we do need resources and tools for more advanced approaches. And then in this area particularly,
political, cultural and communication issues.
Our
strengths are strong physician epidemiology staff. These inter-relations, the collaborations, and that we can still
use this passive surveillance to identify problems through careful review. We can do safety reviews of new vaccines,
and these are communicated to physicians in peer review journals, and we can do
focus reviews of special issues.
Here's
a famous example, rotavirus, nearly a million deaths in developing countries,
far fewer in the U.S. Pre-licensure
clinical trials show the vaccine was very effective. Ten thousand vaccinees, two out of eight thousand receiving the
vaccine, and one out of four thousand receiving placebo got this effect. It is not obviously statistically
significant; however, there was some concern about this. And when the vaccine was licensed, we
decided to include this in the label and require this to be evaluated in the
post-marketing period. There were studies
required for a variety of reasons, but then we also coded into the VAERS
system, intussusception as a specific term, so that if something happened, we
would be liable to detect it quickly.
And bingo, that's what happened in May, very soon afterwards, a VAERS
signal was detected. Six cases, went up
to nine, by July fifteen cases, eleven in the first week after vaccination.
Now
interestingly, if you looked at expected ratios based on known population
incidence, and here we had some reasonable estimates - this wasn't higher. In fact, it was lower. But we don't expect 100 percent reporting,
and so this raised a lot of concerns.
And to make a long story short, studies were set into motion, verified
that this was a probably a true signal, and within a very few months the
vaccine was first temporarily suspended as used, and then withdrawn.
Another
example of more pre-emptive action that I think is more related is related to a
safety concern, but also related to public confidence in vaccines, thimerosal
and mercurial preservative in multi-dose vials of vaccines. A review was undertaken because of growing
concerns about mercury as a neurotoxin, and this showed that some infants could
exceed some recommended exposure when there's no direct evidence of harm, but a
desire to reduce total mercury exposure. I mentioned the importance of
confidence in vaccines, but on the other hand, if we had suddenly said we could
not transition to a thimerosal-free vaccine supply overnight without causing
disruption of vaccine availability, and probably epidemics of transmissible
disease. So what was done is the PHS
got together, FDA contacted manufacturers stating that we had a goal to work
with them to reduce thimerosal in vaccines as a precautionary measure. We had a public workshop. We expedited approval of new formulations
without thimerosal, Institute of Medicine looked at this and concurred. And the accomplishment is now that all
current routinely recommended childhood vaccines are available in
thimerosal-free or reduced formulation.
The science has still largely continued to be negative about this, but
epidemiologic studies are ongoing.
Okay. Now to try to finish off with tissues, and
then some conclusions. IN fairness, to
give me a little time, and I was asked to cover three areas in one talk, but
the tissue safety - there's an increasing number and diversity of
procedures. People are shocked, I was
shocked when I came to CBER and figured this out, but there are now over a
million tissue transplants a year in the United States. These are not the sexy liver transplants,
these are tendons, muscle, skin for burns.
Some of these are elective processes, like plastic surgery, et cetera,
et cetera. But there were some cases of
serious infection transmission in the last few years. This led to a lot of attention, and a lot of people in our center
working with a lot of other people put together a new risk-based tissue safety
framework. This requires establishments
making these tissues to register and list with FDA. It requires comprehensive donor eligibility screening and
testing. These are usually cadaveric
donors similar in quality to what's done in the blood system. It was much more limited before. And a set of core good manufacturing
practices, called Good Tissue Practices, to try to assure that measures to
reduce contamination are in place in processing facilities. And gets us adverse event reports which you
can analyze, active surveillance is an alternate goal, and there's a lot of
training, et cetera, done with this.
Now
one of the things we had an opportunity to do here is to do business a little
differently and to say starting from the front of a safety system, how do you
visualize this? Now I have to say that
is also under some real resource constraints.
But we formed a team, saying we're not going to silo this into different
parts of the organization, compliance over here, communication over here, the
product experts over here, the epidemiologists over here. So we put them all together, this Alphabet
Soup, and formed a safety team, and they've developed operating procedures to
be sure we properly receive evaluated adverse reports, go out to the facilities
if we need to, have databases which everyone has access to and can contribute
to, and then liaison with our appropriate organizations; for example, CDS is
involved in laboratory testing and field investigation, and helps us interact
with the states, and there's many other components here.
Here's
an example we recently had a possible transmission of streptococcus through
tissue alografts. Sounded good, a lot of concerns; three recipients with knee
infections following transplants, all of the same bacteria, all from the same
tissue bank, got CDC involved, got the State Department of Health out there to
investigate, got our staff physician epidemiologist to make calls, get more
historical information, conducted a directed facility inspection, Department of
Health aided us on the epidemiologic investigation, CDC performed the cultures
of retained tissues from these donors from the original samples, all of which
were negative. And the epidemiologic
investigation showed other hypotheses for what could have happened. And this was all done very quickly within
days, and in this case was a negative study.
I
think based on time I'll try to just zip through this. There are strengths of this which are
obvious in what I just said, but there are also challenges. There's a lot of education and outreach to
do. There's a lot of issues about
workload. There's hundreds of new
establishments coming under at a time when our inspection resources are
challenged. We'd like for drugs and
other products to have more active surveillance. There is no reason that if we build an active surveillance system
for medical products, that something like tissues would not be captured well
under that.
This
is also an area which has been a little bit of an area not paid attention to by
medicine or medical science. And we
need to look at what's happening out there now that we're going to get all this
experience, and learn from it, and say are we doing this right? What are the scientific needs? Can we
sterilize tissues? All kinds of nice
things we could do here.
We're
doing a pilot with CDRH. Again, this
issue of when we have not enough resource - CDRH has an interesting active
surveillance system, very labor-intensive called MedSUN, where they have people
running around the hospital saying have you seen an adverse event from this or
that? And so they've agreed to work
with us and do one at several of their programs, I think actually at all of
them, to include tissue adverse events.
And this will help us a snapshot of what's going on with tissue
transplantation, and identify causes of problems.
Okay. So to conclude, assuring the safety of
vaccines, blood, and tissues, and I didn't get into our cell and gene therapy
area, provides for pretty unique scientific and public health challenges, but
there's also many common underlying principles and needs with the other medical
products. There's some differences and
some commonalities.
Stressing
some of the commonalities, we need automated methods to screen databases for
potential concerns. And as I said,
we're now doing that routinely with our passive vaccine adverse event reporting
system. We're doing the data mining,
but there's a lot more that could be done, and it could be done better. Increased availability and use of
computerized healthcare databases - this is the holy grail. It's really the healthcare system where much
of that challenge lies, and the tremendous amount of resources that it takes to
do that, and do it right, and my point before about infrastructure not only to
get the data, but to interpret it, we all discussed. It's a lot easier said than done, and I don't know why -- IT, why
does it cost -- you can buy a Dell computer for $400, but if you want anything
done in IT, how many more zeros do you have to put on that? I wonder about it. I often say I should get the kid who's calling me on the phone to
just write the programs, and we'll be done with it - pay him twenty bucks an
hour and he'll be very happy.
We
have new programs in science-based risk assessment, management, and
communication, as I said, to help inform policy and the public. We're implementing those, but again, that's
resource-intensive to train your people, and to keep training them is something
we need to keep doing to get the right outside connections.
We
need a better science base. That was
emphasized in one of the comments for product safety and quality, including all
the sciences, population, laboratory, manufacturing. And again, I look on this as not deficiency, necessarily, but
opportunity.
Our
current systems and organizational interactions I think have generally
functioned well in these areas, especially considering the terrible challenges
we face, but I'm not sanguine about that.
