[Senate Hearing 109-67]
[From the U.S. Government Publishing Office]
S. Hrg. 109-67
FDA'S DRUG APPROVAL PROCESS: UP TO THE CHALLENGE?
=======================================================================
HEARING
OF THE
COMMITTEE ON HEALTH, EDUCATION,
LABOR, AND PENSIONS
UNITED STATES SENATE
ONE HUNDRED NINTH CONGRESS
FIRST SESSION
ON
EXAMINING FOOD AND DRUG ADMINISTRATION'S (FDA) DRUG APPROVAL PROCESS,
FOCUSING ON FDA'S DRUG APPROVAL PROCESS AFTER A SPONSOR DEMONSTRATES
THAT THEIR BENEFITS OUTWEIGH THEIR RISKS FOR A SPECIFIC POPULATION AND
USE, AND THAT THE DRUG MEET MEETS STANDARDS FOR SAFETY AND EFFICACY
__________
MARCH 1, 2005
__________
Printed for the use of the Committee on Health, Education, Labor, and
Pensions
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99-761 WASHINGTON : 2005
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COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS
MICHAEL B. ENZI, Wyoming, Chairman
JUDD GREGG, New Hampshire EDWARD M. KENNEDY, Massachusetts
BILL FRIST, Tennessee CHRISTOPHER J. DODD, Connecticut
LAMAR ALEXANDER, Tennessee TOM HARKIN, Iowa
RICHARD BURR, North Carolina BARBARA A. MIKULSKI, Maryland
JOHNNY ISAKSON, Georgia JAMES M. JEFFORDS (I), Vermont
MIKE DeWINE, Ohio JEFF BINGAMAN, New Mexico
JOHN ENSIGN, Nevada PATTY MURRAY, Washington
ORRIN G. HATCH, Utah JACK REED, Rhode Island
JEFF SESSIONS, Alabama HILLARY RODHAM CLINTON, New York
PAT ROBERTS, Kansas
Katherine Brunett McGuire, Staff Director
J. Michael Myers, Minority Staff Director and Chief Counsel
(ii)
C O N T E N T S
__________
STATEMENTS
TUESDAY, MARCH 1, 2005
Page
Enzi, Hon. Michael B., Chairman, Committee on Helth, Education,
Labor, and Pensions, opening statement......................... 1
Kennedy, Hon. Edward M., a U.S. Senator from the State of
Massachusetts, opening statement............................... 3
Clinton, Hon. Hillary Rodham, a U.S. Senator from the State of
New York, prepared statement................................... 5
Kweder, Sandra L., M.D., Deputy Director, Office of New Drugs,
Food and Drug Administration, U.S. Department of Health and
Human Services, Rockville, MD.................................. 6
Joint prepared statement of Dr. Kweder and Dr. Woodcock...... 8
Murray, Hon. Patty, a U.S. Senator from the State of Washington,
prepared statement............................................. 22
Davenport-Ennis, Nancy, executive director, National Patient
Advocate Foundation, Washington, DC; Thomas R. Fleming,
professor and chair, Department of Biostatistics, University of
Washington, Seattle, WA; David Fassler, M.D., clinical
associate professor, Department of Psychiatry, University of
Vermont, College of Medicine, and clinical director, Otter
Creek Associates, Burlington, VT, on behalf of the American
Academy of Child and the Adolescent Psychiatry and American
Psychiatric Association; Scott Gottlieb, M.D., resident fellow,
American Enterprise Institute, Washington, DC; Abbey S. Meyers,
president, National Organization for Rare Disorders, Danbury,
CT; and William B. Schultz, partner, Zuckerman, Spaeder, LLP,
Washington DC.................................................. 28
Prepared statements of:
Ms. Davenport-Ennis...................................... 30
Mr. Fleming.............................................. 36
Dr. Fassler.............................................. 42
Dr. Gottlieb............................................. 51
Ms. Meyers............................................... 55
Mr. Schultz.............................................. 60
ADDITIONAL MATERIAL
Statements, articles, publications, letters, etc.:
Questions of Senator Murray for the panels................... 74
Questions of Senator Clinton for Dr. Kweder.................. 75
Response to questions of Senator Enzi by Dr. Kweder.......... 75
Response to questions of Senator Gregg by Dr. Kweder......... 78
Response to questions of Senator Hatch by Dr. Kweder......... 78
Response to questions of Senator Kennedy by Dr. Kweder....... 80
Response to questions of Senator Enzi by Ms. Davenport-Ennis. 85
Response to questions of Senator Enzi by Mr. Fleming......... 87
Response to questions of Senator Kennedy by Mr. Fleming...... 89
Response to questions of Senator Enzi by Dr. Fassler......... 90
Response to questions of Senator Enzi by Ms. Meyers.......... 91
Response to questions of Senator Enzi by Mr. Schultz......... 93
(iii)
FDA'S DRUG APPROVAL PROCESS: UP TO THE CHALLENGE?
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TUESDAY, MARCH 1, 2005
U.S. Senate,
Committee on Health, Education, Labor, and Pensions,
Washington, DC.
The committee met, pursuant to notice, at 9:30 a.m., in
Room 106, Dirksen Senate Office Building, Hon. Mike Enzi,
chairman of the committee, presiding.
Present: Senators Enzi, Burr, Isakson, DeWine, Hatch,
Kennedy, and Murray.
Opening Statement of Senator Enzi
The Chairman. I'll call the Committee on Health, Education,
Labor, and Pensions to order for the hearing on the ``FDA's
Drug Approval Process: Up to the Challenge?''
Good morning and welcome to the first in a series of
hearings on prescription drugs and the process that is used to
ensure their safety and effectiveness.
I strongly believe that Congress needs to engage in strong
oversight to help maintain the public's confidence in the FDA.
Congress needs to understand the facts before deciding on a
course of action. Changes to the drug safety system should be
carefully considered to ensure they do not unduly impact
patient access to important therapeutics, and benefits and
risks must be weighed on the same scale. Separating
consideration of safety from consideration of efficacy is the
wrong direction to go.
Today's hearing will examine how the Food and Drug
Administration, better known as the FDA, makes decisions about
new drugs. As we focus on the FDA, we will also take a look at
some of the recent controversies that have come to light
regarding the drug approval process and the FDA's mission to
protect and promote public health.
Our next hearing on Thursday will look in greater detail at
the steps the FDA is taking to address public concerns about
the safety of our prescription medications. We will also take a
glimpse into the future and try to determine if the FDA will be
able to handle the challenges the agency will face in the years
to come. We are going to look at what the FDA is doing to
modernize.
I am not a physician. I am not a lawyer. I am not an expert
on biostatistics. But I am a patient. All of us are patients.
In fact, I would venture to say that we have all at some point
used prescription drugs to maintain or improve our health, and
many of us rely on them on a daily basis. Most of us don't
think twice about the work the FDA does every day to ensure
that our drugs are safe and effective, or at least we don't
think about it until questions about drug safety make the news.
So what is it that we expect of the FDA? At the risk of
oversimplifying, I would say that we expect the following. We
expect the FDA to approve a new drug only if it is safe,
effective, and the known benefits of the drug outweigh the
known risks if it is used as intended. We expect the FDA to
ensure that companies are communicating the benefits and the
risks of their drugs to patients and physicians in a clear and
consistent manner. We expect the FDA to keep tabs on the drugs
on the market to ensure their continued safety and to take
appropriate action if new information demonstrates new risks
that were not apparent when a drug was initially approved.
So the questions we as Senators need to ask as we look at
the FDA process are the following. Does the FDA properly assess
and weigh the benefits and risks of drugs? Does the FDA ensure
that information about benefits and risks of drugs are
communicated fully? And does the FDA keep appropriate watch
over drugs once they are approved on the market? I believe
these questions provide the lens through which this committee
should focus its attention as we oversee the FDA.
Through holding these oversight hearings, we will bring out
the facts beneath the recent controversies so that we can
understand whether the FDA's current system worked as intended
or whether something broke down. We will learn what the FDA and
drug companies did in response to the current safety concerns,
whether things should have been done differently, and whether
legislation is necessary to address these concerns. We will
discuss how the new initiatives that Secretary Leavitt recently
announced will further the FDA's effort to meet the
expectations that I described earlier. We will also look into
whether the FDA and the industry can continue their efforts to
reduce drug development time without compromising safety, and
whether these steps are steps that Congress and the FDA need to
be taking to make that happen.
The past dozen years have brought big changes to the drug
approval process. The Prescription Drug User Fee Act, the Food
and Drug Administration Modernization Act, and the subsequent
amendments to both were bipartisan efforts that brought more
consistency, transparency, and accountability to the drug
approval process. But it is time for the reevaluation of the
FDA's organization and processes. We must not sacrifice safety
to speed drugs to the market. However, we must weigh benefits
and risks on the same scale.
Every time we take a drug, we take a risk. So we should not
overreact to recent events by trying to develop a system that
gets us to zero risk. I do have kind of a rule of legislating
that I have found over the years to be true, and that is that
if it is worth reacting to, it is worth overreacting to, and
part of our job is to make sure that we don't overreact but
that we appropriately react.
The FDA doctors and patients all have roles to play in
evaluating the benefits and risks of a particular drug. But a
drug that is unavailable, while it may be safe, can never be
effective.
I appreciate Senator Kennedy being here, the other half of
the team. Somebody last week asked me what you get when you
cross the fourth most liberal Senator with the fifth most
conservative Senator and I said, a reasonable bill.
[Laughter.]
The Chairman. I think that was a Democrat----
Senator Kennedy. Who is ahead of me?
[Laughter.]
I will wait until the election and I will find out.
The Chairman. I asked the same question on my side.
[Laughter.]
But I do want to congratulate all the members of the
committee for the great job that was done on the genetics
nondiscrimination bill, which is now through the Senate. Our
job is not finished. We have to get the House version passed
and then we have to work out any differences. Hopefully, there
will be none. They will recognize the great work that was put
into our bill, and the 5 years of effort, and we will get it
done.
But I appreciate the bipartisan spirit that the committee
has been working on all issues on, and we do have a pretty big
plate. I have mentioned that out of the President's top ten
priorities, we have 21, so he did combine a few in one or two
of his priorities.
At this point, we will have Senator Kennedy make his
opening statement and then we will hear from Dr. Sandra Kweder.
Opening Statement of Senator Kennedy
Senator Kennedy. Thank you very much. Thank you, Mr.
Chairman. I commend you for calling this very important hearing
on the safety of prescription drugs.
When patients go to their medicine cabinets to open a
prescription bottle, they deserve an assurance that the
medicines that they take are safe and effective. Each one of us
relies on the FDA for that assurance.
So I commend Senator Enzi for his leadership in making drug
safety a priority for this oversight committee by calling
today's hearing. There is no doubt that FDA's ability to assure
the safety and effectiveness of medicine is under stress today
as never before, and I look forward to working closely with our
distinguished chairman on legislation to restore the ability of
the FDA to deal effectively with the challenges it faces.
This week's hearings will allow us to examine carefully the
issues under consideration for the new legislation. These
include better monitoring for drugs already on the market,
greater independence for the offices that assure safety, and
better protections against improper conflicts of interest on
essential FDA panels.
Today's hearing is the first step in the process and I am
optimistic it will lead to a comprehensive proposal to make
certain that every American can count on the FDA to protect
their health.
Obviously, new drugs can pose risks, and the mission of the
FDA is to strike the right balance between testing them in
advance and withholding them from the market for too long.
Since we don't know all the risks in advance, especially long-
term risks, FDA has a special responsibility to monitor drug
safety after new drugs go on the market.
Last fall, the Food and Drug Administration required anti-
depressants, such as Prozac and Zoloft, to be labeled to
reflect an increased risk of suicidal thoughts and behavior for
children and adolescents. We also began to realize that Vioxx
and other drugs in its class increase the risk of heart attack
or stroke. The FDA's Advisory Committee last week concluded
that these drugs do increase this risk and it made
recommendations on how to mitigate the risk of these drugs,
which FDA says it will act on soon.
Questions certainly need to be asked about why FDA was
reluctant to modify the label on these anti-depressants,
especially in cases where they would be used by children.
Hindsight is 20/20, but there is a real concern that the
agency may have been too willing on safety issues to protect
the pharmaceutical companies instead of the public interest.
Why should it take nearly 2 years after the so-called VIGOR
clinical trial raised serious questions about Vioxx for the
agency to act on the safety risk? And why should it take 5
years to discover that Vioxx, used by tens of millions of
patients, may double the risk of heart attack or stroke?
When the drug user fees were enacted in 1992, Congress gave
FDA the funds to review drugs much more quickly, and most new
drugs in the world are now approved first in the United States,
a rather dramatic contrast from the conditions prior to that.
But drug safety checks have not kept pace with the speed of
drug approval. Inevitably, when new drugs first come to market,
we don't know enough about their use by large numbers of
patients since clinical trials may not detect a rare but
serious problem. Effective FDA oversight after approval is
essential to detect problems and the agency needs the resources
and the authority to act quickly and effectively to make
ongoing assessments of the risks of drugs in use.
It also needs clear authority to require relabeling a drug,
if necessary, after approval once a drug is found. Negotiations
with a drug maker should never delay accurate information for
patients and doctors.
The FDA needs clear authority, as well, to require a drug
company to conduct further clinical trials to study a serious
safety concern after a drug goes on the market, and it needs a
way to enforce these study requirements.
We also need to examine so-called direct-to-consumer
advertising, especially when it may lead to excessive use of
new drugs whose safety records can't be fully known when they
are first approved for use.
The FDA approval process needs to become more open.
Conflicts of interest of its Advisory Committee members must be
dealt with and fully disclosed in advance to the public when
their expertise requires their participation in a study. Many
of us were troubled by the reports last week that ten of the 32
members of the Advisory Committee had ties to the drug industry
and their votes were decisive in the recommendations that Vioxx
and Bextra be allowed to return or remain on the market.
Patients also need better information about drugs written
in understandable language so they can understand the risks and
the benefits.
I welcome our witnesses today and I look forward to their
testimony.
Mr. Chairman, there are only a few good reasons to be
absent from your committee meeting, only a few good reasons,
but I think Senator Dodd is entitled for his good reason today,
and that is he just was the proud father of a baby girl born at
1 a.m. this morning, seven pounds, very healthy. There is no
name yet. Enzina, Enzina Dodd has a ring to it.
[Laughter.]
But anyway, I think for all the committee, we wish Senator
Dodd and his lovely wife, Jackie, and their marvelous baby girl
all the health and happiness in the world. Thank you.
The Chairman. I know Grace made a tremendous difference in
their life and I am sure that the new baby will, as well. It is
great to see that family together. That is tremendous news. I
appreciate your sharing it with us.
Senator Kennedy. Thank you very much.
The Chairman. I would like to submit a statement from
Senator Clinton for the record.
[Prepared statement of Senator Clinton follows:]
Prepared Statement of Senator Clinton
I would like to thank Senator Enzi and Senator
Kennedy for convening today's hearing on the important issue of
drug safety and the approval process at the Food and Drug
Administration (FDA).
In the 1990s, we passed several landmark pieces of
legislation that allowed the FDA to considerably shorten the
amount of time needed to approve drugs for use by consumers.
These changes meant that patients suffering from serious
diseases, like AIDS and cancer, could gain quicker access to
potentially lifesaving medications.
While First Lady, I was proud to work with the FDA
on developing the Pediatric Rule, which ensures that drugs
marketed to pediatric populations have first been tested on
children. During my time in the Senate, Senator DeWine and I
introduced the Pediatric Research Equity Act of 2003,
legislation that gave the agency the legal authority necessary
to continue enforcing the Pediatric Rule. I also worked with
Senators Dodd and DeWine on the Best Pharmaceuticals for
Children Act, which provides incentives for companies to ensure
that their drugs are safe for children.
For many years, the FDA and its approval
mechanisms have been considered the gold standard among the
world's drug safety bodies. And no one here doubts the desire
of the agency's many employees to continue to carry out its
mission of keeping our drug supply safe for all Americans.
Despite this, we know there have been breakdowns
at the agency. We know that, at times, it has taken too long
for the FDA to act when a drug may pose a threat to Americans.
Recent concerns about the safety of drugs that
have been approved and are available to consumers point to the
need to develop guidelines for ways to monitor drugs once they
reach the market.
Today, we will have the opportunity to hear about
the controversies involving both Cox-2 drugs and antidepressant
use in children. These events demonstrate the need to better
understand, identify, and monitor the risks that drugs pose
after they have been approved for use by the public.
With my work on both the Pediatric Rule and the
Best Pharmaceuticals for Children Act, I have tried to
encourage both the FDA and drug companies to implement changes
to the system in which they test, approve, and market drugs for
use in the pediatric population. From these experiences, I know
that there are a variety of methods through which we can
involve both the industry and the FDA to ensure the safety of
products on the market. And I look forward to continuing to
work with all stakeholders to improve the safety of our drugs,
not just the products marketed to children.
In addition to further demonstrating the need for
post-marketing monitoring, the Vioxx controversy highlights the
role comparative effectiveness can play in ensuring the use of
the most appropriate treatment for a specific condition. I
pushed for inclusion of comparative effectiveness studies in
the recent Medicare law, and I would note that one of the first
studies to be carried out under this provision is a systematic
review of Cox-2 drugs. I believe that this information will
assist physicians and patients in selecting the best treatment
and help reduce inappropriate uses of treatments that pose
unnecessary safety risks to patients.
I hope that in today's hearing, we can begin to
explore the ways in which we can strike a balance between the
speed with which we get lifesaving drugs to the market, and the
safety that has been, and should remain, a hallmark of the FDA
name.
Again, I would like to thank Senators Enzi and
Kennedy for convening today's hearing, and I look forward to
working with my colleagues on the HELP committee to developing
some practical, bipartisan solutions to continue to ensure that
the drugs approved by the FDA are safe for all Americans.
The Chairman. At this point, I would like to welcome Dr.
Sandra Kweder, the Deputy Director of the FDA's Office of New
Drugs. Dr. Kweder is a Captain in the Uniformed Public Health
Service. Dr. Kweder will review FDA's drug approval process and
discuss how approval, labeling, and postmarked surveillance are
all considered by the FDA. Dr. Kweder.
STATEMENT OF SANDRA L. KWEDER, M.D., DEPUTY DIRECTOR, OFFICE OF
NEW DRUGS, FOOD AND DRUG ADMINISTRATION, U.S. DEPARTMENT OF
HEALTH AND HUMAN SERVICES, ROCKVILLE, MD
Dr. Kweder. Good morning, Senators. Thank you very much. I
am very pleased to be here today to talk about drug safety and
say some words about the drug approval process.
FDA's review of drugs prior to approval and throughout
their life cycle on the market is recognized worldwide as a
gold standard. We believe that FDA has maintained the highest
standards for drug approval, oversight of the investigational
process, and for safety in the world.
Like drug development, postmarketing safety, though, is
dynamic. While no amount of study before we approve a drug will
ever identify all the information about drug effectiveness or
risk that there is, our ability to monitor safety has to keep
pace with changes in science as well as with changes in
marketing patterns and how drugs are used by doctors and
patients.
Acting Commissioner Crawford is committed to strengthening
drug safety at FDA. He, in conjunction with Secretary Leavitt,
announced new measures to increase public knowledge about drug
safety issues just recently. Our goal is to assure that full
and rigorous scientific and regulatory judgments are
consistently applied to oversight of safety issues at FDA. Our
actions will follow Dr. Crawford's announcement last fall of a
five-step plan for greater drug safety, but in the coming year,
we will also significantly increase our resources devoted to
drug safety.
The five-step plan that we announced last fall included a
study by the Institute of Medicine of drug safety in the United
States, and in particular, FDA's role in assuring that. We have
begun planning that with the Institute of Medicine.
Second, a national search for a permanent director of our
Office of Drug Safety, and we have begun that process, as well.
We have also implemented a formal process for resolving
scientific disputes within our agency among our own scientists,
where those exist.
We have begun the fourth point of Dr. Crawford's plan,
which was conducting workshops and meetings of our Advisory
Committees to discuss complicated safety issues. Our recent
meeting on the COX-2 selective inhibitors last week is a very
good example of this effort.
And fifth, final publication of three important guidance
documents for industry to help companies identify safety issues
early and develop effective programs for monitoring them and
helping physicians and patients manage those risks. We expect
final publication of these guidances this month.
In addition, what was recently announced is that FDA will
establish a Drug Safety Board composed of independent senior
experts from within and outside the agency to oversee on a
routine basis new and ongoing drug safety concerns. This board
will also ensure that the public is provided with important
emerging information about drug safety issues through modern
communication tools, including a drug watch page on the FDA
website. Our goal is to provide consumer-friendly information,
especially for patients and health care professionals, about
emerging risks that they should be concerned about.
As we develop our communications tools, the agency does
plan to solicit public input on how we should manage them, make
them most effective, and address concerns about disseminating
emerging information before we take regulatory action.
In my written testimony, I outline the process of drug
development, including how therapies undergo clinical trials
under close FDA scrutiny and how sponsors conduct thorough
safety and effectiveness analyses, submit applications to the
agency, and how we go about the process of exhaustive review of
the data unlike any regulatory agency in the world.
But even before FDA approves a drug, the postmarketing
monitoring and planning for postmarketing monitoring begins. To
do this requires the input of my experts, experts in pre-
marketing safety assessment and in postmarketing safety, so
that we can put together a systematic approach to each unique
product.
The sponsor, once the product is on the market, must submit
periodic safety updates to the agency so that our safety
experts can review and analyze adverse event reports. How we
respond to information from this ongoing surveillance depends,
of course, on the drug's overall safety and benefit profile.
When a serious risk is identified, if the public health benefit
outweighs the known risks for the intended population in use,
FDA allows continued marketing of the drug. We may ask
manufacturers to revise the labeling or add new warnings and
precautions. We may issue public health advisories and
information sheets. We may even consider working with the
company to restrict distribution of the product or remove it
from the market. Our action depends on the frequency of the
reports, the seriousness of the disease, the availability of
alternative treatments, and the consequences of not treating
the disease if there aren't available treatments.
In 1992, Congress enacted the Prescription Drug User Fee
Act. PDUFA, as we call it, emphasizes timely action by FDA but
does not alter or compromise our commitment to ensuring that
drugs are safe and effective. These fees are essential to our
efforts to improve drug safety. The focus on safety begins with
the earliest work on drug discovery, and as the drug
development process continues, we evaluate the safety of the
therapeutic compound in every stage of development. Thanks to
PDUFA, we are able to commit far greater resources to these
safety responsibilities. Your committee played a significant
role in PDUFA, and on behalf of patients, countless patients
who have benefited from therapies approved under PDUFA, I want
to thank this committee.
In conclusion, at FDA, providing the American public with
safe and effective medicines is our core mission. The recent
initiatives we have announced will improve our current system
to assess drug safety. Moreover, as we strive for continuous
improvement, we will evaluate new approaches to advance drug
safety. As always, we value input from the Congress, from
patients, and from the medical community as we develop and
refine our initiatives.
I am happy to take your questions.
The Chairman. Thank you for your testimony. I appreciate
the tremendous summarization you did. I want to assure that
your entire statement will be a part of the record. We and our
staffs rely on that volume of information to be able to do the
job.
[The joint prepared statement of Dr. Kweder and Dr.
Woodcock follows:]
Joint Prepared Statement of Sandra L. Kweder, M.D. and Janet Woodcock,
M.D.
INTRODUCTION
Mr. Chairman and members of the committee, I am Dr. Sandra Kweder,
Deputy Director of the Office of New Drugs at the Center for Drug
Evaluation and Research (CDER), United States Food and Drug
Administration (FDA or the Agency). I am pleased to be here today to
discuss drug safety and the drug approval process.
Because of the importance of these issues, you are holding two
hearings over the course of 3 days. Dr. Janet Woodcock, FDA's Acting
Deputy Commissioner for Operations, will appear at your hearing on
March 3. We have one written statement to address both hearings.
SAFETY IS A HIGH PRIORITY
Let me begin with a few words about safety, and I will return to
this issue throughout our written testimony. Modern drugs provide
unmistakable and significant health benefits. FDA's drug review process
is recognized worldwide as a gold standard. Indeed, we believe that FDA
maintains the highest standards for drug approval. There have been
significant additions to those standards during the last several
decades, in response to advances in medical science. Currently, FDA
approves drugs after they are studied in many more patients and undergo
more detailed safety evaluation than ever before. FDA grants approval
to drugs after a sponsor demonstrates that their benefits outweigh
their risks for a specific population and a specific use, and that the
drug meets the statutory standard for safety and efficacy. However, no
amount of study before marketing will ever elucidate all the
information about effectiveness or all the risks of a new drug.
Therefore, post-marketing surveillance is extremely important.
Adverse effects that are not detected during clinical trials are
identified after approval through post-marketing clinical trials,
spontaneous reporting of adverse events, or observational studies based
on more widespread use of the product following approval. That is why
Congress has supported and FDA has created a post-market drug safety
program designed to collect and assess adverse events identified after
approval for all drugs we regulate.
This program serves as a complement to the pre-market safety
reviews required for approval of prescription drugs in the U.S. FDA
also evaluates and responds to adverse events identified in ongoing,
post-market clinical trials that test approved drugs for other
indications. We also evaluate and respond to events reported by
physicians, their patients, or drug manufacturers. With this
information, we make label changes and take other regulatory action as
needed.
It is important to emphasize that all approved drugs pose some
level of risk, such as the risks identified in clinical trials and
listed on the labeling of the product. Unless a new drug's demonstrated
benefit outweighs its known risks for its intended population, FDA will
not approve the drug. However, we cannot anticipate all possible
effects of a drug based on data from the clinical trials that precede
approval.
NEW FDA INITIATIVES TO STRENGTHEN DRUG SAFETY
November 2004 Five-Step Plan
At FDA, we are constantly striving to improve our processes and
methods, and thereby better serve the public health. Recent
developments have prompted us to refocus our drug safety efforts and
take additional steps to identify drugs that may have unacceptable risk
profiles.
On November 5, 2004, Acting Commissioner Crawford announced a five-
step plan to strengthen FDA's drug safety program. First, it called for
FDA to sponsor an Institute of Medicine (IOM) study to evaluate the
current drug safety system. An IOM committee will study the
effectiveness of the U.S. drug safety system, with an emphasis on the
post-marketing phase, and assess what additional steps FDA could take
to learn more about the side effects of drugs as they are actually
used. We will ask IOM to examine FDA's role within the health care
delivery system and recommend measures to enhance the confidence of
Americans in the safety and effectiveness of their drugs.
Second, Dr. Crawford announced that CDER would implement a program
for addressing differences of professional opinion. I am pleased to
report that CDER recently put this program into effect. Currently, in
most cases, free and open discussion of scientific issues among review
teams and with supervisors, managers and external advisers, leads to an
agreed course of action. Sometimes, however, a consensus decision
cannot be reached, and an employee may feel that his or her opinion was
not adequately considered. Such disagreements can have a potentially
significant public health impact.
In an effort to improve the current process, CDER has formalized a
program to help ensure that the opinions of dissenting scientific
reviewers are formally addressed and transparent in its decision-making
process. An ad hoc panel, including FDA staff and outside experts not
directly involved in disputed decisions, will have 30 days to review
all relevant materials and recommend to the Center Director an
appropriate course of action.
Third, CDER will conduct a national search to fill the currently
vacant position of Director of the Office of Drug Safety (ODS), which
is responsible for overseeing the post-marketing safety program for all
drugs. CDER is seeking a candidate who is a nationally recognized drug
safety expert with knowledge of the basic science of drug development
and surveillance, and a strong commitment to protecting the public
health. CDER is working with the Office of Personnel Management on this
search.
Fourth, in the coming year CDER will conduct additional workshops
and advisory committee meetings to discuss complex drug safety and risk
management issues. Most recently, for example, the Agency conducted a 3
day Advisory Committee meeting that examined COX-2 selective non-
steroidal anti-inflammatory drugs and related medicines. The Committee
held its meeting on February 16-18, 2005, and heard presentations from
more than 25 experts. At the end of the meeting, the Advisory Committee
issued recommendations that the Agency is promptly and carefully
reviewing before taking further action.
Finally, FDA intends to publish final versions of three guidances
that the Agency developed to help pharmaceutical firms manage risks
involving drugs and biological products. These guidances should assist
pharmaceutical firms identify and assess potential safety risks not
only before a drug reaches the market but also after a drug is already
on the market. FDA expects to publish the final guidances in the second
quarter of 2005.
February 2005 Drug Safety Announcement
On February 15, 2005, HHS Secretary Leavitt and Acting Commissioner
Crawford unveiled a new, emboldened vision for FDA that will promote a
culture of openness and enhanced oversight within the Agency. As part
of this vision, FDA will create a new independent Drug Safety Oversight
Board (DSB) to oversee the management of drug safety issues, and will
improve transparency by providing emerging information to health
providers and patients about the risks and benefits of medicines.
Under this proposal, FDA will enhance the independence of internal
deliberations and decisions regarding risk/benefit analyses and
consumer safety by creating an independent DSB. The DSB will oversee
the management of important drug safety issues within CDER. The DSB
will be comprised of individuals from FDA who were not involved in the
initial review of the drug, as well as medical experts from other HHS
agencies and government departments (e.g., the National Institutes of
Health and Department of Veterans Affairs). CDER's Deputy Director will
serve as the Chair of the DSB. The DSB also will consult with other
medical experts and representatives of patient and consumer groups.
FDA will also increase the transparency of the Agency's decision-
making process by establishing new and expanding existing communication
channels to provide drug safety information to the public. These
channels will help ensure that established and emerging drug safety
data are quickly available in an easily accessible form. The increased
openness will enable patients and their health care professionals to
make better-informed decisions about individual treatment options. The
Agency is also proposing a new Drug Watch webpage that will include
emerging information about possible serious side effects or other
safety risks for previously and newly approved drugs. This resource
will contain valuable information that may alter the benefit/risk
analysis for a drug or affect patient selection or monitoring
decisions. The web resource may also contain information about measures
that patients and practitioners can take to prevent or mitigate harm.
This information resource will significantly enhance public knowledge
and understanding of safety issues by discussing emerging or potential
safety problems even before FDA has reached a conclusion that would
prompt a regulatory action. As always, FDA is committed to maintaining
patient privacy as it implements these measures.
As FDA develops these communication formats, the Agency will
solicit public input on how FDA should manage potential concerns
associated with disseminating emerging information prior to regulatory
action. The Agency will also issue draft guidance on procedures and
criteria we will use to identify drugs and information that will appear
on the Drug Watch webpage. In addition, FDA will actively seek feedback
from health care professionals, patients and consumers on how best to
make this information available to them.
Increased Funding for the Office of Drug Safety
FDA has a longstanding commitment to provide a strong resource base
for ODS. As the graph set forth below demonstrates, we have steadily
increased the financial and human resources dedicated to post-market
drug safety over the past decade.
The budget for fiscal year 2006 continues this commitment. The
President has proposed a 24 percent increase for FDA's post-market
safety program to help further ensure that America's drug product
supply is safe and effective, and of the highest quality. Under this
proposal, CDER's ODS would receive increased funding to expand the
Agency's ability to rapidly survey, identify and respond to potential
safety concerns for drugs on the market. ODS will hire additional staff
to manage and lead safety reviews, will increase the number of staff
with expertise in critical areas such as risk management, risk
communication and epidemiology, and will increase access to a wide
range of clinical, pharmacy and administrative databases. The
Administration's proposed budget for ODS will increase by $6.5 million,
including $1.5 million in user fees, for a total fiscal year 2006 ODS
funding level of $33.4 million. PDUFA resources will represent nearly
one-third of the ODS budget for the coming year. Our commitment to
increase resources available for post-market safety will enhance the
structural changes we are proposing to advance drug safety.
THE DRUG APPROVAL PROCESS
Pre-Approval Focus on Safety
FDA's focus on safety begins at the earliest stages of drug
development, when we review a product under an investigational new drug
(IND) application. During the IND period, products must complete three
phases of clinical (human) trials. Phase I studies involve the initial
introduction of an IND drug into humans to assess the most common acute
adverse effects and examine the size of doses that patients can take
safely without a high incidence of side effects. However, before
beginning human trials, the sponsor must perform extensive animal
toxicity studies. Researchers closely monitor these studies. They may
conduct Phase I trials in patients, but often rely on healthy volunteer
subjects. In general, these studies yield initial safety data and
useful information to establish the appropriate dose of the drug.
Phase II includes the early controlled clinical studies conducted
to obtain additional information on appropriate dosing, as well as
preliminary data on the effectiveness of the drug for a specific
indication in patients with the disease or condition. This phase of
testing also helps identify short-term side effects and risks possibly
associated with the drug. Phase II studies are typically well
controlled, closely monitored and conducted in studies that usually
involve several hundred patients. In these studies, researchers compare
results of patients receiving the drug with those who receive a
placebo, a different dose of the test drug, and/or another active drug.
At the conclusion of these studies, FDA and the sponsor meet to
determine if the drug's development should advance to Phase III and how
to design and conduct further trials.
Finally, researchers design Phase III trials for a larger number of
patients and build on the data gained from the first two phases of
trials. These studies provide the additional information about safety
and effectiveness needed to evaluate the overall benefit-risk
relationship of the drug. Phase III studies also provide the basis for
extrapolating the results to the general population and provide
essential information for the package labeling. Once the results of all
the clinical trials are available, the sponsor of the application
(usually the manufacturer of the product) analyzes all the data and
submits a new drug application (NDA) or biologics license application
to FDA for review.
Post-Approval Risk Assessment
Once FDA approves a drug, the post-marketing monitoring stage
begins. The sponsor (typically the manufacturer) is required to submit
periodic safety updates to FDA on their drug. Also during this period,
we continuously receive adverse event reports through our MedWatch
system from other sources such as health care providers and patients.
Safety experts review and analyze the reports to establish the
frequency and seriousness of the adverse events. Our response to
information from this ongoing surveillance depends on an evaluation of
the aggregate public health benefit of the product compared to its
evolving risk profile. FDA carefully considers the seriousness and the
frequency of reported adverse events as well as the estimated number of
patients who benefit from the drug. The occurrence of a rare event,
even a serious event, may or may not, by itself, be sufficient to take
a drug product off the market. Adverse event reports do not solely
provide all the data necessary to identify any potential risks that may
be associated with a specific product or class of products; however,
over time, they provide us with another piece to a complex puzzle.
If the public health benefit of the product outweighs its known
risks for the intended population and intended use, FDA allows the
continued marketing of the drug. Often, as more becomes known about the
potential risks or benefits of a product, its label will be revised so
that it better reflects information on appropriate use. For example,
FDA may ask the manufacturer to revise the labeling to add information
on adverse reactions not previously listed, to add new warnings
describing conditions under which the drug should not be used, or to
add new precautions advising doctors of measures to minimize risk. FDA
often issues Public Health Advisories and information sheets for health
care providers and patients that discuss the new safety information. In
the event of reports of death or life-threatening injury, FDA and the
sponsor may consider restricting the distribution of the product or
removing it from the market. Our action will depend on the frequency of
the reports, the seriousness of the diseases or conditions for which
the drug provides a benefit, the availability of alternative therapy,
and the consequences of not treating the disease.
The issue of how to detect and limit adverse reactions can be
challenging. How to weigh the impact of these adverse drug reactions
against the benefits of these products on individual patients and the
public health is multifaceted and complex, and involves scientific as
well as public health issues.
STATUTORY CHANGES TO DRUG APPROVAL AT FDA
FDA was founded in response to concerns about safety, and attention
to safety pervades everything that we do. In the Federal Food, Drug and
Cosmetic Act of 1938, Congress gave FDA the authority to review the
evidence that a drug was safe for its intended use. In 1962, Congress
added a requirement that drug sponsors also demonstrate that a drug is
effective, using adequate and well controlled studies. Thus, drug
safety means that the demonstrated benefits of a drug outweigh its
known and potential risks for the intended population and use. In
recent years, Congress has enacted legislation that provides
significant additional tools to improve our focus on safety: the
Prescription Drug User Fee Act (PDUFA) and the Food and Drug
Administration Modernization Act (FDAMA).
In 1992, Congress enacted PDUFA. This landmark legislation provided
significant resources for FDA to hire more medical and scientific
reviewers to conduct pre-market reviews, to hire support personnel and
field investigators to speed the application review process for human
drug and biological products, and to acquire critical information
technology infrastructure to support our review process.
In 1997, following the success of PDUFA I, Congress reauthorized
the program for an additional 5 years when it enacted FDAMA of 1997.
With PDUFA II came higher expectations for product reviews and
additional goals designed to reduce drug development times.
In 2002, Congress reauthorized PDUFA for a third time. PDUFA III
places great emphasis on ensuring that user fees provide a sound
financial footing for FDA's new drug and biologic review process and,
for the first time, gives FDA authority to expend PDUFA resources on
risk management and drug safety activities during the approval process
and during the first 2 to 3 years following drug approval. Mr.
