[Senate Hearing 109-850]
[From the U.S. Government Publishing Office]



                                                        S. Hrg. 109-850
 
   BUILDING A 21ST CENTURY FDA: PROPOSALS TO IMPROVE DRUG SAFETY AND 
                               INNOVATION

=======================================================================

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                       ONE HUNDRED NINTH CONGRESS

                             SECOND SESSION

                                   ON

EXAMINING PROPOSALS TO IMPROVE DRUG SAFETY AND INNOVATION, AND S. 3807, 
TO AMEND THE PUBLIC HEALTH SERVICE ACT AND THE FEDERAL FOOD, DRUG, AND 
           COSMETIC ACT TO IMPROVE DRUG SAFETY AND OVERSIGHT

                               __________

                           NOVEMBER 16, 2006

                               __________

 Printed for the use of the Committee on Health, Education, Labor, and 
                                Pensions


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                                 senate


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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

                      THURSDAY, NOVEMBER 16, 2006

                                                                   Page
Enzi, Hon. Michael B., Chairman, Committee on Health, Education, 
  Labor, and Pensions, opening statement.........................     1
Kennedy, Hon. Edward M., a U.S. Senator from the State of 
  Massachusetts, opening statement...............................     4
    Prepared statement...........................................     5
Burke, Sheila P., Co-Chair, Committee on the Assessment of the 
  U.S. Drug Safety System, Institute of Medicine.................     7
    Prepared statement...........................................     9
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah......    14
Murray, Hon. Patty, a U.S. Senator from the State of Washington..    17
Reed, Hon. Jack, a U.S. Senator from the State of Rhode Island...    18
Isakson, Hon. Johnny, a U.S. Senator from the State of Georgia...    20
Clinton, Hon. Hillary Rodham, a U.S. Senator from the State of 
  New York.......................................................    20
Thompson, Diane E., Vice President, Public Policy and 
  Communications, Elizabeth Glaser Pediatric AIDS Foundation; 
  Steven E. Nissen, M.D., Chairman, Department of Cardiovascular 
  Medicine, Cleveland Clinic Foundation; Adrian Thomas, M.D., 
  Vice President, Benefit-Risk Management, Johnson & Johnson 
  Pharmaceutical Group; Jim Guest, President and Chief Executive 
  Officer, Consumers Union; and Greg Simon, President, 
  FasterCures....................................................    24
    Prepared statements of:
        Diane E. Thompson........................................    26
        Adrian Thomas, M.D.......................................    32
        Jim Guest................................................    40
        Greg Simon...............................................    58

                          ADDITIONAL MATERIAL

Statements, articles, publications, letters, etc.:
    Advanced Medical Technology Association (ADVAMED)............    69
    American Society of Health-System Pharmacists (ASHP).........    70
    National Association of Chain Drug Stores (NACDS)............    72
    Response to questions of Senators Enzi, Kennedy, Murray, and 
  Clinton 
      by:
        Sheila Burke.............................................    74
        Diane E. Thompson........................................    76
        Steven E. Nissen, M.D....................................    80
    Response to questions of Senators Enzi, Kennedy, and Murray 
      by Adrian Thomas, M.D.                                         85
    Response to questions of Senators Enzi, Kennedy, Murray, and 
      Clinton by Jim Guest.......................................    90
    Response to questions of Senators Enzi, Kennedy, and Murray 
      by Greg Simon..............................................    95

                                 (iii)

  


   BUILDING A 21ST CENTURY FDA: PROPOSALS TO IMPROVE DRUG SAFETY AND 
                               INNOVATION

                              ----------                              


                      THURSDAY, NOVEMBER 16, 2006

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 10:02 a.m., in 
Room SD-426, Dirksen Senate Office Building, Hon. Michael B. 
Enzi, chairman of the committee, presiding.
    Present: Senators Enzi, Isakson, DeWine, Hatch, Kennedy, 
Murray, Reed and Clinton.

                   Opening Statement of Senator Enzi

    The Chairman. Good morning and welcome to today's hearings 
on ideas and proposals for reforming our Nation's regulatory 
framework for reviewing and approving prescription drugs. For 
decades, the United States has been the standardbearer in 
bringing new drugs and medications to the world market. 
However, in the past few years there have been some concerns 
that caused the public to lose confidence in our drug safety 
system.
    At the beginning of the 109th Congress last year, Senator 
Kennedy and I pledged to work together with the Food and Drug 
Administration and its policies and procedures for bringing new 
drugs to the marketplace. In fact, two of the very first HELP 
Committee hearings in this Congress were focused exclusively on 
drug safety. Overall we've had 10 hearings on issues involving 
the FDA. We incorporated the witnesses' recommendations and 
comments from a series of stakeholder meetings into the 
development of the Enhancing Drug Safety and Innovation Act, S. 
3807.
    We also took the extra step of posting the draft of the 
Enzi-
Kennedy drug safety bill on the HELP Committee Website so the 
public could comment, and we received dozens of comments from 
consumer groups, from patient advocates, industry, and other 
members of the public, and we've incorporated as many as 
possible of those into the introduced bill.
    Just like the bipartisan effort that led to the 
Prescription Drug User Fee Act and the Food and Drug 
Administration Modernization Act, now's the time for our 
bipartisan legislation to bring more consistency, transparency, 
and accountability to the drug approval process. This 
legislation would create a more structured framework, leverage 
advances in science and technology to build a more effective 
and efficient FDA. This is further evidenced by the fact that 
many of the recommendations made by the recent Institute of 
Medicine report on drug safety were already part of the bill 
well before the release of the report.
    Now, throughout our oversight process we heard repeatedly 
that all drugs have risks and the risks and benefits must be 
weighed together, not separately. We also learned that the FDA 
has considerable existing statutory authority. However, the 
application of that authority can often be too blunt an 
instrument for the situations currently faced by the agency. 
Perhaps that's because we do not have a confirmed commissioner.
    Witness after witness recommended that the agency be 
granted a variety of intermediate authorities so that the 
agency can more finely calibrate its actions to match the 
problem and challenges presented to it. For example, granting 
FDA special authority for label changes, post-marketing 
studies, or delays in direct-to-consumer advertising.
    However, rather than enact a series of solutions to 
accommodate each and every potential situation, we must look at 
a way to accommodate any needed change in the drug approval 
process and post-market monitoring. Under our legislation the 
FDA would begin to approve drugs and biologics and new uses for 
these products with risk evaluation and mitigation strategies, 
otherwise known as REMS. The REMS are designed to be an 
integrated, flexible mechanism to acquire and adapt to new 
safety information about a drug. The drug company sponsor and 
the FDA would assess and review an approved REMS at least 
annually for the first 3 years, as well as during review of 
applications for a new use for the drug, when the sponsor 
suggests changes, or when the FDA requests a review based on 
new safety information.
    Another significant problem faced by the FDA is that the 
development of tools to evaluate medical products has not kept 
pace. New tools are needed to better predict safety and 
effectiveness of drugs, which in turn would increase the speed 
and efficiency of applied biomedical research. Our bill would 
spur innovation by establishing a new public-private 
partnership at the FDA to advance what's known as the Critical 
Path Initiative. This is the FDA's effort to improve the 
sciences of developing, manufacturing, and evaluating the 
safety and effectiveness of drugs, devices, biologics, and 
diagnostics. We can accelerate and assure its continued 
vitality by creating a permanent locus at the FDA, which we're 
calling the Reagan-Udall Institute for Applied Biomedical 
research.
    Our bill also establishes a central clearinghouse for 
information about clinical trials and their results to help 
patients, providers, and researchers access these materials so 
they can make more informed healthcare decisions.
    Finally, the act would make great improvements to the FDA's 
screening process for advisory committee members.
    When we began our hearings early last year, the FDA asked 
the Institute of Medicine to conduct a study covering the 
agency and the U.S. drug safety system. That report was 
released in late September of this year. I've been struck by 
how closely the Institute of Medicine's exhaustive report 
recommendations parallel provisions in S. 3807. I look forward 
to hearing more today from Ms. Sheila Burke, Chair of the 
Institute of Medicine Committee on the Assessment of the U.S. 
Drug Safety System about those recommendations as well as the 
other findings and recommendations in the report. I'm also very 
interested to hear the reaction of our second panel to the 
recommendations raised in the IOM report and pending 
legislative proposals. I'm confident we can continue with the 
open process we've initiated to address the few areas of 
difference.
    I want to thank the dozens of stakeholders, including the 
Food and Drug Administration, patient and consumer groups, 
industry associations, individuals, companies, and scientific 
experts, who have taken the time and effort to give us their 
comments and input on the bill. Their assistance has been 
invaluable.
    I also look forward to working with my colleagues to 
advance this important piece of legislation. In the upcoming 
year we face an exceptionally full agenda with respect to the 
FDA. Besides updating the FDA's authorities--as proposed in S. 
3807--we need to reauthorize both the drug and device user fee 
programs, as well as the Best Pharmaceuticals for Children and 
Pediatric Research Equity Acts. Also, we should move to confirm 
the nomination of Dr. Andrew von Eschenbach to be the 
Commissioner of Food and Drugs, and hopefully we'll do that 
before we leave this time. Dr. von Eschenbach has a strong 
record. He is an accomplished scientist, a proven manager, a 
man with vision. He's also a cancer survivor and has brought 
the perspective and compassion that goes with it to his 
government service. He gave up a job he loves directing the 
National Cancer Institute to offer his service in what I 
believe is a much more challenging and often thankless job of 
leading the FDA.
    Dr. von Eschenbach has received significant support from 
the HELP Committee. I urge my colleagues who are not on the 
committee to give Dr. von Eschenbach the chance to effectively 
run the FDA with full statutory authority. The FDA needs a 
leader with the backing and the mandate that Senate 
confirmation provides. This Congress must take up Dr. von 
Eschenbach's nomination before we adjourn.
    Before I invite Senator Kennedy to make his opening 
statement, I want to congratulate him as he prepares to take 
the gavel of this committee in the next Congress. I know that 
he has served as Chairman of this committee before and wields 
the gavel well.
    Senator Kennedy. Lightly, lightly.
    The Chairman. After the first of the year, he will be my 
favorite chairman.
    [Laughter.]
    Senator Kennedy. But until then----
    The Chairman. It's a line I borrowed from him 2 years ago.
    Senator Kennedy. There you go. Thank you.
    The Chairman. I'm proud that this committee has worked 
together to achieve a lot over the last 2 years. We approved 37 
bills. Twenty-five of those bills passed the Senate and 15 
bills were signed into law. Most of the bills passed with 
overwhelming bipartisan support and took up very little time on 
the floor. We still have more to do.
    This committee has worked together to: strengthen our 
pension system, update our mine safety laws, create a national 
network of cord-blood stem cell banks, improve our career and 
technical education programs, help the chronically ill navigate 
our healthcare system and afford health insurance, and allow 
doctors and nurses to work together in a protected legal 
environment toward reducing medical errors and improving 
patient safety.
    Now, we have a lot on our plate for the next Congress--No 
Child Left Behind, Head Start, WIA, Higher Education, several 
pieces of food and drug legislation, and a reasonable solution 
for health insurance. If we work together in the same spirit we 
did in the last 2 years, I am confident we can get all of this 
done and more. So when this Congress comes to a close and the 
next one begins, I will be working with Senator Kennedy in 
every way possible to see that we can meet the challenges that 
are left over from the 109th and stand ready to work with him 
on important issues that come before us, just as he has worked 
with me.
    And I thank you for that and I recognize you for your 
opening statement.

                  Opening Statement of Senator Kennedy

    Senator Kennedy. Thank you. Well, thank you very much, 
Chairman Enzi, particularly for your kind and generous 
comments. You've arranged this extremely important hearing 
today with the same kind of consideration and courtesy that 
have been the hallmark of your chairmanship, and your 
bipartisanship is a major reason why this committee has worked 
so effectively over the past years on many, many, many problems 
that affect American families. And you've set a very high 
standard for reaching out and working with all the members of 
the committee to try and find common ground, and that is 
certainly a standard which I'll do the best I can to meet. It's 
been really a great honor and a pleasure to work with you.
    This committee deals with some of the most important issues 
and questions that affect ordinary Americans in so many ways. 
Today is just one very extremely important aspect of it, but 
this committee works in so many different areas. So we have 
worked and I hope we will continue to work closely together as 
we address the unfinished business of our committee and of the 
Congress.
    So I thank you for your kind words and congratulate you on 
really an extraordinary period of service to this committee and 
to the Senate and to Wyoming.
    Millions of Americans rely on the drugs that FDA reviews to 
protect them from sickness and now the FDA itself urgently 
needs treatment. I join my colleague and friend. The agency 
needs to have a confirmed leader. We have been nearly 5 out of 
6 years with acting directors. We need to make sure that we 
have a leader in the FDA, and I join the Chairman in hoping 
that the Senate will confirm Dr. von Eschenbach.
    Science has too often had to take a back seat at the very 
agency which should be setting the standards for objectivity 
and integrity. There's growing evidence that the dedicated 
professionals at FDA have been pressured to trip the scientific 
views to prevailing patient winds. These are symptoms of a 
serious illness and we should act without delay to provide the 
cure.
    The Institute of Medicine has done a valuable service for 
the Nation by diagnosing the problem and providing a 
prescription for treatment, and it's up to us to see that the 
patient takes the right medicine and hopefully has a quick 
recovery.
    The stakes are high. FDA oversees products accounting for a 
quarter of the U.S. economy. Every day it makes decisions that 
make the difference between life and death for American 
patients.
    It's an honor to welcome Sheila Burke, who served the 
Senate with such distinction on the staff of former colleague 
Bob Dole. Sheila, who is now the Deputy Secretary of the 
Smithsonian, found the time to chair the panel on IOM and made 
these important recommendations on drug safety. As the IOM 
report makes clear, FDA has many needs that Congress must 
address, and we join in welcoming Sheila Burke.
    The FDA budget is $1.8 billion a year. That may sound like 
a lot, but it works out to about $6 a year for every American. 
In Washington, DC., you can barely buy a sandwich for $6. Yet 
with that amount we expect the FDA to assure the safety of the 
food we eat, the drugs we take, the medical devices that save 
so many lives. Clearly we need to increase the FDA's budget so 
that it can do a better job of guaranteeing drug safety.
    When I mention that, I see my friend and colleague from 
Utah, Senator Hatch, who's been the former chairman of this 
committee and also put the issue of the FDA as a high priority 
on his agenda in terms of the safety and making sure that it's 
going to have the kind of support here in Congress, along with 
my other colleagues Senator Murray and Jack Reed.
    Additional authority is needed as well. The Institute of 
Medicine's report recommends the FDA have the power to require 
post-marketing risk assessment, risk management programs for 
new drugs, and require the industry to make the results of drug 
safety studies available to the public. The Enhancing Drug 
Safety and Innovation Act Chairman Enzi and I introduced 
earlier this year addresses these needs and, like the Institute 
of Medicine report, our bill emphasizes the need for a life 
cycle approach to drug regulation both before and after 
approval.
    Mr. Chairman, I will include the rest of my statement, 
which is an analysis of the bill, which you've done very 
capably in your opening statement, in the record. I just wanted 
to mention how glad I am to see Senator Murray, who has been 
such a strong member of this committee and has been such a 
constructive and positive force in ensuring that we're going to 
have the best in terms of scientific integrity at the agency, 
and my colleague Jack Reed, who was a key figure at the time 
that we reauthorized the FDA. He was enormously involved in the 
details of this legislation, as he is in so many. So I welcome 
other members of our committee here and I thank you.
    [The prepared statement of Senator Kennedy follows:]