They could be better, and they are at or beyond capacity. Our people are working hard and burning the
candles. And we are also largely
operating on 20th century technologies. Now it's not because we're stupid, it's because those
technologies work. They work, they do
what they can, and there have been a lot of successes. But we need to be both doing what we do now,
and looking forward, and building the future.
Meanwhile,
the responsibilities and expectations are increasing; some very clear reasons -
new industries, novel products, high information and safety expectations. It's no longer enough to put information on
the shelf and not share it, or not pay attention to it. Demand for rapid access to promising
technologies - everybody wants those technologies.
One
of the comments from America's Blood Centers was about, for example, a
particular product. Well, so there's a
demand for access to new technologies.
On the other hand, we're here today because there's also a demand that
FDA make sure these things be safe and work, and we cannot forget that. I still
do view us as the gold standard globally for regulatory agencies, and we want
to keep it that way. So new approaches
are needed, and while such innovation is underway, they require serious
planning and long-term collaborative investments in multiple areas, the
science, the methods, the training, and the implementation.
So
I think FDA could play a constructive role.
It cannot do all of this, or even most of it in patient protection and
innovation. We need to have vigorous,
yet thoughtful and collaborative approaches.
They can help innovative products with the appropriate risk benefit ratios
come to market, and keep our public health measures particularly safe and
available.
I
think, as I've said, for products such as blood, vaccines, tissues, and cell
and gene therapies, expectations are high, but innovation is very sensitive to
both the risks and the costs, as I pointed out before. IT and modern biological and physical
sciences should be used to try to move this forward, and can be more efficient
if we make the right kind of investments.
They can also be hopelessly inefficient if we make the wrong kinds of
investments.
And
we need to develop best practices and tools, and share them across both the FDA
and with industry, and the public. And
throughout all this, I still think whenever I see a problem, FDA has very
complex product development, but I would say 90 percent of problems are
communication issues, and that occurs whether it's within our agency or outside
our agency. And that's a very important
part of the culture we need to keep building, so we'll try to keep Humpty-Dumpty
together. Thanks.
CHAIRMAN
SHINE: Thank you, Dr. Goodman.
Questions from the committee?
Dr. Thomas.
DR.
THOMAS: I've got a question. How much -- with the reemergence of zoonotic
diseases, how much research is being placed on them, whether it's at NIH or
elsewhere? You've had some interagency
cooperation, but I don't see new technologies such as tissue culture, for
example, in vaccine production. We're
still using the chicken egg.
DR.
GOODMAN: So are we. Yes, it's a very good question and a number
of -- I serve on a similar committee that you're on with the CDC, their Board
of Scientific Counselors of the National Center of Infectious Disease.
And
we have had sessions and we've also had sessions at the IOM in our forum on
emerging infections highlighting the link between human and animal health and
emerging infectious diseases. So I
think there's a lot more recognition than there was five years ago, but I don't
think there's the kind of integration that I would like to see or the kind of support
I would like to see.
I'm
a tremendous believer in the value of veterinary medicine. Steve's not there. He would be nodding -- in informing medicine, in general, but I
also think to monitor -- the pandemic flu threat is there's no more perfect
example of that. And I will say, NIH,
for example, is putting a lot of funding into surveillance of avian influenza
in Southeast Asia. So the short answer
is progress is being made, but this is way under-supported because again, there
aren't economic drivers in terms of the products.
CHAIRMAN
SHINE: DHS has established a center of
excellence in zoonotic diseases that involves --
DR.
GOODMAN: Excellent.
CHAIRMAN
SHINE: Have you been involved in that
activity at all? Do you have
interactions with DHS on such activities?
DR.
GOODMAN: I personally have not. I would hope that at least they made the
connect with CDC and USDA. FDA should
probably be involved. Something that
people often don't realize is actually the veterinary drugs are handled through
Steve Sundlof's center, the Center for Veterinary Medicine at FDA.
Veterinary
vaccines are regulated at USDA which is an interesting situation. But we -- so I don't -- I had not heard of
that committee. It's a good thing if
they have it, but I'll try to find out about FDA participation.
CHAIRMAN
SHINE: Other questions? We heard from Dr. Fitzpatrick two major
concerns. One was whether CBER has the
basic science expertise that it needs in order to do the investigations that
are required. And the second was that
some of the safety enhancements which he mentioned, PRISM, are unavailable
because of quote in his letter "insurmountable roadblocks at FDA."
Do
you have any comments about either of these in terms of your view of the
resources that you have and the necessity to deal with these issues?
DR.
GOODMAN: I think that supporting a
strong science infrastructure at FDA under our current resource situation is
extremely challenging. And we are all
doing what we can.
So
I would say I would love to be able to do a whole lot more. We do have to view that number one of our
responsibilities is the review and regulatory process and so we have to keep
that perspective. But myself as
somebody who was in a sense a clinician/scientist in academic medicine, I very
much believe in the model of having scientists and scientific expertise at FDA
and with involvement and interaction with the review process and I think the
critical path is an effort to help support that, but there are definitely
resource challenges.
Now
taking that at the same, I don't think FDA is the NIH or that we can have
expertise in-house in every conceivable subject and area. So to some extent, it is not negative to
collaborate, bring in and consult outside people, but there are certain areas
where our expertise or where no one else is going to drive it, or our
impartiality are essential and I think those are where the real opportunities
are.
CHAIRMAN
SHINE: So do you believe that there are
limitations on your basic science infrastructure that inhibits your capacity to
perform your function ensuring safety?
DR.
GOODMAN: I think that there are -- I
want to rephrase that a little bit, that there is a lot more things that one
could do to support our scientists and support the breadth of expertise, if we
were able.
On
the other hand, I feel that when we are confronted with issues where we do not
have -- there's two important components.
One, you don't have -- we're talking about very specific things here
like something about platelet function or something like that. And I'm saying in those instances, what's
really important is to know what expertise you need and be sure you avail
yourself of it.
And
frankly, even if we had the scientific expert or somebody who was viewed as an
expert in one particular area, I think even then we want to take their
knowledge and expertise and not say that's it, guys, that's all we're going to
hear. But again, we're going to reach
out and if it's an important decision and get other input. But that's a long answer, but yes, I do
think our resources in science are very strained. Our ability to support that is strained. But frankly, at the FDA now everybody is
working very hard. That's true of our
full-time reviewers as well. And I
think we're doing a good job at a very, very challenging set of issues that we
will never get perfect because one, it's impossible; and two, because one
person or another will not like the answer or decision that we make.
And
I want to back to the issue about the technology you asked about --
CHAIRMAN
SHINE: We're going to have to move on.
DR.
GOODMAN: Okay, but you did ask the
question about products.
CHAIRMAN
SHINE: Yes.
DR.
GOODMAN: And being held up and what I
would like to say is again, that was my earlier statement that our job is to
make sure before a product is licensed in this country that it is safe and
effective and can be manufactured and that's what's expected of us and we are
the only people doing that job.
And
I do want to say we meet with the blood industry extremely extensively. We have regular meetings with American
Association of Blood Banks. And in the
last two years, we've really increased those outreach measures
tremendously. We also are having our
Blood Products Advisory Committee review the priorities of -- in that area,
both scientifically and regulatorily, so we do seek the kind of input that I
know people want to give us.
CHAIRMAN
SHINE: I would emphasize a point that
you made and that is that much of the surveillance activity which is likely to
go on in drugs is applicable to biologics and devices and a variety of other
things and I hope that you continue to work closely together as in FDA as you
move forward with those experiments on reporting on the electronic health record,
whatever, to make sure that we maximize those signatures.
DR.
GOODMAN: No, absolutely, and we're
doing that with CDC in both the blood and vaccine areas too.