Chairman, your Committee played a significant role in creating and
reauthorizing PDUFA, and on behalf of my colleagues at FDA and
countless patients throughout America who benefit from the therapies
approved under the PDUFA process, I thank you for your efforts.
One of the primary goals of PDUFA was to address the significant
delay in U.S. patients' access to new medicines. The objective was to
increase benefits to patients, without increasing risks. Before PDUFA,
drug lag was a serious concern for U.S. patients and practitioners.
Life-saving drugs were available to patients in other countries months
and sometimes years before they were available in the U.S. Because of
the additional resources and process improvements implemented since
PDUFA I became law, the average FDA drug review time has declined by
more than 12 months.
It is important to emphasize that an recent study by Berndt, et al.
of the National Bureau of Economic Research found no significant
differences in the rates of safety withdrawals for drugs approved
before PDUFA compared to drugs approved during the PDUFA era. This
research confirms FDA's analysis on the same subject. In addition, we
are now adding black box warnings sooner than we did before PDUFA. This
indicates that PDUFA has been successful in both speeding access and
preserving safety.
In general, PDUFA authorizes FDA to collect fees from companies
that produce certain human drug and biological products. When a sponsor
seeks FDA approval for a new drug or biologic product, it must submit
an application accompanied by a fee to support the review process. In
addition, companies pay annual fees for each manufacturing
establishment and for each prescription drug product marketed. Before
PDUFA, taxpayers alone paid for product reviews through budgets
provided by Congress. Under the PDUFA approach, industry provides
additional funding in return for FDA's efforts to meet drug-review
performance goals that emphasize timelines but do not alter or
compromise our commitment to ensuring that drugs are safe and effective
before they are approved for marketing.
PDUFA III--GREATER EMPHASIS ON DRUG SAFETY
PDUFA fees are essential to our efforts to improve drug safety. Our
trained health professionals work to help ensure and improve drug
safety using a process of scientific review, monitoring, and analysis
throughout the life cycle of the drugs we approve for marketing. A
focus on safety initiates during the pre-marketing phase, when the
earliest work on drug discovery begins. As the drug development process
continues, we evaluate the safety of the therapeutic compound over a
number of years during pre-clinical testing, clinical trials involving
humans and eventually, with the submission of an NDA for FDA review.
Thanks to PDUFA, we are able to commit far greater resources to our
important safety responsibilities.
Under PDUFA III, Congress granted authority for FDA to expend user
fees for post-market safety review. FDA made this a top priority during
our PDUFA negotiations. Beginning with PDUFA III, for drugs approved
after October 1, 2002, we can spend PDUFA resources on ``collecting,
developing, and reviewing safety information on drugs, including
adverse event reports'' for up to 3 years after the date of approval.
The initiative to address drug safety for PDUFA III products helps FDA
better understand a drug's risk profile, provide risk feedback to the
sponsors and provide essential safety information to patients and
health practitioners.
From October 1, 2002, through December 31, 2004, FDA reviewed 63
risk management plans for drug and biologic products. Twenty-eight of
these related to applications submitted after PDUFA III took effect. We
also conducted pre-approval safety conferences, risk management plan
reviews, drug safety meetings, and meetings with sponsors to discuss
proposed drug supplements.
In response to PDUFA III, FDA held a public meeting in April 2003
to discuss risk assessment, risk management, and pharmacovigilance
practices. On May 5, 2004, based on the valuable information generated
through the meeting process, we published three draft guidances on
these important drug safety topics. FDA received extensive comments on
these documents, and we expect to publish all three final guidances in
the second quarter of 2005.
SAFETY ADVANCES IN FDAMA
Enacted in 1997, FDAMA has been an important addition to FDA's
legal framework. FDAMA passed following a thorough Congressional
examination of the Agency's policies and programs. It instituted a
number of comprehensive changes, reaffirmed the Agency's vital role in
protecting the public health and served as the vehicle for enacting
PDUFA II.
Pediatric Exclusivity and Safer Use of Drugs in Children
For decades, children were prescribed medications that had not been
studied for safety and efficacy in pediatric populations. As a
component of FDAMA, Congress provided incentives to sponsors to conduct
pediatric clinical trials. Section 111 of FDAMA authorized FDA to grant
an additional 6 months of marketing exclusivity (known as pediatric
exclusivity) to pharmaceutical manufacturers that conduct studies of
certain drugs in pediatric populations. The objective of section 111
was to promote pediatric safety and efficacy studies of drugs. With the
valuable information generated by these studies, the product labeling
can then be updated to include appropriate information on use of the
drug in the pediatric population. To qualify for pediatric exclusivity,
sponsors must conduct pediatric studies according to the terms of a
Written Request issued by FDA and submit the results of those studies
in an NDA or supplement.
In 2002, Congress renewed this authority when it enacted the Best
Pharmaceuticals for Children Act (BPCA). BPCA also mandates that FDA
report to the Pediatric Advisory Committee, in a public forum, any
safety concerns during the 1 year period after we grant pediatric
exclusivity. To date, we have reported safety concerns on 34 drugs at
six separate public advisory meetings.
Finally, BPCA contains important, new disclosure requirements.
Outside of BPCA, the Agency generally may not publicly disclose
information contained in an IND, unapproved NDA, or unapproved
supplemental NDA. Once FDA approves an NDA or supplemental NDA, the
Agency can make public certain summary information regarding the safety
and effectiveness of the product for the approved indication.
However, section 9 of BPCA gives FDA important new disclosure
authority. BPCA requires that, no later than 180 days after the
submission of studies conducted in response to a Written Request, the
Agency must publish a summary of FDA's medical and clinical
pharmacology reviews of those studies. Moreover, we must publish this
information regardless of whether our action on the pediatric
application is an approval, approvable, or not-approvable action. Thus
under FDAMA, information on pediatric studies conducted in response to
Written Requests was not available until after the supplemental
application was approved. In contrast, under BPCA, a summary of FDA's
medical and clinical pharmacology reviews of pediatric studies is
publicly available regardless of the action taken on the application.
Since 2002, FDA has posted the summaries of these reviews for 41
products submitted in response to a Written Request on FDA's website
at: (http://www.fda.gov/cder/pediatric/Summaryreview.htm). This
information provides a rich source of valuable safety information to
allow pediatricians to make more informed decisions about whether and
how to use these drugs in their patients.
Post-Marketing Safety Studies
On April 30, 2001, FDA's regulations implementing section 130 of
FDAMA, which requires sponsors of approved drugs and biologics to
report annually on the status of post-marketing commitments, became
effective. These regulations modified existing reporting requirements
for NDA drug studies and created a new reporting requirement for
biologic products.
FDA may request that the sponsor conduct post-marketing studies to
provide additional important information on how a drug works in
expanded patient populations or to identify safety issues that occur at
very low frequency or in special patient populations. The post-
marketing safety study obligations in section 130 are of keen interest
to patient and consumer advocates who track the completion of post-
marketing commitments and FDA's efforts to review study results and
modify drug labeling. The regulations implementing section 130 provide
FDA with a mechanism to monitor study progress through the annual
submission of study status reports. FDA posts the status of post-
marketing studies on its public website and publishes an annual summary
of industry's progress in fulfilling post-marketing commitments in the
Federal Register.
CRITICAL PATH
On March 16, 2004, FDA released a report addressing the recent
slowdown in innovative medical therapies submitted to FDA for approval:
``Innovation/Stagnation: Challenge and Opportunity on the Critical Path
to New Medical Products.'' The report describes options to modernize
the medical product development process to try to make it more
predictable and less costly. The report focuses on ways that FDA could
collaborate with academic researchers, product developers, patient
groups, and other stakeholders to make the critical path much faster,
predictable, and less costly.
Enhancing the Safety of Medical Products
During drug development, safety issues should be detected as early
as possible. However, because of limitations of current methods, safety
problems are often uncovered only during clinical trials or,
occasionally, after marketing. Despite efforts to develop better
methods, some tools used for toxicology and human safety testing are
outdated. Clinical testing, even if extensive, often fails to detect
important safety problems, either because they are uncommon or because
the tested population was not representative of eventual recipients.
Conversely, some models create worrisome signals that may not be
predictive of a human safety problem.
There are opportunities for developing tools that can more reliably
and efficiently determine the safety of a new medical product. To meet
this challenge, FDA has called for a new focus on modernizing the tools
that applied biomedical researchers and product developers use to
assess the safety and effectiveness of potential new products. Many of
these tools--diagnostics such as pharmacogenomic tests and imaging
techniques--would also be used after marketing to monitor safety in the
real world clinical setting. The Critical Path report describes
opportunities for FDA, working with academia, patient groups, industry,
and other government agencies, to embark on a collaborative research
effort. The goal is to create new performance standards and predictive
tools that will provide better answers about the safety and
effectiveness of investigational products, to do this faster and with
more certainty, and to enhance the safety of these products in the
clinic.
In addition to improved safety tools, Critical Path also focuses on
tools that will help individualize therapy. We enhance safety when the
target population does not include individuals who cannot benefit from
the treatment. For these individuals, drug exposure is all risk. Better
tools for individualized therapy will help to identify patients who
will respond to therapy. New science has provided the basic knowledge
to make these tools a reality.
Critical Path is not a fundamental departure for FDA, but rather
builds on the Agency's proven ``best practices'' for expediting the
availability of promising medical technologies. While the report
touches on all aspects of medical product development, identifying new
tools to address drug safety challenges would represent a giant step
down the Critical Path.
CONCLUSION
At FDA, providing the American public with safe and effective
medical products is our core mission. We base decisions to approve a
drug or to keep it on the market if new safety findings surface on a
careful balancing of risk and benefit to patients. This is a
multifaceted and complex decision process, involving scientific and
public health issues. The recent initiatives we have announced will
improve our current system to assess drug safety. Moreover, as we
strive for continuous improvement, we will continue to evaluate new
approaches to advance drug safety. As always, we value input from
Congress, patients and the medical community as we develop and refine
these drug safety initiatives.
Once again, thank you for the opportunity to testify before the
Committee today. I am happy to respond to questions.
The Chairman. I do want to mention that we are trying to be
very thorough in the hearing so that we can get as much
information as possible before we draft the bill. We are trying
to have some restraint, and, of course, I am calling on all
committee members to do that, and so far, we have had success
with that.
Getting back to your testimony, could you describe the
vetting process the FDA uses for Advisory Committee members in
general? Were there any additional criteria for selecting
members for the Advisory Committee that examined the COX-2
inhibitors?
Dr. Kweder. The process for vetting--for members'
participation for an individual meeting is extremely
complicated and we have a whole section of our website devoted
to all the rules and regulations that are required to be met.
We can get that information for you.
I will tell you that one of the things that makes a
potential participant a valuable member of any expert committee
is their experience in drug development, drug safety
assessment, as well as clinical practice. Oftentimes, it is
research experience. Most medical researchers in this country
have at one time or another had funding from--participated in
funding from a pharmaceutical company.
In the case of this recent meeting, we had the unusual
circumstance of reviewing six COX-2 inhibitor products marketed
and not marketed by four different companies, as well as over
30 nonsteroidal anti-inflammatory drugs from numerous different
companies. There was almost not a drug company in the world
that someone didn't have to be screened for having an interest
in for this particular meeting. Our advisors and consultant
staff are experts in that and we think they did a very good job
in screening people for important conflicts of interest.
The Chairman. Thank you. Changing it slightly here, the FDA
recently published a report on the performance of drug and
biologic firms in conducting postmarketing studies. The report
indicates that of the studies concluded between October 1,
2003, and September 20, 2004, no studies were identified where
the commitment was not met. Likewise, the study indicates that
only one percent of the pending studies for drug applications
were delayed.
In your opinion, does this report indicate that
pharmaceutical firms are meeting their postmarketing study
commitments in a timely manner?
Dr. Kweder. To the extent the data tells us that, I think
that things have improved significantly. The number of
postmarketing study commitments that were completed in fiscal
year 2004 was double that number from 2003.
The Chairman. Thank you. We have heard that the FDA
determines safety using a risk-benefit analysis. Can you
explain what factors the FDA considers in its risk-benefit
analysis, and in your opinion, is it ever appropriate to assess
the safety of a drug product without weighing both its risks
and its benefits?
Dr. Kweder. Let me start with the last question. I think it
is never appropriate to look at only benefit or only safety.
There is always a judgment.
First, let me say that the first thing we look at is what
is the risk itself? Is the risk or the safety concern something
that is an annoyance or is it something that is significant and
important? Is it an itch that will go away, or is it liver
failure? Those are very, very different considerations. So what
is the risk?
How common is the risk from what we can tell? Does it occur
in one in 100 people or one in five million?
We look at what is the product--what is the disease or the
condition being treated? Again, is it an annoyance or is it
something important? So what the disease is it is treating is
an important consideration.
We look at how beneficial is the drug? What do we
understand about if this drug were not available, what are the
alternative treatments that might be available? How good are
they?
We also factor in how certain we are of the risk, given all
of those other considerations, and if the disease were not
treated, particularly for something which there is no
alternative therapy available, what are the consequences to the
patient of that?
In order to make these kinds of assessments, it really
takes expertise from a number of different people, experts who
understand how benefit was determined in the first place and
what those studies showed. It also takes expertise from people
who think about drug safety data in the grand scheme of the
population and how certain we are depending on how a risk was
detected and what other sources of information might be able to
help us. And it really also takes the important perspective of
experts who understand how medicines are used by doctors and
patients and the consequences of taking a product off the
market compared to having choices available on the market.
These are tough decisions. If there was a magic formula,
our job would be easy, and honestly, I probably wouldn't work
at FDA. It wouldn't be interesting. And people are always
looking for, what is the magic equation? There just isn't one
and it takes--no one person makes a decision. Someone has to
take responsibility, but it takes lots of people coming to the
table with different perspectives and expertise to decide what
to do.
The Chairman. You mentioned that no one person can make the
decision, and, of course, it isn't one person. There has been
discussion about having a separate safety approval oversight
from the original drug approval. In light of what you just said
on the process, is it possible to have those as two distinct,
separate entities? Will not the safety hold up the approval----
Dr. Kweder. Sure.
The Chairman. And approval hold up the safety?
Dr. Kweder. I actually can address that. I have been at FDA
a long time. I graduated from college when I was 12.
[Laughter.]
I actually spent 2 years in the early 1990s as the Director
of what is now our Office of Drug Safety. So I have had the
opportunity to work, spending most of my day thinking about
safety issues and postmarketing surveillance, as well as from
the drug development side.
In fact, our Office of Drug Safety is independent. It is a
completely separate office from the Office of New Drugs that
does the pre-market reviews. On the other hand, having those in
the same Center is one of the most important things that we can
do to ensure that we are communicating and have a full
understanding of risks and benefits and the judgments that
ultimately have to be made about what would happen with a
product.
The Chairman. Thank you. At this point, I am going to turn
over the gavel to Senator Burr, who will continue here, because
I have to go see a buffalo about a nickel. I will be back.
Senator Kennedy. Senator, I want to tell you, I can give
you a report on your buffalo. I just saw the buffalo outside of
the Russell Building, and behaving reasonably well to date, so
I am sure he is waiting for your appearance.
[Laughter.]
The Chairman. That is because he is from Wyoming.
[Laughter.]
Senator Burr. [Presiding.] I thank the chair and encourage
the chairman not to wrestle that buffalo.
[Laughter.]
Dr. Kweder, welcome. Thank you for your testimony.
Dr. Kweder. Thank you.
Senator Burr. At this time, the chair will recognize
Senator Kennedy for questions.
Senator Kennedy. Thank you very much, Mr. Chairman.
The failure to recognize the safety problems with the COX-2
drugs may have resulted in tens of thousands of patients
suffering heart attacks or strokes and an unknown number of
deaths. Can you assure the committee and the American people
that this kind of lapse will never happen again?
Dr. Kweder. Senator, we were concerned about the potential
safety risks of the COX-2s, and in particular, Vioxx, from the
time the first application came in. We held specific public
meetings to discuss those risks with experts. When the first
data suggesting that there was a risk came out in a clinical
trial in 2000, shortly thereafter, when we had had an
opportunity to review the data, we held another expert Advisory
Committee, including expert cardiologists and gastrointestinal
experts and a number of other safety experts to address
specifically what reactions we should take in order to
determine whether that risk was, indeed, as what it seemed to
be from that one clinical study.
So our actions following that were to work with the company
as the committee asked us to do to try and further investigate
this potential risk, which we did, through clinical trials, as
well as to label the product for--to assure that clinicians in
practice would understand that the risk existed.
I would say that the lapse from my perspective was the
delay that it took to get that information into labeling--it
took over a year--as well as once it was in labeling, the
failure of that information somehow to be in the forefront of
the consciousness of the prescribing clinician.
Senator Kennedy. This goes back to 2000. As I understand, I
think Dr. Crawford told me it was Merck that called Dr.
Crawford and indicated they were the ones that were going to
take it off the market.
Dr. Kweder. In 2004?
Senator Kennedy. Yes.
Dr. Kweder. What happened was the----
Senator Kennedy. I mean, we are trying to find out. I don't
want to use all my time here, now----
Dr. Kweder. Yes. No, they did----
Senator Kennedy. Doing a case study on it.
Dr. Kweder. It was one of the studies----
Senator Kennedy. This is enormously important and
significant.
Dr. Kweder. Absolutely.
Senator Kennedy. There is a lot of time lag. We understand
that you can't press buttons in terms of clinical trials and
review, but I think there is this time lag and we want to try
to make sure that this kind of challenge isn't going to happen
again, that the steps are being taken in the Department.
Dr. Kweder. Absolutely.
Senator Kennedy. Maybe you could give us some analysis
about how we can correct the delay----
Dr. Kweder. Yes. I think one of the ways that----
Senator Kennedy. And hope that we can assure that the FDA's
intentions to address the safety issues are going to work.
Dr. Kweder. Yes.
Senator Kennedy. That is what we are interested in and I
would be interested if maybe you could submit some information
to give us those kinds of assurances.
For most people who took the COX-2 drugs, it didn't work
any better than the older, cheaper drugs that are much safer.
So why were so many people taking the COX-2 drugs when there
doesn't appear to be much of a medical need for them to do so?
Was this the pressure from direct-to-consumer advertising? Were
there inducements to doctors to prescribe them? Are there other
drugs on the market right now that patients are being induced
to buy and that doctors are being induced to prescribe through
clever advertising or high-pressure sales?
Dr. Kweder. I can't--I certainly don't know what
inducements there were for doctors to prescribe them. I think
as a physician and as a member of this society, we always tend
to think that new must be better, which is certainly not the
case, and the company was never, ever allowed to make claims
that they were better, at least in terms of how effective they
were.
Several of the reasons that they may have been used more
often is because they are, for the most part, once a day or
twice a day, where the older drugs are required to be taken
many times a day, and also because there was a great hope that
these would have fewer side effects and people would be able to
tolerate them better without the stomach upset that some of the
other products may have carried.
There certainly was a great deal of marketing, both to
health care providers and to consumers, of these drugs.
Senator Kennedy. You indicated in response the follow-up
that is being done by various drug companies, and I think you
had indicated that there were two times as many responses as
there were in 2003.
Dr. Kweder. Yes.
Senator Kennedy. As I understand it, we have different
kinds of reports. We have one where we have an adverse reaction
and we have another whether the drug companies are going to
have to do the clinical trials about safety issues.
You say that the manufacturers are required to submit
periodic safety reports to the FDA about drugs, and yet,
generally, as I understand it, the FDA has no authority to
require the companies to perform safety trials after approval.
Is that right?
Dr. Kweder. Yes, I think--and you are talking about two--
there are two different things.
Senator Kennedy. That is right.
Dr. Kweder. Yes, that is correct.
Senator Kennedy. If you could----
Dr. Kweder. That is correct.
Senator Kennedy. Spell out those two different
requirements, what you have authority for and the degree of
cooperation----
Dr. Kweder. Sure.
Senator Kennedy. And what you don't have authority for and
whether you think you ought to have the authority.
Dr. Kweder. OK. First, the safety reports. Companies are
required by law to submit to us reports on all new information
they have about the safety of their products--adverse reactions
that are reported to the company, most of which are reported to
companies, new studies that have something to say about the
safety of their product, maybe that weren't done by them but
were done by somebody else. That information regarding safety
must be submitted on a periodic basis to the agency.
For important safety issues, like really severe or life-
threatening events, those reports come in all by themselves in
a very short period of time. They are called 15-day reports.
But also on a periodic basis, companies are required to give a
comprehensive assessment of their safety, usually through
annual reports, or actually more often quarterly reports for
the first 3 years of marketing.
That is separate from any requirements they have to
actually conduct specific studies of postmarketing safety, such
as an additional randomized clinical trial or an epidemiology
study that we might ask them to do. We don't have the authority
to tell them, you must do this particular trial. That is an
authority we don't have.
Now, we certainly have a fair amount of influence in
convincing them to do some of these studies, and we are, for
the most part, reasonably successful. But we don't have the
authority to say, you must do the trial.
Senator Kennedy. My time is up. I would like to get into
this area in a little greater detail about whether this could
be very important authority that could enhance the kind of
safety issues. If I could just have 15 seconds more, Mr.
Chairman.
Senator Burr. I yield to the gentleman.
Senator Kennedy. I think there is a reasonable question
where people would say, shouldn't we buttress inside safety and
give all authority there to the FDA--rather than having an
outside Advisory Committee. But as I understand, your point is
that there are basically two different functions and that the
public is best served by having two different functions, one
within FDA that is going to deal with the various technical,
clinical aspects in terms of safety, and then having an outside
group that takes a de novo view of it and makes an independent
evaluation of the issue.
Dr. Kweder. That is actually what we are proposing in our
program, is to have an independent board of inside and outside
people to oversee the process, which we think will be very
helpful.
Senator Burr. The Senator's time has expired and the chair
would recognize Senator Hatch for questions.
Senator Hatch. Welcome to the committee.
Dr. Kweder. Thank you, sir.
Senator Hatch. I am happy to see you again.
Dr. Kweder, as the senior member of the Senate Finance
Committee, I had the opportunity at a hearing you testified at
last year on drug safety issues. One question I would like to
pose to you is this. Isn't it true that all pharmaceutical
products have, to some degree or not, a degree of risk?
Dr. Kweder. Yes, sir, it is true.
Senator Hatch. In your testimony, you State that the FDA,
quote, ``grants approval to drugs after a sponsor demonstrates
that their benefits outweigh their risks for a specific
population and specific use and that the drug meets the
statutory standard for safety and efficacy,'' unquote.
Would you just please go into a little more detail with
regard to the statutory standard for safety and efficacy?
Dr. Kweder. Well, I won't go into too much detail, but----
Senator Hatch. We could spend all day on that.
Dr. Kweder. We could spend all day on that. In general,
while a product is in development, we are working with the
company to define what it is that would show that a drug works.
What is its intended use? And based on what the company thinks
or it looks like the drug would be useful for, how to do the
studies to show that that use is beneficial. And companies
spend a great--and the experts that they work with, as well as
the agency, spend a great deal of time carving that out for a
particular product and a particular clinical need.
As those studies are being developed, we are also looking
very carefully at what the risks of the drug might be. We have
some clues from animal studies, but they never tell us the
whole story. And ultimately, given the benefit that might be
there, does the drug have a reasonable balance of safety?
You know, you can take the same drug that might be being
studied to treat a minor annoyance condition--let us just pick
something, tension headaches--and that drug turns out in
clinical studies to have a risk of liver failure. The same drug
is also being studied to treat people with strokes, okay, and
it has a benefit in prolonging life in people with strokes, but
it has this same liver toxicity because that is inherent in the
drug. But it is so remarkably effective in preventing mortality
with strokes, we might say--this is all hypothetical--that the
liver risk is worth it because the benefit is enormous in that
population of patients. However, risk of liver failure is
completely unacceptable no matter how effective this drug is in
treating people with tension headaches because tension
headaches go away on their own.
Senator Hatch. Yes.
Dr. Kweder. So, those are the kinds of judgments that we
have to make.
Senator Hatch. Do you know of any drug that has been
approved by FDA that is risk-free?
Dr. Kweder. None that I am aware of.
Senator Hatch. I am not aware of any, either.
Now, I would like to discuss the postmarket drug safety
program. In your testimony, you talk about the FDA evaluating
and responding to events reported by physicians, their
patients, or drug manufacturers. How many times per month or
per year is the FDA contacted by individuals who want to report
adverse events, and how do you get the word out to people that
they are to report these events to the FDA?
Dr. Kweder. We receive about 400,000 spontaneous reports of
adverse events a year, and that is a growing number. We get a
growing number of reports. We always need more.
One thing that we know is that when there are programs to
actively encourage reporting, we get more reports. When we
launched the MedWatch program back in the early 1990s, the
number of reports--which was really kind of a public awareness
campaign to encourage reports--our reports improved and the
quality of them improved.
We try as best we can to encourage reporting through drug
labels, any public health announcement that we do, but we
always need more. There are a lot of barriers to reporting. We
have tried to address some of those by making it easier for
people to report, by making it simpler and more convenient, but
we can always use more.
Senator Hatch. I want to commend the FDA for initiating the
five-step plan to strengthen the FDA's drug safety program. You
mentioned the Institute of Medicine study to evaluate the
current drug safety system. When will that study be done?
Dr. Kweder. We have actually begun planning with the
Institute of Medicine. We expect the study to begin--my
understanding is that it won't be for another 6 months for them
to obtain a panel of experts to begin the process.
Senator Hatch. Thank you. My time is up, Mr. Chairman.
Senator Burr. I thank the Senator.
Senator Murray for questions?
Senator Murray. Thank you very much, Mr. Chairman, and I
would ask unanimous consent to put my statement in the record,
my opening statement.
Senator Burr. Without objection.
[The prepared statement of Senator Murray follows:]
Prepared Statement of Senator Murray
Mr. Chairman, I want to thank you for scheduling these
important FDA drug safety hearings.
As the committee of jurisdiction over FDA, it is imperative
that we have a better understanding of the challenges facing
the FDA approval and the post-market surveillance process.
These hearings are an important first step in determining what
legislative remedies are necessary to protect the integrity of
the FDA drug approval process, as well as the integrity of this
process. We also owe it to the millions of patients who depend
on the FDA to protect their health and safety.
Back in 1997, when I was a new member of this committee,
one of the challenges I faced was reauthorization of PDUFA and
FDA modernization and reforms. It had become clear that
unnecessary bureaucratic delays were jeopardizing access to new
life-saving drugs and therapies. Unnecessary and burdensome
regulatory processes were also adding to the cost of new drugs
and treatments. FDA needed additional resources and authority
to meet the challenges of new biotech and biomedical advances.
However, it was imperative that we did not jeopardize the
underlying public health mission of the FDA.
Striking that balance and developing real reforms that
improved performance, and that reduced unnecessary delays, was
a difficult task.This committee has a long tradition of working
in a bipartisan manner to develop real, effective solutions for
improving FDA. I look forward to working with the Chairman in
developing necessary remedies to protect the FDA drug approval
process and in restoring greater patient confidence in this
process.
I want to thank today's witnesses, and I am particularly
pleased to welcome to this committee Dr. Thomas Fleming,
Chairman of the Department of Biostatistics at the University
of Washington.
Dr. Fleming served on the Drug Safety and Management
Advisory Committee that recently met to discuss the status of
Vioxx and other COX2 drugs. He brings to the HELP Committee 28
years of experience in collaborating on clinical trials and has
nearly 20 years of service on FDA Advisory Committees. I
appreciate his willingness to testify and offer his insights
into what actions Congress and the FDA need to take to protect
the public health.
I really appreciate having this hearing today. I think it
is really important that this committee focus on how we can
better understand the challenges before FDA and determine what
legislative remedies are necessary. So I appreciate the hearing
today.
I especially want to thank Dr. Thomas Fleming, who is the
Chairman of the Department of Biostatistics at the University
of Washington, who will be testifying in the next panel. He has
served on the Drug Safety and Management Advisory Committee
that met to discuss Vioxx and other COX-2 drugs and brings 28
years of experience in collaborating on clinical trials and 20
years of service on FDA Advisory Committees, so I really
appreciate him traveling here and look forward to his
testimony.
But Dr. Kweder, I did want to follow up on Senator
Kennedy's question because I think it is important that we
understand what the current process is and if there are
problems with it, what we need to do legislatively. He asked
you about the FDA clinical trials that Merck shared with you,
the clinical trials on Vioxx, and I think it was 2002 when the
larger study was done on Alzheimer's patients that was given to
you and you said there was a delay in getting a warning on
labels after that. What caused the delay?
Dr. Kweder. Well, what caused the delay is that we don't
have the authority to tell a company, this is how your label
has to look. This is the language that needs to go into your
label. Here is where it goes, end of story. We have to
negotiate with the company the specific language of how things
should be worded, placement, those kinds of things, and----
Senator Murray. So you were talking to them and making----
Dr. Kweder. Correct.
Senator Murray. Did they reject that warning? Did Merck
reject the warning?
Dr. Kweder. You know what? They rejected many of our
proposals, and we similarly rejected many of the proposals--
most of the proposals they sent to us.
Senator Murray. Does FDA need authority, in your opinion,
to change labeling?
Dr. Kweder. I think that stronger ability to require
changes in labeling would be very helpful.
Senator Murray. On the clinical trial issue, FDA cannot
order a company to do a clinical trial, is that correct?
Dr. Kweder. That is correct.
Senator Murray. Is that something that would, if you had
broader authority on that----
Dr. Kweder. I think that we actually have a fair amount of
influence over getting a company to do a clinical trial. There
are circumstances where being able to require it would be very
helpful, but I think those are not on a daily basis. It would
be under extreme circumstances.
Senator Murray. So some kind of authority based on some
premise would be helpful, or do you want broad authority? What
are you thinking?
Dr. Kweder. Well, I think that is something that would need
much further discussion about what the limits of that might be.
Senator Murray. How about changing labels? You don't have
the authority to change labels, correct?
Dr. Kweder. We do not have the authority to require a
specific label change. Most of the time, I have to say, the
discussion with companies about changes in labels doesn't take
as long as it took for that particular one. Usually, you know,
it is just a matter of a few back-and-forths and just getting
the language right and making sure it is clear. It is usually
not a problem.
Senator Murray. How about ordering a company to withdraw a
drug? Do you have that authority?
Dr. Kweder. We have the authority--the authority that we
have--the specific authority we have is much more convoluted
than that, but when we tell a company that we think their
product needs to be withdrawn, that is usually not an issue. It
usually happens pretty readily. And usually, the circumstances
are such that the company is in agreement. If the FDA goes
forward and says to the public that we think a drug should be
withdrawn, the handwriting is on the wall.
Senator Murray. OK. Does FDA have other steps it can take
to alert the public to any kind of----
Dr. Kweder. Actually, one of the things that we are--we
have some. We can issue public health advisories. One of the
proposals that Secretary Leavitt announced last week was that
we would develop what we would call a drug watch page, where we
would advise the public of new, ongoing, emerging safety issues
as well as things that we are concerned about, because putting
things into a label does take time. Even if we come to
agreement with a company, it can take months for them to
actually get it printed and onto the shelves.
So, for example, in the Vioxx situation, having an ability
to have a drug watch page where we could have put the
information about the clinical trial when it became available
would have alerted the public to that well in advance of the
labeling change being--the actual details of a labeling change
being worked out. It would have been very, very useful.
Senator Murray. How long before that drug watch program can
be put into place?
Dr. Kweder. We are in the process of developing processes
and procedures for that that will be made available and will
seek public comment on those. Our goal is not to blindside the
industry on this, which is, of course, a concern. Most of the
kinds of things that would be there would be things that they
are aware we are working on. These wouldn't be surprises.
Senator Murray. Thank you very much. I appreciate your
testimony.
Senator Burr. I thank Senator Murray.
The chair would recognize himself. Again, welcome, Dr.
Kweder. Let me ask you, can a drug be approved without a
clinical trial?
Dr. Kweder. Well, there may have been some back in the
1920s, but not today.
Senator Burr. Not today.
Dr. Kweder. Not today.
Senator Burr. So the questions that deal with clinical
trials, there are clinical trials that are done on all
pharmaceutical products that are approved at the FDA?
Dr. Kweder. That is correct.
Senator Burr. The COX-2 issue was something that was raised
in a study that was looking at other potential indications for
COX-2?
Dr. Kweder. Actually, the first study was looking at a
safety--actually looking at a safety issue, but it wasn't heart
safety. It was looking at stomach bleeds.
Senator Burr. And that is where we saw the first----
Dr. Kweder. Correct. Yes.
Senator Burr. Let me ask you from a standpoint of labeling,
did the COX-2 drugs refer to any cardiovascular concerns on the
original label?
Dr. Kweder. I am trying to remember. I do believe--no, I
don't think so. No, they did not.
Senator Burr. OK. So this was a whole new area?
Dr. Kweder. It was a whole new area, and actually as we
reviewed, particularly Vioxx, as we reviewed that drug, our
medical people looked very, very carefully for any evidence of
heart problems because of what was known from test tube data
about some potential and could not find any.
Senator Burr. Let me go to an area of benefit, if I could,
because the statement was made that few patients benefited from
COX-2 inhibitors. Do you agree with that statement?
Dr. Kweder. No, I don't.
Senator Burr. Is there not a population out there that has
benefited from this innovative therapy?
Dr. Kweder. You know, the options to treat pain are not
great options, and so anybody who has taken one of these
medicines and had relief of their pain, in my estimation, has
benefited from the drug.
Senator Burr. My dad is 83 and after this all became
public, for 3 weeks, I saw him limp. And when finally I asked
why, he said, ``Well, I am off my Celebrex.'' And I said, does
anything else work? He said, ``No, that was the only thing.''
And I said, then go back on it. At 83 years old, you have to
determine whether the ability to be mobile is in the best
interest of your overall health, and today, he doesn't limp
because this drug is available to him. Clearly, we want him to
make an educated decision based upon all the facts.
Let me ask you about patients in general. Do you find that
with the electronic access that patients have that they are
informed or uninformed today about not just the capabilities of
the drugs, but side effects, as well?
Dr. Kweder. You know, I actually have the privilege of
practicing medicine on a weekly basis and teaching medical
students and residents and I am amazed at how savvy many
patients are about their medicines and the risks and benefits
of them. I don't think it is enough. I think we need to find
additional. Electronics are the number one way that they are
finding information on their own and we need to keep that
information coming.
Senator Burr. Should we believe today that every patient
who has a high cholesterol level in their blood takes a
cholesterol-busting drug?
Dr. Kweder. They don't.
Senator Burr. The likelihood is that there is some piece of
information that they read about a drug, that they hear, or
ultimately a health care professional identifies a problem, and
if they go on that drug, what is the benefit to us?
Dr. Kweder. The benefit can be substantial. Most of the
cholesterol agents have shown--many of the cholesterol agents
have shown an improved length of life, decreased mortality.
Senator Burr. As well as overall health care savings to
the----
Dr. Kweder. Absolutely. Unfortunately, some people still
aren't getting care for their--taking care of themselves.
Senator Burr. I think it is important to point this out in
the context of some of the, at least assumptions that some have
led to about direct consumer advertising having no patient
benefit. In fact, it does have a patient benefit because in
many cases, that is the only way to reach certain individuals.
Let me go to an area that Senator Kennedy was in and that
was to ask you to clarify a bit further the proposal on this
new safety mechanism or review mechanism at FDA. Clearly, I am
one that for the last 7 years has questioned MedWatch, only
because it was designed with the primary piece of information
coming from physicians. At a period where we were decreasing
rapidly the reimbursement of physicians, and the ability to
spend time with patients became less and less based upon the
reimbursement we enforced, in many cases. I think to believe
that doctors would fill out adverse reaction sheets and
actually submit them to the FDA, we were dreaming. So I think
we have reached the world of reality now with the creation of
an entity within FDA to review postapproval pharmaceutical
products. But I want to make sure that I clarify the record.
Your inside-outside process, this is an entity within the
FDA to look at postapproval review of drugs, to use individuals
within the FDA that were not reviewers of that application, and
to use outside individuals to come in and be part of your
inside review? This is not the creation of an outside entity
outside of the FDA, correct?
Dr. Kweder. Yes, I think that is a good way to characterize
it.
Senator Burr. It is using the talents of----
Dr. Kweder. Using the talents of--right, inside people who
have not been involved, and I think that is a really important
component is taking people who are at an arm's length from the
workings of the data itself, who have perspective, who have
some broader perspective.
Senator Burr. How much money do you need to improve drug
safety monitoring?
Dr. Kweder. Well, you know, we have--the President's budget
for fiscal year 2006 earmarks $5 million, an additional $5
million for drug safety. That is a good down payment. There are
some--I can't give you an exact figure. There have been--this
committee has looked at this in the past. I know that there is
a letter that was in response to an inquiry of this type from
Senator Jeffords--I believe it was in 2000 or 2002, we can get
that for you--where there is a much more detailed estimate of,
over time, the kind of investment in the system it will take
for postmarketing safety and the life cycle of a drug and those
assessments to keep pace with the increasing dependence, which
is not a bad thing, of our society on medicines to stay
healthy.