            Prepared Statement of Senator Edward M. Kennedy

    Thank you Mr. Chairman. I commend you for calling this hearing on 
the role of the Food and Drug Administration in protecting the safety 
of the Nation's prescription drugs.
    You've arranged today's hearing with the same consideration and 
courtesy that have been the hallmark of your chairmanship. Your 
bipartisanship is a major reason why the committee has worked so 
effectively over the past 2 years on many problems affecting America's 
families, and I'll do my best to see that the committee continues to do 
business in the same spirit in the next Congress.
    Millions of Americans rely on the drugs that the FDA reviews to 
protect them from sickness. But now, the FDA itself urgently needs 
treatment.
    For too long, the agency has been without a confirmed leader. 
Science has too often had to take a back seat at the very agency which 
should be setting the standard for objectivity and integrity. There is 
also growing evidence that the dedicated professionals at the FDA have 
been pressured to trim their scientific views to the prevailing 
political winds.
    These are symptoms of a serious illness, and we should act without 
delay to provide the cure.
    The Institute of Medicine has done a valuable service for the 
Nation by diagnosing the problem, and providing a prescription for 
treatment. It's up to us to see that the patient takes the right 
medicine, and hopefully has a quick recovery.
    The stakes are high. The FDA oversees products accounting for a 
quarter of the U.S. economy. Every day, it makes decisions that mean 
the difference between life and death for American patients.
    It is an honor to welcome, Sheila Burke, who served the Senate with 
such distinction on the staff of our former colleague Bob Dole. Sheila 
is now Deputy Secretary of the Smithsonian, but she found the time to 
chair the panel at the IOM that made these important recommendations on 
drug safety. As the IOM report makes clear, FDA has many needs that 
Congress must address.
    Its budget is $1.8 billion a year. That may sound like a lot, but 
it works out to about $6 a year for every American. In Washington, DC, 
you can barely buy a sandwich for $6--yet for that amount, we expect 
the FDA to assure the safety of the food we eat, the drugs we take, and 
the medical devices that save so many lives. Clearly, we need to 
increase FDA's budget, so that it can do a better job of guaranteeing 
drug safety. But money alone won't meet all the challenges. Additional 
authority is needed as well.
    The Institute of Medicine's report recommends that FDA have the 
power to require postmarketing risk assessment and risk management 
programs for new drugs, and to require the industry to make the results 
of drugs safety studies available to the public.
    The Enhancing Drug Safety and Innovation Act, which Chairman Enzi 
and I introduced earlier this year, addresses these needs. Like the 
Institute of Medicine report, our bill emphasizes the need for a 
``life-cycle'' approach to drug regulation, both before and after 
approval.
    The bill would require every drug approved by the FDA to have an 
enforceable Risk Evaluation and Mitigation Strategy, tailored to fit 
the risk profile of each new drug. Where appropriate, the strategy 
could include special requirements for labeling, postmarket clinical 
studies, and limitations on marketing the drug directly to consumers. 
For drugs with the most dangerous side effects, the strategy might 
require that only doctors with specialized training be allowed to 
prescribe the drug. If a manufacturer fails to implement a precaution 
that it has agreed to, the FDA will have new authority to assess civil 
monetary penalties to enforce compliance.
    By providing a legally enforceable yet flexible way for the FDA to 
oversee safety throughout the life cycle of a drug, the bill gives the 
agency the authority it now lacks to take effective action to ensure 
safety.
    The legislation also creates a public-private partnership to 
improve the science of drug safety and drug development. It will help 
patients and physicians make more informed decisions by requiring the 
results of drug trials to be included in a public database. Our bill 
also takes stronger steps to avoid financial conflicts of interest by 
members of FDA advisory committees.
    Again, Mr. Chairman, I commend you for calling this hearing. I look 
forward to working with you and our colleagues on both sides of the 
aisle to give the FDA the authority it needs to restore public trust in 
the safety of prescription drugs. I welcome our witnesses and look 
forward to their testimony.

    The Chairman. Thank you, and I would mention that anyone on 
the committee that has a statement, we'll make it a part of the 
record without objection.
    I'd like to welcome Ms. Sheila Burke, the Chair of the 
Institute of Medicine Committee on the Assessment of U.S. Drug 
Safety System and a member of the Institute of Medicine. She is 
also the Deputy Secretary and Chief Operating Officer of the 
Smithsonian Institution, Vice Chair of the Robert Wood Johnson 
Health Policy Fellowships Board, and a member of the Medicare 
Payment Advisory Commission.
    Ms. Burke began her career as a staff nurse in Berkeley, 
California, and as Director of Program and Field Services for 
the National Student Nurses Association in New York. She earned 
a master's of public administration from Harvard University and 
a bachelor of science in nursing from the University of San 
Francisco. Ms. Burke will share the Institute of Medicine's 
perspective on what Congress can and should do to improve drug 
safety while preserving patient access to important 
pharmaceutical therapies.

       STATEMENT OF SHEILA P. BURKE, CO-CHAIR, COMMITTEE 
       ON THE ASSESSMENT OF THE U.S. DRUG SAFETY SYSTEM, 
                     INSTITUTE OF MEDICINE

    Ms. Burke. Good morning, Mr. Chairman, Senator Kennedy, 
members of the committee. I thank you very much for the 
opportunity to talk with you this morning.
    The Chairman. I don't think the microphone's----
    Ms. Burke. On?
    The Chairman. Is there a little light on there?
    Ms. Burke. It is.
    The Chairman. Thank you.
    Ms. Burke. I am grateful for the opportunity to talk with 
you about the Institute of Medicine's report. The committee was 
convened in 2005 at the request of the Food and Drug 
Administration. In addition, we were supported by the Centers 
for Medicare and Medicaid Services, the Agency for Health Care 
Research and Quality, the National Institutes of Health, and 
the Department of Veterans Affairs.
    One of the major areas of debate in the world of drug 
regulation is how one can monitor the safety profile of drugs 
once they are on the market. This, in fact, was our focus. As a 
result, while the committee considered a wide array of issues, 
there are several important topics that either fell outside of 
our charge or we were unable to consider.
    For example, we did not undertake a systematic assessment 
of concerns related to the specific drugs that have captured 
the public's interest in recent years. Our report focuses on 
the post-
approval process and period and therefore does not include a 
detailed examination of the pre-approval process, including the 
conduct of clinical trials.
    The committee's attention was solely on prescription drugs 
and the drug safety system, in particular the functioning of 
the FDA's Center for Drug Evaluation and Research, or CDER, 
which is responsible for drug review, approval, and regulation. 
The report puts forth the vision of a transformed drug safety 
system that has at its core a life cycle approach to drug risk 
and benefit. Life cycle describes the level of attention to a 
drug's safety and efficacy that does not taper off after the 
time of approval, but is sustained from discovery and 
development to the end of useful product life. This is not a 
new concept, but it is one that we believe has been implemented 
at best in a limited and a fragmented manner.
    The report contains 25 recommendations in 5 topic areas: 
CDER's organizational culture, science, scientific expertise, 
regulation, communication, and resources. There are 11 
recommendations that may be of particular interest to the 
committee that are, in fact, very similar to provisions that 
are contained in S. 3807, the bill introduced by the Chairman 
and Mr. Kennedy. The key areas covered by these recommendations 
include regulatory authority, agency leadership, resources, and 
credible science.
    First, the FDA's regulatory authorities are derived from a 
statute that has been amended numerous times, yet requires in 
our view strengthening and clarification to allow the agency 
the flexibility to regulate increasingly complex drugs. The 
committee was cognizant of the fact that the outcomes of 
regulation are not simply paper documents, but, in fact, the 
health of living, breathing patients. Delaying approval until 
absolute complete certainty is reached or withdrawing a drug 
once safety problems arise are often not realistic options. Yet 
they reflect the largely all or nothing nature of FDA 
regulatory authorities.
    Our committee recommended that FDA be given a tool kit of 
regulatory options that it can apply as appropriate and 
necessary at any time in the life cycle of a drug and clarified 
authority to enforce sponsor compliance with restrictions or 
limitations on marketing imposed at or after the time of 
approval.
    Second, the committee found that, while CDER staff work 
with great dedication and professionalism, the center's 
organizational culture is in some ways and at some times 
dysfunctional. The report identified several factors that seem 
to shape organizational culture at CDER and offered solutions 
to strengthening collaborations, improving stability and the 
support of leadership's ability to affect organizational 
change.
    We believe that the turnover and the instability in the 
commissioner's office leave the agency without effective 
leadership, and without stable leadership strongly and visibly 
committed to drug safety all other efforts to improve the 
effectiveness and the efforts to improve the agency or its 
position to effectively deal with safety for the truth and for 
the future will be seriously, if not fatally, compromised. To 
this end, the committee, among other things, has recommended 
that the commissioner be appointed for a 6-year fixed term.
    Third, the commitment of public servants, the concern of 
Congress, the advocacy of consumer organizations, among others, 
is not enough to transform the drug safety system. A 
substantial and sustained financial investment is needed. An 
agency whose crucial mission it is to protect and advance the 
public's health should not have to go begging for resources to 
do its job.
    We acknowledge that the user fee program in place has had 
many positive effects on the drug safety and drug approval 
process. However, we prefer that additional funding required to 
implement the recommendations in the report come entirely from 
appropriations. If securing this additional funding entirely 
from appropriations proves impossible, the committee urges that 
restrictions on the use of PDUFA funds be curtailed.
    Fourth, the infusion of additional resources will also 
support the FDA's need for expertise in science and data. 
Research and the data that it produces is in many ways the 
lifeblood of the drug safety system. The committee believes 
that CDER needs to substantially increase the amount and 
quality of the data that accrue after a drug is on the market 
and to ensure systematic reviews of what has been learned about 
a truly novel drug after its launch and its use in the real 
world.
    We recognize that it is not enough to have strong science 
backing up regulatory decisions about safety. Safety science 
has to be credible. The committee has made several 
recommendations intended to expand expertise and research on 
drug safety at CDER. We have recommended measures to increase 
the credibility of the committee process as well, to increase 
opportunities for appropriate review of drug safety issues by 
advisory committees, provide greater transparency for patients 
and for providers of the information accumulated about a drug.
    Our committee is grateful to have had the opportunity to be 
of assistance to the FDA and hopes that the agency and the 
Congress find that the report is useful in moving ahead to 
strengthen drug safety. Again my thanks for the opportunity to 
be with you today and I'm more than happy to answer any 
questions.
    [The prepared statement of Ms. Burke follows:]