CHAIRMAN
SHINE: I think we better move on. Let's hear finally from Dr. Mary Malarkey
who is Director of the Office of Compliance and Biologics Quality.
DR.
MALARKEY: Good afternoon. I appreciate this opportunity to kind of
deviate from the subject matter somewhat this afternoon and concentrate really
on current good manufacturing practice, specifically for our vaccine
products. And I say deviate slightly
because certainly the safety of vaccines is affected by or the continued safety
of vaccines is affected by manufacturers' adherence to what we call good
manufacturing practice. And I'm just
doing vaccines, by the way.
So
in summary, I'd like to touch a little bit on what the rules are, that is, what
statutes and I say there are more than one here, and regulations that govern
the manufacture and review of manufacture of our vaccine products. And the unique challenges that we face with
vaccines. Blood and tissues do pose
challenges, but vaccines have challenges of their own.
I'd
also like to talk a little bit about the problems that we've observed in the
industry and I think you'll see that they're not unique to the vaccine industry
which is why the pharmaceutical GMPs for the 21st Century initiative that we
just completed the two-year assessment phase, I would say, is very applicable
to the vaccine industry and there are things that we had in place at CBER that
came out of the initiative for other pharmaceutical and animal drugs, but then
there were other things that came out that we think will help the vaccine
industry and we're interested in working with them going forward to see if there's
more guidance that we can provide.
There's
also no question that we've had some recent lessons. I think Dr. Galson mentioned this morning about the pendulum
swinging and the press and how things can change with public perception. In the compliance and enforcement area,
sometimes I think that pendulum is more like a metronome. On any given day, we can be told that we're
too hard on the industry, that we need to make products more available, that
we're inhibiting availability, but then on the very next day, we're told that
we're not being hard enough. so it is a
challenge and a delicate balance. So
we'll talk a little bit about these recent lessons and other initiatives.
Now
first of all, vaccines, of course, are biological products and they were the
first biological products that were recognized. They are defined in the Public Health Service Act under Section
351(i). However, vaccines are also drug
products and they are defined as drugs under the Federal Food, Drug, and
Cosmetic Act. So there are the two
statutes that govern -- well, actually the review of licensure manufacturer
vaccines. And vaccines, like other
biologics, are licensed products and they're licensed after submission, review
and that includes an inspection and approval of a biologics license application
and you've heard BLA mentioned this morning and that's where that comes
from. It's actually a Public Health
Service Act application as opposed to a Federal Food, Drug and Cosmetic Act
application.
So
technically speaking, vaccines are licensed biological drugs. And like other pharmaceutical drugs, they
are investigated with the same, under the same IND provisions, that is, parts
312 and 50 and preparation of vaccine products, like human and animal drugs are
regulated under the GMP regulations that we're all familiar with under 21 CFR
Parts 210 and 211. And of course, these
are the drug GMPs and these are the ones that were subject to our two-year
initiative.
Now
we also have additional standards for vaccines. These are, of course, the licensing standards and other testing
and biological standards that are contained in Parts 600 to 680.
Okay,
that's enough of the regulations themselves, but I think it is important to
note what vaccines are and again, they are drug products, but they are unique
in that they're licensed and they are held to other standards. They're also unique challenges, I think for
both FDA and the industry, with respect to vaccines. I won't get into the economic challenges and they are there.
There
is certainly the supply and demand and supply is a function of demand and it's
often a problem. But getting to the
unique challenges that we face in our regulation of vaccines, unlike a
substantial number of injectable pharmaceuticals, vaccines are administered to
a large population of patients that are most often young and healthy. In fact, they're mostly babies. Most vaccines are, of course, childhood
vaccines. An exception, of course, is
flu vaccine, which of course, the elderly would be considered the high risk
population, although younger people are as well. However, by and large, these are given to young and healthy
people.
The
starting materials themselves may have inherent problems, such as inherent
bioburden, that is, certain number of microorganisms that would be expected to
come in with the starting material.
These egg-based vaccines which were mentioned quite recently are one of
those types of vaccines that would be subject to problems with bioburden.
Some
vaccines are infectious until they're inactivated, so their manufacture can be
a tricky operation. And examples of
these are many of our bacterial vaccines.
This
is, I think, a very important point.
From beginning to end, the manufacturing process, that is, to get one
lot of vaccine product, can take several months, up to a year, so if something
goes wrong along the way, you can well imagine what the impact would be. We're talking here about delays or potential
shortages and for those reasons I'll get to later, it is very, very important
for adherence to certain standards and controls. And of course, in some cases, given that these are very old
products, many were licensed before we had modern thinking, modern standard,
even our GMP regulations. So that's a
challenge.
As
with other biological products that we regulate, these products must be
processed from beginning to end and again, we're talking about up to a year
process now, under very defined conditions and controls. Now this is an absolute must consistently
produce a safe, pure and potent product and again to preclude the introduction
of environmental contamination because these products are protein-based. They are a nice growth media for a number of
adventitious agents.
And
also because of that fact, they cannot withstand heat sterilization without
affecting product quality. This means
we can't cook them at the end. We can't
sterilize them at the end in such a way to really ensure their sterility. This is why these controls along the way are
so very, very important. They must be
aseptically processed and I'll get back to that in a second for those of you
who weren't familiar with that, but it is a different thing than terminal
sterilization and it does provide a level of assurance of sterility, but
certainly not the level that one could attain by terminal sterilization.
Now
some of the controls that we're talking about here and this is just an example
of the types of things that we are looking for and that we are looking for more
and more over let's say the last five or 10 years. Bioburden testing, that is testing of the product at various
points throughout the manufacturing process to show what the levels are. There are certain steps in a process that
should make the levels go down, for example, and there are other steps that you
might see a concentration effect, but that should be consistent and at the end,
you should be able to get rid of obviously the bioburden.
Segregation
of pre- and post-inactivation steps, this is to ensure that once activated,
you're not going to have live infectious material within the product.
Cleaning
of facilities and equipment using procedures shown to be effective for both
removal of product residue as well as again that microbiological or what we
call bioburden.
And
finally, monitoring the manufacturing environment itself to continuously assess
conditions. So all these things are GMP
controls that are put into place during the manufacture of the vaccine and all
these things should be in place in order to help ensure safety.
Getting
back to aseptic processing, what it basically is that product is filter
sterilized at some point during the manufacturing process. And basically, after that point that is the
point of sterilization. So everything
that goes after that must be very, very carefully controlled and for vaccines,
this may be very early in the manufacturing process.
Once
conjugated to an adjuvant, which is often an aluminum compound, sterile
filtration is no longer possible because it would actually remove the product, so
again, you have often this filter sterilization step early on and from that
point, subsequent steps must be carefully controlled to ensure the safety of
the product or to preclude the introduction of contaminants. And this is a tricky matter and there are a
lot of drug products that are produced in this fashion as well, but again, this
makes it much more important for us to be concerned about controls.
Certainly,
all materials that contact the product after the step must be sterile and
there's careful adherence to aseptic technique and practice by personnel and
believe me, people are unpredictable and I think it's very true what they say
that they can be one of the main causes of contamination of products in some
cases.
Now
what problems have we seen in the industry?
Well, I think they very much mirror what I just went over which are the
things that are important to have in place.
Often we haven't seen defined conditions or controls and this is often
for the older products. Now if you only
test a product to point A and then again at point Z, and you fail at point Z,
and you have no data points to look at between A and Z, you're in trouble. You don't know what happened and if that
happens a year into your process, then you're in really big trouble. So it is important again to have these
procedures in place and to be able to investigate if there is a problem.