Senator Burr. Dr. Kweder, I thank you. I don't see any
members or Senators who have not asked questions. Hearing none,
I would once again like to thank you for your service and thank
you for your testimony today.
At this time, I would call up the second panel. Let me
introduce those who are on our second panel.
First, Ms. Nancy Davenport-Ennis, CEO of the National
Patient Advocate Foundation. Ms. Davenport-Ennis is testifying
today in partnership with Friends of Cancer Research. Nancy is
a cancer survivor and founding Executive Director of the
National Patient Advocate Foundation, a policy organization
that seeks to improve access to care through regulatory and
policy initiatives at the State and Federal levels. Her
testimony will focus on the advances in the drug approval
process that have helped speed new therapies to market and how
she believes patients have benefited from this.
Dr. Thomas Fleming is a professor in the Department of
Statistics and Biostatistics and is Chairman of the Department
of Biostatistics at the University of Washington. Dr. Fleming
is a member of the FDA's Advisory Committee on Cardiovascular
and Renal Drugs and was a member of the joint committee
convened to examine the COX-2 arthritis drugs. Dr. Fleming will
offer his views on drug safety and risk-benefit analysis.
Dr. David Fassler is a Clinical Associate Professor of
Psychiatry at the University of Vermont College of Medicine and
Clinical Director of the Otter Creek Associates in Burlington,
VT. Dr. Fassler will discuss the FDA's decision to require
black box labeling on anti-depressants for children last year
and he will bring a clinician's perspective to the impact of
that decision.
Dr. Scott Gottlieb is a physician and author of the Forbes-
Gottlieb Medical Technology Investor. He is a former senior
official at the FDA and currently a resident fellow at the
American Enterprise Institute here in Washington. Dr. Gottlieb
will discuss his ideas for improving drug safety, including
using new information tools to improve the process for
postmarketing surveillance.
Ms. Abbey Meyers is a founder and President of the National
Organization for Rare Disorders, a coalition of national
voluntary health agencies and clearinghouse for information
about these little-known illnesses. Ms. Meyers is considered
the primary consumer advocate responsible for passage of the
Orphan Drug Act, the Rare Disease Orphan Products Development
Act, and the Rare Disease Act. Ms. Meyers will discuss her
perspectives on the FDA drug approval process.
Due to the snowstorm, Ms. Meyers is unable to be here in
person, but if you will notice that microphone in the middle of
the table, she is connected technologically through that
conference phone and we will have her participate in as much of
this as possible. Ms. Meyers, can you hear us?
Ms. Meyers. [By telephone.] Yes, I can. Thank you.
Senator Burr. Wonderful. I love it when these things work.
Mr. William B. Schultz is a partner in the Washington, DC
law firm of Zuckerman Spaeder. Prior to joining Zuckerman
Spaeder, Mr. Schultz held the position of Deputy Assistant
Attorney General, where he supervised all appellate litigation
conducted by the Civil Divisions of the U.S. Department of
Justice in the Department's lawsuit against the tobacco
industry. Mr. Schultz also served as the FDA's Deputy
Commissioner for Policy from 1994 to 1998. Mr. Schultz will
discuss his ideas for FDA reform. Bill, it is good to see you
again.
At this time, why don't we start at the left. The chair
would recognize Ms. Davenport-Ennis for your opening statement.
STATEMENTS OF NANCY DAVENPORT-ENNIS, EXECUTIVE DIRECTOR,
NATIONAL PATIENT ADVOCATE FOUNDATION, WASHINGTON, DC; THOMAS R.
FLEMING, PROFESSOR AND CHAIR, DEPARTMENT OF BIOSTATISTICS,
UNIVERSITY OF WASHINGTON, SEATTLE, WA; DAVID FASSLER, M.D.,
CLINICAL ASSOCIATE PROFESSOR, DEPARTMENT OF PSYCHIATRY,
UNIVERSITY OF VERMONT, COLLEGE OF MEDICINE, AND CLINICAL
DIRECTOR, OTTER CREEK ASSOCIATES, BURLINGTON, VT, ON BEHALF OF
THE AMERICAN ACADEMY OF CHILD AND THE ADOLESCENT PSYCHIATRY AND
AMERICAN PSYCHIATRIC ASSOCIATION; SCOTT GOTTLIEB, M.D.,
RESIDENT FELLOW, AMERICAN ENTERPRISE INSTITUTE, WASHINGTON, DC;
ABBEY S. MEYERS, PRESIDENT, NATIONAL ORGANIZATION FOR RARE
DISORDERS, DANBURY, CT; AND WILLIAM B. SCHULTZ, PARTNER,
ZUCKERMAN, SPAEDER, LLP, WASHINGTON, DC
Ms. Davenport-Ennis. Thank you, Chairman Burr. I appreciate
the opportunity to be with the committee this morning and I
thank you, Senator Murray, for also being here, as well as I
would like to acknowledge the Senate staff who is here. Thank
you for the opportunity.
I would like to share with you that while, indeed, I am a
14-year cancer survivor, that is probably the least important
statement that you will hear me say today. The fact that I am
the mother-in-law to a now 29-year-old son-in-law who is a ten-
year survivor of nonHodgkin's is far more significant, not to
mention the fact that I was the aunt to a now-deceased 34-year-
old niece who battled cancer the last 5 years of her life.
I am here to talk to you today on behalf of the 3.2 million
Americans who reached out to the Patient Advocate Foundation in
the calendar year of 2004 as they were trying to seek access to
clinical trials, to newly-approved drugs, and to other areas of
health care that were made unavailable to them within the
national system.
While the American Cancer Society states to us that one in
two men during their lifetime and one in three women during
their lifetime will have cancer, I think every one of us in
this room have been touched by cancer in one way or another. I
am testifying in partnership today and collaboratively with the
Friends of Cancer Research, an organization that raises
awareness and provides public information on cancer research.
I am not here to testify as a regulatory nor a statutory
authority on how the FDA, indeed, implements its business. I am
here to speak with considerable authority on how patients view
the role of the FDA in the United States of America.
I do agree that patients concur with Secretary Leavitt as
in a speech on February 15 he characterized to the Nation that
the FDA is an icon of trust, that they are a certifier of
safety, that they are an enabler of innovation, and they are a
repository of information. Indeed, I think patients expect the
FDA to be all of that.
But patients with cancer are also very reality-focused.
They understand that there is no such thing as a drug that is
100 percent safe. They understand that for any drug that they
may take, there is also going to be a risk. They understand
that in evaluating the risk, they are always looking for the
ultimate benefit.
Cancer patients particularly understand the issue of
toxicity in newly-approved drugs, and when you are diagnosed
with cancer, often, you are making determinations of what are
your tradeoffs to take the alkolating agents that are going to
kill the disease at the same time that they are killing healthy
cells and what do you do to get through that process.
I have to bring you a story of a 27-year-old woman who
works with us in the National Patient Advocate Foundation. She
lives in Portland, Oregon, and was in nursing school at the age
of 22 observing a surgery when she collapsed unconscious on the
floor in the surgical suite. It took 6 months to determine that
she had an inoperable brain tumor that is malignant. She says
to us, in her own words, in a letter written to her doctor when
she was 24 years old, the following. ``I want to give myself
the best shot of surviving as long as I possibly can. I am
willing to deal with toxicity.''
For cancer patients and for most chronically ill patients,
time is the most critical asset that you are looking for in
your battle with a life-threatening illness. PDUFA gives us
time. PDUFA brings drugs to market more quickly. PDUFA has
reduced the standard approval time in 1993 for drugs from 26.9
months to a period of 15.4 months, and if you are fortunate
enough to have your drug move into priority review today, that
period of time for approval can be reduced to 7.7 months.
For Jarrett Minear, a young man who came to the United
States Congress with us last summer, who was diagnosed with
cancer with U.N. sarcoma at the age of 2 years old, time was
what he was looking for for the 10 years after the diagnosis,
for his disease was never stopped. He was never disease-free
for one single day for the remaining 10 years of his life. How
do we measure the impact of time for a patient like Jarrett
Minear, who, due to drug discovery, was able to live for ten
additional years after losing his leg at the age of two?
We must maintain the momentum of research. Hundreds of
products are in the pipeline now. They promise us less
toxicity. They promise us targeted therapies in fields such as
genomics and proteonomics. Patients view the FDA as the
gatekeeper to get the drugs to market safe and effectively.
The FDA has heard the patients. They have created an
Oncology Office. They have initiated an FDA-NCI task force.
They are moving ahead with the critical path objectives.
I bring to you today what I feel are five pillars of safety
reform of FDA. No. 1, patients view safety and efficacy as
united and as the foundation of the FDA process of approval.
No. 2, mechanisms to enhance existing structures for
postmarketing safety monitoring and adverse event reporting
must be explored.
No. 3, efforts to bring greater efficiency and scientific
expertise to the agency's review and monitoring processes must
continue to empower the agency to keep pace with rapid
scientific developments.
The FDA must certainly continue its collaborative work with
members of Congress, with other regulatory agencies, with
patients, physicians, and the industry to enhance the critical
path.
And finally, the FDA must be adequately resourced to
implement a comprehensive suite of reforms.
Just as I started my testimony with a quote from Wendy
Dixon, I must end my testimony with her words. In the same
letter written to her doctor 2 years ago, she said, and I
quote, ``Words cannot express how much I want to live, and
anticipating the loss of my future is devastating. I cannot
control cancer. I can control how I choose to fight it.''
Let me conclude by saying every member of your committee is
to be commended for your thoughtful and deliberative
investigation and deliberate decision making in the matter of
the FDA's drug approval process. As patients, we welcome the
opportunity to work with you collaboratively in that process.
And as patients, we know that a robust dialogue in the area of
policy and reform will at the end of the day improve access to
those drugs that are improving lives of chronically ill
patients every day.
Thank you for the opportunity to testify.
The Chairman. [Presiding.] Thank you very much.
Ms. Davenport-Ennis. Thank you.
[The prepared statement of Ms. Davenport-Ennis follows:]
Prepared Statement of Nancy Davenport-Ennis
Executive Summary
We welcome the recent discussions about how we can make our drug
approval system better, but we are mindful of the fact that patients
with life altering diseases like cancer are given hope because of the
advances of scientific discovery and development. We support reform
that makes drugs safer, but warn against those that might
unintentionally slow down the flow of better technology for treatment,
prevention, and detection--or worse, discourage their creation
altogether. The only way to prevent such unintended consequences is to
have a thoughtful policy discussion not about safety alone, but safety
in combination with benefit and efficiency. While we of course want
safer drugs, we feel that any safety reforms absolutely must be matched
with efforts to enhance the FDA's level of efficiency, scientific
expertise, and overall capacity to fulfill its numerous mandates.
I. Introduction
Chairman Enzi, Senator Kennedy, and distinguished Members of the
Committee, I thank you for the opportunity to discuss the FDA's drug
approval process, and its impact on the availability of safe and
effective tools for combating devastating diseases like cancer.
My name is Nancy Davenport-Ennis, and I am the CEO of The National
Patient Advocate Foundation. We serve as a strong advocate for policy
and legislative reforms that eliminate barriers to patient access to
treatment. Although I am not an expert in the regulatory processes at
FDA or the enabling statutes that govern them, I can speak with
considerable authority about how patients and survivors view the FDA
both today and from a historical standpoint, and what issues like risk,
benefit, and timely access mean to those suffering from life altering
conditions.
I stand before you as a two-time cancer survivor. Not only have I
experienced the burden of this disease first hand, it also has taken
the lives of close friends and family members.
I know that many of you on the committee and in the room here today
have been touched by cancer as well. According to the American Cancer
Society, one out of every two men and one out of every three women will
have some type of cancer. An estimated 564,000 people died from cancer
in 2004. Cancer has recently surpassed heart disease as the leading
cause of death among people under the age of 85.
Although I advocate on behalf of patients with a multitude of life
altering diseases, it is against this backdrop of cancer's enormous
burden and threat that I would like to offer the committee my thoughts
on the FDA's approval process. I would also like to acknowledge that my
testimony was developed in partnership with my colleagues at the
Friends of Cancer Research--a non-profit organization that raises
awareness and provides public education on cancer research in order to
accelerate the Nation's progress toward better tools for the
prevention, detection, and treatment of cancer.
Both of our organizations take pride in knowing that we work on
behalf of patients not only to improve access and quality of care, but
also to support a strong national commitment to the research and
development necessary to produce innovative medical tools that are both
safe and effective
II. Understanding the Cancer Perspective on Safety and Efficacy
Cancer is a cellular disease that begins in the body long before
physical symptoms are usually expressed. Because it is difficult to
catch many cancers early (when the disease is often easier to treat and
survival rates are typically much higher), many diagnoses come in the
later stages of disease where the symptoms are rapidly becoming more
acute and the long-term survival prospects are grim. The conventional
way of stopping the cancerous cells from spreading is to eradicate them
either through surgery, radiation therapy, chemotherapy, or some
combination of these options. Many of the cancer drugs used to stop the
disease from spreading are unable to discriminate between the cancerous
cells and the non-cancerous cells. A great number of healthy cells are
consequently destroyed in the treatment process, which can bring
uncomfortable and sometimes painfully disabling side effects. Thus,
cancer often presents the patient and the physician with the painful
tradeoff between burden of treatment and burden of disease.
Cancer patients understand all too well that there is no such thing
as a drug that is 100 percent safe. Virtually all approved drugs and
biologics have near term side effects and carry some risk. Most agents
also pose known and unknown risks associated with chronic use and
delayed toxicity. The severity of those side effects and the level of
risk will vary from person to person, and from agent to agent. The
question is not whether a drug is completely safe or completely
effective, but rather how effective is it compared to how safe it is.
This risk-benefit balance is the essence of the FDA's review process.
The agency evaluates the risk versus the benefit of a proposed
product using a scientifically derived process conducted by experts
with the knowledge and judgment necessary to assess the balance between
the two. Most importantly, these experts typically have a working
knowledge of the condition the product is designed to address so the
impact of disease is not overlooked when considering safety and
efficacy.
The FDA's review of oncology products differs from its review of
other medicinals in that efficacy is often of greater concern than
toxicity. While safety is always considered in the review and product
label, significant toxicity is generally considered acceptable for
oncology drugs given the severe and often fatal nature of the disease
being treated.
This approach to the review of oncology products is generally
consistent with the manner in which cancer patients and their
physicians select from a complex array of treatment options. The safety
of a drug or other treatment option is not considered in isolation, but
rather the risk of side effects is weighed against the potential
benefits a particular course of treatment may provide compared to the
risk from spread of disease. The decision about whether or not to
deploy powerful and sometimes risky medications in an effort to improve
the life of a cancer patient ultimately rests with that particular
patient and their prescribing physician.
But because the burden of cancer is usually far more damaging and
toxic than the interventions used to stop it, many patients and their
caregivers place a premium on the rate at which cancer products are
approved and the subsequent access to those products.
As a former cancer patient, I can assure you that time is a very
precious commodity to someone diagnosed with cancer. The FDA's capacity
to effectively evaluate safety and efficacy is just as critical as the
speed at which that evaluation is conducted. When you are suffering
from cancer and your expected life span may be months or even weeks,
you shouldn't have to wait any longer than is necessary for the FDA to
approve new medical products.
It is for that reason that many advocacy organizations across the
disease community were so supportive of the Prescription Drug User Fee
Act (PDUFA).
III. The Impact of PDUFA
PDUFA initially had 2 primary objectives: (1) reduce the time
required for FDA review of new drug and biological product
applications, and (2) thereby enable patients to have earlier access to
new therapies. Under PDUFA, the FDA collects user fees from industry to
supplement annual appropriations for review of new drug applications.
According to the Government Accountability Office (GAO), between 1993--
when PDUFA was first implemented--and 2001, FDA utilized user fees to
increase its medical and scientific drug review personnel by 77
percent. Thanks to the additional resources and staff provided by this
legislation and its subsequent versions, the agency has cut nearly in
half its 27-month median approval time for standard drugs. This
accomplishment means that patients gain access to new drug therapies
significantly sooner than they otherwise would.
Based upon an analysis of data available on the FDA's website, the
agency approved 953 new drug applications (NDAs) between 1993 and 2003.
The average total time for the approval of those applications that
underwent ``standard review'' (745 of the 953) was 26.9 months in 1993
compared to 15.4 months in 2003. The average total time for the
approval of those applications that underwent ``priority review'' (208
of the 953) was 16.3 months in 1993 compared to 7.7 months in 2003.
Pursuant to the Food and Drug Administration Modernization Act (FDAMA)
of 1997, ``priority review'' is a designation intended for those
products that address unmet medical needs.
For those drugs classified as new molecular entities (NMEs), a term
used to describe an active ingredient that has never been marketed in
this country, the agency approved 321 applications between 1993 and
2003. The average total time for the approval of those NME applications
that underwent ``standard review'' (192 of the 321) was 27.2 months in
1993 compared to 23.1 months in 2003. The average total time for the
approval of NME applications that underwent ``priority review'' (129 of
the 953) was 14.9 months in 1993 compared to 6.7 months in 2003.
Thanks to improvements made in the pace of the FDA's review process
over the past decade or so, thousands of cancer patients have had
earlier access to new cancer treatments. Consequently, many cancer
patients' lives have been extended or their quality of life improved.
For example, according to information found in the FDA's fiscal
year 2006 Budget Summary:
``a new biologic for the treatment of breast cancer (Herceptin/
trastuzumab) was approved by FDA in less than 5 months. This drug took
18 months to be approved in Europe. There were an estimated 10,000
American patients with advanced breast cancer who received this new
treatment (Herceptin/trastuzumab) during the time that FDA might have
still been reviewing the application, had it not been for the
improvements made possible with the additional funds under PDUFA. This
added an estimated 2,300 years of life to the population who had access
to the new treatment (Herceptin/trastuzumab) following its market
approval in May of 1998.''
In making it possible for drugs deemed safe and efficacious to make
it to market more quickly, PDUFA has made the difference between life
and death for many patients with cancer or other life-threatening
illnesses.
IV. We Stand on the Threshold of Incredible Advances in Cancer Research
We are entering an especially exciting time with respect to the
development of innovative drug treatments. In recent years, the FDA
approved several pharmaceutical products that treat cancer in entirely
new ways, such as Avastin and Erbitux for treatment of colorectal
cancer and Tarceva for lung cancer.
Incredible progress in fields such as genomics and proteomics has
vastly increased our knowledge about cancer's molecular and genetic
signals and processes. Such information allows for the detection of
cancer at a much earlier stage, when treatment options are often more
numerous, less invasive, and more successful. Cancer research also is
moving us closer to more targeted treatments, whereby advanced
technology can be used to target and destroy cancerous cells without
damaging the body's healthy cells. Finally, the scientific foundation
has been laid for the technological capacity to prevent cancer growth
altogether by blocking or interfering with the molecular signals that
turn healthy cells into cancerous cells.
We look to the National Institute's of Health, our Nation's many
academic research institutions and community oncology practices, in
addition to pharmaceutical and biotech firms to invest an enormous
level of resources into Research and Development in order to develop
better tools for preventing disease, detecting it sooner, and treating
it more effectively.
We then look to the FDA to serve as a gatekeeper for the entry of
those products into the market so that patients have access to those
deemed ``safe and effective.'' Once those products are approved, we
rely upon the agency to provide sufficient information about a
product's risks and benefits so that patients and their caregivers are
empowered to make personalized decisions about their care.
With literally hundreds of oncology products now in the
developmental pipeline, the demand upon FDA for advice and review will
rapidly accelerate. Thus, the agency's regulatory oversight of cancer
research must be as rationally and efficiently structured as possible
in order to insure timely delivery of cutting edge science to patients.
The FDA took a positive step in the right direction last July when
it announced the formation of an Oncology Office that would allow for
better consolidation and integration of the Agency's cancer-specific
expertise. The Interagency Oncology Task Force formed between FDA and
the National Cancer Institute in 2003 also has been a positive step
toward enhancing the efficiency of clinical research and the scientific
evaluation of new cancer medications. Through this program, Federal
researchers and regulators have been developing ways to share knowledge
and resources that will accelerate the development of new cancer drugs
that are safe and effective.
However, we are deeply concerned that potential efforts to
legislate unrealistically heightened degrees of certainty with respect
to the safety of drugs could turn back the clock on what we view as
important reforms in terms of improved efficiency and accelerated
access to vital drug therapies achieved by the FDA. Our patients simply
cannot afford unduly burdensome regulatory or bureaucratic requirements
that could halt such progress or unravel the gains made since enactment
of PDUFA.
V. Be Cautious With Safety
We appreciate the committee's scrutiny of recent concerns regarding
drug safety, and we share your commitment to assuring that information
about risks associated with drugs is identified and disseminated as
early as practicable. However, it is important to always keep in mind
that beneficial drug products are going to have associated with them a
certain amount of risk. Aspirin has risks; penicillin has risks; the
vaccines we give our babies to immunize from disease like polio and
diphtheria carry risk. No drug is ever 100 percent safe.
Just like patients and their caregivers must weigh the benefits and
risks associated with a particular product when deciding whether or not
to use it to fight or prevent disease, we feel that the FDA must
continue to carefully weigh the benefits and risks associated with a
product when deciding whether or not to grant approval. For that
reason, we would advise against any effort that creates new regulations
or bureaucracy that isolates or further separates either the drug
safety function or the drug efficacy function from the overall drug
review process. Safety and efficacy must never be viewed in isolation
from each other. The FDA's review process should remain structured in a
way that emphasizes the benefit-risk balance of a medicine as a basis
for approval.
Drug reviews that are not based on this delicate balance will
almost certainly discourage research on new therapies for dread
diseases like cancer and AIDS. It may become very difficult to get a
drug approved for cancer treatment if the regulatory hurdles for safety
are too high because those drugs are likely to have some level of side
effects, and they are likely to be used in a patient population that is
sick and vulnerable to adverse reactions.
Of even greater concern is how an overemphasis on safety might have
a devastating impact on the advancements being made in our ability to
detect cancer early or prevent it altogether. Remember, cancer is a
biological process that starts in the body years or even decades before
a diagnosis is made. The ability to detect that process early or stop
it all together represent our greatest hope for significantly reducing
or eliminating the suffering and death due to cancer. The conundrum is
that the clinical testing and medical application of new technologies
for early detection and prevention will involve people at risk for
cancer who are not yet showing signs of advanced disease and may be
entirely without symptoms. However, the tools for early detection and
prevention are going to have side effects, just like any medical
intervention. If the regulatory hurdles for safety are too high, it
will be very difficult to get new tools for prevention and early
detection approved even though they may save hundreds of thousands, if
not millions, of lives in the not too distant future.
And who is going to pour billions of dollars into the research and
development of new cancer products if they are not likely to be
approved because they might not be considered safe enough irregardless
of their benefits, or if they will face an even longer and less
efficient review process?
VI. What we support
Of course the FDA's role in evaluating and monitoring safety should
be strengthened. But more importantly, we want safer and more effective
drugs moved through the system as efficiently as possible so they can
be used as soon as possible by those who need them most, such as cancer
patients and/or those at high risk for cancer.
We would prefer strategies and solutions designed to improve the
FDA's capacity in the areas of safety, efficacy, and efficiency
simultaneously. At the very least, any effort to improve one aspect of
these factors alone should not be implemented without careful
consideration of how the other two might be impacted. And this means
that FDA's budget must be considered accordingly.
The following are the 5 key ``Pillars of Safety'' that we think are
critical to reforms at the FDA:
1. Safety and Efficacy must continue to be the foundational
elements of the FDA regulatory process. Safety cannot exist in a vacuum
apart from efficacy.
2. Mechanisms to enhance existing structures and processes for post
market safety monitoring and adverse event reporting must be explored.
3. Efforts to bring even greater efficiency and scientific
expertise to the FDA's review and monitoring processes must continue;
such efforts must be done in a manner that empowers the Agency to keep
pace with the rapid advancements now occurring in areas such as
genomics, proteomics, and nanotechnology.
4. FDA must continue to work with industry, patient groups,
physicians, hospitals, academia, and other government agencies to
enhance the critical path.
5. The FDA must be sufficiently resourced in order to insure more
effective pursuit of its existing mandates. Additional resources are
even more essential if FDA is to successfully implement a comprehensive
suite of reforms.
We are encouraged by FDA's plan to allocate more than $70 million
over 5 years to support enhanced monitoring and surveillance of risks
that may be associated with drug products already on the market.
However, no drug is without risk; and it always has been an unfortunate
but unavoidable fact that some adverse effects may not become apparent
until after a drug has been in wide or extended use. We can hope to
minimize such adverse effects and enhance the agency's capacity to
report them, but we must also accept certain risks associated with
beneficial drug products. Moreover, without new monies, every dollar
the FDA shifts towards new regulations and infrastructure for safety is
money taken away from programs that allow the agency to more
effectively and efficiently evaluate risk and benefit together.
Finally, one of the keys to a stronger FDA and a more robust
development pipeline is a clear plan for how the agency will work to
modernize the medical product development process. We are pleased that
such a proposal has been presented in the recently published report:
``Innovation/Stagnation: Challenge and Opportunity on the Critical Path
to New Medical Products.'' This document details the agency's plan to
update the tools currently used to assess the safety and efficacy of
new medical products. We fully support the FDA's willingness to reach
out to numerous stakeholders in an effort ``to coordinate, develop,
and/or disseminate solutions to scientific hurdles that are impairing
the efficiency of product development industry-wide.''
V. In Conclusion
We welcome the recent discussions about how we can make our drug
approval system better, but we are mindful of the fact that patients
with life altering diseases like cancer are given hope because of the
advances of scientific discovery and development. We support reform
that makes drugs safer, but warn against those that might
unintentionally slow down the flow of better technology for treatment,
prevention, and detection--or worse, discourage their creation
altogether. The only way to prevent such unintended consequences is to
have a thoughtful policy discussion not about safety alone, but safety
in combination with benefit and efficiency. While we of course want
safer drugs, we feel that any safety reforms absolutely must be matched
with efforts to enhance the FDA's level of efficiency, scientific
expertise, and overall capacity to fulfill its numerous mandates.
The Chairman. Dr. Thomas Fleming?
Mr. Fleming. Senator Burr, Senator Enzi, thank you for the
invitation to discuss what Congress and the FDA need to do to
both protect and promote public health with respect to drugs
and biologics.
The regulatory approval of drugs and biologics for
marketing in new clinical indications should be based on
evidence from adequate and well-controlled trials that reliably
establish that the product has a favorable benefit-to-risk
profile. Therefore, these clinical trials must give robust and
compelling evidence that the product provides clinically and
statistically significant beneficial effects on outcomes that
unequivocally reflect tangible benefit to patients, such as
relieving disease-related symptoms, improving the ability to
carry out normal activities, and in life-threatening disease
settings, prolonging survival.
In turn, sufficient safety data should be obtained to
provide reliable evidence that these beneficial effects
outweigh safety risks to patients who will use these products
in a real world setting. It follows that the level of safety
risks that would be judged to be acceptable would depend on the
level of benefit provided by the intervention.
Multiple sources of information are useful in monitoring
these safety signals, including pre-marketing evaluations,
usually from randomized control trials, but safety monitoring
in a postmarketing setting is also extremely important and has
many components, including postmarketing passive surveillance,
usually through voluntary submission of AEs thought by
caregivers to be related to treatment, and more informative and
reliable postmarketing active surveillance, such as that
provided by large-link databases, and particularly for products
that will have widespread use.
This source was very informative in assessing safety of
COX-2 inhibitors. Even more informative for the COX-2s were
postmarketing randomized trials to determine if one can rule
out unacceptable increases in the rate of clinically
significant safety risks that are uncommon or occur on a
delayed basis when evidence has been obtained to suggest the
plausibility of such risks.
In evaluating the effects of COX-2 inhibitors on the risk
of cardiovascular mortality, MI, and stroke, the FDA proceeded
in a proper manner regarding the accumulation of data from both
observational studies and randomized trials and regarding the
development of benefit-to-risk assessments for this class of
agents using these data.
Even though the FDA process for drug review is one of the
best in the world, in fact, I think the best in the world, some
modifications would enable needed improvements. I have
outlined, proposed, a number of potential improvements or
approaches in my written testimony.
Among these, when a safety signal is found, I believe FDA
should have greater authority to require control trials,
usually randomized trials, that will have the ability to
determine whether unacceptable safety risks truly exist.
Another point, another recommendation, the accelerated
approval Subpart (h) regulatory process was established to
allow marketing of products that have been shown to have
compelling effects on biomarkers, for example, shrinking
tumors, if these effects are, quote, ``reasonably likely to
predict clinical benefit,'' unquote, and if the sponsor
completes in a timely manner one or more trials that will
validate that the intervention truly does provide meaningful
beneficial effects on true clinical efficacy outcome measures,
such as relieving disease-related symptoms or prolonging
survival.
Unfortunately, many challenging issues arise from the
implementation of the accelerated approval process that can
lead to compromising what is truly in the best interest of
public health, which is the reliable as well as timely
evaluation of interventions' safety and efficacy. Congress and
the FDA should consider policies to reduce the likelihood that
products are used for a lengthy interval of time by patients in
nonresearch settings, even though the efficacy has not been
established, and even though available safety data are much
more limited than what would typically be available from
completed trials evaluating effects on clinical efficacy
outcome measures.
In closing, it should be noted that one change that should
not be made is the creation of a separate group outside FDA to
review safety and efficacy. First, regulatory experts at FDA
have particular experience and familiarity with the drug
approval process, including the Code of Federal Regulations,
and the limits of the authority of the FDA.
Second, it is unclear how recommendations of such an
outside organization would be incorporated into the functioning
of the FDA.
Finally, there are significant conflict of interest issues
for many outside FDA who might be selected to serve in a
separate safety group.
The FDA is not broken. The process of drug review works
very well. In general, the FDA has been very effective in
carrying out its regulatory responsibilities, and in turn, has
had a profoundly favorably influence on the process of
promoting and protecting public health. Thank you.
The Chairman. Thank you.
[The prepared statement of Mr. Fleming follows:]
Prepared Statement Of Thomas R. Fleming, Ph.D.
Thank you for the invitation ``to provide my professional opinion
on what, if anything, Congress and the FDA need to do both to protect
and to promote the public health with respect to drugs and biologics,
including a discussion about what changes might need to be made to
ensure that FDA is fully considering both benefits and risks during
pre- and post-market review''. My testimony is based on 28 years
experience in collaborating on the design, conduct and analysis of
government and industry sponsored clinical trials, and on nearly 20
years service on FDA Advisory Committees.
EXECUTIVE SUMMARY
A. Decisions regarding marketing of drugs and biologics should be
based on robust and compelling evidence that the intervention has a
favorable benefit-to-risk profile.
B. In general, the FDA has been very effective in carrying out its
regulatory responsibilities and, in turn, has had a profoundly
favorable influence on the process of promoting and protecting public
health.
C. In evaluating effects of Cox-2 inhibitors on the risk of
cardiovascular mortality, MI and stroke, the FDA proceeded in a proper
manner regarding the accumulation of data from observational studies
and randomized trials and regarding the development of benefit-to-risk
assessments for this class of agents using these data.
D. The FDA should retain the responsibility for evaluation of
safety of drugs and biologics.
E. Multiple sources of information are useful in monitoring for
safety signals, including (i) pre-marketing evaluations (usually from
randomized controlled trials) that are of sufficient size and duration
to provide robust and compelling evidence that the product has a
favorable benefit to risk profile; (ii) post-marketing passive
surveillance, such as is provided by the Adverse Event Reporting System
(AERS); (iii) post-marketing active surveillance, such as is provided
by large linked data bases, in particular for products that will have
wide spread use; and (iv) post-marketing randomized trials to rule out
unacceptable increases in the rate of clinically significant safety
risks that are uncommon or occur on a delayed basis, when evidence has
been obtained to suggest the plausibility of such risks.
F. Some modifications that would need to be effected by legislation
would enhance the effectiveness of the FDA. These include: (i)
providing increased funding to FDA to support scientific pursuits and
improve regulatory effectiveness of reviewers; (ii) encouraging FDA
reviewers to communicate more effectively with the public; (iii) when
safety risks are found, requiring controlled studies (usually
randomized trials) that have the ability to determine whether an
unacceptable safety risk truly exists be conducted in a timely manner;
(iv) improving methodology for safety monitoring in children; (v)
establishing a funding program at FDA for observational studies and
clinical trials; and (vi) for agents that have received Accelerated
Approval under subpart H, ensuring the FDA has policies in place
regarding timeliness of completion of validation trials and prompt
withdrawal of the product from the market if the validation trials fail
to provide robust and compelling evidence that the product has a
favorable benefit-to-risk profile.
INTRODUCTION
The regulatory approval of drugs and biologics for marketing in new
clinical indications should be based on evidence from adequate and well
controlled clinical trials that reliably establish that the product has
a favorable benefit-to-risk profile. Therefore, these clinical trials
must give robust and compelling evidence that the product provides
clinically and statistically significant beneficial effects on clinical
efficacy outcomes that unequivocally reflect tangible benefit to
patients. Examples of such beneficial effects would be relieving
disease related symptoms, improving the ability to carry out normal
activities, or reducing hospitalization time while, in the setting of
life threatening diseases, the most important beneficial effect often
would be prolonging survival. In turn, sufficient safety data should be
obtained to provide reliable evidence that these beneficial effects
outweigh the safety risks to patients who will use these products in a
real world setting. It follows that the level of safety risks that
would be judged to be ``acceptable'' would depend on the level of
benefit provided by the intervention.
While sponsors from industry and sponsors from government agencies
other than FDA regularly make valuable contributions to the development
of greatly needed interventions for treatment and prevention of
disease, the reality is that important financial and professional
conflicts of interest can result in advocacy for marketing products
that have not been established reliably to be safe and effective,
placing the public at significant risk. In general, the FDA has been
very effective in carrying out its responsibilities to regulate the
activities of these sponsors, to ensure that products that are being
marketed truly do have a favorable benefit-to-risk profile. Through
this achievement, the Agency has had a profoundly favorable influence
on the process of promoting and protecting public health.
Before discussing potential refinements to the FDA drug approval
process, some aspects of the current process for evaluating safety and
efficacy should be reviewed.
EVALUATING SAFETY: SOME BACKGROUND REGARDING AVAILABLE APPROACHES
The review of safety of new products is a complex and
multidimensional undertaking. The FDA considers reports of adverse drug
reactions from available clinical data, pursues concerns raised by
animal toxicology, pursues insights from pharmacokinetic and
pharmacodynamic assessments including potential risks of drug-drug
interactions, looks specifically for class effects, and searches for
rare events. This effort is guided by their wealth of experience. For
example, before approval, lack of adverse effects on patient survival
must be established for most new drugs for heart failure (due to the
experience with inotropes) and for antiarrhythmics (due to the
experience with encainide and flecainide).
There are several clinical data sources providing insights about
safety risks of new products. In the pre-marketing setting, the most
reliable of these sources is the randomized controlled trial. Pre-
marketing clinical trials should be of sufficient size and duration to
provide robust and compelling evidence that the product has a favorable
benefit to risk profile. When evaluating products (such as analgesics,
antihistamines, antidepressants, and asthma remedies) not expected to
reduce mortality or to prevent irreversible morbidity (such as reducing
the risk of stroke, permanent loss of vision, or HIV infection), one
might need evidence from randomized trials that cumulatively involve
more than 10,000 patients. This is particularly important when
available evidence suggests plausibility of clinically significant
safety risks. The evaluation of Cox-2 inhibitor pain relievers provides
an illustration. Given that products in this class provide only a
limited reduction in risk of significant upper GI ulcers and have not
been established to provide improved pain relief relative to non-
specific NSAIDS such as naproxen, new members of the Cox-2 inhibitor
class should not be approved until evidence is available from
randomized trials ruling out the possibility that that these new agents
induce a 50 percent relative increase in the risk of major
cardiovascular (CV) events, including CV deaths, MIs and stroke, (i.e.,
ruling out that the drug causes at least 5 additional major CV events
per 1000 patients treated, in a population having a background rate of
such events of 1 percent).
Once the product is approved, it is important to continue
monitoring for safety signals. Post-marketing passive surveillance,
such as is provided by the Adverse Event Reporting System (AERS), is
useful for detecting large increases in clinically important rare
events, such as establishing the risk of intussusception with a
rotavirus vaccine, or assessing the risk of encephalopathy with the
acellular pertussis vaccines, or detecting the risk of Stevens-Johnson
rash in the treatment of patients infected with HIV. The Office of Drug
Safety is responsible for monitoring AERS. However, this system has
significant limitations. It is based on voluntary submission of
MedWatch forms for adverse events that caregivers believe might be drug
related. Underreporting, the lack of denominators and the lack of
comparator groups make such information very difficult to interpret in
many settings. These types of irregularities in safety information have
led to considerable difficulties in the assessment of the relationship
of the class of Selective Seratonin Reuptake Inhibitor (SSRI) agents
regarding the risk of suicidal ideation and/or attempts.