                 Prepared Statement of Sheila P. Burke

    Good morning, Mr. Chairman and members of the committee. Thank you 
for the opportunity to come speak to you this morning. My name is 
Sheila Burke. I am Chair of the Institute of Medicine (IOM) Committee 
on the Assessment of the U.S. Drug Safety System.
    The Institute of Medicine of the National Academies is an 
independent, nongovernmental, nonprofit organization operating under 
the 1863 congressional charter to the National Academy of Sciences. The 
Institute of Medicine has provided advice to the Nation on matters of 
health and medicine for over 30 years. Early in 2005, the Food and Drug 
Administration (FDA) asked the Institute of Medicine to convene a 
committee of experts to conduct an independent assessment of the 
current system for evaluating and ensuring drug safety postmarketing 
and make recommendations to improve risk assessment, surveillance, and 
the safe use of drugs. In addition to FDA, the study was funded by the 
Centers for Medicare and Medicaid Services, the Agency for Healthcare 
Research and Quality, the National Institutes of Health, and the U.S. 
Department of Veterans' Affairs. The Committee on the Assessment of the 
U.S. Drug Safety System met for the first time in June 2005. The 
committee's areas of expertise include public policy, statistics, 
health informatics, pharmacy, clinical medicine, health plan 
management, pharmacoepidemiology, economics, drug regulation, consumer 
concerns, law and ethics, and academic research. The committee met six 
times, and held several information gathering sessions that were open 
to the public and included presentations from industry representatives 
and a variety of patient, consumer, and professional organizations. 
Some committee members also made two site visits to FDA, and engaged in 
confidential conversations with more than 30 former and current staff 
and leaders from FDA and especially its Center for Drug Evaluation and 
Research (CDER). The committee's report was released September 22, 
2006.
    First, let me speak briefly about what the report does and does not 
cover. The committee considered a wide array of issues, but there are 
several important topics that either fell outside the charge to the 
committee, or that the committee was unable to consider. For example, 
the committee did not undertake a systematic assessment of 
postmarketing safety concerns related to specific drugs that have 
captured the public's interest in recent years, such as the COX-2 
inhibitors or the selective serotonin reuptake inhibitors. The report 
focuses on the postapproval period and therefore does not include a 
detailed examination of the preapproval process. The report also does 
not address over-the-counter drugs, or generics, nor does it treat at 
length the complex issues related to the conduct of clinical trials. 
The committee's focus was solely on prescription drugs and the drug 
safety system, in particular the functioning of FDA's Center for Drug 
Evaluation and Research, which is responsible for drug review, 
approval, and regulation.
    The report recognized at the outset that it is impossible to think 
about safety independent of efficacy, and that the two must be 
considered together throughout the lifecycle of a drug. A drug's 
lifecycle begins at drug discovery and concludes at the end of useful 
product life. Drugs are approved after risk-benefit determinations made 
by FDA, but those determinations are made on the basis of clinical 
trials with carefully selected participants and under controlled 
conditions. The real-life use of drugs is often quite different--a drug 
tested in a few hundred or thousand people is prescribed and used by 
millions often for longer periods and in conjunction with other drugs 
or supplements. That is why approval does not signify the end of 
uncertainty about a drug, and continued monitoring is necessary after 
approval. Most stakeholders in the drug safety system are aware of the 
need for continued attention to a drug's risk-benefit profile during 
the drug's lifecycle. However, the committee found an imbalance in the 
regulatory attention and resources available before and after a drug's 
approval. Staff and resources devoted to preapproval functions in CDER 
are substantially greater than those available for postapproval 
functions. The new drug review process involves sophisticated clinical 
trial design and execution; after approval, few high-quality studies 
are designed, conducted, and completed, and in general, the data 
available is quite limited. Before approval, regulatory authority is 
well-defined and robust; once a drug is marketed, FDA's ability to 
regulate and enforce becomes greatly diminished. Many of the 
committee's recommendations are intended to bring some of the strengths 
of the preapproval process to the postapproval process, to ensure 
ongoing attention to a drug's performance.
    The committee made 25 recommendations in 5 topic areas: CDER 
organizational culture, science and scientific expertise, regulation, 
communication, and resources. A complete copy of the report is 
submitted for the record. Of the 25 recommendations, 11 are uniquely 
within Congressional purview or likely to be of interest to Congress. 
These include recommendations pertinent to expanding funding for the 
agency's mission, strengthening regulatory authority, stabilizing 
agency leadership, ensuring the credibility of regulatory science, and 
establishing a new advisory committee. More detailed discussion of key 
recommendations follows.
    Research and the data it produces is in many ways the lifeblood of 
the drug safety system. The committee believes that CDER needs 
substantially increased resources to conduct and access better 
postmarketing safety research. The committee made a number of 
recommendations to increase the amount and quality of data that accrue 
after a drug is on the market. The committee recognized that it is not 
enough to have strong science backing up regulatory decisions about 
safety--safety science has to be credible. The committee made several 
recommendations intended to expand the expertise and research on drug 
safety at CDER. In addition, the committee recommended increased 
opportunities for appropriate review of drug safety issues by advisory 
committees, and transparency of the information accumulated about a 
drug (for example, the posting of structured field summaries and 
results of all efficacy and safety studies on a government Website, and 
the posting of all NDA and sNDA packages on the FDA Website). Other 
recommendations include: establishing a public-private partnership to 
prioritize, plan, and organize funding for confirmatory drug safety, 
efficacy, and effectiveness studies; demonstrating a commitment to 
research by appointing a Chief Scientist to oversee intramural and 
extramural research and by requesting and applying the necessary 
funding to support intramural research; and taking specific steps to 
increase the credibility of the advisory committee process.
    FDA's regulatory authorities are derived from a statute that has 
been amended numerous times, yet requires some strengthening and 
clarification to allow the agency the flexibility to regulate 
increasingly complex drugs. In its discussion of FDA's ability to 
regulate, the committee was cognizant of the fact that the outcomes of 
regulation are not paper documents but the health of living, breathing 
patients. Delaying approval until complete certainty is reached, or 
withdrawing a drug once safety problems arise are often not realistic 
options, yet they reflect the largely all-or-nothing nature of FDA 
regulatory authorities. The committee recommended that FDA be given a 
tool kit of regulatory options it can apply as appropriate and 
necessary at any time in the lifecycle of a drug, and clarified 
authority to enforce sponsor compliance with restrictions or 
limitations on marketing imposed at or after the time of approval. The 
committee also recommended that CDER establish a milestone moment at 5 
years after the approval of a new molecular entity (NME) (roughly 20-25 
are approved yearly) to review all accumulated safety and efficacy data 
related to that NME. This will ensure that there is a systematic look 
back at everything that has been learned about a truly novel drug after 
its launch and use in the ``real world.'' In another recommendation, 
the committee called for designating a special symbol to mark all new 
drugs, with the function of informing and educating the public that 
those products are placed under greater regulatory scrutiny and perhaps 
subject to stronger regulatory action (such as a moratorium on direct-
to-consumer advertising during the period of time that the special 
symbol is in effect).
    Anyone who has followed drug safety issues over the last several 
years has surely noticed that a theme that often surfaces is some type 
of management problem in CDER. Information has emerged--both in the 
media and in government reports (e.g., from the DHHS Office of the 
Inspector General, and the Government Accountability Office)--about 
scientific disagreement poorly handled, a lack of collaboration among 
divisions, an appearance of interdisciplinary tension, a perception of 
inappropriate management expectations, and so on. On the basis of that 
information and discussions with present and former FDA staff and 
leaders, the committee has found that while CDER's staff work with 
great dedication and professionalism, the Center's organizational 
culture is, in some ways and at some times, dysfunctional. The report 
identified several factors that seem to shape organizational culture in 
CDER, and offered solutions to strengthening collaboration, improving 
stability and support of leadership's ability to effect organizational 
change, and addressing some of the challenges presented by a major 
force in FDA's external environment--the Prescription Drug User Fee 
Act. I'd like to draw your attention to two recommendations from the 
chapter on culture. The committee recommended that postmarketing safety 
staff have a formal role before approval and specific authority after 
approval. Although postmarketing staff, and specifically the staff of 
the Office of Drug Safety, now the Office of Surveillance and 
Epidemiology, are invited to some preapproval meetings, this does not 
occur consistently, it sometimes does not take place early enough in 
the preapproval process. Office of Surveillance and Epidemiology staff 
do not have a formal role before approval or authority after approval. 
This recommendation in the context of others in this report reflects 
the committee's view that keeping postmarketing safety activities 
closely linked with the drug approval process is crucial.
    The committee also recommended a fixed-term for the FDA 
commissioner to stabilize the agency and promote a better integration 
of safety into the work of CDER. In the last 30 years, FDA has had 
eight commissioners and seven acting commissioners (including the 
current acting commissioner) or, when the post was vacant, an acting 
principal deputy commissioner. The eight commissioners have served an 
average of 2.5 years with a range of 2 months to 6.3 years. The 
committee believes that turnover and instability in the commissioner's 
office leave the agency without effective leadership or the potential 
to emphasize safety as having high priority in the work of the agency. 
Without stable leadership strongly and visibly committed to drug 
safety, all other efforts to improve the effectiveness of the agency or 
position it effectively for the future will be seriously, if not 
fatally, compromised.
    In the area of communication, the committee referred to and 
endorsed the sentiment behind recommendations made in the recent report 
of the Committee on Preventing Medication Errors, released July 2006. 
(The summary of that report is found in Appendix E of the Future of 
Drug Safety report.) The committee also recommended a new mechanism--an 
advisory committee with the requisite expertise and representation--for 
improving FDA's communication to and with patients and the general 
public.
    The commitment of public servants, the concern of Congress, the 
advocacy of consumer organizations, the interest of industry, among 
others, is not enough to transform the drug safety system in the ways 
outlined by the committee's suite of recommendations. A substantial and 
sustained financial investment is needed. The suite of recommendations 
put forward in this report--to improve the culture in CDER, attract and 
retain highly qualified staff, improve technological capacity, obtain 
and benefit from access to data and innovative scientific partnerships 
and so on--is dependent on adequate resources. An agency whose crucial 
mission is to protect and advance the public's health should not have 
to go begging for resources to do its job. The committee has 
acknowledged that the user fee program has had many positive effects on 
drug approval. However, the committee gave several reasons why it 
prefers that the additional funding required to implement the 
recommendations in the report for an improved drug safety system come 
entirely from appropriations. CDER's dependence on PDUFA funding with 
its associated restrictions may hurt FDA's credibility. If securing 
this additional funding entirely from appropriations proves impossible, 
the committee urges that restrictions on the use of PDUFA funds be 
curtailed.
    The committee is grateful to have had the opportunity to be of 
assistance to FDA, and hopes that the agency and Congress find the 
report useful in moving ahead to strengthen drug safety.
    Thank you for the opportunity to testify. I would be happy to 
address any questions the committee might have.

    The Chairman. Thank you very much for chairing this very 
important committee and putting out this extremely helpful 
report. I do have, as many may have, some very detailed 
questions regarding the report and I would submit some of those 
in writing. We definitely want to know what we've left out in 
the bill, and there are other people that have proposals and 
we'll have some evaluation of that, too.
    But one of the big items is the benefit versus risk on 
prescription drugs, and I believe that they have to be 
considered together, not separately. Did the panel consider the 
idea of a separate office of drug safety, and if so what did 
the members of the panel think of that idea?
    Ms. Burke. Thank you, Mr. Chairman. We did, in fact, 
discuss that question and do not believe that breaking apart 
the agency and setting up a separate freestanding safety unit 
is in the interests of the kind of changes that we'd like to 
see go forward. We believe, in fact, it is inconsistent with 
the life cycle approach to drug safety and believe that for the 
regulatory staff to work more productively together, both pre- 
and post-marketing, that they are best kept together and have 
made a number of recommendations that would involve the post-
marketing staff much earlier in the process, so, in fact, there 
is this attention to life cycle and they do develop the kind of 
collaboration we think is critical.
    The Chairman. The report talks about life cycle of a 
product and how knowledge changes over time. Could you 
elaborate a little bit more on life cycle?
    Ms. Burke. Literally, Mr. Chairman, it is our view that the 
life cycle is from the point of the initial research until the 
end of a product life cycle. That is, its use in the market is 
really the timeframe in which we ought to really have in place 
a regulatory system that is adept at dealing with all aspects 
of that. That is in the gathering of the information on the 
pre-marketing and the review of that information and a linkage 
with the post-marketing tracking of data and analysis, and 
continue to be informed as new information becomes available.
    One of the challenges I think that we face is in the course 
of clinical trials and the focus of those tends to be on a very 
narrow population, and one of the realities that we face in 
today's world is that once it goes into the market we are now 
in an instance where, in fact, there are patients perhaps that 
have different comorbidities, that may, in fact, be on 
different medications, that present a different picture than 
perhaps was looked at in the narrow range of a clinical trial, 
and that the gathering of that information and the continued 
information review and analysis is important to make sure that 
we fully are aware throughout that period of time of what takes 
place.
    The Chairman. Thank you.
    You also mentioned the cultural and administrative issues 
at the FDA and I appreciate that. Do you think it's possible 
for legislation to change an organization's culture?
    Ms. Burke. No, sir.
    The Chairman. Would the pending legislative proposals on 
drug safety do so?
    Ms. Burke. You raise a very important question. In fact, 
there is nothing that we can do legislatively or, more 
appropriately, you could do legislatively that would, in fact, 
force a change in the culture. There are recommendations 
contained in the report that relate to essentially integrating 
the staffs differently, suggesting that, in fact, there be 
folks brought in from the outside to assist them and look at 
how one implements cultural change within the agency. We 
believe that there are in the normal course the kinds of 
relationships and challenges that occur in any environment 
where there are professionals that have different views, 
whether you have the folks that are managing the clinical 
trials who may approach it differently than the 
epidemiologists, for example.
    But we leave the leadership, the stability of the 
leadership; the integration of those teams, the introduction of 
the safety decisionmaking earlier in the process that forces an 
integration, the placement of safety staff on that team, we 
hope, in fact, will begin to address some of those issues. But 
there is no question that it has to be done within the agency 
and it has to come from the top, which is why we think the 
stability and the leadership is so critical.
    The Chairman. Thank you, and I really appreciate that the 
chairman of this very important committee is so able to speak 
in layman's terms so that even I can understand.
    It's been very helpful, and I know that you have a plane to 
catch at 11 o'clock, so I'll relinquish the rest of my time and 
turn to Senator Kennedy.
    Senator Kennedy. Well, thank you and thank you, Sheila 
Burke, for a wide swath of service to the public interest. 
We're glad to have you here this morning.
    Let me ask you, if we don't implement either the 
recommendations of IOM or some aspect of the Enzi legislation, 
what could you tell the public? I mean, how important is it 
that we do something, both in terms of innovation, and in terms 
of safety. How urgent is it? What's your sense and the sense of 
your committee, about the importance of moving this legislation 
forward? As you know from your own experience, we're going to 
be encumbered with a lot of different choices here in the 
Congress in prioritizing, and I'm just interested, based upon 
your own understanding of this institution and a very detailed 
study, how important is it in terms of the safety and 
innovation in a period I like to call the life science century? 
How important is it that we pass legislation, either what 
you've recommended or what we have recommended?
    Ms. Burke. I think, Senator Kennedy, it is enormously 
important, and I think you have--I mean, often you have 
circumstances where the stars align, where there are 
opportunities that arise. Certainly in the course of the review 
of PDUFA you have an opportunity. I think the timing is 
critical. I think passage of legislation is critical. I think 
the absence of that over the longterm would leave the agency 
starved for resources, I think with unclear authority in terms 
of being able to deal with the industry and to effect the kinds 
of changes that we believe are necessary.
    We are an increasingly complex world with increasingly 
complex drugs dealing with increasingly complex problems. Drugs 
are now used far more consistently and prevalently than they 
ever have been in the course of caring for patients. So I think 
if there were ever a time when it is critical to address these 
issues, it is now.
    Senator Kennedy. I think just as you were mentioning, this 
is for me the life science century, with all of the 
possibilities that are out there. The difference of getting 
drugs on stream earlier can offer incredible opportunities for 
people and yet we have, obviously, as we've seen in the recent 
times, serious kinds of safety issues and we have to bring the 
agency up to speed in terms of being able to do both.
    One aspect of it is information technology. Using 
information technology, we can advance and bring on stream 
these newer prescription drugs and then monitor them more 
completely and get the telltale signals or potential dangers of 
it.
    Isn't this an important area for us to give some focus and 
attention if we're interested in getting drugs on earlier and 
getting a better review of safety?
    Ms. Burke. You are absolutely correct, both in the nature 
of investment in the technology as well as the training of the 
staff in order to be able to use the information. The AIR 
system is a good example, where you are producing an enormous 
amount of information, in excess of 400,000 reports, but the 
ability to mine that information, the ability, for example, to 
partner with Medicare, the new information that will be 
produced in the course of the Part D benefit, we ought to be 
able to utilize that and FDA ought to have access to that and 
be able to utilize it to assist them in tracking what's 
occurring.
    So investments both in human resources as well as 
technology I think are a very wise investment.
    Senator Kennedy. Finally, to underscore the importance of 
having administrative leadership out there in the FDA, if you 
could just underline that point. And finally, the safety issue 
is obviously front and center for many members of this 
committee, and other committees. We have a more elaborate 
description in your report about the administrative steps that 
can be taken, that you think will enhance drug safety in an 
effective way. If you could comment on both of those elements 
I'd appreciate it.
    Ms. Burke. I think the report does contain a number of 
recommendations both with respect to administrative changes, 
the integration of the staff, the placement of the safety staff 
earlier in the process, as well as the commitment on the part 
of the leadership at the agency to essentially instill safety 
as a critical component. Clearly the stability of the 
leadership of the agency is critical to that. The investment in 
human resources and technology resources allowing the staff to 
essentially do their jobs. They are a dedicated group of people 
who need the resources to do so.
    There is currently an imbalance in the pre-approval and 
post-
approval process in terms of resources. Clearly a great 
emphasis has been placed on pre-approval for good reasons in 
terms of the speed of drugs to the market. A similar emphasis 
needs to be placed on post-approval in terms of resources and I 
think that will help to address some of these issues.
    Senator Kennedy. Thank you very much.
    Thank you, Mr. Chairman.
    The Chairman. Thank you.
    Mr. Hatch.