We
have seen issues with segregation of pre- and post-inactivation steps. That could be a serious safety concern. And we have actually seen cross
contamination, either contamination from the facility or from the equipment as
a result of poor cleaning practices. So
that is a real concern. It's not just
something that we're saying is a good idea.
We've
seen environmental monitoring data collected vigorously, but not really looked
at, that is, it's not evaluated and we particularly have seen where the actual
organisms is in the product as well, and yet there's no connection made.
And
finally, inadequacies in the aseptic processing that I spoke about, the
validation of such processes must simulate all the steps that are involved and
basically what happens is media of bacterial growth media is substituted for
the product, it's taken through all the steps and incubated and if it froze,
that's a bad sign. But obviously,
that's got to mimic the manufacturing process.
And then again, poor aseptic technique by operators are often observed
during operations.
Now
many of these observed problems, the bottom line here is we're talking about
what we call quality systems. And
these, as I said, are not atypical.
These are the same problems that we see in the pharmaceutical industry
as a whole. And we talked a lot about
these problems during the two-year GMP Initiative. As part of the steering committee, I can assure you that was a
very, very big point that was made.
And
the key points to a quality system and this is just two key points, but I think
very, very important ones and ones that we see over and over again in our
consent decrees, for example, are management involvement. Management is not involved at all levels and
is not responsible and what happens is when problems occur, no one hears about
them and they just continue to occur.
Often
we don't see adequate systems for identifying problems and correcting them to
prevent their recurrence and it's very much like a snowball effect. If you don't find out why a problem occurred
and correct it, then it's going to come back and it's going to come back bigger
and that has been seen time and time again.
Also,
one of the key points of a quality system is to have a system proactively
identifying trends to prevent problems from occurring in the first place and
these things, again, this is not just related to vaccines, but across the
industry we've seen this as an issue.
And
again, we talked about this for two years and I think we're going to be talking
about it for a while longer in terms of implementation. I did want to point out that CBER was a
member. I believe that the Board here
has heard before of the Pharmaceutical GMP Initiative for the 21st Century, a
risk-based approach. We were involved
in that initiative. I want to point out
that it wasn't just a risk-based, but a science-based initiative and for those
of you who may be scholars or become scholars of the GMPs, if you read them
carefully, you'll see that they really are science-based. But they need to be updated like everything
else.
Now
we had many working groups that came out of the GMP initiative and I have to be
honest that for some of our procedures already in place at CBER, we had these
things and we were happy to inform the other centers and ORA of our procedures
and we'll continue to do so and we will continue to be a member of the Council
on Pharmaceutical Quality which is now the body charged with going forward with
implementation of what came out of the two-year initiative.
What
was already in place at CBER? Well,
we've had an integrated review and inspection process for some time. What this means is our Biological License
Application Review Committee consists of members, in this case, from our Office
of Vaccines, but also from our Division of Manufacturing and Product Quality
and my Office of Compliance, members from the Office of Biostatistics and
Epidemiology and other CBER components as needed. And we've also had consult reviews, of course, from our other
centers, depending on the product type.
Now
these same components participate in all the meetings that are held with the
regulated industry from the pre-IND stage to after the BLA is approved. And we provide advice and guidance on all
aspects, CMC facility, GMP compliance, in addition to the clinical aspects of
an IND.
We
perform what we call pre-license inspections as opposed to pre-approval
inspections, because under the Public Health Service Act, when a product is
approved, a license is issued. And
again, we perform these inspections with a CBER lead. That is, we have again, the DMPQ lead inspector. We have a product reviewer or scientist that
accompanies us on the inspection and actually looks at the manufacturing
process and the data that come from the process and we invite always the Office
of Regulatory Affairs to participate and welcome their participation when they
can.
We
also resolve issues prior to the approval of the application and that's a
somewhat different paradigm than is seen elsewhere and I have to say that we
have a very small inventory of products compared to our sister centers, so we
are able to, I think, do this, but again, some of these principles have been
adopted under the Pharmaceutical GMP Initiative. One is the pharmaceutical inspectorate and the other is having
the product specialists participate during the pre-approval inspections.
We
have the same paradigm here for our pre-approval inspections for supplements,
so for example, new facilities or renovated facilities. And I think most people have heard of the
Team Biologics Program which was established in 1997 and again the
pharmaceutical inspectorate in many ways will be similar to this team.
They
began our vaccine post-approval inspections in 1999. They are a highly specialized team of ORA investigators and we
find that particularly in the area of vaccine production which is so complex,
having the product specialists and scientists available during these
inspections is absolutely essential.
The knowledge base is there and it's just really been helpful in
conducting these inspections.
Now
as with any other program we recognize improvements must be made. We've done an evaluation and we're putting
many such improvements in place. We are
implementing a quality system internally which is always a good thing. We expect that of industry. We should have one ourselves. And this will ensure continuous feedback to
the investigations and compliance officers.
And
then we've established regular communications between investigators and the
product specialists outside of inspections, that is, we have a monthly call and
we have other training programs so that there's a continuous training process
in place.
It's
also important to note that all Team Biologics findings are reviewed back at
CBER. We don't do an exhaustive review
of each and every one, but we do look at the findings and the reports. If there is an action that is recommended,
on the other hand, we do a complete evidentiary as well as a scientific review
and of course, if we agree, we send it to our Office of General Counsel as with
all of our warning letters and actions today for their review. So any action that is taken against the
industry, whether it's vaccines, blood, tissue and otherwise, has levels of
review before such action is taken. So
everything is weighed.
Now
again, getting back to the quality systems, we recognize this as a big issue in
the GMP Steering Committee and we had several work products that came out. Again, I wont mention one which are more the
internal quality systems, but an extremely important one. And I guess one could say it would impact on
the vaccine and all of our industries for us to have a quality system in place,
but I won't go there.
Specific
to impacting on the industry themselves were two particular documents that are
in your briefing packet that you may be familiar with at least one of them and
one is the final Guidance Document on Sterile Drug Products Produced by Aseptic
Processing. And again, given that
vaccines are all aseptically processed and often aseptically processed from
early in the manufacturing process, this document actually has recommendations
for manufacturers, even those that start this early on.
And
then the Draft Guidance for Industry on Quality Systems Approaches to
Pharmaceutical GMP provides the Agency's current thinking on these quality
system principles that I mentioned, and right now, the working group is still
working and reviewing comments to the docket.
And we intend to issue a final guidance and actually use the comments
that we get from the industry to inform us on other parts of the initiative.
And
one of those that's near and dear to my heart is we actually -- this was the
GMP Harmonization Analysis Working Group.
I have been honored being co-chair and we were charged with actually
formally analyzing Parts 210 and 211 against a variety of other regulations
including the EU GMPs, the pharmaceutical inspector cooperation scheme GMPs and
other GMP regulations across the Agency.
The intent here, of course, was to highlight the differences of the
various regulations and report back possible recommendations to the steering
committee for modifications to our GMPs which I will add, have been in place
since 1978. So it's certainly high time
to take a look and see what we can do.
Now
we had involvement across the board here and my co-chair was actually Kim
Trautman from the Center for Devices.
So all the centers were involved and our Office of Combination Products
and Office of Regulatory Affairs were as well.
And this project took about a year.
It was really a very large project where we can compare the drug GMPs to
the food GMPs, what is called HACCP, which is Hazard Analysis Critical Control
Points. The device GMPs were the
quality system regulations and Type A medicated articles, as well as, of course
the EU GMPs.
Now
after this analysis, what did we conclude?
Well, the good news is there really are more similarities than
differences between the various regulations.