Post-marketing active surveillance, such as is provided by large
linked data bases (the Northern California Kaiser data base being a
classic example), provides an improvement over passive surveillance,
through more systematic collection of adverse events, yielding complete
numerators (i.e., safety events) and denominators (i.e., people exposed
to the product). This enhanced approach to post-marketing safety
assessment should be more widely implemented for products that will
have widespread use. This type of evidence could significantly enhance
the insights into whether there is a true causal relationship between
SSRI agents and the risk of suicidal ideation and/or attempts. However,
this approach also has important limitations. Due to lack of a
randomized control group, frequently unavailable confounder information
(such as aspirin use or smoking history when studying Cox-2
inhibitors), concerns regarding outcome specificity (are reported
events truly events?) and sensitivity (are true events reliably
captured?) partly due to recall bias, and concerns resulting from loss
to follow-up and the lack of a proper ``time 0'' cohort, results from
these analyses can be very misleading, especially when one is
attempting to determine whether an intervention induces a clinically
important safety risk that corresponds to less than a 2-fold increase
in rate of occurrence of these safety events. These concerns appear to
be relevant to the setting of Cox-2 inhibitors. While their effect on
the risk of CV deaths, MI and stroke is clinically significant, it
appears that this effect is approximately at the level of a 1.5 fold
increase. In such settings, the FDA properly would view such
``epidemiological'' or ``observational'' evidence to be hypothesis
generating or clues regarding safety signals. The FDA properly
recognized that it was necessary to conduct post-marketing randomized
trials, with large sample sizes and long term follow-up, to reliably
address the CV safety risk of the Cox-2 inhibitor class.
When an important safety signal has been suggested but has not
clearly been established by active and passive surveillance, post-
marketing randomized trials should be conducted to rule out
unacceptable increases in the rate of clinically significant safety
risks that are uncommon or occur on a delayed basis. The aggregation of
evidence from such large scale randomized trials, conducted in pre- and
post-marketing settings, has served as the most reliable source of
information to the address class effect of Cox-2 inhibitors regarding
risk of CV death, MI and stroke. In order to have high reliability in
detecting a tripling in the rate of a serious safety event that would
occur at the rate of 1 per 1000 patients, the post-marketing randomized
trial would need to have approximately 20,000 patients. Several
examples exist, in addition to the Cox-2 setting, where trials of this
type have been conducted. Two such examples are the evaluation of the
cardiovascular mortality risks of anti-psychotics known to induce
increases in QTc, and the assessment of the risk of respiratory-related
deaths and respiratory-related life-threatening experiences in patients
currently receiving prescription asthma medications. Large post-
marketing clinical trials have frequently provide insights about safety
risks that were inconsistent with prior expectations based on
observational studies or effects on biomarkers (i.e., surrogate
endpoints). For example, the ALLHAT trial established that a calcium
channel blocker did not have adverse effects on cancer risk, MI or
death, and the Women's Health Initiative showed that observational
studies improperly characterized the effects of hormone use in women on
cardiovascular risk. In a stunning example, even though encainide and
flecainide had been shown to suppress arrhythmias, a known risk factor
for sudden death (resulting in off-label use annually by hundreds of
thousands of Americans), the 2000 patient CAST trial established that
these antiarrhythmic agents actually tripled the death rate. Even
though the overall death rate was tripled by these agents, this excess
risk was not recognized until the availability of the results of the
randomized trial.
EVALUATING EFFICACY
As discussed earlier, drug safety cannot be considered separately
from drug efficacy/effectiveness since they are both part of an overall
assessment of benefit-to-risk. This was recognized in 1962 when the
Food Drugs and Cosmetic Act was amended to include that drugs should
demonstrate substantial evidence of efficacy as well as safety.
A rich science exists regarding design, conduct and analysis issues
that are influential in the achievement of robust and compelling
evidence that a product provides clinically and statistically
significant beneficial effects. These issues therefore have major
regulatory importance, and draw a great deal of attention from both
clinical and statistical reviewers at the Agency. Some of these that
frequently are most critical in the interpretation of efficacy data
are: (i) factors that influence bias and variability, including the
role of randomization, the influence of loss to follow up, the need to
conduct intention to treat analyses, and the role of blinding; (ii)
choosing proper endpoints, and the role of biomarkers as surrogate
endpoints; (iii) avoiding biocreep when conducting non-inferiority
analyses to establish efficacy of new products when being compared to
standard of care interventions; (iv) the role of subgroup analyses; and
(v) procedures for monitoring registrational trials to address ethical
and scientific concerns.
The second issue in the previous paragraph deserves particular
attention. It is often proposed that regulatory assessments of efficacy
be based on evaluation of effects on biomarkers, such as transient
tumor shrinkage in oncology, or suppression of arrhythmia in
cardiology, or decolonization for antimicrobials, rather than
evaluating effects on clinical efficacy outcomes that unequivocally
reflect tangible benefit to patients, such as duration of survival,
disease-related symptoms, or ability to carry out normal activities.
The use of biomarkers as replacement or ``surrogate'' endpoints for the
clinical efficacy outcomes enables trials to be conducted with smaller
numbers of patients and in shorter periods of time. Regrettably, these
surrogate endpoint trials often give misleading results about whether
the product truly provides beneficial efficacy, as illustrated earlier
by the fact that encainide and flecanide suppress arrhythmias and yet
have an adverse effect on mortality.
The Accelerated Approval (AA) (subpart H) regulatory process was
established to allow marketing of products that have been shown to have
compelling effects on biomarkers, if these effects are ``reasonably
likely to predict clinical benefit'', and if the sponsor completes, in
a timely manner, one or more trials that will validate that the
intervention truly does provide meaningful beneficial effects on true
clinical efficacy outcomes. Unfortunately, as discussed in the
accompanying publication (Fleming TR, ``Surrogate Endpoints and FDA's
Accelerated Approval Process: The challenges are greater than they
seem'', Health Affairs 24: 67-78, 2005), many challenging issues arise
from the implementation of the AA process that can lead to compromising
what is truly in the best interest of public health: the reliable as
well as timely evaluation of an intervention's safety and efficacy.
This publication discusses policies that Congress and the FDA should
consider to reduce the likelihood that products are used for a lengthy
interval of time by patients in non-research settings, even though
efficacy has not been established and available safety data are much
more limited than what would typically be available from completed
trials evaluating effects on clinical efficacy outcomes.
POTENTIAL REFINEMENTS TO THE FDA DRUG APPROVAL PROCESS
The FDA is not ``broken''. The process of drug review works very
well. In general, the FDA has been very effective in carrying out its
regulatory responsibilities and, in turn, has had a profoundly
favorable influence on the process of promoting and protecting public
health. Leaders at FDA such as Robert Temple, M.D., (Director, Office
of Medical Policy; Director, Office of Drug Evaluation I), are
extremely knowledgeable, fair, and highly effective in guiding the FDA
in the achievement of its mission. Such people are national treasures.
Even though the FDA process for drug review is one of the best in
the world, some modifications that would need to be effected by
legislation would enable important improvements. Before discussing
these, it should be noted that one change that should not be made is
the creation of a separate group, outside FDA, to review safety or
efficacy. First, the regulatory experts at FDA have particular
experience and familiarity with the drug approval process including the
Code of Federal Regulations and the limits of the authority of the FDA.
Second, it is unclear how the recommendations of such an outside
organization would be incorporated into the functioning of the FDA.
Finally, there are significant conflicts of interest issues for many
outside FDA who might be selected to serve in a separate safety group.
The following are potential changes regarding FDA that should be
considered:
1. Increase funding to FDA to allow more person power to accomplish
necessary tasks, while allowing reviewers time for scientific pursuits
that will improve their regulatory effectiveness. Increased funding
would also allow better research within FDA on clinical trials
methodology.
2. FDA reviewers should have better communication with the public.
Reviewers should be encouraged to publish important points or summaries
of their reviews in peer reviewed publications in order to better
inform the public regarding efficacy and safety of drugs. (Many
scientific articles published by the academic and industry scientists
have a ``sponsor spin'', resulting in reduced objectivity and biased
presentation of evidence regarding the benefit to risk profile of the
product.)
3. When a safety signal is found, frequently from non-controlled
post-marketing data, FDA should require that controlled studies
(usually randomized trials) that have the ability to determine whether
an unacceptable safety risk truly exists, be conducted. When such
trials are conducted in post-marketing settings, requirements for
timely completion should be in place.
4. Safety monitoring in children needs better methodology.
Currently, the ability to assess rare or long term safety risks, such
as for SSRIs, too often is inadequate. Furthermore, when it is unclear
how to measure an adverse event in a child, the sponsor should be
required to develop methodology to study the safety event in order to
be allowed to pursue an indication if the disease is not serious or
life threatening.
5. An FDA funding program for observational studies and clinical
trials should be established. Among the uses for these funds would be
(i) enabling the FDA to have access to evidence from large linked data
bases, allowing timely detections of safety signals once products are
marketed, in particular for products that will be widely used in
settings where rare or long term safety risks could lead to an
unfavorable benefit-to-risk profile; (ii) enabling the conduct of
important placebo controlled efficacy and safety trials as well as
those with generic drugs that will not be conducted by industry or NIH;
and (iii) providing funding to develop better tools for clinical trials
in the Critical Path program headed by Dr. Janet Woodcock.
6. For interventions that are allowed to be marketed under (subpart
H) accelerated approval, the FDA should have policies requiring that
clinical trials are in place at the time of the accelerated approval
that can reasonably be expected to provide statistically compelling
evidence, within a well-defined rapid time frame, about whether the
intervention as a favorable benefit-to-risk profile by being safe and
by providing clinically meaningful tangible benefit to patients; and
the product will be withdrawn from the market promptly if the
validation trial does not conclusively provide this required positive
evidence.
The Chairman. Dr. David Fassler, please.
Dr. Fassler. Thank you. My name is David Fassler. I am a
child and adolescent psychiatrist practicing in Burlington, VT.
I am also a Clinical Associate Professor in the Department of
Psychiatry at the University of Vermont. I am speaking today on
behalf of the American Psychiatric Association, where I serve
on the Board of Trustees, as well as the American Academy of
Child and Adolescent Psychiatry, where I serve as Vice-Chair of
the Assembly. These organizations would like to thank Senator
Enzi for holding this hearing.
I would like to address four main issues. First, I would
like to emphasize the importance of open access to data from
clinical trials, including data from negative trials and
unpublished research. Already this morning, you have heard a
lot about the issue of clinical trials.
In February of last year, when I testified before the FDA
Advisory Committee, there were only four controlled studies in
the published literature on the use of SSRI anti-depressants in
the treatment of childhood and adolescent depression. However,
as we learned in preparation for the hearing, there were
actually another 11 unpublished studies whose results had been
submitted to the FDA but really weren't known to most
practicing physicians.
Physicians and parents clearly need access to this kind of
information in order to make fully informed decisions about
treatment options. For this reason, the APA and the Academy
have been in the forefront of the call for the development of a
publicly accessible national registry of clinical trials.
Next, let me try and talk about medication in general and
the SSRI anti-depressants in particular. Research has clearly
demonstrated that medication can be helpful and even life-
saving for many children and adolescents with psychiatric
disorders, but medication is most effective when it is used as
a component of a comprehensive treatment plan individualized to
the needs of the child and family.
Let me take a minute to try and address the complex issue
of whether or not the SSRIs increase the risk of suicidal
thinking or behavior. At this point, here is what we actually
know from a scientific perspective. Contrary to frequent
reports in the popular media, there is no evidence to suggest
that these medications increase the risk of suicide in children
and adolescents. It does appear that these medications may
increase the likelihood that a patient, whether it is a child,
an adolescent, or an adult, will actually tell someone about
their suicidal thoughts or even about a suicide attempt. From
my perspective as a psychiatrist, this is actually a good thing
because it means you have the opportunity to intervene and to
keep the person safe.
I believe this is why none of the studies have demonstrated
any increase in actual deaths from suicide in conjunction with
the use of these medications. On the contrary and fortunately,
the adolescent suicide rate in the country has actually
declined by over 25 percent since the early 1990s in a manner
consistent with the increased use of SSRI anti-depressants.
Let me underscore the importance of ongoing research in
this area. There is no question that we need more information
on how to best use these medications in the treatment of our
child and adolescent patients. In particular, we need long-term
follow-up studies on both safety and efficacy. Fortunately,
several such studies are currently underway with funding from
the National Institutes of Mental Health.
The APA and the Academy also support the formation of a
Pediatric and Adolescent Central Nervous System Advisory
Committee at the FDA comprised of experts, including child and
adolescent psychiatrists and pediatric neurologists. We also
need to address the overall shortage of pediatric mental health
specialists, both in research and in clinical practice, and we
appreciate the efforts of Senators Bingaman and Collins on this
important issue.
Finally, let me emphasize the importance of advocacy for
children and adolescents with psychiatric disorders. Parents,
in particular, need to be advocates for their children. They
need to make sure their kids have a comprehensive evaluation by
a trained and qualified mental health professional and that
they have access to the necessary and appropriate ongoing
treatment services. They should also ask lots of questions
about any proposed diagnosis or treatment plan.
To this end, the APA and the Academy have jointly developed
a new website, www.parentsmedguide.org, to provide parents and
physicians with as much information as possible about the
evaluation and treatment of childhood and adolescent
depression. Over a dozen major medical family and patient
advocacy organizations have already endorsed this effort, and
Senator Burr earlier was talking about the importance of
electronic access to information and that is exactly why we
have set this up in this manner.
We at the APA and the Academy are hopeful that today's
hearing and testimony will help promote access to information,
encourage expanded support for research, and enhance the
ability of parents to advocate effectively for the treatment
their children need and deserve.
Thank you for the opportunity to appear before you today.
The Chairman. Thank you.
[The prepared statement of Dr. Fassler follows:]
Prepared Statement Of David Fassler, M.D.
Introduction
My name is David Fassler. I am a child and adolescent psychiatrist
practicing in Burlington, Vermont and a Clinical Associate Professor of
Psychiatry at the University of Vermont. On behalf of the American
Academy of Child and Adolescent Psychiatry (AACAP) and the American
Psychiatric Association (APA), I appreciate the opportunity to submit
this testimony regarding the Food and Drug Administration (FDA)
approval process.
The AACAP is a medical membership association established by child
and adolescent psychiatrists in 1953. With over 7,000 members, the
AACAP is the leading national medical association dedicated to treating
and improving the quality of life for the estimated 7-12 million
American youth under 18 years of age who are affected by emotional,
behavioral, developmental and mental disorders. The AACAP supports
research, continuing medical education and access to quality care.
Child and adolescent psychiatrists are the medical specialists trained
in the treatment of mental illnesses in children and adolescents.
APA is the Nation's oldest medical specialty society, founded in
1844, with over 35,000 members nationwide specializing in the
diagnosis, treatment and prevention of mental illnesses including
substance abuse disorders.
The AACAP and APA would like to thank Senator Enzi (R-WY), chair of
the Health, Education, Labor, and Pensions Committee, for holding this
hearing and for his interest in the Food and Drug Administration's
(FDA) approval process and its impact on pediatric medications used to
treat depression.
The FDA's drug approval process is basically sound. However, based
on our recent experience with the review of the safety and efficacy of
the selective serotonin reuptake inhibitor (SSRI) antidepressants, we
believe the process can be further strengthened by implementing four
recommendations. First, enhanced reporting of and access to data from
clinical trials, including negative trials and unpublished results, in
a centralized, publicly accessible registry. Second, an expanded
emphasis on post-marketing surveillance and increased funding for long
term follow up. Third, the creation of an FDA advisory board focusing
on the child and adolescent central nervous system, and fourth,
strengthening the workforce of researchers, including experts in
pediatric psychiatry and neurology, who can assist with the design,
oversight, interpretation and reporting of clinical research.
1. APA and AACAP Urge Access to Comprehensive Clinical Trial Data
The FDA's mission is to advance public health by helping speed
innovations that make medications more effective, safer and more
affordable; and to provide physicians and the public with the accurate,
science-based information they need to use medications to improve their
health. That mission depends on open access to all relevant information
from clinical studies, especially those that involve children.
The recent discussion of SSRIs brought to light the fact that the
physicians, researchers and the public often do not have access to such
full data sets. For example, of the 15 studies on the use of SSRI's in
the treatment of childhood and adolescent depression, only four had
been published as of February 2004.
Research is key to understanding the cause of depression,
especially in children and adolescents, and access to both negative and
positive research findings is essential to help clinicians develop the
most effective treatment plans. It is this principle that led the AACAP
and the APA, last summer, to urge the American Medical Association, to
join their call for the development of a national registry of clinical
trials. While the AACAP and the APA are primarily concerned with
psychiatric medications, we recognize that a registry will impact all
of medicine. Moreover, we also recognize that there is a bias toward
the publication of positive research findings, which affects all areas
of health care. Physicians and patients must have all available
knowledge about a medication's safety and effectiveness before they can
make informed decisions about treatment options.
The AACAP and the APA encourage the FDA to provide broader
dissemination of information gained from pediatric clinical trials.
Label information and package inserts provide critical information to
physicians, but we would urge the agency to routinely include any and
all data specifically addressing the safety and efficacy of agents when
used in the treatment of pediatric patients.
Our organizations want the public and physicians to get the most
accurate and up-to-date information about SSRIs and about all
psychotropic medication for children and adolescents. For this reason,
the AACAP and APA have recently released two guides on the use of
medication in treating childhood and adolescent depression--one for
patients and families and one for physicians. Both documents were
endorsed by numerous medical, family, and patient advocacy
organizations. A new web site was launched (www.ParentsMedGuide.org) to
share these documents with the public. Material from the website is
appended to this testimony. The parents guide provides advice for
parents to help them make the best decision for their child or
adolescent with depression. It describes what a black box warning
means, what prompted the warning on SSRIs, what treatments are most
effective in treating depression, and the risks associated with not
treating this condition. The physician's guide, while similar to the
parent's guide, includes more specific clinical and research data on
diagnosis, treatment efficacy, and suicidality in children and
adolescents.
a. Prevalence of Depression in Children and Adolescents
Mental and behavioral disorders affect an estimated 20 percent of
children and adolescents, or approximately 10 million young people.
Tragically, only one in five receive any form of treatment for these
disorders (U.S. Surgeon General Report).
Within this total, clinical depression is a frequently occurring
disorder. It is estimated that depression affects 2.5 percent of
children and over 8 percent of U.S. adolescents. These rates account
for approximately 2.6 million youth ages 6-17 (Birmaher et al.).
Depression and related mood disorders are serious illnesses for
most children and adolescents diagnosed with the condition. Depression
can interrupt a youth's normal emotional development, negatively affect
self-esteem, interfere with learning in school, and undermine
friendships with peers. Over 500,000 adolescents attempt suicide each
year and depression is most often the cause (Kochanek, KD et al).
No single cause of depression has been identified. However, we know
that depression is an illness with a pronounced biological basis.
Research has clearly demonstrated that depression is associated with
deficiencies in specific brain chemicals such as serotonin and
norepinephrine. The genes that a child inherits also predispose a
person to the illness, but this predisposition, or vulnerability, to
depression typically is ``triggered'' by life events. Researchers have
begun to identify these triggers, called risk factors, for depression.
A child's risk for becoming depressed may increase with stress or
with an experience of devastating loss or trauma. Behavioral problems
and other psychiatric disorders--for example, conduct, attention-
deficit, learning, anxiety, and substance abuse disorders--frequently
co-occur with depression and may help explain its onset. A family
history of depression or bipolar disorder is also a significant risk
factor for depression in a child or young adult.
Because of the severity of the disorder, the AACAP and the APA
support treatments that have been shown to be effective in reducing the
symptoms of depression and promoting normal development.
b. Antidepressant Medications as Part of Effective Treatment
Medication, specifically antidepressants, can be helpful and even
lifesaving for some children who have complex psychiatric disorders
such as depression. Medication is most effective when it is used as
part of a comprehensive treatment plan, individualized to the needs of
the child and family. All children and adolescents who are taking
antidepressant medication should be monitored closely by a physician,
especially early in the course of treatment, or when medications are
being changed or dosages adjusted.
Findings from the NIMH-supported Treatment of Adolescents with
Depression Study (TADS) show that a combination of medication and
therapy, specifically, Cognitive Behavioral Therapy, or CBT, are more
effective than either option used alone. Family therapy and/or work
with the child's school may also be appropriate components of a
treatment plan. All interventions have potential risks and benefits,
and parents need and deserve access to as much information as possible
in order to make fully informed decisions regarding treatment options.
It is important to remember that the majority of children and
adolescents with depression who are not identified and treated are
likely to have ongoing problems in school, at home and with their
friends. Research indicates that more than half will eventually attempt
suicide, and an estimated 2 to 5 percent will ultimately die as a
result (Formbonne, E., et al.).
At the end of this testimony is an overview from
ParentsMedGuide.org of depression treatment effectiveness, design of
clinical trials and data reporting which sheds additional light on
reports of suicidal thoughts by depressed adolescents.
c. SSRIs, Suicidal thoughts and FDA post-market actions
Many psychiatrists, patients and families have found the SSRI
antidepressants to be extremely helpful for children and adolescents
with depression when they are used in a well-monitored treatment
program. In addition, the current evidence does not suggest that these
medications increase the risk of suicide. It warrants emphasis that in
the data from the clinical trials that the FDA analyzed, which involved
more than 4,400 youth with depression, there were no actual suicides.
It does appear that these medications may increase the likelihood
that a patient will actually tell someone about their suicidal thoughts
or even about a suicide attempt. From my perspective, as a child and
adolescent psychiatrist, this is actually a good thing, because it
means you have the opportunity to intervene and to keep the person
safe. I believe this is why none of the studies have demonstrated any
increase in actual deaths from suicide in conjunction with the use of
these medications. On the contrary, the adolescent suicide rate in the
country has actually declined by over 25 percent since the early
1990's, in a manner consistent with the increased use of SSRI
antidepressants.
We are concerned that the available research findings do not
support a warning that may be misinterpreted by some practitioners or
parents to mean that antidepressant medications actually cause children
and adolescents to commit suicide. Such a conclusion is simply not
supported by the data.
The AACAP and the APA supported both the FDA's evaluation of the
safety data found in clinical trials of SSRIs and the Columbia
University reclassification project, and we continue to support the
public discussion of the resulting analyses. We also agreed with the
FDA's decision to insert warning language with all antidepressant
medications to alert physicians and families to the need to monitor for
signs of new suicidal thinking or activity during treatment, although
we feel that the specific nature and frequency of such monitoring
should be based on the clinical needs of the child.
Both AACAP and APA did not, however, agree with the action
ultimately taken by FDA in October of 2004, to require a ``black box
warning'' on all antidepressant medications prescribed for children and
adolescents. We were concerned--and recent data substantiates our
concern (such as Medco Health Systems data which indicates that from
2003 to 2004, there was a significant decrease in the rate of SSRI
prescriptions for children and adolescents) (Fields) that such a
warning might inadvertently create a greater risk by discouraging
families from seeking treatment and by dissuading physicians from the
appropriate prescribing of these medications.
We are pleased that the FDA recently modified, with scientific
input, the specific language used in the warning to more accurately
reflect the actual research findings. The FDA decided to remove
language that maintained that a causal relationship between medications
and increased suicidality had been established. It also is significant
that FDA added the language ``in clinical trials'' when discussing the
findings on suicidal thinking and behavior. In doing so, they are
acknowledging the challenges and complexities associated with the
translation of research finding into clinical practice. We hope the FDA
will be willing to consider further modifications to labeling, package
inserts and medication guides as more data becomes available.
2. Further Post-Market Research Needed
The AACAP and the APA call for new research on SSRIs to ensure that
these medications are used in the safest and most effective manner
possible. We support research efforts now underway, such as the NIMH
Treatment of Adolescent Suicide Attempters (TASA) study and the NIMH
supported Child and Adolescent Psychiatry Trials Network, a large
simple trials network.
The recently reauthorized Best Pharmaceuticals for Children Act
(P.L. 107-109) and the Pediatric Research Equity Act (P.L. 108-155),
which codifies the 1998 Pediatric Rule, will ensure that pediatric
clinical trials will be included during the development of new
therapeutic medications, providing child and adolescent psychiatrists
with additional safety and efficacy information about new medications.
We also suggest Congress consider the creation of an independent body
to oversee and advise the FDA on post-marketing issues.
3. Create a Central Nervous System Pediatric Advisory Committee
To provide the FDA with critical expertise on pediatric
psychopharmacology, the AACAP and APA support the creation of a Central
Nervous System Pediatric Advisory Committee that would be composed of
child and adolescent psychiatrists, pediatric neurologists and other
experts. This committee would work to improve the quality of life for
the millions of children and adolescents with mental illness and their
families.
We are pleased that the Pediatric Research Equity Act strengthened
the FDA pediatric research efforts by creating a Pediatric Advisory
Committee. While this committee will represent general pediatric
research issues, the FDA also requires specialized guidance in
pediatric psychopharmacology from experts in child and adolescent
mental health and neurology. Pediatricians are not specifically trained
in child and adolescent psychiatry or child neurology, and we should
not expect general pediatric experts to be able to provide the FDA with
the highly specialized expertise in child and adolescent mental
illnesses required in pediatric psychopharmacology.
4. Workforce and Access Issues
Family practitioners are more likely than either pediatricians or
psychiatrists to prescribe stimulants and less likely to use diagnostic
services, provide mental health counseling, or provide follow-up care
(U.S. Surgeon General Report). This is also true for antidepressants.
Child and adolescent psychiatrists are the only medical specialty fully
trained in the diagnosis and treatment of children's mental illnesses,
yet there are only approximately 7,500 of these specialists in the U.S.
We encourage committee members to support the enactment of the Child
Health Care Crisis Relief Act sponsored by Senator Jeff Bingaman.
These bills will help remove one of the main barriers to
appropriate treatment for children and adolescents with emotional and
behavioral disorders through the creation of educational incentives and
Federal support for children's mental health training programs. It will
authorize scholarships, loan repayment programs, training grants, and
specialty training program support. Children's mental health
professionals covered under the bill include: child and adolescent
psychiatrists, child psychologists, school psychologists, school social
workers, school counselors, psychiatric nurses, social workers,
marriage and family therapists and professional counselors.
In addition, access to appropriate mental health treatment for
children and adolescents requires the elimination of discriminatory
policies and practices with respect to health insurance coverage. For
this reason, both the APA and the AACAP fully support the passage of
parity legislation at both the State and Federal levels.
Summary of Recommendations
The AACAP and the APA make the following recommendations:
Enhance the release and dissemination of data from
clinical trials through the development of a centralized, publicly-
accessible, national registry.
Strengthen post-market surveillance and reporting, and
provide funding for more short-term and long-term pediatric clinical
trials, including follow-up studies, on all medications prescribed for
children and adolescents.
Create an FDA Central Nervous System (CNS) Pediatric
Advisory Committee composed of child and adolescent psychiatrists and
child neurologists to provide FDA with expertise on pediatric
psychopharmacology. Also consider the creation of an independent body
to oversee and advise the FDA on post-marketing issues.
Pass legislation to increase the number of children's
mental health specialists available to study and treat disorders such
as childhood and adolescent depression, including the ``Child
Healthcare Crisis Relief Act'' sponsored by Senator Bingaman, and the
``Children's Compassionate Care Act of 2005'' S. 174 sponsored by
Senators DeWine, Dodd and Murray.
Conclusion
The AACAP and APA appreciate this opportunity to submit testimony
on the FDA's approval process as it relates to pediatric
antidepressants. Both organizations are eager to work with Members of
Congress to address the issues related to research into childhood
mental illnesses and the training, treatment and services needed to
assure that children with psychiatric disorders receive the appropriate
and effective intervention that they need and deserve.
Endnotes from written testimony:
Birmaher B, Ryan ND, Williamson, DE, et al. (1996). Childhood and
adolescent depression: a review of the past 10 years. Part I. J Am Acad
Child Adolescent Psychiatry, 35(11), 1427-39.
Fields, Helen, ``Sad kids: Antidepressant prescriptions fall for
the under-18 crowd,'' U.S. News and World Report, February 4, 2004.
Kochanek KD, Murphy SL, Anderson RN, Scott C. Deaths: Final data
for 2002. National vital statistics reports; vol 53 no 5. Hyattsville,
Maryland: National Center for Health Statistics. 2004.
U.S. Department of Health and Human Services. Mental Health: A
Report of the Surgeon General. Rockville, MD: U.S. Department of Health
and Human services, Substance Abuse and Mental Health Services
Administration, Center for Mental Health Services, National Institutes
of Health, National Institute of Mental Health, 1999.
from the parentsmedguide.org
Overview of treatment effectiveness and suicidality
The effectiveness of treatment was demonstrated recently in a
definitive study supported by the National Institute of Mental Health
(NIMH). The Treatment of Adolescents with Depression Study (TADS)
(March, J et al) showed that a combination of fluoxetine (Prozac) and
cognitive behavior therapy (CBT) led to significant clinical
improvement in 71 percent of moderately to severely depressed
adolescent patients. Improvement rates for other treatment groups in
the study were 61 percent for fluoxetine alone, 43 percent for CBT
alone, and 35 percent for placebo. This finding replicated two previous
positive studies in pediatric populations (Emselie GJ, Rush, et al),
(Emslie GJ, Heilgenstein JH, et al).
A key finding of the TADS concerned the positive impact of
treatment on suicidal thoughts and behaviors, or ``suicidality,'' in
depressed youngsters. Suicidal ideation is a key symptom of major
depression. It is typically present before the start of antidepressant
treatment and is one of the major symptoms targeted for treatment.
Since mood disturbances often are among the last symptoms to remit in
treatment, and because antidepressant medications typically require
several weeks to exert a clinical effect, the initial changes in brain
functioning brought about by treatment are often not adequate to
suppress suicidal thoughts. In the event that worsening might occur,
the physician, in collaboration with the child's parents or other
family members, must appreciate the importance of intensively
monitoring a pediatric patient to assure patient safety during the
early stage of treatment. In some instances, hospitalization may be
necessary, although the vast majority of patients respond to outpatient
treatment.
Against this backdrop, it is noteworthy that in the TADS, 29
percent of the depressed young patients reported having clinically
significant suicidal thoughts at baseline. At week 12, the number of
youth reporting any suicidal ideation had declined to 10 percent.
Because youngsters who were most suicidal were excluded from the TADS
sample, the proportion reporting suicidal thoughts when the study began
was substantially lower than rates of suicidal ideation found in the
community samples cited above (reference #3) of youth with major
depressive disorder.
Without appropriate treatment, the consequences of depression are
extremely serious. Four of ten youth will have a second episode of
depression within 2 years. (Lewinsohn PM, et al.) They are also at
increased risk for substance abuse, eating disorders, and adolescent
pregnancy. (Kessler PC, et al.) Research indicates that over half of
depressed youth will eventually attempt suicide, and an estimated 2-to
5 percent will die by suicide in the 10 to 20 years following an
initial episode. (Fombonne et al).
What prompted the FDA warning in September of 2004?
In 2004, the FDA reviewed 23 clinical trials involving more than
4,300 child and adolescent patients who received any of nine different
antidepressant medications. (Hammond). No suicides occurred in any of
these studies. Most of the studies that the FDA examined used two
measures to assess suicidal thinking and behavior.
(1) All used ``Adverse Event Reports,'' which are reports made by
the research clinician if a patient (or their parent) spontaneously
shares thoughts about suicide or describes potentially dangerous
behavior. The FDA found that such ``adverse events'' were reported by
approximately 4 percent of all children and adolescents taking
medication compared with 2 percent of those taking a placebo. One of
the problems with using this approach to measuring suicidal thinking is
that most teenagers do not talk about their suicidal thoughts unless
they are asked in which case no report is filed. (Gould MS, et al.)
(2) In 17 of the 23 studies a second measure was also available.
These were standardized forms asking about suicidal thoughts and
behaviors completed for each child or teen at each visit. In the views
of many experts these measures are more reliable than event reports.
The FDA's analysis of the data from these 17 studies found that
medication neither increased suicidality that had been present before
treatment, nor did it induce new suicidality in those who were not
thinking about suicide at the start of the study. In fact, on these
measures, all studies combined showed a slight reduction in suicidality
over the course of treatment. Although the FDA reported both sets of
findings, they did not comment on the contradiction between them.
Hence, the 2 percent and 4 percent spontaneous report rates need to
be understood in the context of findings from community samples cited
previously in which as many as half or more of teenagers with major
depression are thinking about suicide at the time of diagnosis and some
16 percent to 35 percent have made a previous suicide attempt.
Although only nine medications were re-examined in the analysis,
the FDA applied the labeling changes to all antidepressant medications.
This was done on the basis of the advisory committee's perception that
currently available data are inadequate to exclude any single
medication from being potentially associated with the same increased
risk for spontaneous reports of suicidal thinking and/or behavior found
in the 23 studies.
Suicidality in adolescence
Suicidal ideation and suicide attempts are common in adolescence
and do not have the same prognostic significance for completed suicide
as those behaviors in later life.
The Federal Centers for Disease Prevention and Control, or CDC,
reports that 17 percent of adolescents think about suicide in a given
year. (www.cdc.gov) Among high school students, 12 percent of girls and
5 percent of boys attempt suicide in a given year. Ultimately, 2 per
100,000 girls and 12 per 100,000 boys die as a result of such
attempts--a ratio of attempts to completed suicide that is 6,000 to 1
among girls and 400 to 1 among boys. In the U.S., this translates into
approximately 2000 young people who die each year as a result of
suicide.
Fortunately, the overall rate of suicide in the 10-19 year age
range has declined by 25 percent over the past decade. Since this
decade has been associated with a dramatic increase in the prescription
rates of the newer SSRI antidepressants, a recent study has
demonstrated that a 1 percent increase in prescription of
antidepressant medication was associated with a 0.23 per 100,000
decrease in adolescent suicides (Olfson, M. et al.)
It is important to consider clinical trial data in the context of
these population-based data. In its review of 23 clinical trials
involving child and adolescent subjects who received any of nine
different antidepressant medications, the FDA combined the rates for
suicidal thoughts and suicide attempts under the general term
``suicidality.'' This has fostered a public impression that there is a
high rate of suicide attempts or even completed suicides in children
and adolescents that can be attributed to taking antidepressant
medication; in fact, suicidal thoughts and actions decline with
medication and psychotherapy treatments, and there were no completed
suicides in the studies reviewed by FDA. Suicidal thoughts or attempts
do not equal suicides.
Every suicide is a personal tragedy that may be linked to
inadequate treatment monitoring or severe adverse side-effects of a
medication. Yet the rise in overall population treatment rates with
antidepressant medication has not been associated with a rise in
completed suicides in the larger population--in fact, there has been a
substantial decrease in completed suicides over the past decade.
Likewise, the higher spontaneous reports of suicidal ideation and
attempts (referred to by the FDA as ``adverse events'') in children on
antidepressants compared with placebo, has not been correlated with
systematic assessments of suicidal ideation or attempts increasing with
these medications. Research is needed to determine how the relatively
low rate of spontaneous reports of adverse events is related to the
much higher systematically assessed rates of suicidal ideation and
attempts, and which more clearly indicate a risk for completed suicide.
In an illness where unwanted and spontaneous suicidal thoughts are
integral symptom components, treatment that increases communication
about these symptoms can lead to more appropriate monitoring and
decreased risk for the adverse event of greatest concern--i.e.
completed suicide.
Endnotes from ParentsMedGuide.org
March J, et al (2004). Fluoxetine, Cognitive Behavioral Therapy,
and their combination for adolescents with depression: Treatment for
Adolescents with Depression Study (TADS) randomized controlled trial.
JAMA 292(7), 807-820
Emslie GJ, Rush AJ, Weinberg WA, et al. (1997). A double-blind,
randomized, placebo-controlled trial of fluoxetine in children and
adolescents with depression. Arch General Psychiatry 54(11), 1031-37.
Emslie GJ, Heiligenstein JH, Wagner KD et al. (2002). Fluoxetine
for acute treatment of depression in children and adolescents: a
placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc
Psychiatry 41(10), 1205-15.
Lewinsohn PM, Clarke GN, Seeley JR, and Rohde P (1994). Major
depression in community adolescents: age at onset, episode duration,
and time to recurrence. J. Am. Acad. Child Adolesc. Psychiatry 33 (6),
809-818.
Kessler RC, Avenevoli S, Merikangas KR (2001). Mood disorders in
children and adolescents: an epidemiologic perspective. Biol Psychiatry
49(12), 1002-1014.
E. Fombonne, G. Wostear, V. Cooper, R. Harrington, and M. Rutter.
(2001). The Maudsley long-term follow-up of child and adolescent
depression. 2. Suicidality, criminality and social dysfunction in
adulthood. Br J Psychiatry 179, 218-23; Rao M, Weissman M, Martin JA,
Hammond RW (1993). Childhood depression and risk of suicide: a
preliminary report of a longitudinal study. J Am Acad Child Adolesc
Psychiatry 32(1), 21-27.