                   Opening Statement of Senator Hatch

    Senator Hatch. Well, thank you, Mr. Chairman.
    Welcome to the committee, Sheila.
    Ms. Burke. Thank you.
    Senator Hatch. We're glad to see you again.
    I'm interested in your assessment of the next steps. I 
think the report is very interesting, but one of the questions 
I have is: do we really need legislation or can the 
recommendations in the report be implemented administratively?
    Ms. Burke. Mr. Hatch, we believe very firmly that there are 
areas that do, in fact, require legislation. In addition to 
those dealing with resources, that is obviously the 
appropriations process----
    Senator Hatch. Well, that's obvious. But I'm talking 
about----
    Ms. Burke [continuing]. Clearly you need additional 
resources. But in terms of legislation otherwise, we clearly 
believe that the agency needs far greater clarity in terms of 
its authority, with respect to both the pre-approval and post-
approval process, the ability essentially to do more than 
simply negotiate in good will with the agency--between the 
agency and the drug industry.
    We believe the agency needs to have the authority to 
require that certain things occur, the ability for example to 
call unilaterally for changes in labels, the ability to 
essentially provide for followup to the kinds of studies. 
Intervening sanctions, for example, to encourage compliance we 
think need clear, clarified statutory authority on the part of 
the agency.
    Senator Hatch. It still looks to me like a number of your 
suggestions can be implemented administratively.
    Ms. Burke. Yes, sir, many can, in fact, be implemented 
absent legislation. Some will, in fact, require statutory 
change.
    Senator Hatch. Yes, I agree with you on that.
    Could you please expand on your comments about PDUFA? 
Because you indicated--let's see; I've got your statement right 
here--that you felt like CDER's dependence on PDUFA funding 
with its associated restrictions may hurt FDA's credibility. 
Then you say: ``If securing this additional funding entirely 
from appropriations proves impossible, the committee urges that 
restrictions on the use of PDUFA funds be curtailed.''
    Could you expand on that?
    Ms. Burke. Yes, sir. Our point in making that comment is 
that currently there are limitations in terms of the use of 
PDUFA funding. The bulk of the funding is clearly targeted 
towards the approval process and that is the time prior to 
marketing in terms of the staffing and the assets necessary for 
that process. It has made an enormous difference and a very 
positive one in speeding drugs to the market.
    There have been restrictions on whether or not those funds 
can be used, for example, post-approval in terms of the 
additional safety staff, in terms of both the number of staff 
as well as their capacity, for example, to do research as well 
as contract with the drug companies themselves, but for the 
agency itself to do some of this analysis.
    So again, our view is that, with additional funds 
necessary, our preference would be the appropriations process; 
should, in fact, that not be possible, if PDUFA funds, in fact, 
are the only source of funding that is available, that the 
limitations currently in place that limit largely its emphasis 
on the pre-approval process, be broadened to allow for more use 
in the post-approval safety process as well.
    Senator Hatch. I notice that some of the folks in the 
House, when they resume their leadership after the first of the 
year, have indicated that they would like to do a Hatch-Waxman 
or Waxman-Hatch approach to bio. Could you tell us what the IOM 
recommendations are there?
    Ms. Burke. We did not address that, sir.
    Senator Hatch. I didn't think you did, but do you think we 
should weigh in and get IOM to address that?
    Ms. Burke. Senator, I frankly am not--I couldn't opine 
based on what the committee has done.
    Senator Hatch. Well, it's a big problem because, of course, 
we had a time bringing about the Hatch-Waxman bill----
    Ms. Burke. Yes, sir.
    Senator Hatch [continuing]. Because of the conflicts 
between the generics and the brand companies. And there's no 
question one of the big complaints is that the bio work is so 
expensive that it would be well if we could find some way of 
bringing some of those therapies into generic form. But then 
the next question is how do you do that since it's so difficult 
to duplicate large molecule individual therapy approaches.
    I would like to have the IOM's viewpoint on that and how--
Congressman Henry Waxman's talking about, using terms like 
``comparable'' or ``like.'' That is not as specific as the 
original Hatch-Waxman, which had an easier time being specific. 
These are areas that are really concerning me because I don't 
think they should be political areas. We ought to get these 
down so that they work well in the interests of the whole 
pharmaceutical industry, whether generic or brand name or 
whatever, in the interest of consumers, but also in the 
interest of propelling this type of really outstanding research 
forward.
    So I would encourage you to get the folks there to spend a 
little time on this, because we could really screw this up. 
We're good at that. And I don't want to----
    Ms. Burke. I won't comment.
    Senator Hatch. You're not going to comment? Here I give you 
a perfect opportunity and you won't do it.
    Well, to make a long story short, I'd like to have some 
advice on that.
    Ms. Burke. All right, sir.
    Senator Hatch. I think probably our chairmen would like to 
have advice. Certainly Congressman Waxman and Congressman 
Dingell would like advice. It's an area we just have to work on 
in the next Congress and hopefully we can come up with 
something that will function as well as the Hatch-Waxman bill 
did or has. It's still functioning well and saving over $10 
billion a year in pharmaceutical costs. But we could use your 
help on it.
    Ms. Burke. All right, sir. Thank you.
    Senator Hatch. Thank you.
    Thanks, Mr. Chairman.
    The Chairman. Thank you.
    Senator Murray.

                  Opening Statement of Senator Murray

    Senator Murray. Thank you very much, Mr. Chairman. I really 
appreciate you and Senator Kennedy working together on this.
    Ms. Burke, it's good to see you again and thank you for the 
incredible work your committee's done. I really appreciate the 
opportunity to have this hearing. I hope we have more of them 
as we really try and do this right in the coming Congress, 
because I think we have a real opportunity to restore some of 
the confidence the public needs to have in the health and 
safety mission of the FDA and a real chance to give the 
scientists at the FDA the tools and the authority they need to 
ensure greater safety for all Americans. I hope we really use 
this as an opportunity to restore the FDA to the gold standard 
of safety and efficacy that we all know is so important.
    My colleagues and I have been very concerned about the 
political ideology that has undermined sound science at the 
FDA. I think we need to make sure that we address that and it 
is not a concern in the future. There are several other areas 
I'm concerned about. One of them is the critical balance 
between post-market safety and ensuring timely access to safe 
and effective drugs and devices. We have a system that relies 
heavily on user fees to ensure timely review process of our 
drug applications and I'm concerned the FDA's financial 
dependence on those fees may create a situation where user fees 
are having undue influence on approval decisions, and I want to 
make sure that user fees are providing timely reviews and not 
automatic approvals. It's a difficult balance, but I hope that 
we explore that as we move forward.
    But let me take the short time--I know you need to leave--
to just ask you a question. You touched on this briefly with 
Senator Hatch, but this committee held 2 days of hearings 
talking about drug safety in response to a number of the high 
profile cases involving Vioxx, and it was very troubling to 
hear that FDA spent almost 18 months negotiating with Merck for 
label changes and additional safety warnings. It's my 
understanding that FDA was prompted to propose those additional 
safety regulations because of a growing body of evidence. So a 
number of people were using those drugs while FDA was 
negotiating for 18 months and impeded the ability to get the 
information out there.
    You have talked about this in your proposal of how we make 
sure that FDA has the authority to negotiate but still the 
companies have an ability to respond to that in a timely 
fashion. Can you talk about how you think we need to address 
that?
    Ms. Burke. Thank you, Senator. In fact, one of the 
provisions we believe does need clarity and does need statutory 
change is, in fact, to make it clear that the FDA does have the 
ability to act unilaterally. Clearly our goal here is not to 
prevent nor to discourage a relationship or a discussion 
between the industry and the FDA. But in cases where, in fact, 
evidence has arisen and time is of the essence, we believe, in 
fact, the FDA ought to be given the authority not simply to 
negotiate and depend on the good will of that relationship, but 
rather to intervene. So the report specifically calls for that 
authority to be given to the FDA.
    Senator Murray. Thank you, and I really appreciate your 
attention to that as well. I think that's important.
    The other question I wanted to ask you quickly, both the 
IOM and the Enzi-Kennedy bill place restrictions on direct-to-
consumer advertising for new drugs and I think that is 
something we are all deeply concerned about addressing, and I 
agree with that approach. But I do know that sometimes getting 
information to consumers is just as important. If a parent 
hears about a new vaccine to protect their daughter against 
cervical cancer because of information that they heard, that 
can save lives, too.
    So talk to me about how the IOM is looking at how we 
address that balance between not creating just a market 
situation, but we also assure that people get the information 
that is out there they may not hear otherwise?
    Ms. Burke. The point you raise is an extraordinarily 
important one. One of the questions of course is the balance of 
that information. Our concern obviously with the advertising in 
that period of time when a drug has just come onto the market 
is speeding up the use of the drug before we fully appreciate 
the risks that the drug might, in fact, present, that may well 
not have been fully understand in the pre-approval process.
    Having said that, we also think it is incredibly important 
to provide a much better process for informing the consumer, 
and, in fact, there are a number of recommendations related to 
establishing a group to essentially assist the FDA in looking 
at exactly that question: What is the method by which you best 
communicate both with consumers as well as providers? The 
relationship between the provider, the physician who cares for 
the patient, and the patient is an enormously important one. 
That ought to be the source of the information that the 
patients seek out, rather than simply sitting at a Super Bowl 
and watching ads come up on TV.
    So it is really both of those values that we're trying to 
balance. That is, informing the consumer, but in a way that is 
useful, that doesn't encourage use before perhaps it's best 
known what will happen. And how we deliver the information--
some of the materials to date tend to be very complex, tend to 
be very lengthy, tend not to be very user friendly. We think a 
great deal of attention needs to be given to incorporating 
consumers into that review process and establishing a committee 
that essentially really pulls together the best information, 
frankly, from Madison Avenue and others about how you interact 
and how you inform.
    So certainly, in no way do we intend for there not to be 
information, but the question is how is it delivered, by whom, 
and for what purpose. That we think has to be balanced and 
that's why we've suggested the creation of this committee and 
involving consumers in that process.
    Senator Murray. Thank you very much. I really appreciate 
the opportunity to look at this.
    I do have several more questions. I'll submit them for the 
record because of the timing, but thank you.
    The Chairman. Senator Reed.