Differences were often commodity-related. It's not a surprise, certainly, for example, sanitation and
personnel practices in the food area would be an expectation. We presented our final results to the
steering committee in June 2004 and some next steps were decided on by the
steering committee. And basically, we
agree that modifications to the drug GMPs and Parts 210 and 211 will be undertaken
using an incremental approach. And
we'll continue pursuit of international harmonization through the ICH and PIC/S
processes.
What
are our goals? We need to know why we
want to do these modifications because they will take some time, I have to be
honest. I think that point was made
earlier by Dr. Woodcock, maybe five years.
To encourage timely detection and response to emerging defects or
indications that product quality has been compromised. It's important to note that there are many
of these principles in our GMPs today, but there does need to be, I would say,
a beefing up or a modernization of those concepts. And we also need to provide further clarity in addition to this
modernization.
We
also, of course, would like to harmonize various aspects of the drug GMPs, both
internationally and with other agency regulations as much as possible.
And
on the note of harmonization, in September, we also announced that we will
apply to this pharmaceutical inspection cooperation scheme and for those of you
who aren't familiar with this, it is an interesting organization and that its
membership consists of inspectors and investigators from around the world,
unlike ICH which is an industry and regulator-based organization. This is only regulators and specifically
investigators. So it's a very good
opportunity for us to discuss approaches, to obtain information, exchange
information and to harmonize where possible.
And
we've been active in this organization for a number of years in the blood area,
so we would love to see this expand to vaccines, because we think this would be
important and perhaps even to tissues down the road.
Getting
to those painful recently lessons, frankly, it has been a difficult year in the
vaccine area and particularly in the flu vaccine area. Now typically, we're able to have
inspections of our biological drug manufacturers performed every two years and
this is in keeping with our statutory requirement and again, we are fortunate
here, but we have a very small inventory that allows this to be accomplished.
However,
given the importance of these products and the complexity, starting this year
for influenza vaccine manufacturers, we began annual inspections. Now keep in mind that the influenza vaccine
really is a new product every year.
There's always some change in strain in the three strains that go into
the vaccine. So it's a particular
challenge and there can be great variation in growth characteristics and
potency, so it's always a surprise every year and there are often issues.
We
are also actively analyzing other manufacturers to consider increased coverage,
particularly of medically-necessary products and products that may be produced
offshore.
Another
lesson that we learned is the importance of partnering with foreign regulators,
our foreign regulatory counterparts and sharing of information. Certainly, the Chiron experience drove that
home.
After
that, we were able to establish an agreement with Chiron and with the British
Medicines and Healthcare Products Regulatory Agency, MHRA, that allowed sharing
specifically in the Chiron case, so we were allowed for exchange of
information. Well, that was very good,
but what's much better is that in February we signed, we and MHRA, signed a
general formal confidentiality agreement that will allow sharing in all cases
going forward. So this is a very
important milestone.
We
also have agreements in place with other regulatory counterparts in countries
where vaccines are or may be manufactured for U.S. use in the future. An example of this would be Health Canada or
the EMEA. And we are actively pursuing
other agreements to facilitate sharing of information, specifically on vaccines
now, but I'm sure that will branch out to other product areas as well.
And
finally, outreach to the vaccine industry.
And this is something that we have been doing, but obviously, we feel we
need to do more, both pre- and post-approval.
We have been in discussion with the industry with some representatives
of a possible workshop or a roundtable approach, maybe more regular scheduled meetings that we
would have with the industry. We're
very interested to know what they think of the guidance documents that have
come out under the initiative and whether they feel that the Agency can provide
additional guidance in this area.
We have planned some sessions specifically
on vaccines at several conferences that are going to be coming up this year and
in the next fiscal year. Some examples
of that are the annual GMP by the Sea which is in August of 2005 and then we
have a European conference planned on vaccines in the next fiscal year which
October technically is.
Also
meeting with the individual manufacturers, again, we've been doing this, but
this become even more and more important.
We want to discuss new technologies and other changes, increasing
capacity is always an issue here, particularly with thoughts of a pandemic, for
example. And manufacturing control
could always be increased through these new technologies as well.
We
also are happy to provide advice on potential pathways to approval and to
facilitate approval of new vaccines whenever possible. Again, we don't have a lot of suppliers here
so this is something that we're very interested in.
So
in conclusion, just like other drug products, manufacturers of vaccines are
required to follow what we would all call the drug GMP regulations. However, we feel that vaccines pose a unique
challenge both to the FDA and the industry.
I think we've issued some useful guidance that will help the vaccine
industry, but certainly we're interested in doing more, if we can.
After
the lessons of the last year our approach to regulation has been reviewed
carefully and modified somewhat based on these lessons, for example, the
increased inspections. And partnering
with our foreign regulatory counterparts I think is key, not only really in
this industry, but we have such a global industry today with so many of our
products that this becomes increasingly important and increased outreach is
always important to the vaccine industry.
We want to increase communication and we want to facilitate improvements
and approvals of new products.
So
I thank you very much and I'd be happy to answer any questions in this
particular area.
CHAIRMAN
SHINE: Thank you, Ms. Malarkey. Questions from members of the Committee?
Yes,
Dr. Harlander?
DR.
HARLANDER: Will the IOM study be
focused on vaccines as well as on drugs, in general?
DR.
MALARKEY: My understanding of the
current study is no, it will not be focused on vaccines, but I think anything
that we can learn from the study, as Dr. Goodman indicated, we would certainly
be interested in pursuing avenues.
CHAIRMAN
SHINE: Yes, Dr. Swanson?
DR.
SWANSON: With regard to quality
systems, you mentioned that management commitment and identification of
corrective action are critical parts of that.
I wholeheartedly agree, having worked in HACCP systems for many years.
But
I found that emphasis of internal, on-going verification is also essential to
make sure that the critical elements are done on an on-going basis. Is that included as well?
DR.
MALARKEY: That is included. That is included, absolutely. I agree.
It's the same thing with having the best procedures in place, but if
people don't follow them and you don't verify, yes, that is certainly a
cornerstone of a quality system.
CHAIRMAN
SHINE: Help me to understand one
conceptual issue. My understanding is
that in the area of pharmaceuticals, the FDA undertook a rather extensive
iterative activity in collaboration with industry to agree on good
manufacturing process or procedures.
And in fact, I think a year or so ago we had a report on that activity
about which both industry and the FDA seem to be optimistic.
I
may be missing it, but I don't see the same kind of iterative interactive
approach to manufacturing processes in vaccines that occurred in the same way
that they occurred with pharmaceuticals.
A, am I wrong and if not, why not?
DR.
MALARKEY: Well, I won't say you're
wrong. I think it's a confusion which
is one of the reasons I brought up the initiative that you're speaking of which
was the two-year pharmaceutical GMP initiative. Vaccines, in fact, were part of that initiative and the vaccine
manufacturers did participate in terms of the iterative process, certainly one
of the public meetings that we had downtown, there were vaccine manufacturers
that were represented. And as I said,
since CBER was involved, we reached out to our manufacturers in regard to this.
We
certainly received comments to the docket from a variety of the industry, but
the GMPs are the same, so vaccines were actually part of this.
CHAIRMAN
SHINE: And the industry, if you will,
concurred with, agreed with the practices that emanated from that study, from
that activity, so it did have, in fact, a parallel with the drug manufacturers?
DR.
MALARKEY: That is correct. And we have had very positive feedback from
industry as a whole. I think everyone
has the concept of quality systems and believes in the concept of quality
systems. The implementation is really
the hard part. I think in many of the
pharmaceutical industries, including vaccines, there has been a siloing effect
through the years. You've had
departments that -- I'm talking about within a manufacturing facility, you have
departments that aren't speaking to one another or you don't have management
communicating down and the operators communicating up. And that is really a big issue that needs to
be dealt with with the industry as a whole.