T.A. Hammad. Results of the Analysis of Suicidality in Pediatric
Trials of Newer Antidepressants. Presentation at the FDA Center for
Drug Evaluation and Research (CDER), Bethesda, MD. September 13, 2004.
Available at: http://www.fda.gov/ohrms/dockets/ac/
cder04.html#PsychopharmacologidDrugs. Accessed January 5, 2005.
Gould MS, Velting D, Kleinman M, Lucas C, Thomas JG, Chung M
(2004). Teenagers' attitudes about coping strategies and help-seeking
behavior for suicidality. J Am Acad Child Adolesc Psychiatry, 43(9),
1124-33.
Available at http://www.cdc.gov/HealthyYouth/YRBS/pdfs/trends-
suicide.pdf. Accessed 12/29/2004
Olfson M, Shaffer D, Marcus SC, Greenberg T. (2003). Relationship
between antidepressant medication treatment and suicide in adolescents.
Arch Gen Psychiatry 60, 978-982.
The Chairman. Dr. Scott Gottlieb.
Dr. Gottlieb. Mr. Chairman, thank you for the invitation to
appear before the committee. Today, I want to tell you why I
believe the FDA's mission is becoming increasingly complex, but
with this complexity has also come many new opportunities to
improve medicine, and I want to tell you why I believe that, as
the sophistication of FDA's mission continues to increase, so
must the tools it uses for accomplishing its work, especially
when it comes to drug safety.
To acquire these tools, FDA will need new resources that
allow it to make better uses of advances and information tools
for monitoring the safety of approved drugs. The good news is
that FDA is doing some of these things right now, albeit in
small pilot programs. The bad news is, I believe our current
political discussion seems to ignore these opportunities in
lieu of some more visible changes. These visible changes will
have far less positive impact on drug safety and will limit the
access to medicines. They will make drugs more expensive and
less likely to reach patients who need them.
Mr. Chairman, we are living in a remarkable time of
scientific progress. When I was at the Food and Drug
Administration, the Centers for Medicare and Medicaid Services,
a lot of my time was spent looking at the policies these
agencies followed in the evaluation of new medical
technologies.
When you look at the technologies that have become
available even over a short period of time, it becomes
immediately clear that the improvements in health care follow a
step-wise progression. The introduction of new medical
technologies, the realization of better ways of practicing
medicine or of avoiding illness, all leads to small
improvements in medical care that, over time and aggregated
together, give us major improvements in health.
You can see this, for example, in the strengthening of our
understanding of how the immune system works and the advent of
our ability to manipulate it in order to produce drugs that can
replicate our own immune processes, like monoclonal antibodies.
Or even more recently, you see it in our improved
understanding of the genetic basis of disease. Already, if you
look at the early drug pipeline being submitted to FDA, the
investigational new drug applications, you see many drugs that
were derived in part or entirely through techniques of genomics
and proteonomics.
All of these new medical products are the result of
advances in our science of biology. Past medical products have
taken decades or even centuries to be made manifest on the
heels of the scientific discoveries that enabled them. Today's
FDA is already seeing the early applications of dozens of drugs
derived wholly or in large part from science developed just
several decades ago.
This acceleration in time between the development of
science and the creation of products that capitalize on it is
giving us an awful lot of new opportunity to find fundamentally
better ways of treating disease, but it also presents the
government agencies that evaluate new medical technology with a
lot of challenges, especially the FDA.
More and more of the products the FDA is seeing are very
novel, and as such, the agency has no reference point. So in
more and more cases, regulators are embarking on new ground
each time they pick up a new application.
In the old days, drugs worked through fairly similar
mechanisms. Now the same review division, let us take the
Cancer Division, can simultaneously be reviewing a monoclonal
antibody, a antisense drug, a molecule targeted to a kinase
receptor, a radiolabeled antibody, a cancer vaccine, and a
traditional cytotoxic cancer agent, all on the same day. In
fact, I remember talking to the head of the Division on just
such a day.
On top of all this, the FDA has more factories to inspect,
more patients using more of these medicines more quickly after
they are first approved, and more potentially dangerous imports
seeping through our borders.
I believe the scientific challenges posed by new medical
products will continue to mount, but I also believe this is
good news because novel drugs invariably give us novel ways to
fight old disease and many of today's medicines are simply far
safer and far more effective than those that came before.
But as the science gets more intricate and more advanced,
our tools for evaluating it also need to get more creative.
This is especially true when it comes to how we evaluate drug
safety. Understanding the full scope of any drug's side effects
is the challenge, especially understanding them early.
Every clinician who prescribes medicines has seen adverse
drug reactions, the unintended and harmful effects of drugs.
Human biology, after all, is conservative, meaning our bodies
reuse a fairly small set of very similar molecular processes to
get all our jobs done. It follows, then, that any drug that is
active in blocking some molecular process in order to have its
desired effect will also block the same molecular process in
another part of the body, parts that could lead to unwanted
side effects. So there is no such thing as a completely safe
drug.
The FDA's job is not to guarantee 100 percent safety. It is
to approve medicines with an appropriate risk-benefit ratio by
removing unreasonably unsafe drugs when necessary. The baseline
isn't the perfectly safe drug, but the drug with benefits that
outweigh reasonable risks. This is how we maximize public
health benefits of new medical products.
Patients are rightly angry about recent events because they
want safety questions to be uncovered and resolved much sooner.
They don't want to have to wait many years. The good news is
there are better ways to achieve the environment of improved
drug safety we all desire without sacrificing the scientific
progress we all embrace.
In particular, information technology properly deployed
will enable FDA to pursue fundamentally better ways to monitor
the safety and effectiveness of new medical products after they
are made available in the marketplace. These are things the FDA
is already doing a little, but needs to be doing much more.
Right now, when it comes to drug safety, the FDA relies on
others to undertake the time and cost of monitoring. This
passive reporting system leaves FDA dependent on busy doctors
to fill out lengthy reports.
So far, fixes to our system for monitoring drug safety have
all focused on making this antiquated system work a little
faster by adding only a veneer of sophisticated information
tools. As a result, information is made available to FDA slowly
and takes even longer to analyze by the agency's trained
personnel.
FDA needs systems that allow it to collect more information
about a drug's use in the real world, and in some cases, real-
time clinical practice, and to use this information more
effectively. This requires two simultaneous efforts: First,
tools for detecting and collecting more safety information more
quickly at the point of care in order to detect potential
problems earlier; and second, resources for making better, more
frequent use of practical clinical data culled from real-world
use of drugs in order to conduct more precise and faster
follow-up studies on the potential safety problems.
In conclusion, Mr. Chairman, FDA has already taken some
steps to try and create more active and proactive surveillance
tools. With improved resources for conducting this kind of
surveillance as well as resources for conducting large, simple
safety studies in collaboration with product developers and
health care networks on newly-approved products, FDA can
improve its safety monitoring without burdening the approval
process. Thank you.
The Chairman. Thank you.
[The prepared statement of Dr. Gottlieb follows:]
Prepared Statement of Scott Gottlieb, M.D.
Mr. Chairman, thank you for the invitation to appear before the
committee. Today I want to tell you why I believe the FDA's mission is
becoming increasingly complex. But with this complexity has also come
many new opportunities to improve medicine. And I want to tell you why
I believe that, as the sophistication of FDA's mission continues to
increase, so must the tools it uses for accomplishing its work.
Especially when it comes to drug safety.
To acquire these tools, FDA will need new resources that allow it
to make better use of advances in information tools for monitoring the
safety of approved drugs.
The good news is that FDA is doing some of the right things right
now, albeit in small pilot programs. The bad news is I believe our
current political discussion seems to ignore these opportunities in
lieu of some more visible changes. These visible changes will have far
less positive impact on drug safety, and will limit access to
medicines. They will make drugs more expensive and less likely to reach
patients who need them.
Mr. Chairman, we are living in a remarkable time of scientific
progress. When I was at the Food and Drug Administration and the
Centers for Medicare and Medicaid Services, a lot of my time was spent
looking at the policies these agencies followed in the evaluation of
new medical technologies.
When you look at the technologies that have become available, even
over a short time, it becomes immediately clear that improvements in
healthcare follow a stepwise progression. The introduction of new
medical technologies, the realization of better ways of practicing
medicine or of avoiding illness, all leads to small improvements in
medical care that over time, and aggregated together, give us major
improvements in health.
You can see this, for example, in the strengthening of our
understanding of how the immune system works and the advent of our
ability to manipulate it in order to produce drugs that can replicate
our own immune processes such as monoclonal antibodies.
You see it when you look at the mortality statistics around breast
cancer, were successive product introductions from Taxols to Aromotase
Inhibitors to drugs like Herceptin, each had a small impact that over
time and taken together, led to significantly better odds of surviving
the disease.
Or even more recently, you see it in our improved understanding of
the genetic basis of disease. Already, if you look at the early drug
pipeline being submitted to FDA--the investigational new drug
applications--you see many drugs that were derived in part or entirely
through techniques of genomics and proteomics, the latter of which is
the science of how genes make proteins to carry out all of our complex
human processes.
All of these new medical products are the result of advances in our
science of biology. Past medical products have taken decades and even
centuries to be made manifest on the heels of the scientific
discoveries that enabled them. Today's FDA is already seeing in early
applications dozens of drugs derived wholly or in large part from
science developed just several years ago.
This acceleration in time between the development of a science and
the creation of products that capitalize on it is giving us an awful
lot of new opportunity--to find fundamentally better ways to treat
disease. But it also presents the government agencies that evaluate new
medical technology with a lot of challenges, especially the FDA.
More and more of the products the FDA is seeing are very novel,
and, as such, the agency has no reference point. So in more and more
cases regulators are embarking on new ground each time they pick up a
new application.
In the old days, drugs worked through fairly similar mechanisms.
Now the same review division--lets take the cancer division--can
simultaneously be reviewing a monoclonal antibody, an antisense drug, a
molecule targeted to a kinase receptor, a radiolabeled antibody, a
cancer vaccine, and a traditional cytotoxic cancer agent, the kind of
drug that killed everything a little but hopefully killed the cancer
cells a little more.
In fact, I remember talking to the head of the cancer division on
just such a day. On top of all this, the FDA has more factories to
inspect, more patients using more of these medicines more quickly after
they are first approved, and more potentially dangerous imports seeping
through our borders.
I believe the scientific challenges posed by new medical products
will continue to mount, but I also believe that this is good news,
because novel drugs invariably give us novel ways to fight old disease.
And many of today's medicines are simply far safer and far more
effective than those that came before.
But as the science gets more intricate, more advanced, our tools
for evaluating it need to get more creative as well. This is especially
true when it comes to how we evaluate the safety of new drugs.
Understanding the full scope of any drugs side effects is the
challenge, especially understanding them early.
Every clinician who prescribes medicines has seen adverse drug
reactions--the unintended and harmful effects of drugs. Human biology,
after all, is conservative, meaning our bodies reuse a fairly small set
of very similar molecular processes to get all of their jobs done. It
follows that any drug that is active in blocking some molecular process
in order to have its desired effect, will also block the same molecular
processes in other parts of the body, parts that could lead to an
unwanted side effect. So there is no such thing as a safe drug.
The FDA's job is not to guarantee 100 percent safety. It's to
approve medicines with an appropriate risk-benefit ratio and remove
unreasonably unsafe drugs when necessary. The baseline isn't the
perfectly safe drug, but the drug with benefits that outweigh
reasonable risks. Congress has given a lot of thought to the laws that
set out these parameters, amending the FDA's statute more than a
hundred times. The system that our resulting law contemplates always
took measure of the simple scientific truth that there's no such thing
as a completely safe drug. What have changed today are not the safety
of medicines but the acrimony of our public discussion of these things.
Today, the data that medical reviewers at FDA receive in
conjunction with the approval process for new products are from highly
structured clinical trials, carried out on homogenous populations of
patients that are carefully screened and pre-selected and then given
new drugs under special protocols. There is little chance such trials
will ever provide a complete review of how a new treatment will perform
when it is used in a much broader variety of patients in real world
clinical settings. \1\
---------------------------------------------------------------------------
\1\ Scott Gottlieb and J.D. Kleinke., Is the FDA approving drugs
too fast? United States Food and Drug Administration. British Medical
Journal, October 3, 1998, No. 7163, Vol. 317; Pg. 899.
---------------------------------------------------------------------------
Recent proposals to lengthen clinical trials, or require them to
include more patients, will add to their cost and hence the cost of
drug development and eventually the list price of new drugs. It will
limit access to new medicines. But it will not assuage today's safety
concerns, and it will never unearth the kind of rare side effects that
were eventually revealed with Vioxx, or even yesterday in the case of
multiple Sclerosis drug Tysabri.
Patients are rightly angry about these events because they want
safety questions to be uncovered and resolved much sooner. They don't
want to have to wait many years.
The good news is that there are better ways to achieve the
environment of improved drug safety we all desire, while not
sacrificing on the scientific progress we all embrace. In particular,
information technology, properly deployed, will enable FDA to pursue
fundamentally better ways to monitor the safety and effectiveness of
new medical products after they are made available on the marketplace.
These are things the FDA is already doing a little of, but needs to
be doing much more.
Right now, when it comes to drug safety, the FDA relies on others
to undertake the time and cost of monitoring by sending news of
potential problems to the agency. This passive reporting system leaves
FDA dependent upon busy doctors to fill out lengthy drug safety reports
that are used by the agency to identify and track potential drug side
effects.
Taken together, this passive reporting process is slow and
expensive, and of course, woefully incomplete. Most of the reports FDA
ends up receiving are actually delivered not by doctors, but by drug
makers, who hear about side effects from physicians, often while on
sales calls.
So far, fixes to our system for monitoring drug safety have all
focused on making this antiquated system work a little faster, by
adding only a veneer of sophisticated information tools. For example,
more of the forms that doctors and manufacturers complete are now fully
electronic. But doctors still have to take proactive steps to enter the
information by hand and evaluated by time-consuming, human
intervention.
As a result, information is made available to FDA slowly, and takes
even longer to analyze by the agency's trained personnel. Very subtle
side effects, especially medical problems that occur naturally in a
large population can take years to recognize and fully understand.
FDA needs systems that allow it to collect more information about a
drug's use in real world, and in some cases real time clinical
practice, and to use this information more effectively. This requires
two simultaneous efforts:
First, tools for detecting and collecting more safety information
more quickly at the point of care in order to detect potential problems
earlier.
Second, resources for making better and more frequent use of
practical clinical data pulled from real-world use of drugs in order to
conduct more precise and faster follow-up studies of potential safety
problems.
Both efforts require FDA to have better tools for collecting health
information electronically and then using information tools to be able
to access and manipulate this information.
As electronic medical records and other IT systems gain wider
adoption in healthcare, these kinds of opportunities will be more
easily accessible. It behooves us to implement drug safety reforms that
envision and accommodate these opportunities, rather than implement
more expedient but fleeting fixes to our current--inefficient
monitoring system that are predicated on an old way of doing things.
Consider this scenario: A new drug is launched that has a certain
rare toxicity to the liver. A real-time surveillance network might
eventually be able to detect subtle elevations in the liver enzyme
tests of patients who were started on the drug and also happened to
have blood work drawn around the same time. If enough of these signals
were detected, it might alert FDA that there is a potential liver
problem, and allow the agency to intervene before a patient experiences
more permanent harm.
Under our current system, such a side effect might go unnoticed
until a few patients developed severe liver failure. Even then, it
might have been hard to link the problem to the medicine without taking
months to go back and review the medical record of many thousand of
patients who were started on the same medicine.
While more widespread use of these systems requires greater
adoption of electronic medical records, there is already a critical
mass of these systems. A lot that can be gained by conducting real-time
surveillance on the existing IT infrastructure inside many large
healthcare networks and academic centers.
FDA has already struck collaborations with some of these networks,
including the Veterans Administration hospitals and Columbia
Presbyterian Hospital in New York. Expanding these efforts will require
additional funding.
The second step is developing more proactive determination tools to
complement better detection systems. These are information and
analytical capabilities for evaluating potential safety signals and for
establishing a causal link between a drug and a suspected side effect.
Efforts to make better use of electronic healthcare information to
more easily conduct practical studies, for example, are already well
underway inside FDA and need to be dramatically expanded on if our
safety infrastructure is going to keep pace with the expanding scope of
our scientific opportunities in medicine.
In conclusion, Mr. Chairman, FDA has already taken some steps to
try and create more active and proactive surveillance tools. With
improved resources for conducting this kind of surveillance, as well as
resources for conducting large simple safety studies in collaboration
with product developers and healthcare networks on newly approved
products, FDA can improve its safety-monitoring program without
burdening the approval process.
With all the advances recently made in the science behind discovery
of new drugs, there is little reason we should not be investing
commensurate resources in bringing 21st century science to the task of
ensuring their safety.
The Chairman. Our next witness actually got trapped by the
storm in Connecticut and will be testifying by way of
teleconferencing, and that is Ms. Abbey Meyers. Ms. Meyers.
Ms. Meyers. [By telephone.] Thank you, Mr. Chairman. I
really appreciate the technology that the staff has used to
allow me to testify, even though we are under about a foot of
snow.
FDA has a formidable task. It regulates products that
amount to 25 cents out of every dollar that the American
consumer spends each year. And the recent crises about the
withdrawals of the COX-2 inhibitors and childhood anti-
depressants have shaken the public's trust.
Before 1997, only drugs for serious and life-threatening
diseases were rushed through the approval process in 6 months.
FDA calls this fast track or expedited approval or priority
reviews. The remainder of the drugs, standard drugs, were
reviewed within 1 year, and that process seemed to work very
well.
FDA has two constituencies that it has to satisfy. First is
basically healthy people who have temporary and usually benign
health problems, like the common cold, or people with chronic
diseases like arthritis that are not life-threatening. Those
people are usually unwilling to take major medical risks.
Now, the people with very serious diseases are often
willing to take more risks, such as cancer patients who very
often have to take very toxic drugs. The point, though, is that
they are given realistic information about those side effects
and the risks and they make their choice based on the education
from their doctor about what the risks are.
Clinical trials are fine when a company is studying drugs.
It usually involves a very closely designed patient population
that may not reflect the real world. But once a drug gets on
the market, it is used by people who have other diagnoses and
people who take other drugs and they can suffer unanticipated
adverse reactions because they didn't show up in the clinical
trials.
There should be more of an effort to require companies to
do trials on more realistically diverse populations in order to
minimize the surprise adverse events after a drug reaches the
market.
Consumers want, and Senator Kennedy has been advocating for
us since the late 1970s, and that is we need understandable
medication leaflets with every prescription written in
understandable language. We don't see, and we couldn't read it
even if we could see, the labeling on drugs that is written in
medical language. People, if they have this information, they
gladly make their own risk-benefit decision.
FDA should have the authority to require labeling changes
just as soon as they see new side effects that warrant it.
Right now, they have to negotiate the changes and this can take
months or even years, as we have just heard. They should be
able to change labels immediately because doctors don't have
the information and they continue to prescribe these drugs to
the wrong types of patients.
We also need a permanent FDA Commissioner as soon as
possible because no one really knows where the buck stops at
FDA until that is done.
Appropriations for FDA have never been a Congressional
priority. It is funded by the agriculture committees, not the
health committees. So when Congress doubled the NIH budget a
few years ago, it should have realized that if the NIH is
successful, more innovative treatments are going to come
through the FDA and that FDA would need more resources.
Instead, FDA's increases in appropriations have not kept track
with inflation.
FDA's performance since the PDUFA amendments in 1997 is
measured by its speed in reviewing new drugs and not on the
scientific quality of its work. User fees cannot be spent on
anything other than new drug reviews. We believe that they
should be able to use PDUFA funds for other things in reaction
to health emergence, especially. The agency is grossly
underfunded.
Enforcement authority is lacking at the agency and it can't
set reasonable penalties. For example, the agency has the right
to require drugs that are approved on the six-month priority
review to have Phase 4 studies after the drug is marketed, and
a lot of the companies simply ignore that requirement and never
do the Phase 4 studies. The only enforcement authority FDA has
for Phase 4 studies is to take the drug off the market, and
that would make the patient suffer much more than anybody else.
So instead, they do nothing and they need a way to set
realistic penalties.
Direct-to-consumer advertising, companies can print and
broadcast inaccurate, misleading ads for weeks or months before
the FDA reviews them, and by that time, the damage is done and
millions of people have been influenced. This has to be
changed. They should approve the ads before they broadcast or
print it.
On safety surveillance, the Drug Safety Monitoring Board
that has been proposed, we believe it should truly be
independent and not composed only of government employees. And
if you look at the President's proposed budget for 2006, it
calls for a reduction of factory inspections. Those factory
inspections are really what caused the flu vaccine catastrophe,
so this should be remedied.
On transparency, the public is really demanding greater
transparency. FDA is excessively secretive. They say they can't
post to the public because everything is a trade secret. We
really need to have a way to get consumers' questions answered
at the FDA.
In summary, FDA is the most important public health agency
in our Nation. It must be placed high on Congress's priority
list. It must have greater enforcement authority and it must be
given more resources to protect the public from future
catastrophes.
Thank you, Mr. Chairman.
The Chairman. Thank you.
[The prepared statement of Ms. Meyers follows:]
Prepared Statement of Abbey S. Meyers
Mr. Chairman, members of the committee, thank you for inviting me
to testify today about the Food and Drug Administration's (FDA)
approval process, drug safety and the concerns of patients. I would
like to offer possible solutions to the growing controversy about the
safety of medical products that are regulated by the FDA.
The National Organization for Rare Disorders (NORD) is a non-profit
voluntary health agency dedicated to the identification, treatment and
cure of rare diseases through programs of education, research, advocacy
and services to patients and families. Because most patients with rare
diseases have no or few treatment options, our primary goal is to
encourage research and development of new ``orphan'' drugs and
biologics and ``humanitarian use devices'' (HUD).
We are grateful to Congress, through the Orphan Drug Act and annual
appropriations, for its support of those living with rare diseases.
Today, there are 266 FDA-approved orphan drugs on the US market; and
the National Institutes of Health (NIH) and the FDA are doing more to
help us each year. However, there are more than 6,000 known rare
diseases, so there is still much to be done.
The FDA is the Nation's watchdog for pharmaceuticals, biologics,
medical devices, veterinary medicines, foods and cosmetics. These
products account for about one-quarter of every dollar the American
consumer spends each year. Yet, the FDA is given meager Federal
resources to ensure that these products are safe and effective.
Recent health crises arising from FDA regulated products threaten
to weaken the public's trust in the Agency. Some of these drug safety
issues include:
Cox-2 inhibitors, used to ease the pain of arthritis, have
been found to cause increased rates of heart attack and stroke;
Most antidepressants have inadequate proof of safety and
efficacy in children, but they are commonly prescribed for this
population even though most are not approved for use in children;
The influenza vaccine shortage can be traced to a factory
in great Britain that failed FDA inspection;
Estrogen, taken by millions of women, has been found to
cause increased rates of heart attacks and stroke; and,
In late February, the FDA issued a warning that two new
drugs for psoriasis, which are being widely used off-label on a chronic
basis, have been associated with cancer and serious autoimmune
diseases.
These problems follow other drug withdrawals in recent years that
killed or endangered our citizens, such as Fen-Phen diet pills, the
cholesterol drug Baycol, and the diabetes drug Rezulin.
The public is now asking some important questions. Could the FDA
review process have discovered or anticipated these problems before the
products were marketed? Once these drugs were on the market, could the
FDA have acted to protect the public sooner in any of these or similar
cases?
A key source of misjudgments by the FDA is a relative imbalance in
the time allotted to review drugs for serious- and life-threatening
diseases versus less vital pharmaceuticals. This has been aggravated by
the user fee system and is complicated by the two different patient
constituencies that the agency serves.
First, most of the public are generally healthy and require
medicines for temporary and benign illnesses such as the common cold.
They usually do not want to be exposed to risks. They want the FDA to
ensure their treatments will be near to absolutely safe and reasonably
effective.
The second segment of FDA's constituency is people with serious or
chronic diseases such as rare diseases and cancer. These individuals
want new treatments as quickly as possible and are often willing to
bear substantial risks in exchange for possible efficacy. For example,
cancer drugs are often known to be very toxic, but a person who may
lose his or her life to cancer is usually willing to take highly toxic
chemotherapy drugs and suffer horrendous side effects in exchange for a
hope of recovery.
These disparate groups bring tremendous political pressure to bear
on the Agency. On the one hand, the FDA is pressured to approve drugs
quickly for very sick people, when the drugs have minimal scientific
evidence. On the other hand, the Agency is compelled to review drugs
with more deliberation to avoid risks for healthy people.
Unfortunately, most consumers do not know enough or have sufficient
skill to perform sophisticated risk/benefit analyses applicable to
their own situation. What appears on the official FDA approved
``labeling'' for a drug is rarely helpful. It is written in medical
terminology and printed in tiny fonts. It is very difficult for
patients to get accurate information that is readable and
understandable without medical training.
Instead, on a day-to-day, drug-by-drug basis, patients must rely on
their physicians to interpret whether a particular product is safe and
efficacious for their particular circumstance. And both patients and
physicians must rely on the FDA to weigh risks versus benefits, and to
ensure that the marketed drugs are not unsafe or ineffective.
Another tension arises from the way that clinical trials are
constructed in order to comply with the scientific method. In a perfect
world, a clinical trial would be one in which all patients were
completely identical in every regard, except who received the study
drug and who got placebo. The double-blind, placebo controlled study
does, in fact, bring us closest to knowing whether a drug is safe and
effective. What we often do not learn from clinical trials is the
safety and effectiveness of a medicine when used in the wider
heterogeneous population for which it will ultimately be prescribed.
Clinical trials are never true mirrors of the real world.
Once a drug comes to market, people who take other medicines and
have other diagnoses will take the drug and they may suffer an
unanticipated adverse reaction. This means that labeling changes are
often needed after a drug reaches the market, but the FDA does not
``tell'' companies to add changes to their labels. They ``negotiate''
the changes with manufacturers. Meanwhile, more patients may suffer
adverse events because doctors are unaware of the problems associated
with that particular drug.
The FDA must be given the authority to require manufacturers to do
things that will enhance patient safety without delay, and they
especially need the authority to impose penalties if companies do not
comply.
We see many other areas of concern, some of which represent serious
problems. Congress should examine and then rectify these items:
FDA Commissioner
The FDA has had a Commissioner for only 18 months out of the past 4
years. This also means many of the top managerial positions at the FDA
are vacant. This sends a sad and dangerous message that the public
health is not a high priority to our government. Without a
Presidentially-appointed, Senate-confirmed FDA Commissioner, no one
knows where the buck stops.
Appropriations
I have been dealing with the FDA for over 25 years and no matter
who is in the majority, funding for the Agency has never been a high
priority to Congress. A major problem is that the Agency is not funded
through any of the health-related appropriations committees. Rather, it
is funded, for historical reasons, by the agriculture appropriations
committees. There, FDA's funding must compete against fish farms,
diseases of peach trees, and the tobacco subsidy. One father told me
that the government spends more money researching the diseases of
shrimp than the rare disease that is killing his two sons.
Furthermore, when Congress so generously doubled the NIH budget, no
one seems to realize that the ultimate success of NIH research is the
development of more treatments and cures (NIH Roadmap). So for every
dollar Congress appropriated to the NIH, they should have increased the
budget of the FDA. Instead, the FDA has suffered from meager funding
increases and a higher reliance on user fees.
Measures of Success
Under the Prescription Drug User Fee Act (PDUFA), the FDA's
performance is measured by its speed in reviewing new drugs, not on the
scientific quality of its reviews. The Agency is not allowed to spend
user fee revenues on anything other than new drug reviews, so it does
not have enough funding for post-marketing surveillance of marketed
drugs, nor to monitor pharmaceutical advertising.
Enforcement Authority
The FDA does not have adequate enforcement authority, and it cannot
set reasonable penalties if companies violate regulations. For example,
the FDA sometimes requires companies to conduct Phase 4 studies after a
drug is on the market, the statutory penalty for non-compliance being
the removal of a drug from the market. This would punish patients as
much or more than it would a company. So the FDA continues to require
Phase 4 studies, and the companies continue to ignore the Agency's
directives.
Direct-to-Consumer Advertising (DTCA)
If the FDA sees a misleading television ad about a drug, it can
require the ad to be pulled off the air. Unfortunately, the rules
regulating DTCA for prescription drugs allow companies to print or
broadcast their advertisements before the FDA review and approve them.
So the harm is already done and millions of people have been influenced
by the misleading ad before it is pulled off the air. The Agency needs
adequate staff to monitor and review advertising BEFORE it is broadcast
or printed.
We suggest that companies might be given a ``safe harbor'' if the
FDA approves their advertisement before it is disseminated. Otherwise,
they should suffer high civil monetary penalties if they circulate an
ad that is misleading or inaccurate without FDA's pre-approval.
Safety Monitoring and Surveillance
In response to sharp criticism, the FDA recently announced the
creation of an ``independent'' drug safety monitoring board made up of
government employees. Rather, we believe it should be composed of
medical and scientific experts from outside the Federal Government, and
it should report directly to the Commissioner's Office, with FDA
employees serving in an advisory capacity only. Consumers should also
be well represented. Again, if the perception among consumers is that
the Agency is beholden only to industry, it stands to reason that any
decision coming out of this new safety monitoring board--composed of
government employees only--would be considered suspect.
The post-marketing surveillance system currently in use is
seriously flawed and needs to be reworked at every stage of the
process. The current system relies on voluntary adverse event reports
from doctors and hospitals, but it is generally agreed that only a
fraction of the AE reports are ever reported. Again, the FDA has been
mandated by Congress to monitor the AE database to detect any serious
patterns, but funds were never appropriated for that purpose.
Given the authority to extract monetary penalties from industry
when there are egregious violations of the law, the FDA could use those
funds for post-marketing surveillance safety studies as well as DTCA
monitoring.
Priority Reviews
Since user fees were instituted at the FDA, the Agency has placed
undue emphasis on drugs that are not medically important. Beginning in
the 1980s, through the first half of the 90s, priority reviews were
given only to treatments for serious and life-threatening diseases
(applications were reviewed within 6 months, and sometimes faster).
Standard reviews, averaging 1 year, were given to all other drugs.
Many consumer groups believe that expedited approvals should be
reserved solely for serious- and life-threatening diseases. Drugs for
non-life-threatening diseases and disorders should not be given fast
reviews when there are many alternative treatment options available. As
I mentioned earlier, the majority of consumers do not want to be
exposed to serious risks in exchange for a temporary symptomatic
benefit.
Transparency
The FDA is probably one of the most secretive government agencies
that any consumer will ever have to deal with. Virtually everything
about a drug is considered proprietary. Consequently, Agency officials
will not talk with anyone about the drug unless the manufacturer gives
them permission to do so. Today, consumers are demanding greater
transparency. This is our government and the FDA is here for us. We
should not have to write Freedom of Information letters to find out why
there is a shortage of a medicine, or how many other people taking a
specific medicine have suffered an adverse event. Doctors and patients
need answers. The FDA's secrecy is inexcusable.
The industry counters with the argument that ``trade secrets'' can
not be disclosed, but because of this insistence on secrecy, consumers
become increasingly suspect that important facts that could affect
their health are being purposely hidden. Why were the studies showing
that antidepressants were safe for children published, while other
studies of the same drugs showing that some children died, kept secret?
There is the perception among many consumers that the FDA is
beholden only to the industry. True or not, the FDA decision-makers
should be reminded that their decisions affect lives. They should be
reminded that they are not the Defense Department with national
security concerns. They should feel free to answer the concerns of
consumers readily and factually.
Summary
The FDA is a critically important public health agency that
regulates products consumed or used by every person in this country.
Consequently, the Agency must be high on the list of Congressional
priorities. Public health catastrophes would be less likely to occur if
the Agency were substantially strengthened and had the full support of
key congressional committees.
The FDA needs greater enforcement capabilities, and a substantial
increase in funding to allow it to respond to public health
emergencies. Its performance should be measured not on speed, but
scientific evidence and excellence.
If Congress gives the FDA the tools, the Agency will secure the
public's trust. For all the talk about less government and smaller
government, the FDA is one area of government that the public wants
more of, not less. People want assurances that the food on their table
will not make them sick. They want to be confident that the medicines
they take will enhance, not destroy, their health.
It is up to Congress to reinforce America's trust in the FDA, which
guards our Nation from medical catastrophes. It is Congress'
responsibility to work with ALL stakeholders to strike a balance
between increased innovation and safety and efficacy. Thank you.
The Chairman. Mr. Schultz, I thank you for your patience
and we look forward to your testimony.
Mr. Schultz. Thank you, Mr. Chairman. I certainly
appreciate the opportunity to testify on the important issues
concerning the FDA's drug approval process that you have
decided to have the hearing about today. I think it is useful
to answer the question you posed by separating the agency's
performance, first its performance in reviewing new drug
applications, and second, its performance in monitoring drugs
after they have been approved.
In terms of the review of new drug applications, whenever a
drug is withdrawn from the market, the question is inevitably
raised, did the FDA make a mistake, and, of course, that is an
appropriate question. But the principal point that I would like
to make is that the fact that a drug turns out to have serious
safety problems does not necessarily mean that the FDA made a
mistake. This is because of the necessary disparity between the
number of people on whom drugs are tested and the number of
people on whom they are ultimately used.
Typically, new drugs are studied in a population of about
3,000 people, and yet they may be ultimately used, as in the
case of Vioxx, on millions of people. The small studies that
are used for the basis of approval simply are not designed to
detect rare adverse reactions, and I should say it is not
realistic to increase the size of these studies to be large
enough to detect those reactions. This is just something we
have to live with in the drug approval process. And yet, these
rare reactions become very significant when the entire
population is potentially exposed to the drug.
The studies done before approval also are not capable of
detecting relatively small increases of common adverse effects,
such as heart attacks and strokes. These are obviously very,
very serious, but because they are common, if you have even a
50 percent increase, it simply will not be detected typically
in the studies done before drug approval.
Of course, it may be true that the FDA made mistakes with
respect to Vioxx or any of the other COX-2 inhibitors and it is
appropriate to investigate the question. But at this time, I
personally am not aware of any evidence that FDA made a mistake
in approving those drugs.
We do know that new drugs have more risk than drugs that
have been on the market for a long period of time. This is
because less is known about them, but it is a fact of life and
should inform us on how drugs should be regulated after they
have been approved, and that is the issue that I would like to
spend the remainder of my time from my prepared statement.
My main message here is that there is work to be done,
constructive work to be done in terms of monitoring drugs after
they have been approved. Under the Prescription Drug User Fee
Act, Congress gave FDA additional resources and set goals for
making decisions on new drug applications. The FDA, I think,
did a terrific job doing exactly what Congress asked, but as it
focused its attention on new drug approvals, the postmarket
program has languished, and today, there is a tremendous
opportunity to improve drug safety by focusing on the
monitoring and regulation of drugs after they enter the market.
I have got six specific proposals. I will go through them
very quickly. I wish I could say they were all original, but
after hearing the testimony of this panel and of the FDA, I am
actually happy to be able to say that I think there is broad
agreement on many of them and there is a real opportunity to
make some progress.
First, the FDA needs to take a leadership role in educating
patients about the inherent risks of drugs. I think Dr. Kweder
said that FDA maybe didn't do a good enough job in the Vioxx
case about getting information to physicians once there were
early indications about the risk of the drug. But the publicity
of these drugs, other COX-2 inhibitors, other drugs that we all
know about, just underline what everybody in this room knows,
which is that there are inherent risks to prescription drugs.
Senator Hatch talked about this in his opening statement. But
my feeling is many patients, particularly those who don't have
serious disease, really don't focus on this, and many doctors,
as well, in prescribing drugs that maybe don't need to be
prescribed, or that if they are new, maybe shouldn't be the
first choice.
Second, FDA should consider limits on direct advertising to
the consumer of prescription drugs. Today, the drug industry
spends billions of dollars on this advertising and it is
probably an important factor in the vast number of sales of
newly-approved drugs, Vioxx, for example. This needs to be
studied and limitations ought to be considered. One possibility
is to limit this advertising in the first number of years the
drug is on the market. Another is to require disclosure that in
the case of new drugs there are going to be unknown risks.
Third, Congress should increase the resources for
postmarket activities. The fiscal year 2006 budget for the
Center for Drugs provides about $500 million--this is the
administration's request--about $500 million for the drug
approval process. About six percent of that is allocated for
postmarket activities. I think that is insufficient and I think
a lot of the other witnesses have agreed.
My last three points are very important. They relate to the
agency's legal authority. As we know, before a drug is
approved, the burden is really on the company to show safety
and efficacy. But after it is approved, the dynamic really
shifts and FDA ends up having the burden of showing the
problem.