                   Opening Statement of Senator Reed

    Senator Reed. Well, thank you very much, Mr. Chairman.
    Welcome, Sheila Burke, and thank you, not only for your 
great public service, but for your service to the Kennedy 
School.
    Ms. Burke. Thank you, sir.
    Senator Reed. Good to see you again.
    I have just two questions because I know your time is 
curtailed this morning. One of the recommendations in the IOM 
report was the introduction of specific safety-related 
performance goals as a means to restore the appropriate balance 
between the FDA's competing goals, speeding access as well as 
safety of the product. What kinds of safety and performance 
standards did you envision would be necessary to do this?
    Ms. Burke. Thank you, Senator Reed. One of the things that 
concerned the committee is, in fact, currently under the PDUFA 
structure there are very clearly established goals that are in 
place with respect to timing, that are, in fact, tracked and 
used to assist both the agency as well as the industry in 
understanding whether or not the agreements are being kept. 
There are no such similar requirements with respect to safety 
either in the course of the advisory committee process, the 
frequency with which they're used, when they're called 
together, the kind of followup in terms of safety information 
that's being gathered, the reports that have been required or 
requested by the agency prior to approval, then what occurs 
post-approval.
    Our thought is that there ought to be a discussion and 
introduction of safety-related, whether it is about the 
advisory committee process, whether it is about the followup in 
terms of studies, that also ought to be tracked so that the 
Congress as well as the agency can fully understand whether, in 
fact, those requirements are being kept. So there really is--
there are no specifics in terms of we've not listed specific 
goals, but rather suggested that conversation needs to occur. 
But those are the kinds of things that we're thinking about.
    Senator Reed. So it's more procedural than substantive 
recommendation?
    Ms. Burke. It is exactly that, yes, sir.
    Senator Reed. Let me follow on Senator Murray's questioning 
about advertising. I know the report recommends direct-to-
consumer advertising on products be reviewed at least. A lot of 
the advertising, a lot of the promotion of these products, is 
done by representatives of the companies to physicians. Are you 
thinking about that as a way or an issue that you have to deal 
with?
    Ms. Burke. Senator, we only focused on the direct-to-
consumer advertising. However, having said that, clearly there 
is also this issue of the information given to providers as 
well. One of the things we think needs great attention by the 
agency is the nature of the material that is given both to 
physicians as well as to consumers--its appearance, its 
content, its presentation, whether, in fact, it is easily 
understood, the frequency with which it is changed and updated, 
how one delivers it. So really both of those issues, but the 
specific moratorium issue relates specifically to direct-to-
consumer.
    Senator Reed. With respect to the later issue, that is 
something, obviously, the agency can do. Are they interested 
and engaged in that process? Is that something that we have to 
pay attention to, the company-to-physician relationship?
    Ms. Burke. I can't speak for the agency. Certainly it was 
of interest to the committee, because again we believed so 
firmly that the physician ought to be the source of information 
in many instances and the first contact for the patient, as to 
how one delivers that information, the timing by which it is 
delivered, the nature of the information. So while it is not 
something we spent a great deal of time on, it is certainly 
something that clearly the agency ought to be concerned about.
    Senator Reed. Thank you very much.
    Ms. Burke. You're welcome, sir.
    The Chairman. Senator Isakson.

                  Opening Statement of Senator Isakson

    Senator Isakson. Ms. Burke, I apologize. I missed your 
testimony and I wasn't going to ask a question, but Senator 
Reed piqued my interest when he talked about the advertising. I 
thought I heard him say you made a recommendation on the 
direct-to-consumer advertising; is that correct?
    Ms. Burke. Yes, sir, we do.
    Senator Isakson. What is that recommendation?
    Ms. Burke. It relates specifically to new drugs coming on 
the market, that the FDA ought to have the authority to 
essentially curtail direct-to-consumer advertising during the 
startup period when the market is just new in terms of the 
drugs, that first 2 years or less, depending on what the agency 
decides makes sense. It will obviously relate to the risk 
issues with respect to the drug, to what extent they expect to 
have new information as a result of its broader use in the 
community.
    So it's specifically to new drugs. It is specifically 
within that timeframe in which they are first introduced into 
the market.
    Senator Isakson. In the case of mature--I don't know if 
``mature'' is the right word, but drugs that have been on the 
market-
place----
    Ms. Burke. Yes, sir.
    Senator Isakson [continuing]. For some time, more than 2 
years, did you find any problems with direct-to-consumer 
advertising?
    Ms. Burke. We didn't examine that question, sir. Our focus 
was really on that new period when, in fact, we don't really 
yet have information about its use in a broader community.
    Senator Isakson. Thank you very much.
    Ms. Burke. You're welcome.
    The Chairman. Senator Clinton.

                  Opening Statement of Senator Clinton

    Senator Clinton. Thank you very much, Mr. Chairman, and 
it's wonderful to be here, and especially to see Sheila Burke. 
Welcome back to the Senate.
    Ms. Burke. Thank you.
    Senator Clinton. I want to thank you for really embarking 
upon this important effort. You know, from my perspective there 
couldn't be anything more critical that we turn our attention 
to. I was able to get briefed on some of the questions and 
comments that were made before I arrived.
    I want to ask the witness about something that I'm very 
concerned about. We're talking about post-approval, but I 
believe strongly in comparative effectiveness studies. I was 
able to get that through an amendment into the Medicare 
Modernization Act. One of the first studies to be carried out 
under that provision was a systematic review of the COX-2 
drugs, and the results of the study, which were released in 
September, found no difference in the effectiveness of COX-2 
painkillers compared with over-the-counter pain relieving 
drugs.
    So I believe strongly that as we're looking at how to 
modernize the FDA, how to provide it additional resources, 
additional statutory authority where appropriate, that we 
really look at these comparative effectiveness studies, because 
they complement the drug approval work of the FDA. As we know, 
the agency's approval process focuses largely on ensuring that 
the drugs that come to market are safe for consumers. There is 
nothing more important than that, safe and efficacious.
    But newer drugs are not always better drugs and they may 
not be the clinically appropriate choice for all patients with 
a given condition. Comparative effectiveness studies allow us 
to determine the benefits of a range of treatments for certain 
conditions and to make sure that providers and patients are 
making treatment choices that, frankly, are not unduly 
influenced by direct-to-consumer advertising or other marketing 
efforts.
    So I would like to see us use the so far quite promising 
results of the comparative effectiveness studies through the 
Medicare Modernization Act amendment that I introduced and was 
approved, and I would like to ask our witness how she sees 
comparative effectiveness fitting into the pre-approval, post-
approval, almost spectrum of concerns that we should be 
constantly addressing as we move forward.
    Ms. Burke. Thank you, Senator. We, in fact, didn't as a 
committee look specifically at that question. Having said that, 
there is clear attention in our recommendations to the value in 
the FDA both partnering with the private sector as well as 
seeking partnerships with the VA, with Medicare, with other 
Federal agencies that essentially have the ability to either 
sort out information, provide information, support studies 
either done with partnerships with either the industry or 
individually having the FDA seek out these kinds of studies to 
inform them farther along in the process.
    Our particular attention, too, was that period largely just 
post-approval. Having said that, we know that the life cycle 
would produce lots of new information. The introduction of sort 
of new treatments, new opportunities, will inform us about 
drugs on the market as well as those coming on the market. 
Again, we believe the agency ought to have the resources to be 
able to test those questions, either again through partnerships 
in the private sector or individually with the companies or 
individually through the agency having the resources to conduct 
its own studies or call for those studies.
    So clearly the life cycle, the point of that is, in fact, 
to inform us throughout that period of time where new 
information could well become available.
    Senator Clinton. Well, Mr. Chairman, I hope that as we move 
forward under your leadership and Chairman-to-be Kennedy's 
leadership that that will be part of our consideration. I would 
underscore the point that has been made by a number of my 
colleagues. You know, the FDA truly is the gold standard of 
drug approval for the entire world, and we've got to get back 
to absolute scientific impeccably independent judgments, so 
that no one can second-guess them. Scientists may be wrong. We 
all know that. Research may not be complete or it may be in 
some way inadequate for the purposes for which it was intended. 
But we shouldn't be engaged in any political debates about 
whether other agendas, ideological or other agendas, are 
driving the decisions made at the FDA.
    Whatever we can do to guarantee the independence and the 
open scientific discourse that is needed as part of drug 
approval and review I am certainly going to support strongly, 
and I want to echo Senator Hatch's concern that we begin to 
look carefully at biologics, because this is an area of 
extraordinary complexity and we just don't have the range of 
infrastructure, intellectual capital, yet in the government to 
be a partner with the drug companies as they move forward.
    The Chairman. I want to thank you for your time today in 
testifying, and your outstanding answers. Of course, we will be 
relying on you to give answers to any written questions that 
will be submitted. We'll keep the record open for 10 days.
    But beyond that, we hope that you'll continue to work with 
us as we work through this very complicated piece of 
legislation to make sure that you and the members of your 
committee's ideas are properly represented as we do it.
    So thank you very much----
    Ms. Burke. Thank you, Mr. Chairman.
    The Chairman [continuing]. And we're getting you out before 
your plane deadline.
    Ms. Burke. You are. Thank you, sir.
    The Chairman. Thank you very much.
    As the next witnesses take their place at the table, I'll 
introduce the witnesses all at once and then they can give 
their statements and then we'll move to questions.
    Ms. Diane Thompson is Vice President of Public Policy and 
Communications for the Elizabeth Glaser Pediatric AIDS 
Foundation, the worldwide leader in the fight against pediatric 
AIDS. Diane is a public policy manager with over 20 years 
experience in government and nonprofit organizations. She holds 
a bachelor's degree from Vassar College and a law degree from 
George Washington University's National Law Center.
    The foundation is a founding member of the Alliance for 
Drug Safety and Access, which is comprised of 11 patient and 
provider organizations. ADSA members advocate on behalf of over 
31 million patients, including those suffering from HIV-AIDS, 
spinal cord injuries, paralysis, multiple sclerosis, and over 
6,000 known rare diseases.
    She will share patient views on whether the IOM proposal 
and pending legislation would contribute to improving drug 
safety while preserving patient access to innovative 
pharmaceuticals.
    Dr. Steven Nissen is the--did I get that right?
    Dr. Nissen. You got it right.
    The Chairman [continuing]. Chairman of the Department of 
Cardiovascular Medicine at the Cleveland Clinic and President 
of the American College of Cardiology. From 2000 to 2005 he 
served on the FDA Cardio-Renal Advisory Panel, chairing this 
committee during the final year of his term. Dr. Nissen is 
actively involved in drug development and has served as 
principal investigator for several clinical trials designed to 
explore drug efficacy. He has also been an active proponent for 
improved drug safety.
    Dr. Nissen is speaking on his own behalf today and not for 
any of the institutions he's affiliated with. He will discuss 
pending legislative proposals from his perspective as a 
physician who both treats patients and conducts large clinical 
trials to evaluate pharmaceutical benefits and risks.
    Dr. Adrian Thomas is Vice President of Benefit-Risk 
Management at Johnson & Johnson Pharmaceuticals Group. Dr. 
Thomas is a visiting professor at Temple University and a 
research-trained clinical pharmacologist and vascular 
specialist. Dr. Thomas is an internationally recognized expert 
in drug safety and has 12 years experience in the 
pharmaceutical industry. His research experience includes 
clinical trials design and methodology, public health and 
preventive medicine.
    Dr. Thomas has held academic and research appointments in 
epidemiology and preventive medicine at Monash University, 
Australia. Dr. Thomas will discuss current requirements for 
pre- and post-market safety evaluation by industry, as well as 
what Johnson & Johnson is doing beyond those requirements and 
how the IOM proposals and pending legislation would impact both 
drug safety and drug innovation.
    Mr. Jim Guest is President and Chief Executive Officer of 
Consumers Union. Mr. Guest became President of Consumers Union 
in February 2001 after a long career in public service and the 
consumer interest, including 21 years as chair of Consumers 
Union's board of directors. Consumers Union is an independent 
nonprofit organization whose mission is to work for a fair, 
just and safe marketplace for all consumers. Consumers Union 
publishes Consumer Reports and consumerreports.org.
    Mr. Guest's public service career has spanned more than 3 
decades. He will share his perspective as President of a 
leading consumer organization on the challenge of ensuring drug 
safety without compromising patient access to important 
pharmaceutical advances.
    Mr. Greg Simon joined as President of FasterCures in July 
2003. FasterCures is an action tank committed to saving lives 
by saving time. The nonprofit, nonpartisan organization 
examines the medical research and development process to 
discover and promote ways to accelerate the discovery, 
development, and deployment of new medical treatment for 
today's deadly diseases.
    Prior to joining FasterCures, Mr. Simon was a principal of 
Infotech Strategies, a Washington, DC., consuming firm, with 
special expertise in health technology, biotech, education 
technology, and communication technology. Earlier he was the 
CEO of Simon Strategies-Mindbeam, a consulting firm 
specializing in biotech-
nology, healthcare technology, and information technology, 
among other issues.
    Mr. Simon received his bachelor's degree from the 
University of Arkansas and his law degree from the University 
of Washington School of Law. He will share a somewhat different 
patient perspective on whether the IOM proposals and pending 
legislation would contribute to improving drug safety while 
preserving patient access to innovative pharmaceuticals.
    Ms. Thompson, you may begin.