Once that's in place, we think quality systems will move fairly
smoothly.
CHAIRMAN
SHINE: One of the big -- there was a
lot of criticism, the Team Biologics approach, because of a concern that
industry had not, in fact, either had enough advance understanding of where you
were going or concurred in the directions.
Do you feel that since the GMP process that you've recently undertaken
has developed, that there's a pretty good understanding as to what the
expectations are and what they can look forward to in terms of inspections?
DR.
MALARKEY: Yes. I think again the Team Biologics began the
vaccine inspections in 1999, so now there are six years of experience and we
recognized several years into the program that we needed to really look at it
critically and we did. This is two
separate things. We have the GMP
initiative and then we have the Team Biologics program which is already in
place.
CHAIRMAN
SHINE: Yes.
DR.
MALARKEY: So we did a very extensive
evaluation and we recognized that improvements were needed and I believe we've
done quite a bit of outreach to the industry.
We've had public meetings on Team Biologics with the industry and
specifically the biologics industry, of course, so I think people are
understanding and I think the inclusion of the product specialists are really
making sure that they participate, whether it's on site or being available by
phone has helped as well as the continuous training and the communication
between the investigators and the product specialists.
But
we always are improving the program.
It's not something that we stop doing.
We always are looking to improve.
CHAIRMAN
SHINE: This may not be the perfect
question for you, personally, but I'd be interested in anyone commenting.
This
country lacks a national vaccine policy.
We have serious difficulties in this country with how and in what we
we're going to ensure the delivery of all the vaccines we need including ones
which you're not going to make a profit on, it's very large and as you know
from your own experience, we are dependent on single manufacturers for a number
of vaccines. If those production
facilities go down, we don't have those vaccines and so forth.
What
role, if any, do you see the FDA playing in terms of its experience being
reflected in the necessity to effect, move towards some kind of national
vaccine policy?
DR.
MALARKEY: Jesse?
DR.
GOODMAN: Well, I mean I feel very
passionately about vaccines and the need to strengthen and diversity this very
fragile infrastructure in our country and I view events in recent years
including the flu this year as what I describe as teachable moments and so I
think one of the things FDA can do is working with our partners and HHS and the
Congress, etcetera, is essentially try to facilitate strengthening our ability
in this country to produce needed public health products.
I
do agree that a high level strategy is needed.
Now it's important to realize that and I said this in Congress, that the
main drivers are the market forces and the demand for the vaccine. And there are some positive things
there. Actually, Chiron, one of the
issues for them was having an old manufacturing facility and they had actually
made a choice that they were planning to build a new manufacturing
facility. So they have decided to
invest in influenza manufacturing and we had already been in discussions with
other manufacturers, some foreign manufacturers, also interested in entering
the U.S. market, so I think in recent years, in part, because of increasing
recognition of the public health benefits, the flu vaccine and increasing
demand and use of the vaccine, we're starting to see something positive.
The
other positive thing that's happened is the incredible potential of vaccines
for these next generation of diseases.
While people, as I said, may not pay attention to measles any more and
view that as a commodity, the potential with at least two different major
companies developing vaccines likely to be affected in preventing cervical
cancer.
The
childhood pneumococcal vaccine which is the first billion dollar vaccine
product, it's still minuscule compared to the drug market and the investment is
minuscule compared to the public health benefit and importance, but I'm in the
position of trying to really push to support this infrastructure while at the
same time not being
-- you know, being somewhat a little more
positive and again, I think you've seen publicly in the post-flu vaccine thing,
you know that we have had at least two companies, one American, one Canadian
state that they intend to enter the U.S. flu -- from the FDA point of view,
what I view our job is is to help inform the policy makers in these areas and
then be a facilitator, you know, and we've done that by coming up with a
pathway using accelerated approval for flu vaccines and we do this by very
intense interactions with the manufacturer.
Now
we still have to do our job. We
sometimes have to tell people things they may not like, but what I've told
people is feel free to disagree and discuss them with us and I think we've had
very constructive forward-looking relationships, but that's the FDA piece, but
I completely agree with you and I'd also like to say that it's not limited to
vaccines. Look at drug products whether
or not big market forces. We have had
shortages of penicillin, streptomycin.
We don't have a lot of investment in new antibiotics.
Again,
I'm seeing some positive trends, but as a society, the society benefits from
these products that prevent and treat infectious diseases and yet our societal
investment and the market investment is not commensurate with that benefit. There's a disconnect between the benefit and
the market.
CHAIRMAN
SHINE: Thanks, Dr. Goodman. My question is not totally idle. I'm thinking very seriously that the Science
Board ought to draw on FDA's experience in these issues, some of the insights
that can be gained from these issues in terms of, in fact, communications
through the Commission with regard to some of the issues that have to be
resolved to deal with problems of vaccines.
And I think FDA, because of its experience and I think Ms. Malarkey made
it very clear, the manufacturer of vaccines is a different kettle of fish than
making pills and that that means there have to be some serious considerations
to the way in which we create the incentives of people to want to do that.
So
this is something I hope we're going to come back to as a Science Board,
because I think that it's a national problem for which FDA just has an enormous
amount of insight and not necessarily that they're going to solve the problem.
Yes,
Alan?
DR.
ROSES: I think if we're going to go off
into that direction, I think we should.
And at the time that's brought before the Science Board, we also ought
to have industry representatives --
CHAIRMAN
SHINE: Absolutely --
DR.
ROSES: Talk about the issues for that.
CHAIRMAN
SHINE: Absolutely.
DR.
ROSES: I just have one question that's
been bothering me months ago, but it came up while you were talking. So Chiron went down. We did a quick count and found out that we
had about four or five million extra doses available and I -- what was the
barrier between taking a vaccine that was available on 61 other markets in the
world which was the GSK form of flu vaccine and just bringing it in in a time
of emergency?
DR.
GOODMAN: Well, you know, we can have a
very long conversation about that and some of that would involve perhaps your
own commercial confidential information.
What
I would say is that, in fact, we were already working with GSK to do that and
to help achieve U.S. licensure and as you know, GSK has said that they think
they can provide the data to do that this year. So that's pretty fast.
And we did recognize that one of the first things we did and I have to
give Secretary Thompson and others credit, is we said let's do anything we can
to get additional vaccine in case there is a major flu epidemic and we need it
and GSK and other companies were extremely cooperative in identifying vaccine
that had been evaluated by other regulatory authorities that might be available
in the market and in fact, we conducted this very rapid evaluation of the
manufacturing facilities, data master files.
We had people working day and night and weekends and the firms also were
extremely cooperative and traveling all around the world.
And
within a couple of weeks performed an assessment on that and basically decided
that -- and gave input to the Secretary's Office, we decided to go ahead and
create contingency plans to bring that vaccine here, albeit under IND.
But
again, our regulations require a certain standard of demonstration of safety
effectiveness and manufacturing quality which some vaccines licensed in other
countries can meet, some may not and part of the purpose of the kind of efforts
that Mary describe to harmonize also the inspection on regulatory processes
would put us in a much better position to do that and in fact, I was
contributing to a WHO meeting where we talked about trying to produce more
global harmonization in regulation of flu vaccines for pandemic purposes. It's a perfectly good question and I think
we've accomplished a lot in that area.
CHAIRMAN
SHINE: Thank you very much. Thank you, Ms. Malarkey.
For
the remaining members of the panel, we do have a couple of other questions
we've been asked for advice about and I would like to get any comments that you
have before we sort of wrap up.
We
were asked about additional sources of useful data that might help with
post-marketing surveillance. We've
touched a little bit on that in our earlier discussion. But we were also asked, given that FDA has
limited resources, in what areas should the Agency focus those resources to
most effectively assure drug safety?