And so my fourth suggestion is that the agency be given
authority to order changes in the drug label when there is new
information. The FDA finds new information about a drug like
Vioxx, it shouldn't just have the option of withdrawing the
drug from the market or bringing a misbranding action. It ought
to be able to order that the label be changed, and, of course,
the company ought to be able to appeal that decision within the
agency or in court or discuss it with the agency.
Fifth, Congress should give FDA authority to require
manufacturers to conduct postmarket studies. This is both after
the time of approval and after approval of new information
comes forward.
And sixth and finally, Congress should consider giving FDA
authority to limit drug distribution, and in some cases, to
actually direct the doctors how to prescribe drugs.
Thank you very much for the opportunity to testify and I
will be happy to answer any questions.
The Chairman. Thank you very much.
[The prepared statement of Mr. Schultz follows:]
Prepared Statement of William B. Schultz
I appreciate the opportunity to testify on the important issues
concerning the FDA's drug approval process. I have worked in this area
as a public interest attorney, as a Congressional staffer, as an FDA
official and now as an attorney in private practice. I have listened to
criticisms that the FDA is too slow in approving prescription drugs and
that it acts too quickly; that it approves too few drugs and that it
approves too many; that it is too strict in controlling advertising and
that it is too lax.
Today's hearing concerns important questions about drug safety that
affect all patients who use prescription drugs. The recent studies
about the safety of Vioxx and other COX-2 inhibitors have raised
questions about whether the FDA is adequately carrying out its
responsibility to protect patients from unsafe drugs. Essentially, the
issues concern whether the FDA is doing a good job in: deciding whether
to approve drugs; identifying drug safety issues that appear after a
drug is approved; and monitoring drug advertising, particularly direct
advertising to the consumer. Two other issues that I think should be
added to this list are whether the FDA should devote more attention and
resources towards informing and guiding physicians about how to use
drugs; and informing the public about the safety of drugs. I now would
like to address each of these issues.
A. The Drug Approval Process
Chronologically, the first question is whether there are serious
flaws in the evaluation of applications to market new drugs, and in
particular whether drugs such as Vioxx should have been approved in the
first place. The same question could be asked of drugs such as Baycol,
the cholesterol-lowering drug that was withdrawn after it caused more
than 30 deaths and thousands of cases of severe muscle disease, and
fenfluramine, one of the drugs that comprised the combination diet drug
known as ``Phen-Fen,'' which caused thousands of heart defects. The
first point to make is that just because a drug was withdrawn for
safety reasons does not mean that the FDA made a mistake in approving
it. This is something that many patients do not understand.
The reason that we sometimes find out about safety risks after the
drug has been marketed is explained by the necessary difference in the
number of people on whom new drugs are tested and the number of people
who ultimately use those prescription drugs. Typically, new drugs are
studied in a population of about 3,000 people. Such a study can detect
drug-related injuries that occur at a rate of between one in 500 and
one in 1,000. Yet, if the drug is used by 200,000 people, a serious
adverse event appearing in as few as one in 10,000 people is very
significant, since it would occur 20 times. If the drug is used in 2
million patients, which is not uncommon, these serious, adverse events
would occur 200 times. For this reason, rare adverse drug reactions
often can be identified only after a drug has been widely used. Common
adverse reactions, such as the increase in heart attacks and strokes
observed in the case of Vioxx, are even more difficult to detect during
the clinical trials conducted during drug development.
On the question of whether the information learned about drugs that
have been withdrawn over the last several years demonstrates that there
are serious problems with the FDA drug approval process, my answer is
that the case has not been made. Whenever a prescription drug causes
death and serious injury, it is appropriate to ask whether the drug
should have been approved in the first place. And it is appropriate to
investigate that question. My point is that based on what we know
today, I cannot identify any fundamental problems with the drug
approval process at the FDA.
B. Drug Safety After Approval
The important issue, in my view, is whether, with appropriate
resources and regulatory authority, the FDA could do a better job in
monitoring and regulating drugs after they are approved. At the outset,
it must be acknowledged that the FDA is taking a number of steps to
address the criticism of how drugs are evaluated after they enter the
market. The most significant initiative relates to how information
gathered by the agency's Office of Drug Safety should be evaluated and
how decisions about the safety of marketed drugs should be made. At
various times, it has been suggested that a separate drug safety agency
should be established or that at least a separate drug safety center
should be established within the FDA. This is a very tricky problem. On
the one hand, the drug reviewers will have the greatest knowledge about
the drug and the data reviewed in connection with its approval. On the
other hand, any system must guard against the tendency of any decision-
maker to defend his or her decisions. In other words, the charge that
the reviewer who approved the drug will have a tendency to defend that
decision must be taken seriously.
I do not believe that the best approach would be to completely
separate the post-market function from the new drug application
approval function. But it is important to elevate the post-market group
in terms of resources and status and to create a mechanism so that an
official who did not make the decision to approve the drug in the first
place is charged with resolving disagreements. It seems to me that the
agency's recent announcements about restructuring the decisionmaking on
post-market issues are a step in the right direction. I do not know
whether they go far enough. It is important that their implementation
be closely monitored.
I am also aware that important steps are being taken to make
studies of prescription drugs publicly available and to allow a public
airing of opposing view before agency advisory committees.
I would now like to turn to other steps that should be considered
to strengthen the agency's post-market program.
1. The FDA Should Initiate Programs to Educate Patients about the
Inherent Risks of Drugs and It Should Consider Restrictions on
Direct Advertising to Consumers
a. Educating Patients about the Inherent Risks of Drugs
The publicity around Vioxx and the other COX-2 inhibitors has
highlighted the inherent risks of virtually all prescription drugs. In
some cases, these risks are known when the drugs are approved, but the
FDA has made a determination that the benefits of the drug (in terms of
treating disease, for example) outweigh its risks. Everyone is aware of
severe risks of chemotherapy drugs used to treat cancer. It has also
been estimated that approximately 10-15,000 people die yearly from
gastrointestinal complications caused by non-steriodal, anti-
inflammatory pain medications (such as aspirin and the prescription
alternatives to the COX-2 inhibitors). Many prescription drugs have
documented risks.
Other risks are not known, and in some cases the risks of a drug
will never be identified because they simply cannot be detected. The
FDA should take a leadership role in educating patients about the risks
of drugs so that patients consider these risks when deciding whether to
take prescription drugs. In particular, the FDA should take on the
responsibility to remind physicians and patients about the additional
risks of newly approved drugs and it should advise caution in taking
drugs to which large numbers of patients have not yet been exposed.
b. Consider Limiting Direct Advertising to Consumers of
Prescription Drugs
It is not uncommon for a drug to reach very high sales soon after
entering the market. Often new drugs (with their inherently greater
risks) are unnecessarily prescribed to patients. Until the mid-1990's,
drug companies were effectively prohibited from advertising. Today the
drug industry spends billions of dollars advertising directly to
consumers, and it has been suggested that consumer advertising is an
important factor in the increasing sales of prescription drugs,
particularly new drugs entering the market place. This needs to be
studied and limitations on consumer advertising should be considered.
One possibility is to ban consumer advertising for a period of time
(one or two years) after a drug has been approved, as additional data
are collected on the drug's safety. Another alternative is to require
more explicit and more prominent disclosures about the safety of
prescription drugs. In the case of new drugs, manufacturers could be
required to include a standard disclosure about the inherent risks of
new drugs.
2. The FDA Should Be Given the Resources and Authority to Establish an
Effective Program for Monitoring Drugs After They Are Approved
One unfortunate consequence of the Prescription Drug User Fee Act
(``PDUFA'') is that the FDA's program for monitoring drugs after
approval has languished while the Center for Drugs focused its energies
on meeting the Congressional directives regarding new drugs.
Understandably, in recent years, the agency's focus has been on getting
drugs reviewed, but in order to meet PDUFA targets that a certain
portion of the drug approval process be funded with Federal money, the
agency has cut funds for post-market studies.
Congress should consider sending the FDA a strong message that it
expects the agency now to turn its attention to monitoring, identifying
and controlling adverse reactions to drugs on the market. This can be
done by giving the FDA the resources and legal authority it needs to
devise an effective post-market program.
In terms of resources, the fiscal year 2006 budget for the FDA's
Center for Drugs is $505 million, but only $33 million is allocated for
post-market activities, an increase of $6 million over fiscal year
2005. This funding level is insufficient to adequately monitor drugs
after they enter the market or to initiate studies if questions do
arise. The resources could be made available through appropriations or
by allowing the agency to use PDUFA funds for this purpose.
Congress should give the FDA adequate legal authority to act when
it obtains information about a drug on the market. In essence, before a
drug is approved, the company that has the burden of establishing
safety and effectiveness. As a practical matter, the FDA has the upper
hand in deciding whether to approve a drug and in deciding on the
content of the drug's label. Once the drug enters the market, the
dynamic changes. Now the company has the upper hand. Some of my
suggestions are designed to give the agency more authority after the
drug is approved and to make it clear that the company has the
continuing obligation to demonstrate the safety and efficacy when new
data become available raising questions about the safety of the drug.
a. Authority to Order Changes to the Drug Label Based on New
Information
All known information about the safety of a drug is supposed to be
included on the drug's label, and the FDA has sufficient leverage to
require appropriate information at the time the drug is approved. The
problem comes when new information is discovered after the drug is
already on the market. When that occurs, there is no explicit authority
for the FDA to order that the label be changed to include new
information or new warnings. The FDA's only recourse is to withdraw the
drug from the market or to bring a misbranding action. These options
are usually inappropriate and cumbersome. Thus the FDA is left to
negotiate labeling changes with the company and it does not have
sufficient leverage to require the changes that it deems appropriate.
Congress gave the FDA the authority to order appropriate changes in
the labeling of prescription drugs. This authority could be used if the
agency reaches an impasse in discussions with the drug manufacturer.
This new authority should be accompanied by the opportunity for the
affected company to appeal a decision with which it disagrees,
administratively and in the courts, but ordinarily implementation of
the changes should not be delayed while any appeal is pending. Finally,
the agency should have authority to require the manufacturer to notify
physicians of important labeling changes.
b. Authority to Require Manufacturers to Conduct Post-market
Studies
When the FDA approves a drug, there are often unanswered questions
that need to be studied. In other cases, these questions become
apparent only after a drug is approved. Today, the FDA sometimes
obtains commitments from companies to undertake post-market studies as
a condition of approval, but often the companies do not fulfill those
commitments, and the agency's legal authority to require the studies is
questionable at best.
The FDA has the authority to require post-market surveillance of
medical devices, but oddly it never has been given this authority for
prescription drugs. The law should be amended to give the FDA the
explicit authority to require companies to conduct post-market
surveillance of prescription drugs, both at the time of approval and
after the drug has been approved.
c. Authority to Address Misuse of Drugs by Physicians
The FDA should actively intervene when physicians misuse drugs. It
is almost gospel at the FDA that the agency does not interfere with the
``practice of medicine.'' This means that once a drug is approved for a
single use, physicians are free under Federal law to prescribe it for
any use. Sometimes off-label uses are appropriate and represent good
medical care. Other times, these unapproved uses can become widespread
and dangerous.
In some instances, physicians have ignored the FDA's directions,
risking the health of their patients. For example, the FDA has approved
the drug Accutane only for treating severe acne. Accutane is very
effective, but it causes deformities in 25 percent of children born to
women who take it during pregnancy, and strong warnings have not been
enough to discourage physicians from limiting its use. For years,
evidence has accumulated that physicians prescribe Accutane for
moderate and mild forms of acne. The FDA should be given the legal
authority to limit physicians' use of drugs when deviations from FDA-
approved uses can lead to severe injuries. This should include explicit
authority to limit the distribution of drugs to certain specialities.
The authority to require physicians to follow important label
directions also should be considered.
As an observer and for a time as an insider, one thing that is
clear to me is that The FDA listens very carefully to Congress. An
excellent example of this is the Prescription Drug User Fee Act, first
enacted in 1992. Before PDUFA, there were endless articles in
newspapers and scientific journals accusing the FDA of denying sick
people drugs that they desperately needed, while at the same time those
drugs were available in Europe and other developed countries. According
to these charges, the FDA was responsible for the ``drug lag.''
Congress passed PDUFA because user fees were seen as the only realistic
method of increasing the funds for reviewing prescription drugs, thus
eliminating the delays that could be attributed to inadequate funding.
As a result, drug review times have been cut in about half, so that
today the FDA makes decisions on drugs that represent important
advances in medical care in 6 months and on all drugs in 10 months. It
can no longer be said that the United States is the last country to
approve important prescription drugs; more often we are the first.
As with the drug lag, there is significant room for improvement in
our system for monitoring drugs after they enter the market. With an
appropriate direction from Congress in the form of adequate resources
and legal authority, the FDA could make significant progress in
identifying the risks of drugs after they enter the market.
Thank you very much for the opportunity to testify. I would be
happy to answer any questions.
The Chairman. I want to thank the entire panel for their
depth of knowledge and their willingness to share it with us. I
want to assure you that your entire testimony will be part of
the record. I want to particularly thank those who did kind of
executive summaries. Sometimes it is a little easier for me to
get my colleagues to read the executive summaries than it is
the whole testimony, but there will be people looking in-depth
at all of this information. It is not only critical, it is kind
of a hot issue right now, which always stimulates Congress to
do a little bit more.
Dr. Fleming, in your recent Health Affairs article, you
note that while there is interest in accelerating FDA's
approval to allow potentially life-saving new treatments to
come to the market, caution should be exercised not to
compromise reliable and timely evaluation of the safety and
efficacy of the new treatments. My question to you is, how do
we exercise the right level of caution? How do we appropriately
weigh the timely access and safety?
Mr. Flming. Senator Enzi, this is certainly a very
challenging issue. The Subpart (h) accelerated approval process
has been established to allow the public to get earlier access
to interventions that are promising in life-threatening disease
settings where there is a considerable unmet need.
While that, in fact, has very significant potential
benefits, the risks that are incurred in that process are that
we could end up having fairly extensive marketing of products
where we don't yet know reliably whether or not an agent that
has a biological effect--shrinking a tumor, which, for example,
is hopefully going to ultimately lead to clinical benefit to
the patient, reducing symptoms or prolonging survival--we don't
know for certain whether or not that relationship truly exists.
Meanwhile, we have lesser amounts of safety experience because
the accelerated approval process allows for the marketing of
the product based on lesser benefit-to-risk information than
you would have for full approval.
So the challenge or the difficulties here are that once a
product is in the market, it is often very much more difficult
to now complete the clinical trials that will reliably tell us
whether or not this intervention truly has a favorably benefit-
to-risk profile. Patients are less willing to go on to
randomized trials. Sponsors will tend to have a lesser sense of
urgency to get these studies done in a timely way.
And so the results of this is, in many instances, while the
intention had been to allow earlier access while the validation
trials were being completed in hopefully what would be a very
timely way, this can turn out to be a very extended time
period. And then when those validation studies are complete,
the difficulty is very often they are not persuasive and the
agency is put in a very difficult position, and I believe
Congress and the agency need to have a clear sense of a pathway
to be followed when those validation trials are not, in fact,
conclusive.
The bottom line is, as I had mentioned in my comments, what
is extremely important here is that we need to have policies to
ensure that products that are, in fact, being used under an
accelerated approval do not, in fact, have an extended period
of time of being used where we could, in fact, be putting
patients at risk of having greater safety concerns than
efficacy. There needs to be a clear procedure here to ensure
that the validation trials are completed in a timely way and
that if they aren't, in fact, conclusively favorable, that the
product doesn't end up being marketed for an extended period of
time.
The Chairman. Thank you. Dr. Fassler, public discussions
focused on adverse drug events, increased suicidal thinking and
behavior in pediatric patients, particularly treated with the
SSRI anti-depressants. Few have commented about the bad
outcomes that may occur if the black box warning
unintentionally discourages prescription of the drug for
children who might benefit significantly from its use. What is
the practical effect of the black box warning?
Mr. Fleming. Senator, we have recently received data which
indicates that there has been a very significant decline in the
prescription rate for these medications across the country, and
that is of concern. This happened over a very short period of
time. My concern is, are kids who actually have depression
getting the appropriate treatment that they need and deserve?
This is a very serious illness, as you noted. Forty percent
of kids who have depression go on to have a second episode
within 2 years, and we know that appropriate treatment,
including treatment with medication, significantly reduces that
relapse rate. Over half of the kids with depression will
eventually attempt suicide, the follow-up studies have
demonstrated to us, and between two-and-a-half and five percent
of these kids will ultimately die as a result of these
attempts. So this is a very serious illness.
I would ask some of my colleagues on the panel to see this
rapid shift in prescription patterns across the country as very
concerning. I think all these kids really need evaluations. We
need to make sure that they actually have the disorder. But I
am concerned that the action that we have taken has
unintentionally frightened some parents and just made them less
likely to get help for their kids with problems like
depression.
I also know from my own experience and from talking to
colleagues across the country that, in particular, a number of
pediatricians and other primary care physicians have become
increasingly hesitant to prescribe these medications. Although
these physicians have not had full training in the diagnosis
and evaluation of psychiatric disorders, they are integral
members of the treatment team for these kids. We really need
them to be working with us.
So we need to be monitoring this extremely carefully. I
mentioned in my testimony that the adolescent suicide rate has
actually declined over 25 percent since the early 1990s. This
is very good news and it will be devastating if we start to see
that rate climb back up again because we have made this
decision.
The Chairman. Thank you. My time has expired.
Senator Burr.
Senator Burr. Thank you, Mr. Chairman.
Dr. Fleming, your number five proposal establishes an FDA
program for observational studies and clinical trials. Real
quickly, could that be done extramurally or would that have to
be solely done within the FDA?
Mr. Fleming. Senator Burr, this is certainly an important
issue. We clearly need to have collaboration in all sectors in
order to be able to have the type of information in a timely
way about potential safety risks. I think, as Mr. Schultz had
pointed out in his commentary, as well, the FDA needs to have
the authority and the ability in those settings where these
types of observational studies that need to be done aren't
being done by the industry or by NIH, are completed.
Senator Burr. Can we accomplish that through academia----
Mr. Fleming. Academia can----
Senator Burr. Through extramural----
Mr. Fleming. Academia can and does contribute, and yet the
reality is, there needs to be a mechanism to empower the FDA to
more broadly have the ability to have these large-link
databases, which in the COX-2 inhibitor setting were an
important mechanism to be able to identify safety signals. So
we need to enhance what is----
Senator Burr. I think we all agree that the larger the
pool, the more information that is relevant we can get.
Dr. Fassler, you are interested in a publicly-accessible
registry, you said for doctors and for patients. I just want to
ask you to very briefly answer this. Do you believe that
patients can fully understand the data that comes from a
clinical trial or is that just a degree of openness that you
feel you have to include if you are going to lobby for doctors?
Dr. Fassler. Senator Burr, I am not sure that physicians
can always understand the information that comes from clinical
trials, but I do think that physicians, patients, and
researchers really need access to this kind of information. You
would be amazed how sophisticated a lot of patients are, and
again, others on the panel can speak to this, who come to
physicians who have really done a tremendous amount of research
and do know a lot about----
Senator Burr. I think you ended on a very key point, and
that is that patients who are faced with disease have learned
to do a tremendous amount of education on their own, and
electronically, there is nothing that is not at their
fingertips, with the exception of the data. The question is,
could they put it in the right context like a researcher, and I
think that is a question mark that we have to leave out there.
But it does lead me to the heart of my next question, which
is really to Bill Schultz. And by the way, let me thank you
publicly for your service. You have gone above and beyond at
the FDA, on the Hill. You have got a very varied background and
it is a tremendous asset to have you here as a witness on this
issue today because I believe that we are in a very delicate
area as we talk about what we do next because there are some
things, as witnesses have pointed out, that could have a
devastating effect on certain populations that exist and their
potential access, especially those patients who have a choice
between nothing and nothing today.
So let me turn to you if I could, Bill. You raised two of
your six points, educate patients of the risk. Why not doctors?
Mr. Schultz. That is a big part of it, too----
Senator Burr. Do they not come before patients? I mean, are
they not our conduit?
Mr. Schultz. You know, it is interesting. By the way, I
really appreciate your comments. They mean a lot. When the
issue of direct advertising to the consumer first came up in
really the late 1980s, my view--and I think I was asked to
testify on this, and my view was you ought to allow it because
you have the doctor in between the patient and the decision and
that should be full protection. And it really should be. But
the reality is, I think patients very often go to doctors and
they get drugs when they shouldn't, and so it is really both.
Senator Burr. But the point that you make is educate
patients, but limit direct-to-consumer advertising. The two
contradict each other to some degree. Educate them only on what
you want them to have, but don't educate them on the benefits
of a pool of drugs, and I think that is an inconsistency that--
it is a policy question that we have got to decide. There are
up-sides and down-sides to every decision that we make. As I
have covered with the FDA in their panel, the benefit of it is
that we now have many patients across the country that are on
cholesterol-busting drugs that are not bypass patients today
that ultimately increase their quality of life and save us
money in the system.
You also said the FDA should have the authority to limit
drug distribution. Actually, limit doctors' ability to
prescribe. I would like to ask you just to be a little more
specific on that one. One of the challenges that we always have
as legislators, and I think we look at FDA and other agencies,
is that we are not here to practice medicine in a doctor's
office. We are here to set the guidelines. And I think to some
degree, I am confused with the blurring of the line there.
Mr. Schultz. This is a tough one. I think the easiest place
to look at is maybe the FDA ought to be able to limit in
certain cases drugs to certain specialties. It is authority
they have for medical devices. And so there may be certain
drugs that they see that are just prescribed too widely and
that it would be limited to certain specialties or certain
types of doctors to prescribe.
Senator Burr. If you took that outside of the arena,
though, that is one of the issues about off-label use today, is
that because we tightly control what we are willing to let be
on that label, doctors have more of a tendency when they find
something that works that is off-label that they go to it.
Mr. Schultz. Right.
Senator Burr. I understand the spirit in which you suggest
it. It is a very----
Mr. Schultz. It is a tough issue. I think we all recognize
that off-label use in many cases is good medical care, but I
think we also have to recognize that sometimes it isn't. I use
the example of Accutane in my testimony, which is a very
effective drug for severe cystic acne. FDA has done everything
it can to basically tell doctors that is the only place it
should be used, particularly in women, because it also creates
a 25 percent risk of abortion if it is taken by somebody who is
pregnant. They have had no luck. And so the question is, should
they be able to do more in that kind of an extreme example?
Can I make a comment about direct advertising to the
consumer?
Senator Burr. Yes, sir.
Mr. Schultz. Because I think you raise some very good
points. I think the benefit of it is it educates patients, and
that is the plus. The negative in my mind, particularly for new
drugs, is that it can vast increase the number of people taking
these drugs, and maybe that is not a good thing in the first
few years before we know very much.
And so what I suggest for consideration is perhaps in the
first few years, it shouldn't be allowed for new drugs, or
perhaps there ought to be an extra warning on new drugs to
inform patients that really we know less about these products
than we do about drugs that have been on the market for a long
time.
Senator Burr. I am not sure DTC would be the subject of
conversation if we didn't have as many ED advertisements on TV
today from the industry, and that is something that we can take
up.
Let me just point out, if I could, Mr. Chairman, that the
wish by FDA now to create a more robust postapproval
surveillance program is a change that is happening because I
think that, Bill, when you were there, and we certainly pursued
PDUFA, the focus was on the reporting by doctors. We are now at
a different time. We have got to come up with a different
system. It is my hope that we can get all parties to try to do
something that is not only responsible, but addresses exactly
what Ms. Davenport-Ennis talked about, and that is that you
have got to make sure that you never forget that there is a
population out there that is on the edge. How we handle this
affects the degree of research and development that is done.
Even though I didn't have an opportunity to ask Ms. Meyers
questions, some of the concerns that she expresses are amazing
to me as a representative of the rare disorders because those
are the ones that are affected most and first by the lack of
research dollars going in when we make the world unpredictable.
So at the end of this, it has to be predictable. I thank each
of them. Thank you.
The Chairman. Thank you. Senator Isakson?
Senator Isakson. I apologize to the panel for being late.
Dr. Fleming, I would like to ask you, do you concur in
general with Mr. Schultz's remarks with regard to advertising
limitations?
Mr. Flming. I think the reality here is that we want to get
the truth to the public. The advertising to the public in
direct-to-consumer advertising is certainly one aspect, but in
many instances, it doesn't reflect the essence of the truth.
One of the comments that I had made in my recommendations
was to encourage the FDA reviewers to be more forthcoming in
their communication. One experience that I have had on FDA
monitoring committees, FDA advisory committees, is that it is
striking how often what you read in the clinical literature is
not fully capturing the essence of really what is known in the
evidence about benefit-to-risk. There is what I call a sponsor
spin in what gets into the clinical literature because much of
what is written is influenced by academics and industry that
have some conflicts of interest.
Certainly even more so, what gets presented in direct-to-
consumer advertising can't be expected to be an independent,
objective assessment of the truth. In some instances,
particularly in settings where there are significant concerns
about safety risk, as has been identified by the COX-2s, there
are real concerns, then, about direct-to-consumer advertising
giving a misrepresentation of the true benefit of what is truly
known about benefit to risk.
Senator Isakson. That being said, I take it that, in part,
is some of the reason for your recommendation, the conclusions
that the one thing we should not do is have an external review
panel established, is that correct?
Mr. Flming. Well, part of my concern here is not only the
fact that I think FDA brings the greatest overall insight into
regulatory issues. Clearly, FDA is benefited greatly by having
external advice from industry and from the academic community.
And yet the reality is, there are conflicts of interest. I
believe that it is one of the issues that concerns me, as to
the influence of that on the objectivity of the input that
would occur in that process.
Senator Isakson. Thank you. One last question of Dr.
Fleming. In recommendation number three that begins, when a
safety signal is found, frequently from noncontrolled
postmarketing data, FDA should, and I didn't hear the
testimony, so I apologize if I am behind the curve here, but
that tells me or portends to me that a postmarketing situation
is a drug that is already on the market, and then they get some
notice that there may be a problem, or there was an episode or
there were a sequence of episodes. What currently--your
solution begs the question that currently, there is not a
standard time line and methodology upon which that is measured
and tested. Is that true or not true?
Mr. Fleming. Well, I don't--I am not sure about the
standard time line. What I know is that there is a clear
recognition and acceptance that there must be postmarketing
safety assessment, and there are many levels for that. As we
have discussed, passive surveillance using MedWatch is useful
at a certain level. More effective are large-link databases
that allow us to more reliably get assessments of signals.
But ultimately, when you see those signals, the most
reliable way to assess the degree of benefit and risk is
through randomized trials, and my concern is there are
settings, such as in the COX-2 inhibitors, where there is great
need for having postmarketing randomized trials of sufficient
size and duration that we are going to be able to detect safety
risks that could be sufficiently rare that you wouldn't be able
to reliably assess them except in the randomized trials, but
could have the influence to tip the scale on benefit-to-risk.
And I believe the FDA should have the authority in those
settings to indicate that those studies should be done in a
timely way.
Senator Isakson. Thank you very much. And not a question,
Mr. Chairman, but a comment to Ms. Davenport-Ennis. I had the
chance to skim most of your testimony, although I didn't get to
hear it. I want to commend you on your advocacy in balancing
safety and timeliness and also not thwarting research and
development. Cancer survivors, of which my sister is one, from
radical treatments and things like that appreciate the dynamics
of the pharmaceutical industry and new innovation, and safety
is important, but we have got to recognize the balance for
those that life is in the balance at any one given point in
time. So I appreciate your testimony.
Ms. Davenport-Ennis. Thank you.
Senator Isakson. Thank you, Mr. Chairman.
The Chairman. Thank you. I am going to take a little
chairman's prerogative and ask a few more questions. I will
note that the record will stay open for an additional 10 days
so that all members of the committee will have an opportunity
to submit questions in writing, and hopefully you will provide
us with the answers to those, plus any expansion on comments
that you would like to make.
Dr. Gottlieb, some argue that the so-called ``me-too''
drugs raise costs while diverting R&D funds from true
innovation. Should the FDA raise the bar for approving follow-
on drugs, or are those drugs just an example of competition at
work, generating lower prices and better products?
Dr. Gottlieb. Well, the reality is that the FDA does raise
the bar for the approval of those drugs. When you look at
second- and third-in-class drugs, the trial size is usually
significantly higher than the first-in-class drugs. That is
just a fact of life inside the agency.
But the other reality is that those drugs do provide a
significant benefit to patients, not only differentiation
between molecules that don't all have the same effect on
patients, but also price competition. Study after study shows
when there is multiple drugs in a class, that it does bring
down the price.
Mr. Chairman, if I may just make one comment about the
discussion here for mandatory authority to the agency for the
requirement of trials, you know, people have discussed giving
the agency the authority to require postmarket trials and
require label changes. I think another fact of life inside the
agency, with all due respect to my former colleagues who I have
a lot of admiration for, is that the agency doesn't use its
existing authority there very well. Very often, the first pass
at label changes that the FDA works on aren't worded very well
and the dialogue that goes on between the agency and sponsor
results in a much better label change.
The same thing is true of the postmarket studies that the
agency often proposes. These proposals are made very frequently
late in the process, very close to the time of approval. They
are sprung on the sponsor days before approval, sometimes even
hours before approval, giving the sponsor very little time to
have any give and take with the agency about what is a
postmarket study that can be accomplished. That is why I think
in some cases you have postmarket studies that are unrealistic,
because the sponsor didn't have enough time to have that
dialogue.
So I think the agency has the opportunity to use the
existing authorities better and have a better dialogue about
label changes and about postmarket studies with sponsors
without the requirement to be able to mandate it. I think, in
fact, mandating it will take away that dialogue and take away
the opportunity to have the input from the sponsor, which more
often than not results in a better product.
The Chairman. Thank you. Another question for you, though,
because you are familiar with the agency's structure from your
tenure as an FDA Senior Policy Advisor with Commissioner
McClellan. Do you believe that the FDA needs to be reorganized
to separate the Office of Drug Safety from the rest of FDA?
Dr. Gottlieb. No, I don't. I think that is moving the issue
of safety oversight in exactly the wrong direction. There are
many reasons why I think the evaluation of safety needs to be
integrated with the evaluation of efficacy. First of all, you
can't measure safety outside of some kind of measure of what
the benefit is of the drug in the postmarket. The reality is
that both move in different directions. They move in the same
direction in postmarket, but they do evolve.
A good example of this is the TNF inhibitors class of drugs
that are used for rheumatoid arthritis, among other things. If
you look at those drugs, if you take a static measure of their
benefit and measure it against what we know about their safety
today, you probably wouldn't approve them today because we have
learned in the postmarket that they have many more risks than
what we knew when they were first approved. But the reality is,
we also know they have far more benefits than we knew when they
were first approved.
So now when you look at them, when you line up today's
notion of risk against today's notion of benefit from these
drugs, it makes a lot of sense to have these drugs on the
market. So you need to have both evaluated within the same
context.
Just within the structure of the agency itself, I think
removing the evaluation of safety and, in fact, creating a new
Office of Drug Safety, as some have proposed, is going to make
it harder to recruit good people into that function. I think
any time you take a line of drug review outside of the
management structure of the Center for Drugs and outside of
their senior managers, who are the most accomplished people
inside the agency, they have risen up the ranks to leadership
positions, I think you get a worse result. I think the same
would be true here if you tried to carve out drug safety and
move it away from the Review Division.
And the reality is that having the drug safety integrated
into the Review Division, I think reminds people every day, it
gives them input every day to the safety parameters they need
to be looking at, and again, isolating that, creating a
separate entity, will just further remove that from the
consciousness of the work that goes on every day inside the
agency.
The Chairman. Thank you. Ms. Davenport-Ennis, under the
current ethical guidelines, if the data are strong enough to
indicate that a drug is safe and effective before the
conclusion of a clinical trial, the trial is halted, the
therapy is given to everybody in the trial. Some people have
proposed long-term studies be required prior to approval of the
drug. It seems to me that a long-term pre-approval study would
run afoul of these ethical guidelines. How do you see these
additional requirements intersecting with ethical guidelines
for conducting clinical trials?
Ms. Davenport-Ennis. Thank you for the question. I think
that on behalf of the patient, if we look at a drug such as
IRESSA, we will take that, because there has been so much
coverage about it in the United States. For lung cancer
patients who were in the trial at the time that the drug was
being tested and the results were so phenomenal during that
trial, to bring the trial to conclusion and allow that drug to
go to market because those cancer patients had very few options
of drugs that were available to them, indeed, I think, made
sense, and from the patient perspective, the population was
glad to get it.
At the same time, I think the fact that we continue to
collect information about that drug and to report additional
information around that drug was also beneficial to the patient
community. I think at the end of the day, having an informed
patient population also means that part of that information
allows them to understand what the benefits are, what the risks
are, and when they enter a clinical trial, I think most
patients understand that there may accrue to them an added
benefit if they choose not to be in one.
So I think my answer to the question on behalf of patients
is it was a very good process and we are happy to see that it
is available in the market.
Mr. Chairman, if I may, may I also hazard a response to a
question that was asked earlier about direct-to-consumer and
the well-informed patient?
The Chairman. Yes, certainly.
Ms. Davenport-Ennis. Earlier, the observation was made that
patients are extremely well-informed and that they often go to
physicians with requests for particular therapies, and I would
certainly concur with that. But having said that, I do think we
still have a nation that has a digital divide. And while we may
have certain patients that get on the Internet and they become
very well informed and have a lot of material, we still have
citizens that are very dependent upon electronic media to bring
to their attention newly-developing products, newly-developing
protocols that may be helpful.
I think when we consider the role of direct-to-consumer
advertisement, the patient community feels that that process
has to be responsible and the ads have to be held accountable
for identifying what are the benefits to the drug, what are the
risks to the drugs, what specifically can a consumer expect if
they are prescribed a drug. And at the end of the day, if they
walk into the physician's office with direct-to-consumer
information in their hand to say, ``Prescribe this for me,'' at
that point, we have a health provider in the country who can be
the gatekeeper, who can further educate the patient that, yes,
indeed, that is a wise request, or we need to revisit that and
look at another option. So I just wanted to point that out to
the committee and for the record.
The Chairman. Thank you very much.
Ms. Davenport-Ennis. You are welcome.
The Chairman. Again, of course, I need to mention, then,
that people that are doing research on the Internet should not
believe everything on the Internet. There are a few rumors
going around about Congress out there that are absolutely not
true. I would like to make the kind of retirement that they are
mentioning that we do, but it is not going to happen and
shouldn't happen. But it is a great tool for people to get
additional information.
I really thank the panel for all of their answers and their
information, and as I mentioned, the record will stay open for
another 10 days. The kinds of questions you will get will be
far more detailed than what we had here because we try to limit
the ones that might put the audience to sleep but are really
essential pieces of information that we need to have to make
the kind of decisions we need to do.
I would remind you again that your entire testimony will be
part of the record, and if you wish to expand on any of the
comments that you had or any of the other questions, we would
appreciate that information, as well. Statements by members,
their entire statement will also be made a part of the record.
Thank you very much for being here today, and this
concludes our hearing.
[Editors Note-Due to the high cost of printing, previously
published materials submitted by witnesses may be found in the files of
the committee.]
[Additional material follows:]
Additional Material
Questions of Senator Murray
FOR PANEL I--DR. SANDRA KWEDER, DEPUTY DIRECTOR, OFFICE OF NEW DRUGS,
FDA
Question 1. As we struggle with the conflicting information
surrounding FDA's action regarding Vioxx, I think it is important to
understand what current process is in place to ensure that adverse
events are promptly reported to the FDA--and that FDA act on these
reports.
It is my understanding that Merck shared the FDA clinical trials
data that showed an increase of heart attacks and strokes in patients
taking Vioxx, as early as 2002. A link showing a higher rate of heart
attacks and strokes was evident in ongoing clinical trials.
Did FDA have this information? What prevented FDA from requiring
additional warning on the label and advertisements? Why were patients
and their doctors kept in the dark about the growing evidence of heart
attack and stroke risk associated with the use of Vioxx.
Question 2. 2. Many of us are now looking closely at the post-
market approval process. Because it would be almost impossible for FDA
to rule out every single risk associated with new drugs and therapies,
it is imperative that we have aggressive post-market surveillance.
Additional clinical trials can provide more information and risks can
be documented over a longer period of time.
Is the FDA Drug Safety process compromised because it is not a
separate, independent agency? Why is it important to have the Office of
New Drugs involved in the post market surveillance process? And
finally, what additional authority or resources does FDA need to meet
the current challenges of drug approval and drug safety?
Question 3. Since enactment of PDUFA and FDAMA, there is growing
pressure on FDA to eliminate unnecessary delays in new drug approvals.
Tight performance standards and requirements could have the appearance
of jeopardizing patient safety.
Do you believe that this is true?
Question 4. Does FDA need additional authority to require post-
market clinical trials for safety only? Many companies will continue to
conduct clinical trials in the hope of achieving FDA on-label approval
for a new indication. In fact, Merck continued to study Vioxx to
support claims that it reduced GI risks and for treatment of additional
diseases like Alzheimer's. It was this process that brought to light
the increased risk of heart attack and stroke.