STATEMENTS OF DIANE E. THOMPSON, VICE PRESIDENT, PUBLIC POLICY 
AND COMMUNICATIONS, ELIZABETH GLASER PEDIATRIC AIDS FOUNDATION; 
STEVEN E. NISSEN, M.D., CHAIRMAN, DEPARTMENT OF CARDIOVASCULAR 
  MEDICINE, CLEVELAND CLINIC FOUNDATION; ADRIAN THOMAS, M.D., 
  VICE PRESIDENT, BENEFIT-RISK MANAGEMENT, JOHNSON & JOHNSON 
PHARMACEUTICAL GROUP; JIM GUEST, PRESIDENT AND CHIEF EXECUTIVE 
     OFFICER, CONSUMERS UNION; AND GREG SIMON, PRESIDENT, 
                          FASTERCURES

    Ms. Thompson. Mr. Chairman, members of the committee, thank 
you very much for the opportunity to participate in today's 
hearing. I am Diane Thompson, Vice President for Public Policy 
and Communications at the Elizabeth Glaser Pediatric AIDS 
Foundation. I am testifying today on behalf of the Alliance for 
Drug Safety and Access, a coalition of 11 patient and provider 
organizations whose members advocate on behalf of over 30 
million patients suffering from serious life-threatening 
illnesses and diseases, and also represent over 100,000 
providers of care to children and individuals with mental 
illnesses.
    As a representative of the Elizabeth Glaser Pediatric AIDS 
Foundation, I am proud to offer the perspective of an 
organization that has been focused on speeding patient access 
to safe medicine since its inception in 1988. The foundation's 
creation was sparked by Elizabeth Glaser's outrage over the 
lack of safe and effective options for treating her two HIV-
infected children. Although Elizabeth's efforts were too late 
to save her daughter Ariel, who died from AIDS at the age of 7, 
her legacy includes her son Jake, now 22 years old, and the 
thousands of HIV-infected children around the world who now 
have the chance to grow up healthy thanks to the search for 
life-saving pediatric medicines that Elizabeth Glaser and the 
foundation have championed.
    I would like to thank the committee for your leadership on 
this issue, for moving beyond the headlines to take on the 
difficult task of crafting bipartisan legislation to truly 
reform our Nation's drug safety system. We appreciate your 
efforts that you and your staff have made to work with patient 
advocates and your willingness to adopt so many of the 
recommendations of our coalition. We know you share our goal of 
ensuring that patients continue to have timely access to new 
therapies while strengthening and improving the drug safety 
system.
    Simply put, we do not accept that patients should have to 
choose between safety and speedy access to new medications. The 
history of our foundation, of the broader HIV-AIDS community, 
and that of many of our coalition is the story of the power of 
patients' contributions to regulatory and scientific 
decisionmaking. One mom's determination to fight for her 
children's survival helped transform drug development for 
children in this country.
    Given that no one stands to lose more than patients in drug 
safety decisions, we urge you to ensure that patient voices 
have an important place in the development of risk safety plans 
and particularly in the resolution of risk management disputes 
as provided for in the legislation.
    We are pleased to see that both S. 3807 and the IOM report 
propose a fundamental paradigm shift in this country's approach 
to drug safety. There is agreement that attention to safety 
must be integrated throughout the life cycle of every drug and 
that continuous assessment of benefit and risk is every bit as 
important once a product is on the market and in the hands of 
patients as it is during the drug review phase.
    Changing the paradigm will require leadership, 
determination, clarity, and resources. In addition to the 
important changes already included in S. 3807, we agree with 
the IOM's recommendation that FDA's safety staff must have a 
greater formal role in drug review and in development of risk 
management plans. We also strongly agree that safety-related 
performance goals must be added to PDUFA.
    We applaud the focus of the legislation and the IOM report 
on strengthening FDA's ability to enforce requirements for 
continuing safety monitoring, on the importance of public 
dissemination of clinical trials data, and on the need for 
sufficient resources for the FDA to implement its new 
responsibilities. We need to make certain that we close the 
gaps that exist in each of those areas.
    As the IOM report notes, a recent study found that 21 
percent of prescriptions are written for off-label uses. Any 
effort to reform the drug safety system that fails to address 
one-fifth of the use of drugs in real world settings would 
create a significant safety gap, a safety gap particularly 
important to children because still far too few drugs are 
tested in children. The FDA's authority to require post-market 
safety studies must clearly extend to both on-label and off-
label uses if we are to close that gap.
    FDA needs enforcement mechanisms, including civil money 
penalties, that are substantial enough to be effective. By 
providing FDA the flexibility to impose fines for 
noncompliance, we can avoid the worst possible outcome for 
everyone, that FDA would have to resort to pulling a drug from 
the market that still holds some benefit for some group of 
patients because it has no other effective recourse.
    In terms of clinical trials, we endorse the IOM 
recommendation that a mandatory clinical trials database 
incorporate phase two trials. In our view, however, that 
database should also include trials completed prior to 
enactment of this legislation and those for medical devices. 
From the point of view of a patient it is irrelevant whether a 
new therapy comes in the form of a drug or a device. The 
results of all such studies should be made publicly acceptable.
    For FDA to succeed in implementing these reforms, it must 
have resources paired with its new responsibilities. A drug 
safety system that incorporates these core elements ultimately 
will benefit all stakeholders and we believe the changes 
outlined above, if adopted and resourced, will serve both 
timely review and safety.
    Mr. Chairman, members of the committee, this committee has 
before it a historic opportunity to finally match our Nation's 
success in speeding new therapies to patients with a system 
that can better ensure the safety of those products once on the 
market. We very much appreciate your interest in the patient's 
perspective on these critical issues and we look forward to 
continuing to work with you over the next year to accomplish 
these goals. Thank you.
    [The prepared statement of Ms. Thompson follows:]

                Prepared Statement of Diane E. Thompson

    Mr. Chairman, Senator Kennedy, and members of the committee, thank 
you for the opportunity to participate in today's hearing. I am Diane 
Thompson, Vice President for Public Policy and Communications at the 
Elizabeth Glaser Pediatric AIDS Foundation. Today, I will be testifying 
on behalf of the Alliance for Drug Safety and Access (ADSA), a 
coalition of 11 patient and provider organizations. Collectively, 
members of ADSA advocate on behalf of over 30 million patients, 
including those suffering from HIV/AIDS, Parkinson's disease, spinal 
cord injuries, paralysis, multiple sclerosis, leukodystrophies, 
Tourette Syndrome, and over 6,000 known rare diseases. In addition, our 
members represent over 100,000 providers of care to children and 
individuals with mental illnesses.
    As a representative of the Elizabeth Glaser Pediatric AIDS 
Foundation, I am also proud to offer the perspective of an organization 
that has been focused on speeding patient access to safe medicines 
since its inception in 1988. This issue is at the heart of our 
mission--the Foundation's creation was sparked by Elizabeth Glaser's 
outrage over the lack of safe and effective options for treating her 
two HIV-infected children. Although Elizabeth's efforts were too late 
to save her daughter, Ariel, who died from AIDS at the age of 7, her 
legacy includes her son Jake, now 22 years old, and the thousands of 
HIV-infected children around the world who now have the chance to grow 
up healthy and even start families of their own, thanks to the search 
for lifesaving pediatric medicines that Elizabeth Glaser and the 
Foundation championed.
    First, let me begin by thanking the Chairman, Senator Kennedy, 
Senator Dodd and other members of the committee for your leadership on 
this issue, for moving beyond the headlines to take on the difficult 
task of crafting bipartisan legislation to truly reform our Nation's 
drug safety system. We certainly appreciate the magnitude of the task 
and the historic nature of this undertaking.
    We also appreciate the efforts you and your staff have made to 
incorporate the recommendations of our coalition. We know that you 
share our interest in both continuing the timely access of patients to 
new therapies and strengthening oversight of drugs already on the 
market. And, we believe that with sufficient resources both goals are 
achievable. Simply put, we do not accept that patients should have to 
choose between safety and speedy access to new medications.
    Patients with serious illnesses understand that bringing drugs to 
market in a timely way means that not every risk can be identified in 
advance. However, what they also demand is sufficient information for 
them and their providers to continue to assess risks and benefits--
which often means further testing of the drug after approval. Yet, as 
the report by the Institute of Medicine (IOM) so clearly illustrates, 
the Food and Drug Administration (FDA) has virtually no authority to 
compel drug manufacturers to continue to study the safety of products 
after they have been approved, to force changes to drug labels if 
dangerous side effects are uncovered, or to require that the results of 
critical studies be shared with patients and providers. In addition, at 
current funding levels, FDA lacks the resources to successfully 
accomplish many activities it is authorized to undertake, including 
effective collection and analysis of postmarket safety data.
    Giving FDA these authorities and flexible tools to enforce them, as 
legislation pending before the committee would do, ultimately benefits 
both patients and drug manufacturers. Allowing FDA to require 
additional testing of drugs when there are clear signals of safety 
problems could actually allow the FDA to approve drugs more quickly, 
knowing it will have the ability to act if there are new safety 
concerns once the drug is in the hands of patients. Also, by giving FDA 
the flexibility to impose fines for noncompliance, we can avoid the 
worst possible outcome for everyone: pulling a drug from the market 
that still holds some benefit for some group of patients.
    We were pleased to see that S. 3807 essentially contains these 
critical elements. Perhaps most importantly, it frames them in a 
context of a risk-based approach. That model, rather than a one-size-
fits-all approach to patient safety, will be key to the appropriate 
balancing of drug risks and benefits that is so critical to patients 
with life-threatening illnesses. Similarly, we welcome the IOM's vision 
of applying a ``life-cycle'' paradigm to drug risks and benefits, with 
its emphasis on the continuing pursuit of knowledge about a drug's 
safety profile and timely communication of that information to patients 
and providers. As recommended by the IOM, we hope that this will 
include the significant improvements to FDA's capacity to collect and 
analyze safety data through passive and active surveillance systems, as 
well as through prospective studies.
    We are concerned however, that S. 3807 lacks sufficient mechanisms 
to elicit much needed patient and provider input. Some of the most 
critical patient safety decisions under the new structures proposed in 
the legislation will be those that relate to the development of risk 
evaluation and management strategies (REMS) plans. Yet, the bill 
currently assigns the responsibility for developing those plans and 
resolving related disputes solely to FDA and to an internal board 
composed entirely of Federal employees, with no opportunity for input 
from outside experts, patients, or providers.
    The history of our Foundation and of the broader HIV/AIDS community 
is the story of the power of patients' contributions to scientific 
decisionmaking. Although they began as three mothers around a kitchen 
table with no formal training in science and medicine, Elizabeth Glaser 
and the other founders of the Foundation ultimately changed the 
accepted thinking of both the National Institutes of Health and FDA 
about the risks of not studying AIDS drugs in children--a success story 
that is repeated throughout the histories of patient organizations.
    Given that no one stands to benefit or lose more than patients in 
drug safety decisions, we ask that you consider a greater role for 
patients in the development of REMS plans and resolution of REMS 
disputes. Specifically, we recommend that an existing or new advisory 
committee be utilized rather than the Drug Safety Oversight Board. Such 
a committee could draw on more diverse expertise, including the voices 
of patients and providers, and could make its deliberations public, 
which would be an important step in improving public trust in the 
process.
    To further improve the depth and breadth of input into drug safety 
decisionmaking, we ask the committee to adopt the recommendation of the 
IOM that the Office of Surveillance and Epidemiology (OSE) be given a 
greater role in drug review and the development of safety plans. The 
lack of communication and cooperation between that office and the 
Office of New Drugs, highlighted in both the IOM report and a March 
2006 report by the Government Accountability Office, is deeply 
troubling. At minimum, we urge the committee to formally assign OSE 
staff a role in the review of new drug applications and postapproval 
regulatory actions, as the IOM recommends.
    We also urge the committee to clarify that the authority of FDA to 
require studies of postmarket safety concerns is not confined to on-
label uses of the drug. In our efforts to improve the drug safety 
system, we need to pay particular attention to not only what happens 
inside the FDA, but also what goes on in the real world. As the IOM 
report notes, a recent study found that 21 percent of prescriptions 
written in 2001 were for off-label uses. Any effort to reform the drug 
safety system that fails to address \1/5\ of the use of drugs in real-
world settings would create a significant safety gap.
    Children would be placed at particular risk by the failure to 
clarify this authority, since as much as \3/4\ of pediatric prescribing 
is off-label. Thanks to the efforts of Senators Dodd, Clinton, and 
DeWine, there are mechanisms available to both encourage and require 
manufacturers to study their products for children. However, there are 
gaps in those mechanisms. The existing pediatric study requirement does 
not apply to off-label uses. While the existing incentives can be 
applied to off-label studies, they are voluntary--and we are seeing 
that manufacturers are increasingly opting not to conduct the studies 
FDA requests. Unambiguous authority to require such studies when the 
off-label use is significant will help ensure that children too can 
reap the benefits of an improved drug safety system.
    We applaud the significant focus placed by S. 3807 on the public 
dissemination of trial results through a clinical trials database. The 
establishment of such a database would be a significant step forward in 
providing patients and providers with additional information with which 
to assess benefits and risks. By linking the registration of new trials 
with final outcomes, this database could also help prevent selective 
reporting of positive results and further revelations about the 
withholding of negative trial results. And, not incidentally, given 
that clinical trials could not exist without patients' willingness to 
give of their time and health, such a mechanism could help restore 
patients' trust in the integrity of the clinical trials process.
    However, in our view, a number of additions should be made to the 
database established by S. 3807 to ensure that it is as comprehensive 
and complete an accounting of trials as possible. We endorse the IOM 
recommendation that the database incorporate Phase II trials. We also 
believe that to satisfy the objective of providing patients and 
researchers with the full body of evidence on a drug or a class of 
drugs, there must be an element of retroactivity, perhaps beginning 
with trials of already approved products--both for the approved use and 
for any uses that were studied but not approved.
    Following the recommendations of a previous report by the IOM in 
July 2005 on the postmarket safety of pediatric medical devices, we 
also ask that device clinical trials be added to the database. From the 
point of view of patients it is irrelevant whether a new therapy comes 
in the form of a drug or a device; the results of all such studies 
should be made publicly accessible. And, finally, while we endorse the 
concept of a single, comprehensive, national database that provides 
``one-stop-shopping'' for patients and providers, until the concerns 
noted previously are remedied, we do not support pre-empting any 
efforts by States to also collect this information.
    We applaud the inclusion of civil money penalties in S. 3807 as a 
critical step in providing FDA with graduated, flexible enforcement 
authority. However, we are concerned that the current penalties are too 
low to have much impact, particularly for higher sales products, and 
ask that they be increased. To ensure compliance with the requirements 
of the clinical trials database, we ask that the authority for FDA to 
impose fines for other types of violations also be applied to this 
section.
    Finally, we agree with the IOM recommendation that specific safety-
related performance goals be added when the Prescription Drug User Fee 
Act (PDUFA) is reauthorized next year. Clearly the experience from 
PDUFA thus far is that deadlines generate attention and focus. Even 
with additional funding, if postmarket activities without performance 
goals have to compete with pre-market functions with performance goals, 
we would be concerned they would remain an afterthought.
    Obviously, the drug safety reforms proposed by both S. 3807 and the 
IOM create considerable new responsibilities for the FDA. For FDA to 
succeed in implementing these reforms, it is essential that new and 
expanded safety activities be explicitly paired with increased 
resources. We would suggest a combination of an increase in user fees 
targeted to drug safety activities and an increase in appropriations. 
We also recognize that it may be necessary to prioritize the reforms 
that can be implemented in the short- and long-term depending on the 
availability of new resources and we look forward to working with the 
committee to do so.
    Mr. Chairman, the committee has before it an historic opportunity 
to finally match our Nation's success in speeding new therapies to 
patients with a system that can better ensure the safety of those 
products once on the market. We appreciate your interest in patients' 
perspectives on these critical issues and look forward to working with 
you over the next year to accomplish these goals. Thank you again for 
the opportunity to share our views.