I
wondered whether the panel has any advice with regard to either of those
questions.
John,
any thoughts?
DR.
THOMAS: Certainly incorporating new
technologies into the various centers and we've heard some of that yesterday
seems to be what I will call a generic enough issue that should get concern and
support by most of the centers, I would think because there's some, what I'll
call woefully inadequate technologies that are used in certain centers and I
think generally if some R & D monies were put into method and analytic
developments it would certainly be -- it would seem to me almost across the
board type of benefit and it relates to R & D.
But
then you get into the argument should FDA be doing R & D or should NIH be
doing some of these things or should it be done by industry. The answer is probably all of them, but if
no one has the incentive to take the lead, why oftentimes it gets overlooked.
CHAIRMAN
SHINE: Thank you. Dr. Swanson, thoughts?
DR.
SWANSON: I think that some of the
presentations that we heard today related to the guidance, the attempt to
further standardize what you're doing, improve communications electronically
will reap all kinds of benefits in efficiencies of work force that might help
to find internal resources that are already there. Systematic approaches sometimes can be viewed as bureaucratic and
they can, if you let the system run the people, but if the people are looking
at the systems that are developed, tweak them to make sure you maximize the
efficiencies, I think that some of the steps they're taking are very worthwhile
and can help in providing the resources to look at drug safety.
CHAIRMAN
SHINE: Dr. Harlander?
DR.
HARLANDER: I heard a little today and I
think there can be some exciting opportunities in public/private
partnerships. I know that you mentioned
that a lot of folks have come forward.
I think to accelerate those and to tap into any kind of private industry
academic involvement with the Agency, to be able to tap into data, to do data
mining. I mean it looks like you're
sitting on tons of wonderful information that engaging some academic institutions
or even if there's some anonymous ways that industry can do data mining because
they're pretty good at that too and I know there's lots of challenges around
that, but I think there's huge opportunity there to leverage the limited
resources you have within FDA, with private companies that I think you know, my
experience was highly ethical and want to do the right things in this area.
CHAIRMAN
SHINE: Thank you. Dr. Roses, thoughts?
DR.
ROSES: Yes. When there's big problems I think the best way to try to approach
them is at the pilot stage. Trying to
start off with an IT system, rather than a bioinformatic systems, top down
system that already can do everything doesn't exist. And so -- I had this conversation with Dr. Lightfoot yesterday or
the day before yesterday about training of people and how to get them
trained. But I think the best way to do
an industrial academic regulatory collaboration is actually to have the people
doing the work together in the labs together.
Some of the things that require big laboratories of new technology are
just not going to be available here, but they are available elsewhere and
people learn how to use those. I think,
in particular projects.
And
I've suggested a couple at the other end of the -- Larry Lesko, et al., but it
would be very useful and wonderful if, in fact, in going ahead with some of the
risk-management plans that we can go ahead with on our own, but it would be
very, very useful and helpful if we had the positive collaboration in the planning
and how we are going to look at some of those data.
One
part of industry that I know of is amenable to it.
CHAIRMAN
SHINE: We heard in the public sessions
the argument that there should be routine -- that FDA should routine require
post-market surveillance of approved drugs including the special emphasis on
those that are likely to be widely used and/or likely to have large off-label
uses and we specifically heard a suggestion that FDA should seek authority, so
called Phase 4 studies, I'm curious as to the Committee's reaction to those
recommendations in terms of your view of those?
Dr.
Roses?
DR.
ROSES: Well, I have actually published
a view of this. It's a personal view,
but I did publish it. I really think
that all drugs should have post-marketing surveillance, but I think there has
to be an inefficient surveillance system that allows for the accurate
collection of data with some defined inputs by the people in the health care
sector that use these drugs.
A
lot of the managed care companies in large payer kind of group medicine have
placed some of these systems into the way they practice medicine. I think if
we're going to be in the position to develop predictors, that we ought to at
least have the track record of what we collect to be accurate information and
the first thing that I hope the Institute of Medicine really pays attention to
is what goes in, what data comes in and how we can get it in real time.
CHAIRMAN
SHINE: thank you. Other comments?
Well,
let me just make some comments and then you can shoot them down.
First
of all, in the overall area of safety we have had a good report of the Agency's
response with their five-part plan in terms of the IOM study, the Safety Board,
getting ahead of the Safety Unit, improving the method for adjudicating
internal disagreements with regard to the science and the importance of
outreach of information regarding safety.
I
think the committee, from our discussions last time and this time, concur with
the notion that these were very useful and important steps.
I
would suggest, however, that the IOM Committee be asked to look at vaccine and
nonpharmaceutical safety. It seems to
me that if they're going to look at how and in what way we want a safe system,
while I recognize the precipitating factor was drugs, to not take a holistic
view of this, in my opinion, is not taking advantage of an opportunity and if
it was possible, I would like to see that as a broader study.
Secondly,
I already made reference to the fact that I believe the concept of the Safety
Board within the Agency is a wise and judicious one. I would emphasize that no matter how efficiently and effectively
it works, it is, in my view and in the Agency's best interest to have some
mechanism by which some oversight, not of the operations, but of the overall
policies and activities are carried out by either committee or an independent
committee or a subcommittee, this committee, or some other mechanism such that
individuals who are in no way connected with the drug approval process, but who
can, in fact, understand the issues associated with safety and their impact,
can on some kind of regular basis, report not to the Director of CBER, but to
the Commissioner in a public statement that they are comfortable that the process
is moving forward in a manner that is consistent with the public interest and I
know all the arguments about you've got to have experts do all this stuff and
so forth.
People
who know all the ins and outs of the FDA, our regulation and so forth, I believe
that some highly responsible individuals with proper perspectives and
backgrounds would give enormous credibility to the process if they're included.
John,
are you going to --
DR.
THOMAS: Yes. I was just going to say the Consumer Product Protection Agency
letter was very thoughtful and one of the issues was looking towards an
independent Safety Review Board, probably legally speaking and I'm not a
lawyer, that's not possible, but on the other hand, there's got to be a
perception on the part of the public that there's sufficient independence of
the Safety Drug Review Board to the extent that while these will be difficult
decisions in many cases, it should have highly represented unbiased
individuals.
Having
said that, there still needs to be the input from all of the stakeholders as
well.
CHAIRMAN
SHINE: I agree. I personally believe that some of the
suggestions about taking this process out of the Agency are not wise. On the other hand, as I look at the proposed
make up of that Committee, its chair, the other participants, it's a government
organization with a couple of patient and consumer participants. I would like to see some mechanism that's
added to that that gives it --
DR.
THOMAS: Perception is going to be
extremely important.
CHAIRMAN
SHINE: But I think this is what a lot
of this is about.
Alan?
DR.
ROSES: I agree with most of what you
said. I just -- the word independent is
what's throwing me off. I think the
Safety Board, first of all, it's a risk-safety analysis and a free-standing
safety board is independent of the FDA, makes to me no sense at all.
CHAIRMAN
SHINE: Absolutely, I agree.
DR.
ROSES: But, in fact, it would be very,
very useful if it did contain people experienced and had the proper backgrounds
to actually be perceived and in real life being separate, not independent, but
a separate review body. So I agree.
CHAIRMAN
SHINE: What I'm arguing is that the
body as proposed is perfectly reasonable to do the business of identifying the
risk in doing its work. I'm not arguing
with that.
I
think that's a sensible group. I'm
simply saying I'd like to have, in addition to that, some oversight that has
some increase in -- some more distance from it so it can periodically review
its activities and say yeah, it's functioning in the way the public would like
to have it function.
This
is just my own personal view on that, asking for the Committee to endorse
anything specifically.