Can FDA, today, order companies to conduct additional clinical
trials? Can FDA order a change in a label? Can FDA order a company to
withdraw a drug? Does FDA have other steps it can take to alert the
public to potential safety concerns, short of a recall?
FOR PANEL II
Question 1. There is a great deal of conflicting information being
reported about the FDA and the overall safety of drugs and therapies.
Many patients are concerned and are having a hard time evaluating this
information. Even looking at the conflicting reports from the FDA
Advisory Committee meeting in February, one can understand why patients
and their doctors are concerned.
Is the FDA drug approval and safety process broken? How can we
restore patient confidence in FDA without reducing timely access to new
life-saving drugs?
Question 2. Much has come to light recently about the passive
adverse events reporting structure that is currently in place for
tracking post-market drug safety. Adverse events are reported to drug
companies who then share this information with FDA.
Should we have a more aggressive reporting structure, one which
requires physicians to report directly to the FDA? Are there benefits
to mining safety data from other databases?
FOR THOMAS FLEMING, PH.D.
Question 3. Again, thank you for your willingness to be here this
morning to give all of us the benefit of your 20-plus years of
expertise.
In your prepared statement, you mention that in evaluating the
effects of Cox-2 inhibitors on the risk of cardiovascular mortality,
MI, and stroke, the FDA proceeded in a proper manner regarding the
accumulation of data. You also conclude that in general, the FDA has
been very effective in carrying out its regulatory responsibilities
and, in turn, has had a strong positive influence on the promotion and
protection of public health. These statements appear to conflict with
testimony that has been presented to Congress that indicates that the
FDA process has not worked and that the agency has not been effective
in protecting public health. In fact, there have been allegations of
thousands of people suffering heart attacks and strokes because of the
failure of the FDA.
Has the FDA process failed? Can we take steps to improve overall
public safety without dismantling FDA?
Questions of Senator Clinton for Sandra L. Kweder, M.D.
Question 1. In your testimony, you mention Acting Commissioner
Crawford's November 5, 2004 pledge to fill the position of Director at
the Office of Drug Safety. Can you please update us on the status of
this search?
Question 2. One of the first studies to be performed under the
comparative effectiveness provisions of the new Medicare law is a
systematic review of the Cox-2 drugs, which will be completed in August
2005. Could you please comment on the ways in which such comparative
effectiveness reviews can be used to enhance the work of the Office of
Drug Safety?
Question 2a. What expansions and improvements to the comparative
effectiveness program would be helpful to the FDA in allowing them to
ensure that drugs are safe for all populations?
Question 3. The Pediatric Rule requires companies submitting new
drug applications to prove that their products are safe and effective
in children before marketing them to the pediatric population. This
rule has helped ensure the safety of the drugs prescribed to our
children. Are there lessons to be learned from the use of the Pediatric
Rule that can be applied to all populations?
Question 4. The FDA is proposing a new Drug Watch webpage that will
be used to post emerging information about possible serious side
effects for approved drugs. Could you describe in greater detail how
information may be disseminated from the Drug Watch website to
consumers and providers once potential adverse effects of a drug are
noted? How will the voluntary reporting mechanisms of the FDA's current
MedWatch system be used to provide data for the Drug Watch website?
Question 5. Would giving the FDA the authority to mandate post-
approval monitoring studies improve the ability of the agency to ensure
the safety of the drugs available to American consumers?
Response to Questions of Senator Enzi by Sandra Kweder, M.D.
Hon. Mike Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
Washington, D.C. 20501-6300.
Dear Chairman Enzi: Thank you for the facsimiles dated March 21,
2005, including questions for the record related to the Committee's
recent hearings, March 1 and 3, 2005, entitled, ``FDA's Drug Approval
Process: Up to the Challenge?'' We have repeated your questions below,
followed by the Food and Drug Administration's (FDA or the Agency)
response.
Question 1. Could you go into further detail about the interactions
between the Office of New Drugs and the Office of Drug Safety? How
frequent and in what form are communications during the approval
process? During the post-market surveillance process?
Answer 1. The Office of Drug Safety (ODS) and the Office of New
Drugs (OND) interact frequently on issues of drug safety for
applications under review and marketed products. OND and ODS staff
communicate often, both informally and in more formal settings as
described below.
ODS includes safety evaluators (clinical pharmacists),
epidemiologists (M.D.s and Ph.D.s), medical officers (physicians),
health science analysts, project managers, contracts specialists, and
database and information technology support in three divisions: the
Division of Drug Risk Evaluation (DDRE), the Division of Surveillance,
Research, and Communication Support and the Division of Medication
Errors and Technical Support.
DDRE's Safety Evaluators are located in the same three buildings as
OND review division staff to facilitate communication. DDRE staff have
regularly scheduled monthly meetings to discuss pending consults and
other safety issues with the Division of Neuropharmacologic Drug
Products; bimonthly meetings are held with the Division of
Gastrointestinal and Coagulation Drug Products; and DDRE has initiated
regular meetings with other OND components including the Division of
Reproductive and Urologic Drug Products and the Division of Oncology
Drug Products and the Division of Therapeutic Biological Oncology
Products.
OND and ODS staff participate in Regulatory Briefings that solicit
input from senior Center for Drug Evaluation and Research (CDER)
management on regulatory decisions for specific products or classes of
products. OND and ODS staff attend a variety of internal meetings. ODS
sends representatives to weekly meetings of senior management in OND.
ODS and OND management meet bimonthly to discuss topics that affect
these offices.
In fiscal year 2004, ODS completed over 1200 reviews of adverse
drug reactions, epidemiology studies, medication guides and patient
labeling, medication errors, proposed proprietary product names, drug
use analyses and database searches. Prior to the initiation of these
reviews, during their preparation, and after completion, OND and ODS
may informally communicate to define the questions being asked, to
provide status information, and contact information, and to explain
methodology, content and recommendations for regulatory actions.
ODS staff are involved in the preparation for and may give
presentations at advisory committee meetings initiated by OND or ODS
involving safety issues and risk management for pending or approved
applications and when post-marketing safety information is available
for similar products. ODS works closely with the Advisors and
Consultants Staff to coordinate the use of the Drug Safety and Risk
Management Advisory Committee (DSaRM). DSaRM may meet alone as a full
committee, jointly with another CDER advisory committee, or members of
DSaRM with relevant expertise may join other CDER advisory committees
associated with OND review divisions to provide input on various issues
associated with drug safety and risk management.
During the Pre-Market Phase, ODS works with OND before, during, and
after pre-new drug application (NDA) and pre-biologics license
application (BLA) meetings with industry to review safety information
and to discuss proposed risk management plans and the need for any
post-approval risk management studies. During NDA and BLA review, ODS
and OND work together in the development and review of risk management
programs. ODS provides expertise in the review of proposed proprietary
drug names, labeling, and packaging to minimize medication errors; in
the review of information for patients such as patient labeling and
Medication Guides to ensure that product information is communicated
clearly and effectively to patients, especially those with lower
literacy readability and to ensure adherence to required content and
format; and in the review of the need for and the implementation of
Phase 4 safety study requirements. OND schedules meetings with ODS
called ``Pre-Approval Safety Conferences'' to discuss safety issues for
new chemical entities prior to approval.
During the Post-Market Phase, one of ODS' primary roles is to
provide expertise to OND in the review of post-marketing safety data
and to maintain and coordinate CDER's post-marketing surveillance and
risk assessment program. ODS staff evaluate the safety of marketed
drugs through the review of adverse drug event reports submitted
voluntarily by consumers and health care professionals through the
MedWatch program and required submissions by sponsors of approved NDAs
and BLAs. They estimate the public health impact of safety signals and
recommend appropriate regulatory actions to OND. They also provide to
OND the results of epidemiologic research on drug safety issues,
reviews of epidemiologic study protocols and results, and
recommendations on risk management programs.
ODS staff are responsible for the acquisition, analysis, and
interpretation of information from databases on drug use in various
populations, including in-patients, children, and patients over time to
which CDER has access under contracts and that help place safety
signals into context and inform regulatory decision-making. For newly
approved products with important safety concerns, ODS independently
evaluates product utilization to evaluate whether these products are
being used in a safe manner and works collaboratively and pro-actively
with OND and industry on related issues.
ODS reviews reports of medication errors that have occurred with
marketed products and recommends changes to product names, labeling,
and/or packaging to OND and the Office of Generic Drugs (OGD) to
prevent future errors. ODS works with OND and OGD to review risk
management programs for approved products to assess their
implementation and effectiveness. ODS and OND clinical review staff
together develop the scientific basis for labeled warnings, post-
marketing safety studies, drug withdrawals and compliance activities.
The Best Pharmaceuticals for Children Act (BPCA) of 2002 mandates
that during the first year that a drug receives market exclusivity, any
reports of adverse events will be referred to the Office of Pediatric
Therapeutics (OPT) and shall be provided to the Pediatric Advisory
Subcommittee. In support of this initiative, ODS staff provides reviews
of these adverse event reports to OPT and OND.
Question 2. Merck, the manufacturer of Vioxx, conducted the VIGOR
trial to support a new indication for the drug. It is my understanding
that the sponsor of a drug application proposes labeling language for
new indications. When did Merck first propose new labeling language
after the VIGOR trial? How long after the first draft label was
received did FDA respond with comments on Merck's proposal? How many
rounds of changes did it take to finalize the label?
Answer 2. FDA began discussions with Merck (also referred to as the
sponsor) about labeling changes for Vioxx after completing the review
of the multiple data sets provided by Merck over the spring and summer
of 2001. FDA transmitted changes on October 10, 2001, to the sponsor's
original labeling changes submitted as part of NDA 21-042/S007 on June
29, 2000.
The sponsor's response was received on November 6, 2001. Merck's
response had little change from the original proposed label that
accompanied the NDA supplement submitted in June 2000. A telecon was
arranged with the sponsor and Division of Anti-Inflammatory, Analgesic
and Ophthalmologic Drug Products (DAAODP) explained its position
regarding the sponsor's annotations to their counterproposal of
November 6, 2001. This telecon took place on November 21, 2001. DAAODP
requested that the sponsor reconsider its proposal in light of the
division's comments and resubmit the proposal.
Merck submitted a revised response on December 5, 2001. Because
there were still substantial differences between the sponsor's and the
division's positions, the division presented an update of the labeling
discussions regarding cardiovascular (CV) safety at a predecisional
meeting at the Center level on January 6, 2002. This venue allows for
open discussion of difficult issues with experienced leaders in the
Center. There was consensus that the data from the various large
databases was of concern and that labeling should include information
related to CV findings associated with Vioxx. This was similar to
comments made by multiple Committee members at the February 2001
meeting.
FDA transmitted a response to Merck on January 7, 2002. A telecon
with Merck took place January 30, 2002. There were still substantial
differences between Merck and the division. FDA continued labeling
discussions with Merck in teleconferences on February 8 and 20, and
March 7 and 20, 2002, until a final label was issued on April 11, 2002.
In April 2002, FDA approved the rheumatoid arthritis indication
along with labeling changes that included the results of VIGOR study
and changes to the Precautions, Drug Interactions and Dosage and
Administration sections of the label to reflect all that was known at
the time about the potential risk for CV thrombotic events in Vioxx.
Question 3. Could you describe how staff private-sector experience
and financial holdings are reviewed to identify potential conflicts of
interest when determining who should be involved in review, approval,
and post-market monitoring of a drug?
Answer 3. All employees of FDA are subject to criminal conflict of
interest statutes including Title 18, United States Code (U.S.C.) 208,
Acts Affecting a Personal Financial Interest, the Standards of Ethical
Conduct for Employees of the Executive Branch, and the Supplemental
Standards of Conduct for Employees of the Department of Health and
Human Services. FDA employees who work on drug reviews at the GS-13
level and higher are generally prohibited from holding stock in a
significantly regulated company. Employees who come from the private
sector may not work on issues related to their previous employer for a
period of 1 year after the employment relationship has ceased. If the
required disqualification period Title 5, Code of Federal Regulations
(CFR) 2635.502 has expired, FDA has an unwritten policy on
``reviewing one's own work'' and would require the employee to be
recused from working on the product. FDA's Ethics and Integrity Staff
conduct reviews of the financial disclosure reports filed by FDA
employees and provide advice on recusal obligations as needed.
Employees not required to file a financial disclosure form
(generally administrative positions, and scientific positions GS-12 and
lower) may hold up to $15,000 of stock in a company and participate in
a matter affecting that company. This determination is in concert with
the regulatory waiver issued by the Office of Government Ethics, CFR
2640. New employees are required to receive a 1-hour ethics
orientation. Ethics' New Employee Orientation covers a variety of
topics including financial interest restrictions, outside employment,
impartiality in performing official duties as well as an overview on
the Office of Government Ethics Standards of Ethical Conduct, DHHS
Supplemental Standards of Conduct and the Criminal Conflict of Interest
Statutes. Information on FDA's Ethics program is also available on the
FDA Ethics website: http://www.fda.gov/opacom/ethics/.
Employees are informed of the rules and regulations and are
responsible for complying with these rules. The Ethics and Integrity
Staff are available to assist employees and their managers when
questions arise regarding the ethics requirements.
Response to the Question of Senator Gregg by Sandra Kweder, M.D.
Question. During the hearings, when questioned about whether the
FDA needed additional authority to require label or labeling changes on
prescription drug products it appeared that Dr. Sandra Kweder and Dr.
Janet Woodcock--the FDA witnesses at each of the hearings--responded
differently to the question. Does FDA have adequate authority for the
drug approval and postmarket surveillance processes? Does FDA need any
additional authority to require label or labeling changes on drug
products, to require phase IV clinical trials, or to withdraw marketed
drug products? Does FDA need any additional authority to ensure the
safety and efficacy of new and marketed drugs?
Answer. We do not believe new statutory authority is needed. We
will use all existing regulatory authority and enforcement powers when
negotiating label changes with drug companies or when monitoring or
managing drug safety issues. In most cases, FDA and the sponsor are
able to reach agreement on the labeling text fairly quickly (a few
weeks). As Dr. Janet Woodcock testified on March 3, 2005, a key factor
in labeling changes is that once a label change is made, old labels in
paper form are still in distribution and it takes time to get newer
labels into circulation. Dr. Woodcock testified that the new strategy
of posting drug safety information sooner using the Drug Watch
mechanism will help alleviate that factor because it will enable FDA to
get information directly to the people who need it in a timely manner.
In addition to the Drug Watch web page, our February 15, 2005,
announcement included plans to create a new Drug Safety Oversight Board
(DSB) to provide independent oversight and advice on the management of
important drug safety issues and to manage the dissemination of certain
safety information through FDA's website to health care professionals
and patients. For more information on this initiative, please visit:
http://www.fda.gov/oc/factsheets/drugsafety.html. Also, FDA is
intensifying our current efforts to provide the public with the most
important information for the safe and effective use of drugs in
patient-friendly language. Two tools, Patient Information Sheets and
Health care Information Sheets, will allow FDA to deliver emerging
safety information to patients and health care providers.
To carry out these enhancements, the Agency's fiscal year 2006
budget request includes an increase of $5 million for the Office of
Drug Safety, bringing total funding to $22.9 million (a nearly 25
percent increase).
Response to Questions of Senator Hatch by Sandra Kweder, M.D.
Question 1. You stated that it would be helpful for FDA to have a
stronger ability to require changes in labeling to address emerging
safety issues. Doesn't FDA already have extensive authority to affect
labeling changes under the misbranding provisions of the Federal Food,
Drug, and Cosmetic Act (FDC Act)? For instance, Section 502(f) of the
FDC Act states that a drug is misbranded if its labeling fails to bear
``such adequate warnings . . . as are necessary for the protection of
users.'' Likewise, Section 502(j) provides that a drug is misbranded if
it is ``dangerous to health'' when used according to its labeling. Why
aren't these provisions adequate to empower FDA to require labeling
changes when new safety issues are identified? How would additional
authority provide more power than FDA's existing misbranding authority?
Answer 1. You are correct that FDA presently has authority to
affect labeling changes under the misbranding provisions of the Federal
Food, Drug, and Cosmetic (FD&C) Act. Accordingly, we do not believe new
statutory authority is needed. We will use all existing regulatory
authority and enforcement powers when negotiating label changes with
drug companies or when monitoring or managing drug safety issues.
Further, cooperation between FDA and its regulated industries has
proven over the years to be the quickest and most reliable method to
remove potentially dangerous products from the market. This method has
been successful because it is in everyone's interest to remove unsafe
products from the market as soon as possible. Manufacturers carry out
most withdrawals of FDA regulated products voluntarily. In some
instances, a company makes a discovery that results in initiation of a
withdrawal by the company. In other cases, FDA informs a company of new
findings and suggests or requests a withdrawal. Usually, the company
will comply. FDA encourages health care practitioners and consumers to
use drug products as directed in product labeling and within a
product's intended population.
Question 2. You also stated that labeling negotiations between FDA
and sponsors usually are not a problem. Can you please expand on this
statement? How often do sponsors and the FDA agree on labeling changes
in a timely manner? In your opinion, are significant delays rare?
Answer 2. Significant delays in labeling negotiations are rare. In
most cases, FDA and the sponsor are able to reach agreement on the
labeling text fairly quickly (a few weeks). However, in some cases FDA
and the sponsor remain far apart on interpretation of the data and
proposed labeling text. In those cases it may be necessary to have
meetings with the sponsor involving upper level CDER management and/or
to seek the advice of an advisory committee.
CDER has established internal review goals of no more than 180 days
to complete changes to labeling. In many cases, such as where the
change involves the addition of new safety information, the labeling
changes may be submitted under FDA regulations as a Changes Being
Effected (CBE) Supplement. These regulations allow the sponsor to
implement the changes prior to specific FDA review and approval. The
prioritization of review of labeling supplements within CDER is based
on a variety of factors, but most importantly the significance of the
change and the potential impact of the change to furthering the safe
and effective use of the drug. Some of the factors that CDER considers
include the seriousness of the new information with regard to the
health risk posed, the change it represents from the current label, the
benefits provided to physicians and patients, the seriousness of the
condition the drug is intended to treat, and the number of patients
potentially affected. Additionally, the quality of the new safety data
may vary from ironclad evidence of a problem to only a subtle
suggestion of a signal.
In most cases, the sponsor of the application submits draft text
for the new labeling along with supporting data and other information
for FDA review. The amount of supporting information can vary from a
few pages to many volumes of reports of newly completed analyses of
existing or newly completed studies. Following FDA's review of the
data, FDA makes any necessary changes to the sponsor's draft labeling
text and sends the revised labeling back to the sponsor. Depending on
the degree of agreement or disagreement between FDA and the sponsor on
the interpretation of the data and the new labeling text, there may be
additional rounds of back and forth exchange of draft labeling text.
In all cases, CDER strives to ensure that significant new safety
information is communicated to the public as quickly as possible.
Sometimes this communication occurs via changes to the labeling and in
other cases it occurs through other mechanisms such as Public Health
Advisories even while the discussions with the sponsor regarding the
final labeling text are proceeding.
As part of its new safety initiatives, FDA is committed to making
the process of communicating new safety information about drugs even
more transparent and effective, and we have already taken steps to
implement those goals such as posting physician and patient information
sheets on FDA's website and the issuance of Public Health Advisories.
Question 3. During the March 1, 2005 hearing, Dr. Scott Gottlieb of
the American Enterprise Institute stated that the labeling process
benefits from a vigorous dialogue between FDA and the drug sponsor. Do
you agree that there is value in the process of discussing labeling
changes with a sponsor? Dr. Gottlieb also stated that providing
additional authority to permit FDA to impose labeling changes on
sponsors could result in less effective risk communication because it
likely would circumscribe this important dialogue process. Do you agree
that this is a risk?
Answer 3. FDA agrees that there is value in the process of
discussing labeling changes with a sponsor.
As noted above, we do not believe new statutory authority is
needed. We will use all existing regulatory authority and enforcement
powers when negotiating label changes with drug companies or when
monitoring or managing drug safety issues.
In general, cooperation between FDA and its regulated industries
has proven over the years to be the quickest and most reliable method
to remove potentially dangerous products from the market. This method
has been successful because it is in everyone's interest to remove
unsafe products from the market as soon as possible. Manufacturers
carry out most withdrawals of FDA regulated products voluntarily. In
some instances, a company makes a discovery that results in initiation
of a withdrawal by the company. In other cases, FDA informs a company
of new findings and suggests or requests a withdrawal. Usually, the
company will comply. FDA encourages health care practitioners and
consumers to use drug products as directed in product labeling and
within a product's intended population.
We cannot speculate whether additional authority would result in
less effective risk communication between FDA and sponsors. FDA will
continue to work with Congress to ensure it has sufficient authority in
drug safety matters, and will continue to work with sponsors to make
safe and effective drug products available to those who need them as
fast as possible without compromising safety and efficacy.
Question 4. In your testimony you stated that FDA will be
implementing a new initiative to ensure that established and emerging
drug safety data are quickly available to health care providers and the
public in an easily accessible form. In the rare instances where FDA
and a sponsor cannot reach agreement in a timely manner on appropriate
labeling changes, wouldn't this initiative provide an effective
mechanism for FDA to notify health care providers and the public of
important new safety concerns with the product in question?
Answer 4. Yes. Simultaneous with FDA's labeling discussions with
the manufacturers, FDA strives to inform public health professionals of
what is known about safety risks associated with products of concern
through public health advisories and updates on FDA's website. FDA's
new drug safety initiatives will improve transparency by providing
emerging information to health care providers and patients about the
risks and benefits of medicines.
Senator Kennedy
Response to Questions of Senator Kennedy by Sandra Kweder, M.D.
Question 1. In the VIGOR trial, compared with naproxen, Vioxx at 50
mg increased the risk of heart attacks by a factor of 5. At that dose,
the approved indication was the short-term treatment of acute pain.
Please provide all drafts of the formal or informal FDA risk-benefit
analyses that, in the light of the VIGOR results, supported the
continued marketing of the 50 mg strength of Vioxx. Do these risk-
benefit analyses still seem reasonable to you?
Answer 1. FDA carefully considered all the CV findings from the
VIGOR study, and available data from other trials, in assessing the
impact of the VIGOR data on the continued safe use of the drug. FDA
presented the results of the VIGOR study at a public Arthritis Advisory
Committee meeting on February 8, 2001. The GI, CV, and general safety
results of the VIGOR study were presented and discussed extensively.
The expert panel, which included two cardiologists, recommended that
both the positive GI information (reduced risk of serious
gastrointestinal bleeding versus naproxen) as well as the potential
increased risk of CV events (compared to naproxen) be included in the
label. The panel did not recommend withdrawal of the 50 milligrams (mg)
dose from the market.
Vioxx 50 mg was originally approved only for the short-term
management of acute pain. Based on the data available to FDA at that
time, we concluded that the potential risk of short-term use of VIOXX
50 mg did not outweigh the potential benefits. FDA did however, request
changes to the VIOXX labeling that were implemented that specifically
stated that the prolonged use of the 50 mg dose was not recommended and
that the maximum recommended dose for prolonged use in osteoarthritis
and rheumatoid arthritis was 25 mg daily.
FDA's analysis of VIOXX was based on our assessment of the
available data, the recommendations from the advisory committee, and
our best judgment of the potential benefits of the drugs compared to
the potential risks of the drug when used according to the
recommendations included in the revised labeling.
As you know, FDA convened a joint meeting of the Arthritis Advisory
Committee and the Drug Safety and Risk Management Advisory Committees
in February 2005 to discuss overall benefit to risk considerations,
including CV and GI safety concerns for COX-2 selective non-steroidal
anti-inflammatory drugs (NSAIDs). The Advisory Committees analyzed all
available information from recent studies of Vioxx, Celebrex, Bextra,
naproxen, and other data for non-selective NSAIDs and COX-2 selective
products.
Following the joint meeting, FDA scientists conducted a thorough
internal review of the available data regarding CV safety issued for
COX-2 selective and non-selective NSAIDs. It was determined that Bextra
was associated with an approximately two-fold increased risk of serious
CV events compared to placebo. On April 6, 2005, FDA completed a
``Decision Memo--Analysis and Recommendations for Agency Action--COX-2
Selective and Non-Selective NSAIDs'' based upon the internal review.
The Decision Memo stated that, based upon detailed conclusions, the
Agency should ask the manufacturer of Bextra, Pfizer Pharmaceuticals,
to voluntarily remove Bextra from the U.S. market. Pfizer agreed to do
so.
On April 7, 2005, FDA issued the enclosed Public Health Advisory,
indicating that the Agency had asked Pfizer to voluntarily remove
Bextra from the U.S. market. The Agency is also asking manufacturers of
all marketed prescription NSAIDs, including Celebrex (celecoxib) to
revise the labeling (package insert) for their products to include a
boxed warning, highlighting the potential for increased risk of CV
events and the well described, serious, potential life-threatening GI
bleeding associated with their use.
Further, manufacturers of non-prescription (over-the-counter)
NSAIDs are also being asked to revise their labeling to provide more
specific information about the potential CV and GI risks of their
individual products and remind patients of the limited dose and
duration of treatment of these products in accordance with the package
instructions. In addition, FDA advised the public to contact their
health care providers to see if other marketed NSAIDs may be helpful in
treating their pain. For more information on FDA's recent actions,
please visit: http://www.fda.gov/cder/drug/infopage/COX2/default.htm.
Regarding the Senator's request for ``all drafts of the formal or
informal FDA risk-benefit analyses that, in the light of the VIGOR
results, supported the continued marketing of the 50 mg strength of
Vioxx, these were supplied to the Arthritis Advisory Committee and the
Drug Safety and Risk Management Advisory Committee in connection with
their February 2005 meeting where they analyzed all available
information from recent studies of non-selective NSAIDS and COX-2
selective drug products.'' The information is available online at:
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090b1-01.htm.
Question 2. Some have estimated that thousands of people suffered
fatal heart attacks or strokes because they used Vioxx. You have
described these as ``theoretical deaths.'' What did you mean by that
statement?
Answer 2. Studies that project the numbers of deaths from adverse
drug reactions are usually epidemiological studies. Epidemiology takes
certain information that is received and attempts to apply that
information to the entire population. Conclusions from this data are
not conclusive, but are merely estimates. Any epidemiological study
that says a million patients suffered adverse events is a theoretical
estimation of the total adverse drug reactions that is derived by
extrapolating the actual numbers observed to the population as a whole.
Therefore, these can be considered ``theoretical'' deaths. The accuracy
of projection is highly dependant on the accuracy of the information,
methodology, and assumptions used in the study. While theoretical
deaths are estimates and must be distinguished from confirmed deaths,
this nevertheless provides valuable information about potential
outcomes, and FDA takes this information very seriously in determining
whether to revise the risk/benefit profile for a particular drug.
Question 3. FDA officials have suggested that Dr. David Graham's
research on Vioxx was flawed and attempted to delay or block its
publication and to undermine his integrity as a scientist.
Answer 3. Dr. Graham was the sole FDA investigator on the study
with Kaiser on Vioxx and other drugs. At the time comments were made,
other FDA scientists had not been able to review the full study
documentation, and thus, independently confirm the scientific
assumptions and accuracy of the reported findings. FDA's review had
been limited to the final work products provided by Dr. Graham, which
included 2 abstracts, a poster presentation, a study report, and a
draft manuscript.
Dr. Graham worked with scientists outside of FDA on the Vioxx study
on this rather complex epidemiologic design, which included use of
statistical scoring to try to compare the sicker patients receiving
COX-2 agents to those receiving traditional NSAIDs. Of particular
concern to FDA officials was their incidental discovery that in May
2004, Dr. Graham and his collaborators had published findings with the
Conference Proceedings of the American College of Rheumatology that
were notably different from their findings in August-September 2004.
Analysis and review by FDA officials could find no simple or
satisfactory explanation for the differences, and so they made their
concerns known to Dr. Graham. When Dr. Graham did not address these
concerns, FDA officials made them known to the Lancet.
Dr. Graham eventually provided a partial response to FDA concerns
about his study, and in that response noted that several analytic and
quality control errors had occurred in the conduct of the study. Full
explanation or documentation of the Vioxx study still has not occurred.
Its reported results continued to vary until its final publication in
the Lancet. Major FDA concerns were addressed, and so the study was
cleared with an FDA disclaimer. Full FDA endorsement of the study would
require the typical rigorous FDA review process of the full study
documentation. As detailed elsewhere, FDA scientific review standards
often exceed those of scientific journals? peer review, since FDA
requirements capture design limitations, errors, and modifications
often unknown to journal reviewers.
By way of background information, Dr. Graham initiated his Vioxx
study with supervisory agreement in 2001. In February 2004, Dr. Graham
submitted an abstract to the International Society for
Pharmacoepidemiology for presentation at the group's August 2004
meeting in Bordeaux, France. The abstract included no results. Dr.
Graham submitted his written results and conclusions as a poster
presentation to his ODS supervisors for their review and clearance on
August 11, 2004. In the course of FDA review and clearance of the
proposed poster presentations, several FDA scientists in ODS and OND
raised questions about the methods and conclusions in the poster. Like
most posters, the proposed poster presented the study methods, results,
and conclusions in an abbreviated form and so did not describe the
study methodology in a sufficiently complete form to allow others in
FDA to review it and determine whether they agreed with its methods and
conclusions.
Dr. Graham voluntarily chose to revise his conclusions based on FDA
official input and traveled to France to present it. Upon his return,
Dr. Graham's ODS supervisors asked him to submit a draft study report
detailing his methods and his findings and this was done on September
30, 2004. It was in the review of this study report and accompanying
draft manuscript that FDA officials found and raised the concerns
described at the beginning of this response.
Question 4. Do you believe that his studies are flawed? If so, how?
Don't you believe that publication of research in a peer-reviewed
journal, as Dr. Graham was pursuing for his study, is the best process
for evaluating the strengths and weaknesses of scientific data?
Answer 4. Again, FDA places great importance on Dr. Graham's work.
However, publication in a scientific journal is not always the best
process for evaluating the strengths and weakness of scientific data.
Over the years, FDA has drawn attention in letters-to-the-editor of
scientific journals of selective and favorable publication of study
findings where FDA's own review standards (including independent review
of primary data according to pre-established study endpoints) showed
otherwise. FDA reviewers operate under strict rules pertaining to
financial conflict of interest, such that editors of prestigious
medical journals have specifically sought FDA reviewers as being the
most free of financial and intellectual conflicts of interest.
First, it is a standard practice for FDA employees to have their
work peer-reviewed according the Agency's longstanding process. This is
critical for reasons of data quality and validity, since no individual
can fully and objectively critique his own work. Without peer review,
studies risk errors in their methods, findings, and conclusions from
overlooked problems and flawed assumptions. Such errors can adversely
affect the public health by misleading the scientific and medical
communities about safety or efficacy information that is incorrect.
Sound science depends on a rigorous peer-review process to ensure that
any assumptions and conclusions made are scientifically valid.
In addition, each journal's peer review process is not identical.
They vary in the extent of and thoroughness of their expert review.
Some journals ask for primary study data to be made available to them,
while others do not. Peer reviewers may be misinformed if the data that
are shared with them have been ``cleaned'' or otherwise edited without
their knowledge.
Further, FDA is always open to ideas to make its drug safety
program even better. Acting Commissioner Lester M. Crawford recently
announced a five-step plan to strengthen FDA's drug safety program,
including an Institute of Medicine (IOM) study to evaluate the current
drug safety system. In an effort to improve the current process
immediately, CDER has instituted a program to formally address the
opinions of dissenting scientific reviewers to ensure that the
decision-making process is transparent. For more information on this
plan, please visit: http://www.fda.gov/bbs/topics/news/2004/
NEW01131.html.
In addition, FDA will enhance the independence of internal
deliberations and decisions regarding risk/benefit analyses and
consumer safety by creating an independent DSB. The DSB will oversee
the management of important drug safety issues within CDER. The DSB
will comprise members from FDA and medical experts from other HHS
agencies and government departments (e.g., Department of Veterans
Affairs) who will be appointed by FDA's Commissioner. The board also
will consult with other medical experts and representatives of patient
and consumer groups. For more information on this initiative, please
visit: http://www.fda.gov/oc/factsheets/drugsafety.html. CDER's Manual
of Policies and Procedures has been updated to reflect the organization
of the DSB; you may view this document by visiting: http://www.fda.gov/
cder/mapp/4151-3.pdf.
Question 5. You explained in your testimony that FDA is required to
disclose to the public its medical and clinical pharmacology reviews of
studies conducted under the pediatric exclusivity provision. You also
say how rich and valuable this source of information is for
pediatricians. Why shouldn't such disclosure be the rule for all drug
applications? Why should other patients and their doctors be routinely
denied this information, as is the case now?
Answer 5. Outside of the scope of the Best Pharmaceuticals for
Children Act, the Agency generally may not publicly disclose
information contained in investigational NDAs, unapproved NDAs, or
unapproved supplemental NDAs. Only after an NDA or supplemental NDA is
approved can the Agency make public certain summary information
regarding the safety and effectiveness of the product for the approved
indication.
FDA is open to any recommendations that the IOM study may make in
this area. In the meantime, the Agency is moving forward with the
creating of the ``Drug Watch'' web page for emerging data and risk
information and increased use of consumer-friendly information sheets
written especially for health care professionals and patients. These
specific proposals, announced on February 15, 2005, by HHS Secretary
Mike Leavitt and Acting FDA Commissioner Lester M. Crawford, are
immediate and fundamental steps to improve the way FDA manages drug
safety information. FDA has recently issued a draft guidance entitled,
``FDA's `Drug Watch' for Emerging Drug Safety Information,'' which
articulates the Agency's current thinking on the topic. This draft
guidance is open for public comment and may be viewed by visiting:
http://www.fda.gov/cder/guidance/6657dft.pdf.
Question 6. You testified that a drug stays on the market if the
benefit exceeds the risk its intended use and intended population.
Suppose a drug is killing people for an off-label use or outside its
intended population. Can the FDA take it off the market?
Answer 6. If a company does not voluntarily withdraw an unsafe
product from the market, FDA can pursue a variety of legal action under
the Federal Food, Drug, and Cosmetic Act. These legal actions include
seizure of available product, and/or injunction of the firm, including
a court request for recall of the product. FDA can also initiate
administrative proceedings to withdraw the approval of the drug
product. Cooperation between FDA and its regulated industries has
proven over the years to be the quickest and most reliable method to
remove potentially dangerous products from the market. This method has
been successful because it is in everyone's interest to remove unsafe
products from the market as soon as possible. Manufacturers carry out
most withdrawals of FDA regulated products voluntarily. In some
instances, a company makes a discovery that results in initiation of a
withdrawal by the company. In other cases, FDA informs a company of new
findings and suggests or requests a withdrawal. Usually, the company
will comply. FDA encourages health care practitioners and consumers to
use drug products as directed in product labeling and within a
product's intended population.
Question 7. Did the FDA's passive post-market adverse event
surveillance system produce any signal that Vioxx or other COX-2 drugs
were causing heart attacks or strokes? If not, what enhancements to
post-market surveillance are needed?
Answer 7. During early surveillance after marketing, the Division
of Drug Risk Evaluation within CDER's Office of Drug Safety examined
the passive surveillance system several times looking for adverse
events of heart attacks or strokes associated with COX-2 agents. None
of these reviews was able to convincingly discern whether these adverse
outcomes were likely related to COX-2 use. This inconclusiveness is due
to an inherent limitation of passive surveillance systems in detecting
an elevation in the risk of a commonly occurring adverse event such as
a heart attack or stroke.
Passive surveillance systems are incomplete in the number and
nature of the reports they receive. As a consequence, only unusual or
distinctive drug-related adverse events stand out as safety signals
(e.g., liver failure, Torsade de Pointes (TdP), Stevens Johnson
syndrome.)
Expansion or refinements to FDA's adverse event reporting system
are unlikely to help the system discern whether a relatively common
condition or outcome with other probable causes such as heart attack or
stroke is caused by a drug. Individual case reports cannot reliably
answer such a question unless the person is distinctively free of risk
factors for the adverse event in question.
Determining if the risk of a common event is elevated by a drug
product with long term use is probably best assessed by population-
based studies, where people receiving the drug are compared to a
similar group of individuals who have not received the drug. The best
population-based studies of this type would be randomized clinical
trials, where patients of similar illness and risk factors are randomly
assigned either to drug treatment or placebo. Observational
epidemiologic population studies are much more difficult to conduct and
interpret since people who are prescribed drugs are often sicker and
have more risk factors than people who do not receive drugs. This is
called confounding by indication. Complex statistical corrections (also
known as controlling for differences) are done in an attempt to make
the comparisons fairer. This can be difficult in some cases, such as in
the Kaiser study where the patients who were prescribed COX-2 agents
had many more risk factors for CV disease at the outset than the people
who were not prescribed these drugs. Such a baseline imbalance makes
interpreting epidemiologic analyses difficult.
