[Senate Hearing 109-67]
[From the U.S. Government Printing 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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          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?

                              ----------                              


                         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.
---------------------------------------------------------------------------
    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.]