Let
me make a few other observations. I
think we all agree that there are some really important opportunities for
information gathering that should take advantage of other sources of
information and I pick up again on Alan's use of the word pilot. Some of the things we were talking about in terms
of teaming up with existing electronic health records, new developing records
so that we can do some of the things, solve some of the problems that Dr.
Goodman has identified, namely, you've got to know what to do with the data,
how to analyze it and what the infrastructure is, that those kind of pilots
would be very important.
On
a number of occasions we emphasize standardization, standardization of
terminology, standardization of approaches and analysis. I think, although we need to think more
about this, I think the sense of the Committee is that we must find a way to do
more effective post-marketing surveillance and I would suggest to the
Commissioner that the Agency do a briefing for us on what they would believe to
be an optimum national pharmacovigilant system.
In
other words, I think it's worthwhile to do the exercise and without, at this
point, limitations of cost and whatever and say what would you do if you were,
in fact, going to invent a system that met the various needs and let's debate
it. Let's argue about it. Let's see if it makes sense. If it does, then the issue of resources
obviously becomes important, but the Board can decide whether such an approach
is likely to produce what we want.
We've talked about bits and pieces of how something might work, but I
think it would be very useful if we took the time to actually say how would we
invent such a system.
Now
the IOM may, in fact, make some recommendations of that kind but I don't
believe that that should preclude us from thinking about a pharmacovigilant
system as opposed to what they think about which may run the gamut in terms of
how and what way they think business ought to be done.
I
think that -- yes ma'am.
DR.
HARLANDER: When will be have the IOM
study done? Do we have an estimate of
that?
DR.
WOODCOCK: It's expected to last about
18 months from its inception. It hasn't
really started yet, but Steven said the membership will be posted soon.
DR.
HARLANDER: Two years.
DR.
WOODCOCK: Yes, something like that.
CHAIRMAN
SHINE: And I don't think we should wait
two years to try to think out what such a system might look like. And in fact, if the Agency does have some
suggestions that we can interact with, you can give the ideas to the IOM that
they're not necessarily the font of all knowledge, even though certain times in
my career, I believe that.
But
in any case, but I would like to challenge the Agency to help us in this regard
and put some of the thoughts together that we've talked about.
I
think Cato was very concerned that the public information and the labeling
material be more
-- have some more explicit information about
special populations and I would argue, Dr. Woodcock, that it might say special
populations, none identified or no data available or if there is data
available, whether the special population is kids or women or the elderly or
African Americans or Asians or whatever, that there be something in that block.
I
think that's the intent, but I think Dr. Laurencin wanted to see that that was
very explicitly stated.
I
would love to -- yes, please.
DR.
THOMAS: Let me throw out a thought
while you're on the issue of pharmacovigilance. Of course, we don't have socialized medicine and we don't capture
all these things like some of the Scandinavian and European countries do, but do
you suppose if you could marry pharmacovigilance with pharmacoeconomics, and
then perhaps find a role for the Center for Medicare and Medicaid to monitor
these things since you're going to single out a population of generics,
perhaps, or geriatrics, excuse me. But
this might be a distance from the Agency itself and if you could incorporate
the pharmacoeconomics that would have the interest for the Center for Medicare
and Medicaid.
CHAIRMAN
SHINE: Well, you could very easily -- I
could conceive of a pharmacovigilance program which included a database which
is a very rich system for identifying diagnoses, drugs, and could, in fact, try
to college that information, particularly now.
If it's going to have a drug benefit, albeit with a hole in the donut,
but still a drug benefit.
I
think there was some reference to that.
You may have already been thinking about something like that. Someone said something about CMS.
DR.
WOODCOCK: Yes, we're talking to CMS
about -- Paul Seligman pointed out that as they assemble their drug benefit, a
lot of this has to do with how you structure the data that you collect and make
sure you can actually analyze it and so we are talking to them about that, but
they don't currently have that kind of capability.
CHAIRMAN
SHINE: I think there were a number of
other specific ideas that deserve some additional thought. One was -- and we understand the limitations
-- was the role of pharmacists and pharmacy in this whole effort and obviously,
there are resource issues there. But we
may be -- this may be an area that we ought to explore.
The
pharmacists certainly have been very interested in the medical areas,
medication area business and the question is can we come up with some creative
partnership to help with regard to adverse drug events. The possibility of developing a website
which would be easily accessible and which would allow people to look at the
range of drug interactions perhaps with identifying the really important ones
and the ones that are not so important.
And
I think repeatedly we've heard reference to the notion that we've got to find
better ways to educate policy makers and the public about risk and risk benefit
and the role of the FDA in balancing efficacy against risk and maybe the Board
can think about some creative ways that we might accomplish that over time.
Clearly,
this is a work in progress and should fit into the continuous quality rubric
that FDA and the Board has talked about so frequently in terms of trying to
make sure that whatever we learn about adverse events is translated into
appropriate kinds of programs.
My
own sense about where to put the resources is it's the data. I mean I really think that at this stage
trying to get rational ways that we can collect meaningful data, that we can
mine the data within the institutions, that we can figure out ways to validate
data. Once you've got that, then you
have an opportunity to see trends, to determine where your problems are and
then to devote resources in each of those.
So I would concur, I think it was Dr. Swanson who emphasized the
importance of that part of the equation.
I
was pressing Dr. Goodman about the science issue because I am worried about the
overall commitment to science. I know
you're stressed. I'd like the Board, as
we think forward over the next year or two to think about whether we ought to
do some kind of assessment with or without others, science based within the
FDA, whether in fact, it's adequate, whether it needs strengthening. If so, where and what kind of resources will
be required to do it? It seems to me
that as Dr. Goodman articulated, it's tremendously stressed.
We've
already heard one person in the public presentation argue for stronger science
base. Perhaps we ought to look at that
very carefully. Whether we do that in
the course of our review of different components, whether we look at it across
FDA, I would throw open both to the committee and to the Commissioner and ask
his advice with regard to how we'd like to do it.
But
I think for us, as a science board, to remain silent while the basic science
capacity of the Agency is not getting what some of us think is the support that
it should have, is not responsible. And
so we need to take a look at it.
Granted, there are all kinds of resource needs that the Agency has to
deal with, but I think we have a responsibility as the Science Board to take a
close look at that.
I
want to thank our colleagues. I thought
the morning presentations were terrific in giving us an overview of the safety
and they were all on time. The
afternoon presentations were very comprehensive and they weren't on time. But that's all right. We learned a lot from them and the -- are
there any other comments that any Members of the Board want to make?
Dr.
Woodcock, any final observations you'd like to make?
DR.
WOODCOCK: No. If the decision is to pursue more briefings on pharmacovigilance,
we did publish a report, I believe in 2001 called "Managing the Risks of
Medical Products From the FDA." It
was a comprehensive report at the time.
Obviously, our thinking has advanced, but you would probably want to get
that well in advance of any briefing if, in fact, you decided to go down that
path.
CHAIRMAN
SHINE: We're going to do a little bit
more thinking, Dr. Woodcock, about some of the priorities here and talk with
you and the Commissioner about them, but my thought is that pulling that
together with some focus so that we can, in fact, say well, what would the
vision for that be, what can we get now, where could we go long term, what kind
of resources would be required? It
could be something where we could be helpful to you over the long haul and I'd
like to do that.
I
want to congratulate all of you on these -- if we can always get over this
business that contains nonbinding recommendations --
DR.
WOODCOCK: Talk to your lawyers.
CHAIRMAN
SHINE: The quality of the material, I
think, is outstanding. I think the
committee believes that and we congratulate you. With that, we are adjourned.
(Whereupon,
at 4:22 p.m., the meeting was concluded.)