Question 8. You stated that any person who experienced reduced pain
while using Vioxx benefited from using the drug. Do you also think that
it was safe for them to take it?
Answer 8. ``Safe'' is not an absolute term when discussing drugs.
All drugs have risks. A physician who prescribed Vioxx should have been
knowledgeable about drugs risks and benefits so as to make the best
choice of therapy for a patient. FDA takes very seriously its role in
making sure that the official labeling for a drug reflects all that is
known about the benefit/risk profile of the medication.
FDA worked diligently to change the Vioxx label after the VIGOR
study results. In September 2004, after Merck's withdrawal of Vioxx
from the market, FDA issued a Public Health Advisory stating that the
risk that an individual patient taking Vioxx will suffer a heart attack
or stroke related to the drug is very small but noting that patients
who are currently taking Vioxx should contact their physician for
guidance regarding discontinuation and alternative therapies.
In December 2004, the Agency issued another Public Health Advisory
following recently released data from controlled clinical trials
showing that the COX-2 selective agents (Vioxx, Celebrex, and Bextra)
may be associated with an increased risk of serious CV events (heart
attack and stroke) especially when they are used for long periods of
time or in very high risk settings (immediately after heart surgery).
In this Public Health Advisory, FDA noted that physicians prescribing
Celebrex (celecoxib) or Bextra (valdecoxib), should consider this
emerging information when weighing the benefits against risks for
individual patients, that patients who are at a high risk of GI
bleeding, have a history of intolerance to non-selective NSAIDs, or are
not doing well on non-selective NSAIDs may be appropriate candidates
for COX-2 selective agents, and that individual patient risk for CV
events and other risks commonly associated with NSAIDs should be taken
into account for each prescribing situation.
Most recently, following the joint meeting of FDA's Arthritis and
Drug Safety and Risk Management Advisory Committees, Agency scientists
conducted a thorough internal review of the available data regarding CV
safety issued for COX-2 selective and non-selective NSAIDs. It was
determined that Bextra was associated with an approximately two-fold
increased risk of serious CV events compared to placebo. On April 6,
2005, the FDA issued a ``Decision Memo--Analysis and Recommendations
for Agency Action--COX-2 Selective and Non-Selective NSAIDs'' (copy
enclosed) based upon the internal review. The Decision Memo stated
that, based upon detailed conclusions, the Agency should ask the
manufacturer of Bextra, Pfizer Pharmaceuticals, to voluntarily remove
Bextra from the U.S. market. Further, the Decision Memo stated that if
Pfizer did not agree to remove Bextra from the U.S. market, FDA would
initiate the formal withdrawal procedures.
On April 7, 2005, FDA issued the enclosed Public Health Advisory,
indicating that the Agency had asked Pfizer to voluntarily remove
Bextra from the U.S. market. The Agency is also asking manufacturers of
all marketed prescription NSAIDs, including Celebrex (celecoxib) to
revise the labeling (package insert) for their products to include a
boxed warning, highlighting the potential for increased risk of CV
events and the well described, serious, potential life-threatening GI
bleeding associated with their use. Pfizer has suspended marketing of
Bextra at this time.
Further, manufacturers of non-prescription (over-the-counter)
NSAIDs are also being asked to revise their labeling to provide more
specific information about the potential CV and GI risks of their
individual products and remind patients of the limited dose and
duration of treatment of these products in accordance with the package
instructions. In addition, FDA advised the public to contact their
health care provider to see if other marketed NSAIDs may be helpful in
treating their pain. For more information on FDA's recent actions,
please visit: http://www.fda.gov/cder/drug/infopage/COX2/default.htm.
Sincerely,
Patrick Ronan,
Assistant Commissioner for Legislation.
______
Response to Questions of Senator Enzi by Nancy Davenport-Ennis
Question 1. In light of recent controversies, some people have
proposed requiring longer-term and larger studies of drugs before they
are approved. Could you comment on whether and how this might impact
patients?
Answer 1. Time is a highly precious commodity to someone diagnosed
with a life altering and/or life threatening condition like cancer,
AIDS, or diabetes. The diagnosis not only impact the patient, but also
their families, friends and communities. When you are suffering from a
potentially fatal or severely debilitating disease, you shouldn't have
to wait any longer than is necessary for the FDA to approve new medical
products. Any attempt to mandate longer or larger clinical trials would
obviously increase the length of time before patients would have access
to new products if they are deemed safe and effective. When you are
suffering and dying, the risk/benefit ratio of significantly different
than in patient populations in other circumstances.
The process for the review of new drugs draws upon the most
complete and appropriate medical evidence collected through carefully-
controlled clinical trials, the expert judgment of FDA staff, and the
advice of patients and doctors on the advisory committees. Approval
comes down to decisions about how much risk and uncertainty should be
tolerated and, in turn, depends on the strength of the evidence on the
benefits that a new drug or device will provide. The invariable feature
of drug development is that no matter how extensive or carefully
designed the pre-approval clinical trials, a full understanding of
benefit and risk is possible only after millions of patients have been
treated, often times, for many years.
Such decisions about the size and length of a trial should continue
to be conducted on a case-by-case basis by scientific and medical
experts who are the most qualified and best equipped to make decisions
about the design of clinical trials and who have experience that may be
very similar. That is not to say that in some cases, a longer and/or
larger clinical trial might be appropriate for the proper evaluation of
a proposed product's safety and efficacy, even if that means a
potentially longer waiting period for patients. For example, a longer
trial may be necessary in order to detect delayed toxicities. A larger
number of trial participants may be necessary in order to detect very
uncommon toxicities. However, this decision should be determined on a
case-by-case basis by the clinical trial Institutional Review Board
(IRB).
However, in many cases, smaller and/or shorter clinical trials may
be sufficient for the rigorous evaluation of a new product.. Because
the appropriate clinical trial design may vary greatly depending on the
specific human testing proposed and what the testing is intended to
demonstrate, imposing a uniform requirement that all clinical trials
should include a greater number of subjects or extend for a greater
length of time would not be scientifically grounded. IRBs in both
hospital and clinical settings have historically been charged with
answering those questions.
Our preliminary background research on the matter revealed that
current FDA regulations provide conceptual parameters for different
phases of trials (i.e., Phases 1, 2, and 3), but they do not specify a
standard number of subjects in, or lengths of time for, clinical trials
to support a new drug application. Companies are required to justify
the size and length of study in their clinical protocol, which is
submitted to FDA prior to initiation of the study as well as through
the IRB that will monitor and track clinical trial status. FDA does not
require a particular number of
patients or length of follow-up. Rather, the appropriate sample
size is derived strictly from statistical calculations, and the length
of follow-up is dependent on the safety and efficacy endpoints being
measured. We believe these standards are sufficient to ensure that both
safety and efficacy can be proven.
FDA recommends that applicants follow the ``Guidance for Industry:
Good Clinical Practice'' in developing clinical studies.\1\ This
Guidance was developed in conjunction with the International Conference
on Harmonization (``ICH''), and provides unified standards applicable
to studies intended to generate clinical data for submission to
regulatory authorities in the United States, European Union, and Japan,
thus socializing data from country to country for enhanced reporting of
clinical trial activities and results.
---------------------------------------------------------------------------
\1\ FDA/ICH ``Guidance for Industry: Good Clinical Practice:
Consolidated Guidance'' (April 1996) available at http://www.fda.gov/
cder/guidance/959fnl.pdf.
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The exciting news for present and future patients is that
scientific discovery, particularly in emerging fields such as genomics
and proteomics, is laying the foundation for an ability to effectively
gauge safety and efficacy through smaller and perhaps shorter clinical
trials. For example, diagnostic tools are being developed that will
allow physicians to identify those patients with a particular type of
cancer or those who are likely to develop a particular type of cancer,
and then match those patients with the best available treatment or
preventive option for that specific cancer. This technology might also
dramatically improve the safety of trials as well.
FDA is taking new steps to develop better information about
pharmacogenomics--the differences in the way people respond to drugs
and the types and dosages of medications from which they are most
likely to benefit and least likely to suffer an adverse event. The
application of this knowledge will provide the ability to screen
patients for their level of susceptibility to certain side effects,
which will help physicians determine in advance which clinical trials
and/or treatment options may be the most appropriate in terms of
balancing safety and efficacy. (There is a recent example of this in
the approval of the Roche AmpliChip Cytochrome P450 Genotyping test;
please see http://www.fda.gov/cdrh/mda/docs/k042259.html).
Thus, science is rapidly developing a capacity to identify the best
candidates for particular clinical trials from both a safety
perspective and an efficacy perspective, which in many cases would
provide an opportunity to conduct smarter, shorter, smaller, and safer
clinical trials. With the emergence of this technology already on the
horizon, a requirement for longer and larger clinical trials could
prevent one of the most useful applications of such advancements.
Consequently, such requirements could unnecessarily expose patients to
greater risk for longer periods of time and unnecessarily impose
additional burdens in terms of time and resources on those who design
and conduct clinical trials.
The length and size of the clinical trial is one of the most
expensive aspects of the research and development process. According to
recent industry estimates published by Cutting Edge Information, the
average per-patient cost of a Phase I trial is about $5,500; the
average for a Phase II trial is $6,500; and the average Phase III trial
costs more than $7,600 per patient. A widely cited study on drug
development costs conducted by Tufts University estimates that the
average per patient cost to conduct clinical trials is $23,572. The
National Cancer Institute (NCI) estimated that its average per patient
cost for a clinical trial ranged from $3,861 to $6,202 (depending upon
the year) for the DCP Cooperative Group Treatment Trials conducted
between 1993 and 1999.
Any mandate for larger and longer clinical trials would
dramatically increase the overall cost of research and development.
Such increases could have a chilling effect on the pace of scientific
discovery.
Fortunately, the continued development of new, scientifically based
capacities to enable shorter, smaller, and smarter clinical trials
holds great promise for dramatically reducing the skyrocketing costs
associated with the clinical trials component of research and
development. Since the cost of conducting a clinical trial sometimes
prevents companies from pursuing promising new products (particularly
those that would be used only in certain patient sub-populations), any
technological advancements that reduce the cost of clinical trials
could provide a heretofore lacking economic incentive to expand the
scope and scale of the research and development pipeline to include new
products for diseases and conditions that would otherwise be considered
too great of a financial risk. For many patients with limited to no
treatment options for their particular disease, a robust research and
development pipeline offers them and future patients the best hope for
potential improvements in their quality of life and/or life expectancy.
Question 2. Many have called for a greater separation between the
Office of New Drugs, which is responsible for drug approvals, and the
Office of Drug Safety, which is responsible for post-market
surveillance of drugs that have already been approved. Are you
concerned that an independent Office of Drug Safety would only look at
risks and problems, potentially ignoring the benefits?
Answer 2. Patients and their families, physicians and caregivers
must always weigh the benefits and risks associated with a particular
treatment option. Similarly, we feel that the FDA must carefully weigh
the benefits and risks associated with a new drug when making decisions
about approval or post marketing activity.
Safety and efficacy are the inseparable foundation of the FDA's
ability to best define the appropriate risk/benefit ratio of a product.
Risk cannot be considered separately from benefit, nor safety from
efficacy. To review one without an equal measure of the other could
easily lead to misjudgments and false conclusions. For that reason, we
would advise against any effort that creates new regulations or
bureaucracy that isolates or further separates the drug safety function
from the overall drug review and monitoring process.
Rather than an independent drug safety office operating in
isolation, we would prefer strengthening of the existing Office of Drug
Safety so it can do a better job in a more timely fashion. Adding new
levels of bureaucracy at FDA that only consider safety without
consideration for efficacy will almost certainly discourage research on
new therapies for deadly diseases like cancer and AIDS. Assuming they
could even be approved, it could be difficult to keep new treatments
for these diseases on the market if the regulatory hurdles for safety
are too high because those drugs are likely to have some level of side
effects, and they are likely to be used in patient populations that are
sick and vulnerable to adverse reactions.
Of even greater concern is how an overemphasis on safety might have
a devastating impact on the advancements being made in our ability to
detect deadly diseases early or prevent them altogether. The conundrum
is that the clinical testing and medical application of new
technologies for early detection and prevention will involve people at
risk for the specific disease who are not yet showing signs of advanced
disease and may be entirely without symptoms. However, the tools for
early detection and prevention are likely to have side effects, just
like any medical intervention.
If the regulatory emphasis on safety is too great, it will be very
difficult to get new tools for the treatment, prevention and early
detection approved and then keep them on the market even though they
may save hundreds of thousands, if not millions, of lives in the not
too distant future. Such potential uncertainty can easily discourage
the public and private sectors from investing hundreds of millions of
dollars into the research and development of new products in this
country if those products are likely to face intense scrutiny over
safety concerns regardless of their benefits. We can evaluate the
number of off-shore clinical trials toady, as opposed to 5 years ago,
and see that many US clinical trials have been moved to foreign
locations. The patients of the United States would benefit greatly from
additional clinical trials taking part in our country.
It always has been an unfortunate but unavoidable fact that some
adverse effects may not become apparent until after a drug has been in
wide or extended use. We can hope to minimize such adverse effects and
enhance the agency's capacity to report them, but we must also accept
certain risks associated with beneficial drug products.
With that in mind, we do feel strongly that the FDA can do a better
job with its post marketing surveillance activity. We applaud Dr.
Lester Crawford's announcement that FDA will enhance the independence
of internal deliberations and decisions regarding risk/ benefit
analyses and consumer safety by creating an independent Drug Safety
Oversight Board (DSB). The DSB will oversee the management of important
drug safety issues within the Center for Drug Evaluation and Research
(CDER). The DSB will comprise members from the FDA and medical experts
from other HHS agencies and government departments (e.g., Department of
Veterans Affairs) who will be appointed by the FDA Commissioner. The
board also will consult with other medical experts and representatives
of patient and consumer groups.
Another important initiative is for FDA to continue to increase the
transparency of its decision-making process by establishing new and
expanding existing communication channels to provide targeted and
timely drug safety and efficacy information to the public. These
channels can be used to help ensure that established and emerging drug
safety and efficacy data are quickly available in an easily accessible
form to those who will bear the risks: patients and their caregivers.
The increased openness will enable patients and their healthcare
professionals to make better-informed decisions about individual
treatment options. To address these objectives, the FDA must stress
efficient risk management--finding the least costly approach to
achieving the most risk reduction for patients. Efficient risk
management requires using the best scientific data, quality standards,
and efficient systems and practices that provide clear and consistent
decisions and communications for the public and regulated industry.
Although we see it only as a first step, we are pleased that the Agency
is proposing a new ``Drug Watch'' Web page for emerging data and risk
information and increased use of consumer-friendly information sheets
written especially for healthcare professionals and patients. Finally,
we believe FDA will need to employ more user-friendly, automated
adverse event reporting systems.
In order to achieve these objectives, we strongly believe
additional financial resources will be required. Moreover, without new
resources, every dollar the FDA shifts towards new regulations and
infrastructure for safety is money taken away from programs that allow
the agency to more effectively and efficiently evaluate risk and
benefit together in the New Drug Approval process.
Response to Questions of Senator Enzi by Thomas R. Fleming, Ph.D.
Question 1. What are some of the strengths and limitations of
``observational'' or longitudinal studies versus placebo-controlled
studies? Is it appropriate to pull a drug from the market based solely
on observational studies without some sort of active control?
Answer 1. In the post-marketing setting, multiple sources of
information are useful in monitoring for safety signals. Recalling my
testimony on March 1, 2005, these sources include:
``(i) post-marketing passive surveillance, such as is provided
by the Adverse Event Reporting System (AERS); (ii) post-
marketing active surveillance, such as is provided by large
linked data bases, in particular for products that will have
wide spread use; and (iii) post-marketing randomized trials to
rule out unacceptable increases in the rate of clinically
significant safety risks that are uncommon or occur on a
delayed basis, when evidence has been obtained to suggest the
plausibility of such risks.''
The first two sources are ``observational'' studies. The strengths
of these passive and active surveillance methods are their ability in
some settings to provide timely detection of safety signals for
products as used in real world settings. These approaches are
especially useful when there is a strong temporal relationship, (i.e.,
the safety risks occur immediately after the administration of the
product), when there are biological factors supporting plausibility of
risk, and when the intervention induces a very large increase in the
relative risk of safety events that otherwise would have occurred very
rarely in clinical practice, (e.g., detecting the association of
intussusception with use of the rotavirus vaccine, or Stephens-Johnson
rash with use of an HIV/AIDS drug, or ruling out an association of
encephalitis with use of an acellular pertussis vaccine).
These sources of information provided a sufficient basis to remove
the rotavirus vaccine from the market, because this vaccine did induce
a large and temporally related increase in the rate of the usually rare
event of intussusception. More often, however, due to important
limitations in these passive and active surveillance ``observational''
studies, such sources of information are more useful for hypothesis
generation regarding safety signals, where such hypotheses then need to
be rigorously assessed using post-marketing randomized trials. This is
particularly true when the intervention provides a moderate increase in
the risk of a clinically significant safety event, especially if this
increase might occur on a delayed basis. The identification of the
increased risk of cardiovascular (CV) death, MI and stroke, caused by
use of Cox-2 inhibitors, is a classic example of this situation.
Recalling my testimony on March 1, 2005 about limitations of passive
and active surveillance sources of evidence regarding detection of
safety signals:
Due to lack of a randomized control group, frequently
unavailable confounder information (such as aspirin use or
smoking history when studying Cox-2 inhibitors), concerns
regarding outcome specificity (are reported events truly
events?) and sensitivity (are true events reliably captured?)
partly due to recall bias, and concerns resulting from loss to
follow-up and the lack of a proper ``time zero'' cohort,
results from these analyses can be very misleading, especially
when one is attempting to determine whether an intervention
induces a clinically important safety risk that corresponds to
less than a 2-fold increase in rate of occurrence of these
safety events. These concerns appear to be relevant to the
setting of Cox-2 inhibitors. While their effect on the risk of
CV deaths, MI and stroke is clinically significant, it appears
that this effect is approximately at the level of a 1.5 fold
increase, an important but not dramatic increase. In such
settings, the FDA properly would view such ``epidemiological''
or ``observational'' evidence, with all its limitations, to be
hypothesis generating or clues regarding safety signals. The
FDA properly recognized that it was necessary to conduct post-
marketing randomized trials, with large sample sizes and long
term follow-up, to reliably address the CV safety risk of the
Cox-2 inhibitor class, so that risks could be reliably weighed
against the proven benefits.
This testimony also gave several examples to illustrate that more
reliable large post-marketing randomized clinical trials often provide
substantially different conclusions from observational studies
regarding the frequency and severity of safety risks. Results from
observational trials usually should be viewed with caution, in the
spirit of hypothesis generation, and usually should not serve as the
sole basis to justify removing a drug from the market.
Question 2. Your testimony includes some very interesting
statistics as to the size of a clinical trial that would have to be
conducted to pick up adverse events of a given frequency. It's all well
and good to say that a risk is equal to a ``1.2 fold increase over
background,'' but that doesn't mean much to most people. Do you have
any thoughts on how to best communicate to doctors and patients the
absolute and relative risks of side effects?
Answer 2. While one useful approach to summarizing the magnitude of
a safety signal is to report the estimated increase in relative risk,
such as a ``1.2 fold increase over background'', you correctly note
that additional ways of conveying risk are very helpful to patients and
care givers. For example, the ``CV mortality, MI and stroke'' safety
signals for Cox-2 inhibitors have been evaluated in a large number of
completed randomized clinical trials involving more than 75,000
patients. The proportion of patients in the control arms of these
trials who experienced the outcome of ``cardiovascular death, MI and
stroke'' was approximately 1 percent (i.e., 10 per 1,000 patients) per
year. (This proportion was smaller in settings such as rheumatoid
arthritis and larger in settings such as Alzheimer's disease and
coronary artery surgery). In such instances where the background rate
is 1 percent, if a drug induces a 1.5 fold increase in the risk of ``CV
death, MI and stroke'', it might be helpful to recognize that this
indicates the drug causes 5 additional ``CV mortality, MI, and stroke''
events per 1000 patients treated, increasing the expected number of
events from 10/1000 to 15/1000 per year. (If the background rate were 2
percent per year, a 1.5 fold increase would correspond to increasing
the expected number of events from 20/1000 to 30/1000 per year). This
risk then needs to be considered in the context of the totality of
information about the benefit-to-risk profile of the intervention.
Response to the Question of Senator Kennedy by Thomas R. Fleming, Ph.D.
Question. In the VIGOR trial, compared with naproxen, Vioxx at 50
mg increased the risk of heart attacks by a factor of 5. At that dose,
the approved indication was the short-term treatment of acute pain. Do
you believe there is a benefit to 50 mg of Vioxx over other treatment
options that outweighs this risk?
Answer. Data from clinical trials evaluating several Cox-2
inhibitors in a variety of clinical settings and doses strongly suggest
that these agents, as a class, increase the risk of CV death, MI and
stroke. This evidence is particularly strong for Vioxx at evaluated
doses of 25mg and 50mg. From the 8000 patient Vigor trial, it is
estimated that patients receiving the 50 mg dose of Vioxx have
approximately 2.4 times the risk of these irreversible morbidity/
mortality events. Due to ``regression to the mean'' or to use of lower
doses, validation trials involving an additional 15,000 patients have
indicated that the true level of increased risk of these events is
likely smaller (probably closer to a relative risk of 1.5).
Nevertheless, this increased risk in treatment induced mortality and
irreversible morbidity is more clinically significant than the
beneficial reduction in the risk of significant upper GI ulcers
provided by Vioxx relative to non-selective NSAIDS. Given that Vioxx
has not been established to provide improved pain relief relative to
non-selective NSAIDS such as naproxen, the totality of available
information does not suggest that Vioxx, at evaluated doses, provides a
benefit-to-risk profile that is favorable relative to that of non-
selective NSAIDS.
There is anecdotal evidence suggesting that Vioxx might provide
substantial benefit to some patients with significant pain who have not
obtained relief from other treatment options. Such evidence could
motivate conducting randomized trials that would compare the relative
pain relief provided by Vioxx versus standard-of-care, in a cohort of
patients who have not received benefit from multiple regimens involving
non-selective NSAIDS. It might be possible to establish that Vioxx has
a favorable benefit-to-risk profile relative to other treatment options
in this restricted clinical setting if such trials were conducted and
yielded strongly positive results regarding the ability of Vioxx to
provide significantly superior pain relief relative to these other
treatment options, in particular if these efficacy results were to be
achieved using lower doses of Vioxx that could be shown to induce
smaller increases in the risk of CV death, MI and stroke.
While future trials might establish that certain doses of Vioxx
have a favorable benefit-to-risk profile relative to other treatment
options in some restricted clinical settings, marketing of a product
should be based on what has been, rather than what might be,
established. Currently available data have established that Vioxx
induces serious safety risks and have not shown that it provides
advantages over available treatment options where these advantages are
of comparable or greater clinical significance than the induced safety
risks. Hence, on the February 16-18 2005, while serving on the FDA
Advisory Committee reviewing safety of Cox-2 inhibitors, I voted ``No''
to the question, ``Does the overall risk versus benefit profile for
rofecoxib support marketing in the United States?''
Response to Questions of Senator Enzi by David Fassler, M.D.
American Academy of Child & Adolescent Psychiatry,
Washington, D.C. 20016,
April 1, 2005.
Hon. Michael Enzi,
Chairman,
Committee on Health, Education, Labor, and Pensions,
U.S. Senate,
Washington, DC. 20510.
Dear Chairman Enzi: Thank you for your inquiries regarding the U.S.
Food and Drug Administration drug approval process following my
testifying at the H.E.L.P. Committee hearing you convened March 1,
2005. I am pleased to provide the following response to your questions.
Question 1. You have supported the call for additional large-scale
research studies on both the safety and efficacy of all of the SSRI
medications. These are clearly post-market studies. Do you support
larger scale and/or longer pre-approval studies on drugs that may be
used in children and adolescents?
Answer 1. Many of the clinical trials currently conducted in
conjunction with the approval of a new medication are relatively short-
term. However, children and adolescents often take medication for an
extended period of time. Both the American Psychiatric Association
(APA) and the American Academy of Child and Adolescent Psychiatry
(AACAP) support both larger scale and longer studies on the safety and
efficacy of medications used in the treatment of pediatric patients.
Such studies should be conducted both prior to and after approval. Data
from these trials should also be included in a centralized registry,
accessible to the general public. Physicians and parents need and
deserve access to such information in order to make appropriate
decisions regarding treatment options.
Question 2. The British Medicines and Healthcare Products
Regulatory Agency and the American FDA took different actions to modify
the use of SSRI anti-depressants in children and adolescents. The
British agency limited NHS prescribers to one SSRI only, Prozac. FDA
went with a label change. Can you compare and contrast these two
approaches. In your professional opinion, what is the impact of these
two approaches on treating depressed children and adolescents?
Answer 2. The British regulators correctly concluded that the Food
and Drug Administration has more information regarding the use of
fluoxetine in the treatment of pediatric patients. However, the general
clinical consensus in this country is that the SSRI antidepressants are
roughly equivalent in terms of overall safety and efficacy. The
selection of a specific medication is influenced by a number of factors
including the side effect profile (e.g., effects on sleep, appetite,
etc.), pharmacological properties (e.g., the half-life of the
medication), and previous history with a specific medication, including
positive or negative experience among other family members. Research
indicates that approximately 60 percent of children and adolescents
with depression will respond to an initial medication. However, many of
the remaining 40 percent will respond to a second, or sometimes even a
third medication. Prohibiting prescribing of medicines for those 40
percent of pediatric patients can hinder effective treatment of mental
illnesses. For this reason, physicians need continued access to the
full range of possible treatment interventions.
With respect to the SSRI antidepressants, several large scale
ongoing studies are currently underway which will significantly enhance
our knowledge regarding the use of these medications in children and
adolescents. These include TADS (Treatment for Adolescents with
Depression Study), TASA (Treatment of Adolescent Suicide Attempters),
and TORDIA (Treatment Of Resistant Depression In Adolescents). The
results of these studies will help us refine our ability to determine
which children and adolescents are most likely to respond to a specific
intervention.
Question 3. One of the problems pediatric researchers face are the
small number of patients available for study. That is particularly
important where a side effect may be identical in appearance to the
natural history of the disease, such as in depression. Do you think
that these problems impacted FDA's actions with respect to the SSRIs?
How could we improve FDA's ability to respond?
Answer 3. It is particularly challenging to evaluate potential side
effects which are similar or even identical to symptoms associated with
an underlying illness. FDA made an attempt at this challenge with
respect to the SSRI antidepressants. In its process, FDA may not have
fully considered the side effect profiles and the psychopharmacologic
profiles of the antidepressants on its studies' patients. This
observation underscores the importance of ensuring that the FDA has
access to, and queries, researchers and clinicians with appropriate
background and expertise to assist regulators in distinguishing between
side effects and underlying symptoms. In particular, I have suggested
the development of a Pediatric Central Nervous System Advisory
Committee which could provide such input, as necessary, to improve
FDA's ability to respond.
Thank you again for the opportunity to share with the Committee my
professional and experiential opinions. On behalf of the American
Psychiatric Association and the American Academy of Child and
Adolescent Psychiatry, I look forward to working with you in the future
on these critical pediatric psychiatry matters.
Sincerely,
David Fassler, M.D.
______
Response to Questions of Senator Enzi by Abbey S. Meyers
National Organization for Rare Disorders (NORD),
Danbury, CT, 06813-1968,
March 24, 2005.
Hon. Michael B. Enzi,
Chairman,
Health, Education, Labor, and Pensions Commmittee,
Washington, DC. 20510.
Dear Mr. Chairman: Thank you for the two questions regarding my
testimony at the drug safety hearing of the HELP Committee. My answers
are as follows:
Question 1. As you know, there are things about rare disorders that
make a different approval standard appropriate. Could you discuss
whether rare disorders are the right model for approval for drugs to
treat more common disorders, and if so, how that model would translate?
Answer 1. The Orphan Drug Act of 1983 does not provide a different
standard for orphan drug approvals. During 3 years of intense debate
about the design of the law, consumers made it very clear that we
wanted orphan drugs to comply with the same standards of safety and
efficacy as other pharmaceuticals and biologics. We do not want
treatments that are less safe, or less effective than other treatments.
Rather, the law provides financial incentives to entice companies into
developing drugs for small populations of patients (fewer than 200,000
patients in the United States), because the industry felt that such
small populations represent a limited market that would not be
profitable enough. However, the law does provide a mechanism for
patients to have access to orphan drugs while they are still
investigational if the patient is not eligible to participate in a
controlled clinical trial. In this case the patient gives informed
consent and the doctor provides the medicine under an IND.
At the beginning of the AIDS/HIV epidemic FDA was under pressure to
speed the development of new AIDS drugs, but consumers representing
other deadly diseases felt that the rules should not be changed for one
disease. Rather, the new rules should allow an accelerated approval
process for treatments applicable to any serious or life-threatening
disease when other treatments were unavailable or unsatisfactory.
Subsequently, then Commissioner Frank Young created an ``accelerated
approval'' or a ``fast-track'' process allowing drugs for serious and/
or life-threatening diseases to show less efficacy data than is
required for drugs to treat less serious conditions, or serious
conditions where there were already available therapies. However, the
manufacturer had to promise to conduct clinical trials (to confirm the
efficacy or treatment benefit) after the drug was on the market.
Section 506 of the Food and Drug Modernization Act of 1997, which
codifies the regulation instituted in the 1980s by Commissioner Young,
defines fast-track as follows:
Designation of Drug as a Fast Track Product.--In general. The
Secretary shall, at the request of the sponsor of a new drug,
facilitate the development and expedite the review of such drug
if it is intended for the treatment of a serious or life-
threatening condition and it demonstrates the potential to
address unmet medical needs for such a condition. (In this
section, such a drug is referred to as a ``fast track
product''.)
Thus, since the mid-1980s until now, drugs for many diseases, both
rare and common, were eligible to use this process if the drug fit
within the serious or life-threatening parameters of the regulation.
However, the drug had to have concrete clinical evidence that it was
probably safe and effective before it could be approved for patients
under the fast track system, and manufacturers had to promise they
would conduct these confirmatory post-approval (Phase 4) trials if the
FDA asked them to. As you know, not all of those Phase 4 trials have
been done, and those that have been done may have taken longer than FDA
required.
Question 2. Ms. Meyers, you have testified previously that the
primary purpose of the FDA Modernization Act ``was to speed the
approval of more new drugs and devices, even if those drugs and devices
were relatively unimportant to the public health.'' But we know that no
two drug compounds are exactly the same in terms of how they affect
patients. Each patient has a unique genetic predisposition that affects
how a drug affects him or her. Each patient has his or her related or
unrelated medical complications that affect how a drug reacts. A drug
that might be right for me, might not be right for you--so who decides
which drugs are important or not important to the public health?
Answer 2. There has been much written about ``personalized
medicines'', but they are not yet available for general use. This is
primarily because science does not yet have the tools to understand the
genetic differences between humans. The first DNA test to examine how a
person's liver may metabolize certain drugs has very recently been
approved by the FDA, and some cancer drugs can be aimed at certain
types of tumors but not others. Everyone expects that science will
evolve so that personalized medicines will eventually become available
in the future, but it is not available now, and doctors generally
cannot prescribe a treatment based on a person's genetic profile.
It is indeed true that a drug that works for me may not be good for
you. Companies spend a lot of money developing ``me-too'' drugs for
common diseases that are similar to other available therapies (e.g.,
many companies have or were recently developing Cox-2 inhibitors for
the most common form of arthritis, osteoarthritis). There are minor
differences between these drugs in order not to violate a competitor's
patent. But in terms of speeding approval of any new drug, FDA should
recognize that arthritis is not life-threatening, there are dozens of
available treatments already on the market for arthritis pain, and the
people who take pain drugs are either healthy people who want minimal
risk from any medication (e.g., for a sprained ankle or dental pain),
or elderly people with other diagnoses who are taking other drugs. The
risk of a dangerous interaction with other medicines, the difference of
metabolism between young healthy patients and older people, and the
problems of taking a medicine long-term for a chronic disease like
arthritis, should raise significant safety questions before a new drug
for arthritis pain enters the market.
The only way for a doctor to tell which drug will work better on a
person with arthritis is to prescribe each one, one at a time. The
manufacturers of Vioxx and Celebrex have never claimed that their
products are more effective than other anti-inflamatories. In general
they were marketed to be ``as effective'', but with greater safety on
the stomach. However, there are other anti-inflamatories on the market
that are manufactured to dissolve in the intestines rather than the
stomach, for patients who have stomach problems. Additionally, long-
term studies of the Cox-2 inhibitors have shown that people who took
the drugs for more than one year had an equal incidence of stomach
ulcers to those who took older anti-inflammatories.
So I agree with you, Senator Enzi, that ``me-too'' drugs that are
similar to other medications, are good because they provide more choice
for consumers, even though doctors are usually unable to determine
which may be better for each patient. But these kinds of treatments for
non-life threatening diseases, that will be taken chronically for a
disorder such as arthritis, and used by a frail elderly population with
other illnesses, should not be approved for marketing on a priority
review. Instead such drugs should be studied longer on a population
that reflects the ``real world'' market, not a pristine group of
individuals who have no other complicating factors. Once these drugs
reach our local pharmacies, people with heart conditions, diabetes,
high cholesterol, etc., take them. Even if FDA thought that the first
Cox-2 inhibitor was a break-through drug, then the second and third
Cox-2 drugs should not have been reviewed on a shortened priority
basis.
We believe that fast-track reviews of pharmaceuticals should revert
to their original intent: They should be used as treatments for serious
and life-threatening diseases that have no other satisfactory
treatments available (an unmet medical need).
I hope this answers your questions.
Abbey S. Meyers,
President, National Organization
for Rare Disorders (NORD).
Response to Questions of Senator Enzi by William B. Schultz
Question 1. You have proposed giving the FDA the authority and
responsibility to limit how doctors can prescribe medicine for their
patients. Each patient's situation is different, and I'm concerned that
a regulatory agency that weighs risks and benefits of a drug on a
population level is ill-equipped to make those decisions on a personal
level. Once a drug has been approved by the FDA, isn't it best left to
doctors and patients to make decisions about the risks and benefits?
Answer 1. I am not proposing that FDA be given authority to direct
how physicians treat individual patients. Unfortunately, however, there
are examples of where physicians simply do not pay attention to the
FDA-approved label. Since we, as a Nation, have given FDA the
responsibility to review available data and to analyze the risks and
benefits of drugs (a task which few physicians or patients are
qualified to undertake, even if they had the time), in limited
circumstances FDA should have authority to ensure that physicians
follow the Agency's directions. One possibility is to give FDA the
authority to limit certain drugs to specific medical specialties. The
Agency already has this authority for medical devices. The other
possibility would be to give FDA explicit legal authority to place
limitations on the use of particular drugs (such as where a drug can be
used safely only in connection with a certain test or where certain
uses are clearly unsafe). I do not know whether this last option is
viable, but I offer it for consideration.
Question 2. Many have called for a greater separation between the
Office of New Drugs, which is responsible for drug approvals, and the
Office of Drug Safety, which is responsible for post-market
surveillance of drugs that have already been approved. Are you
concerned that a separate Office of Drug Safety would only look at
risks and problems, potentially ignoring the benefits?
Answer 2. I think that it is important that the expertise of the
Office of New Drugs be used in assessing safety problems that are
identified after a drug is approved. Whomever is given the
responsibility for deciding whether to limit the use of a drug or to
withdraw the drug must be directed to consider both risks and benefits,
just as FDA must consider both risks and benefits when deciding whether
to approve a drug.
Question 3. You suggest that FDA does not have clear statutory
authority to require a postmarket study, but it appears that FDA
successfully gets postmarket study commitments. In fact, the vast
majority of drug approvals (73 percent) between 1998 and 2003 included
a postmarket study commitment. Can you comment on how FDA is able to
get postmarket study commitments from drug sponsors in these cases even
though it may not have clear statutory authority?
Answer 3. You are correct that prior to approval FDA sometimes
obtains commitments from companies to conduct postmarket studies.
However, as the case of Vioxx demonstrates, after a drug is approved,
it is often essential to obtain additional information, and at that
time the agency has no leverage or authority to obtain postmarket
commitments. My understanding is that the agency does not often (if
ever) seek or obtain commitments to undertake postmarket studies after
a drug has been approved. In my opinion, FDA should be given legal
authority to require companies to conduct postmarket studies where new
information raises questions about a drug after it has been approved.
Even at the time of approval, with no legal authority, the Agency
has inadequate leverage to obtain commitments to conduct the necessary
postmarket studies. And even when commitments are made, it has no
authority to require companies to fulfill their commitments. At various
times, it has been estimated that drug companies do not meet a
significant percentage of their commitments to conduct postmarket
studies. Legal authority to require postmarket studies would allow FDA
to negotiate adequate studies at the time the drug is approved and to
enforce the postmarket study commitments that it obtains from
companies.
[Whereupon, at 11:43 a.m., the committee was adjourned.]