    The Chairman. Thank you. I appreciate any summarizations 
that any of the presenters do. Your full testimony will be a 
part of the record, so if you hit on key points that'll give us 
more time for questions.
    Dr. Nissen.
    Dr. Nissen. Thank you very much. My name is Stephen E. 
Nissen, M.D. I am Chairman of the Department of Cardiovascular 
Medicine at the Cleveland Clinic and President of the American 
College of Cardiology. My testimony does not reflect the views 
of either the Cleveland Clinic or the ACC. As an individual who 
has frequently served as the point on the end of the spear 
during the public debate on drug safety, I appreciate the 
opportunity to provide an independent perspective on the 
Enhancing Drug Safety and Innovation Act of 2006 introduced by 
Chairman Enzi and Ranking Member Kennedy.
    We face a crisis in public confidence in the FDA following 
an unprecedented series of revelations about drug and device 
safety. The American people no longer trust the FDA to protect 
their health. Unfortunately, patients are increasingly 
suspicious of new therapies and sometimes are reluctant to 
accept potentially life-saving medications or devices. Strong 
and decisive legislative action is now essential to improve the 
safety of drugs and medical devices and restore public 
confidence in this critically important regulatory agency.
    The initiative now before you represents the best 
opportunity in many years to fix these chronic problems. We 
need new laws to strengthen the authority of the FDA. Currently 
the agency must negotiate with industry to make even simple 
changes in drug labels. I served on a 2001 advisory panel that 
recommended a warning label for Vioxx, but it took 14 months 
before the FDA could secure agreement from the company to 
accept a weakly written warning. Companies routinely make 
commitments to perform phase four studies, but never actually 
launch the promised clinical trials, and the agency is 
powerless to act.
    When drug studies reveal toxicity or efficacy, the agency 
is not permitted to release the results and the findings are 
often not published, thereby denying patients and physicians 
access to vitally important safety information. The problem of 
negative publication bias, the practice of suppressing and 
never publishing unfavorable studies, has a catastrophic effect 
on the drug development system. When drugs show serious 
toxicity in patients, the results are rarely published. 
Accordingly, other companies subsequently expose patients to 
closely related drugs without knowing that their competitor's 
study of a similar agent showed significant harm.
    I am aware of a class of drugs where more than a dozen 
compounds showed serious toxicity, resulting in termination of 
development, but without a single publication of results. In my 
view, when a patient volunteers to participate in a drug or 
device study there is an implicit moral obligation that 
patients' participations will benefit medical science. When 
studies are not published, we learn nothing from the experiment 
and make the same mistakes over and over again.
    The post-marketing surveillance system for drugs and 
devices functions poorly. Adverse event reporting is voluntary 
and studies show that only 1 to 10 percent of serious adverse 
events are ever reported to the agency. Accordingly, the actual 
incidence of serious or life-threatening complications cannot 
be calculated accurately.
    The current legislation proposed by Senators Enzi and 
Kennedy addresses many of these problems in a thoughtful 
fashion. The bill's authors have sought to simultaneously 
facilitate development of innovative therapies while 
aggressively protecting public safety. The proposed risk 
evaluation and mitigation strategy is a step toward a more 
robust post-marketing surveillance system. The system for 
dispute resolution is fair to the industry but makes certain 
that safety concerns are promptly addressed. The requirement to 
register clinical trials is essential and the establishment of 
a mandatory clinical trials results registry will guarantee 
that society reaps the benefits of knowledge whenever a study 
is conducted in human subjects. Finally, the improvements in 
the advisory committee process will help to ensure FDA 
consultants are less likely to be influenced by financial 
conflicts of interest.
    Although this bill is a major step forward, I would like to 
see further legislative actions. The agency should be better 
funded. Virtually every American takes one or more medications, 
so drug safety affects every one of us. However, the annual 
expenditure for drug regulation approximates only about $500 
million and is largely supported by user fees, creating a 
conflict in loyalty for FDA employees. We cannot expect 
outstanding performance from an agency operating on a poverty 
budget.
    For high-risk drugs, another approach to drug approval 
should be considered: provisional approval, a limited term 
approval that would automatically expire unless certain 
criteria for efficacy and safety are met.
    I believe that direct-to-consumer advertising requires 
legislative action. The standard for acceptable DTC advertising 
should require demonstration of a compelling public health 
benefit for this type of communication. Drugs with an addiction 
potential, such as sleeping medication, should be specifically 
prohibited from consumer advertising.
    Finally, there is an important drug safety problem not 
addressed in this bill--the nutraceutical industry. I recognize 
that the HELP Committee has made progress by unanimously 
approving legislation requiring serious adverse event reporting 
for diet supplements. However, more needs to be done. These 
products are often worthless and occasionally harmful. It must 
be recognized that some patients take dietary supplements 
instead of effective medications, with negative implications 
for their health.
    The current bill is an important step toward improving the 
safety of drugs and devices and restoring public confidence in 
the FDA. I strongly support its passage and commend the 
Senators for their bipartisan leadership. Let me add, if there 
was ever a bipartisan issue protecting the health and safety of 
the 300 million Americans who take drugs, this is a bipartisan 
issue and I really strongly support your efforts.
    Thank you.
    The Chairman. Thank you.
    Dr. Thomas.
    Dr. Thomas. Thank you. Mr. Chairman and members of the 
committee: I'm pleased to be here today on behalf of Johnson & 
Johnson to discuss the important topics of drug safety and 
innovation. I am Dr. Adrian Thomas. I serve as Vice President 
of Benefit-Risk Management, which is drug safety for the J&J 
pharmaceutical companies.
    J&J and this committee share a common goal of ensuring that 
doctors prescribe and patients use healthcare products safely. 
We commend you for the deliberative approach you've taken in 
crafting your bipartisan legislation, S. 3807, and we thank you 
for the opportunity to speak here today. J&J believes that 
patient needs are best served when benefits and risks are 
considered together in the context of how our medicine is 
actually being used. We know, for example, that patients and 
physicians often consider different levels of risks acceptable 
depending upon the disease being treated, the patient 
population, an individual's health status, and the availability 
of alternative therapies. The full benefits and risks of any 
medicine often emerge, however, over a significant period of 
time after approval. Rare risks will only appear after a 
medicine has been used in many thousands of patients. Thus any 
legislative solution should balance established benefits for 
populations against potential risks for individuals.
    As important as this bill is, it is no substitute for 
enhanced tools for monitoring patient safety or adequate 
appropriations to ensure a strong and science-based FDA.
    I'll now provide some highlights of our analysis of S. 
3807. With respect to the risk evaluation and mitigation 
strategies, recent concerns have rightly attracted attention on 
improving drug safety. Whilst we agree that safety issues must 
receive the attention they deserve, we cannot consider risks in 
isolation from product benefits or we risk denying patients 
access to valuable therapies.
    Anti-cancer drugs are an obvious example of the complex 
relationship between risks and benefits. However, more common 
drugs such as statins and aspirin similarly provide a clear 
benefit, but are nonetheless accompanied by distinct and 
manageable risks. In fact, if aspirin were under review today 
one could speculate whether or not it would be improved.
    This bill integrates risks and benefits through the REMS 
mechanism. We support this concept for products where the 
potential for risk is greatest, such as new products, novel 
mechanisms of action, or products that will be used in 
vulnerable populations, particularly the aged and children. 
That said, we have a number of concerns that I discussed in my 
written testimony. I would like to highlight three.
    First, regarding potential requests for industry to conduct 
trials, we agree that--we recommend that such requests be 
limited to on-label indications under the context of an IND 
application.
    Second, the committee may want to consider whether options 
such as restricted distribution should be authorized in the 
bill, as patient access could potentially be affected.
    Third, the moratorium on DTC advertising has some problems. 
Appropriate DTC advertising can play a valuable role in 
education of patients about disease and treatments, although we 
acknowledge that there are many issues.
    Regarding the dispute resolution process, it's important 
that drug safety oversight boards' considerations regarding 
product safety be integrated with the appropriate reviewing 
division to ensure a holistic view of the product.
    I'd like to now comment on clinical trials. We are 
generally supportive of the legislation's clinical trial 
provisions. We would like to highlight one concern, the chief 
of which is the bill's requirement for registration and 
disclosure of results from exploratory clinical trials. These 
trials are designed to generate hypotheses about medicine, not 
confirm findings. As such, these results, either positive or 
negative, could be confusing or misleading and need to be 
placed in the appropriate scientific context.
    With respect to the conflicts of interest, there is a 
general need--there's a genuine need for sufficient numbers of 
qualified experts for service on FDA committees. This is an 
issue of concern for FDA, for industry sponsors, patients, and 
providers. Greater transparency of the FDA decisionmaking 
process will enhance public confidence and reassure all these 
stakeholders. FDA should also be mindful of non-financial 
biases, such as institutional affiliation, in the context of 
specific advisory committee meetings.
    In conclusion, the bill reflects the desire that we all 
share, to enhance patient safety and access to new therapy, and 
J&J greatly appreciates the opportunity you have provided to 
discuss these issues with you today. However, it is important 
to note that your efforts to strengthen FDA could be undermined 
by increased reliance on user fees to fund FDA activities, as 
we've heard today. There is a perception that the agency is 
overreliant on user fees in a way that compromises the 
integrity of the decisionmaking process. To address this 
perception, Congress must increase FDA's appropriated funding 
to enable the agency to fulfill its mission and restore public 
confidence in its independence. Although we appreciate this 
committee is not responsible for appropriations for FDA, your 
status as the authorizing committee for FDA allows you to 
exercise considerable influence on your colleagues in the 
Senate.
    On behalf of Johnson & Johnson, we look forward to working 
with you and your colleagues to address these important issues 
of patient safety and information. I want to thank you for the 
opportunity to speak with you today. I'm happy to answer any 
questions you may have.
    [The prepared statement of Dr. Thomas follows:]

               Prepared Statement of Adrian Thomas, M.D.

    Mr. Chairman, Ranking Member and members of the committee, I am 
pleased to be here today on behalf of Johnson & Johnson to discuss the 
important topics of drug safety and innovation. I am Dr. Adrian Thomas, 
and I serve as Vice-President for Benefit-Risk Management for the 
pharmaceutical companies of Johnson & Johnson.
    Let me start by saying that Johnson & Johnson and the Senate 
Health, Education, Labor, and Pensions Committee share a common goal of 
ensuring that doctors prescribe and patients use healthcare products 
safely. We commend you for the deliberative approach you have taken in 
crafting your bipartisan legislation, S. 3807, and we thank you for the 
opportunity to speak here today.
    I will begin by setting forth the broad perspectives of my company 
on the topics of drug safety and innovation. Then I will provide some 
background on how companies such as Johnson & Johnson assess the safety 
of our products over their life cycles. Finally, I will comment on key 
provisions of S. 3807, Enhancing Drug Safety and Innovation Act of 
2006, as well as recommendations of the Institute of Medicine's (IOM) 
Committee on the Assessment of the U.S. Drug Safety System regarding 
proposed changes to aspects of the system whereby the Food and Drug 
Administration (FDA) regulates medicines.

                              PERSPECTIVES

    Since before Hippocrates first cautioned that physicians should 
``help, or at least, do no harm,'' treating disease has always involved 
balancing a therapy's benefits with its potential risks. At Johnson & 
Johnson, we believe that patient needs are best served when benefits 
and potential risks are assessed together, in an integrated, holistic 
way, and within the context of how a medicine is actually being used. 
We know, for example, that patients and physicians often consider 
different levels of risk acceptable, depending upon the disease being 
treated, the population being served, a patient's health status, the 
availability of alternative therapies, and other variables.
    It is also important to note that as society addresses issues of 
drug safety, the full benefits and risks of any medicine often emerge 
over a significant period of time after approval. Many risks are 
exceedingly rare and may only emerge after a medicine has been used in 
many thousands of patients. So as Congress develops new legislative 
approaches, it should also continue to make it possible for patients to 
access a broad range of existing, and new, therapeutic options. This 
requires balancing protections for broad populations with access for 
appropriate patients.
    I would like to make a few other broad comments: We support the use 
of Risk Evaluation and Mitigation Strategies proposed in S. 3807 to 
enhance safety, where these strategies are most needed. We believe the 
proposed Reagan-Udall Institute could be a valuable impetus to spur 
scientific innovation if consistent and adequate appropriations are 
provided. We support the provisions of S. 3807 and the IOM report 
regarding the registration and disclosure of results of confirmatory 
clinical trials. We support efforts to manage conflicts of interest in 
FDA Advisory Committees and to enhance transparency while retaining 
FDA's access to expertise. Finally, we believe that Congress should 
adequately fund the Food and Drug Administration in the interest of all 
Americans.

               COMPANY SAFETY AND SURVEILLANCE ACTIVITIES

    As I mentioned earlier, I serve as Vice-President for Benefit-Risk 
Management for Johnson & Johnson's pharmaceutical companies. In that 
capacity, my department and I work with the pharmaceutical research and 
development units and with the medical affairs organizations in our 
commercial operating companies to ensure that we appropriately consider 
safety, together with efficacy and outcomes data, throughout the life 
cycle of our products.
    Like other pharmaceutical manufacturers, we evaluate the benefit-
risk profiles of our products continuously, since important additional 
information is gained after approval of a medicine during real world 
use. At the time of submission, our knowledge of the risks and benefits 
of products, though quite detailed, is based typically on experience of 
the medicine in thousands of patients in a controlled clinical setting, 
whereas in the postmarketing life of the product additional data is 
gathered from many times more patients in settings that are less 
controlled. For example, in a study with 3,000 patients, one can 
identify adverse reactions that occur at a rate of 1 in 100 patients, 
but it is not possible in such a study to reliably identify an adverse 
reaction that occurs in fewer than 1 in 1,000 patients.
    Monitoring the safety profile of products postapproval requires 
effective pharma-
covigilance and postmarketing surveillance. Like others in our 
industry, we collect, assess, and evaluate safety reports from 
consumers, physicians, healthcare providers, regulatory agencies, 
clinical investigators, the literature and other sources globally. This 
requires numerous technical tools and substantial medical expertise, 
underpinned by a variety of specific processes to ensure diligence.
    Not all products have the same level of risk. The degree of 
scrutiny for a given product depends on a number of variables, such as 
the stage of the product in its life cycle, known safety issues 
associated with the product or class, or specific requests from 
regulatory agencies. All products, however, are regularly reassessed as 
new knowledge routinely emerges about medical interventions; and 
science is not static. Companies such as ours continually invest in new 
technologies and methodologies to conduct pharmacovigilance and risk 
management. In the postapproval environment, we rely primarily on 
safety information from postmarketing reports, but we also conduct 
additional research, including epidemiologic studies and targeted 
trials, to evaluate potential safety concerns. In instances of serious 
unexpected safety issues, this integrated approach has proven to be 
successful in assuring patient safety while maintaining access for 
patients with significant medical needs.
    Risk management cannot be undertaken in isolation by a 
pharmaceutical company, but requires interaction and cooperation 
between regulatory agencies and the company, as well as communication 
of benefit-risk information in a timely and transparent manner to 
healthcare professionals and ultimately to patients. The interaction 
between the company and regulatory agencies is a critical partnership 
from the time of early drug development throughout its marketed life, 
with the ultimate goal of providing and maintaining patient access to 
beneficial therapies. In this regard, it will be important for the 
committee to hear from FDA when its Study Groups report back early next 
year on any additional steps the agency may take to ensure the safe use 
of medicines.

                          ANALYSIS OF S. 3807

Title I--Risk Evaluation and Mitigation Strategies
    Reports of unanticipated adverse effects associated with medicines 
taken by, in some cases, millions of Americans have undermined public 
confidence in the ability of the FDA to ensure the safe use of 
medicines. In that regard, today's hearing represents a step forward in 
defining specific activities that could make a real difference in 
safety margins, without unduly burdening the efficiency or speed of the 
FDA approval process. Access to novel treatments is of particular 
concern for patients suffering from serious or life-threatening 
diseases--especially in cases where previous therapies have failed.
    Safety issues have attracted much attention, both in the Congress 
and among academicians. Some of the proposals (legislative and 
otherwise) have sought to elevate the profile of safety considerations 
by creating separate safety offices within FDA that would have equal or 
superior authority over drug approvals to that of the reviewing office, 
without having line of sight to the data on efficacy. This effective 
veto power over approval of new medicines fails to appropriately take 
into account the importance of benefit or efficacy considerations in 
achieving a balanced understanding about a medicine.
    For example, many traditional cancer drugs are associated with 
substantial toxicities, but those toxicities are inseparable from the 
effectiveness of the drugs. Oncologists who administer those drugs are 
well aware of the toxicities and are capable of managing them for the 
benefit of their patients with cancer. Cancer patients also understand 
that the benefits of chemotherapy come with risks and those who elect 
to take these therapies accept the risks that are inherent in these 
drugs. If safety considerations had been permitted to trump drug 
efficacy or benefit, many of these life-extending drugs might never 
have been approved and might never have been available to cancer 
patients.
    While anti-cancer drugs offer an obvious example of the complex 
relationship between risks and benefits, there are many other examples. 
Medicines known as TNF-inhibitors provide substantial relief to 
patients with rheumatoid arthritis, not only alleviating pain but 
actually affecting the progression of the disease. The drugs' 
mechanism, however, can interfere with normal immune system 
functioning, and use of TNF inhibitors requires careful management. 
Other more common drugs, ranging from statins to aspirin, similarly 
provide clear benefit but are nonetheless accompanied by distinct, 
though manageable, risks.
    Your legislation, S. 3807, appropriately gives equal consideration 
to the inseparable elements of safety and benefits. It accomplishes 
this primarily through a mechanism called a Risk Evaluation and 
Mitigation Strategy, or REMS. At the core of REMS is a 
pharmacovigilance statement that creates a plan for managing the risks 
associated with a particular drug. The pharmacovigilance statement is 
based on an assessment of key variables, including estimated size of 
the treatment population, the seriousness of the disease or condition 
being treated, duration of treatment, availability of a comparable drug 
or other therapy, and the seriousness and incidence of the risk in the 
treatment population.
    We support the concept of REMS for products where the potential for 
risks is greatest, such as new product classes, products with new 
mechanisms of action, or products that will be used in particularly 
vulnerable populations, such as the aged or children.
    Through the REMS approach, S. 3807 takes into account both the 
benefits and risks of potential therapies, as is appropriate, to reach 
a balanced regulatory decision. S. 3807 is also commendable in 
providing a comprehensive menu of potential remedies that can be 
tailored to meet particular risks to be included in a REMS, ranging 
from a required medication guide or patient package insert and a 
communication plan for healthcare providers, through postapproval 
registries and clinical trials, to restrictions on advertising or on 
distribution and use.
    We agree that these elements of the REMS should reflect the 
seriousness of the risks associated with a particular product and 
should be considered in a step-wise fashion. Regarding potential 
requests for industry to conduct clinical trials, we recommend that 
such requests be limited to on-label indications. The committee should 
consider whether an additional funding mechanism for off-label studies, 
as has been put forth in the context of pediatric drugs, would be 
appropriate. In addition, it would be reassuring to industry, 
practitioners and patients if it were clear that the most severe of 
these approaches--distribution restrictions, for example--would be 
limited to situations of very serious risk. Some of the more extreme 
elements that could be included in a REMS as set forth in the 
legislation, such as restrictions on distribution or direct-to-consumer 
advertising, have rarely been used to date and then only with the 
acquiescence of the sponsor.
    Voluntary restrictions on distribution have occurred in a few 
situations in which there was a known serious risk to public health, 
with thalidomide being the signal example. A very different situation 
is created if the agency is authorized by statute to impose such 
restrictions, notwithstanding the negotiation and dispute resolution 
process. We recommend that the language of S. 3807 make clear that such 
newly authorized remedies should be utilized only in extreme and rare 
circumstances. The standard for restrictions on distribution should be 
no less than in the current Subpart H regulation on accelerated 
approval, 21 CFR 314.520, which permits restrictions ``. . . if FDA 
concludes that a drug product shown to be effective can be safely used 
only if distribution or use is restricted'' and ``. . . the limitation 
imposed will be commensurate with the specific safety concerns 
presented by the drug product.'' Certainly, restrictions on 
distribution will limit patient access. We believe access to new 
therapies should be assured.
    Indeed, the committee may want to consider whether some of the 
remedies are ever appropriate or in fact have been proven to be useful 
in reducing risk. For example, the requirement that a patient must see 
a board-certified physician could present a real access problem for a 
sick patient who lives many miles from an appropriate doctor. The same 
could be said about potential restrictions on pharmacies. We urge the 
committee to very carefully weigh issues of patient access as it 
further considers this bill.
    Another remedy that should be reconsidered is the proposed ability 
of FDA, under the legislation, to impose a moratorium on direct-to-
consumer (DTC) advertising for up to 2 years. This restraint on 
advertising represents a troubling change. Many members of the 
industry, including Johnson & Johnson, have voluntarily agreed to 
exercise restraint with respect to DTC advertising, especially during 
the period of time after approval. But appropriate DTC advertising 
plays a valuable role in educating patients about diseases and 
treatments. The value of this education to patients, as well as the 
important first amendment issues that arise from banning truthful 
speech, even for a period of time, must be carefully considered before 
legislating in this area. At a minimum, the standard for imposing DTC 
advertising restraints should be much higher than is currently 
articulated in the legislation, to ensure appropriate application of 
this new authority.
    Regarding the dispute resolution process, we have a concern about 
the elevation of the Drug Safety Oversight Board, an administrative 
creation with no previous statutory authority, to the role of primary 
final decisionmaker. As noted earlier, focusing solely on the risks of 
a medicine without the context of the medicine's benefits could result 
in limited access for patients. Given the enhanced status of the Drug 
Safety Oversight Board under this legislation, the committee should 
provide clearer definition of its composition and its place in the 
governance of FDA. In addition, in connection with dispute resolution, 
the Board should receive explicit statutory direction regarding the 
appropriate balance of safety and access and should be required, in 
resolving disputes, to apply a standard that balances safety concerns 
against benefits, particularly in the case of serious or life-
threatening diseases.
    S. 3807 provides a valuable platform for discussing how to address 
the concerns that have been raised about drug safety, without 
jeopardizing medical progress against serious and life-threatening 
diseases. We note that many of the recommendations of the Institute of 
Medicine (IOM) report on drug safety are consistent with the terms of 
the legislation, although they diverge in several significant respects. 
It is important to consider whether the IOM recommendation to assign 
joint authority for post-approval drug safety reviews to both the 
Office of New Drugs (OND) and the Office of Surveillance and 
Epidemiology (OSE) creates an unworkable situation with split 
accountabilities. We believe such authority should reside with OND, 
though with appropriate input from OSE. It is important to note that 
while OND reviews both benefit and safety information, OSE sees only 
safety data, potentially skewing the OSE's perspective on a particular 
medicine.

    TITLE II--REAGAN-UDALL INSTITUTE FOR APPLIED BIOMEDICAL RESEARCH

    While the drug safety reforms embodied in title I of the 
legislation are necessary to restore the confidence of legislators, 
regulators and the public in the safety use of marketed products, S. 
3807 also makes a significant contribution to product innovation by 
operationalizing the FDA vision of a ``critical path'' to discovery. 
The industry knows that we lack the predictive tools to make drug 
discovery and development more efficient and cost-effective. This is 
particularly unfortunate, given the Nation's substantial investment in 
biomedical research, through both public and private funding. 
Recognizing this shortfall, FDA has fashioned what it terms a Critical 
Path Initiative to streamline the drug development and review process.
    FDA has met with numerous stakeholders to explore options for 
developing its Critical Path Initiative, but lack of resources and 
coordination among public and private entities has resulted in 
relatively little progress in the development of biomarkers and other 
tools that will, in the words of the legislation, ``modernize medical 
product development, accelerate innovation, and enhance product 
safety.'' The Reagan-Udall Institute for Applied Biomedical Research 
could fill an important role in bringing together the best of the 
public and private sectors to address this unmet need in a coordinated 
manner. The challenges of developing new drugs, biologics, devices and 
diagnostics may warrant the creation of a new entity utilizing the 
expertise and funding of both public and private entities.
    In light of the proposed scope of this new entity's mission and its 
potential for advancing the science of drug development and life cycle 
management across many disciplines, we question whether it is 
appropriate to lodge the Institute within FDA, as currently provided in 
S. 3807. Rather it would seem preferable that the Institute be placed 
within the Department of Health and Human Services (HHS), reporting 
directly to the HHS Secretary with liaison to FDA, the National 
Institutes of Health and other relevant agencies within HHS and perhaps 
even outside it.
    Among the issues of potential concern for industry would be sources 
of funding for the work of the Institute. The contribution of Federal 
dollars is an important indicator of the Government's commitment to the 
process and may make it more likely that industry will choose to 
participate financially as well. Funding must be consistent and 
sustained for a research-related program of this sort to succeed, and 
the Federal contribution must not come from moneys currently allocated 
to operations at FDA. Even though this initiative may produce savings 
in administrative costs over the very longterm since the drug approval 
process may be shortened and simplified, new funds must be made 
available during the foreseeable future to avoid shortchanging FDA's 
current efforts.
    Other issues that may emerge are those that are typical when there 
are collaborations among private entities or between private and public 
sector players. These include balancing transparency of operations 
against the need for confidentiality. Intellectual property issues may 
also pose obstacles that need to be addressed before the Institute can 
fulfill its mission. Early and frequent consultation with industry on 
these and other issues will be essential to the Institute's success.

                       TITLE III--CLINICAL TRIALS

    Johnson & Johnson's pharmaceutical companies have a well-
established policy for registering our clinical trials and publishing 
our clinical trial results, both positive and negative. Our policy is 
based on our conviction that ``. . . well-informed risk-benefit 
assessments about our products rely upon the availability of product 
information that is accurate, comprehensive, fair-balanced and 
timely.''
    Thus, we now publicly register all confirmatory clinical trials of 
both marketed and investigational drugs regardless of location. For 
studies related to serious and life-threatening diseases, we register 
all that include efficacy endpoints, regardless of trial design or 
location. Registration is made to the National Library of Medicine's 
Website, http://www.clinicaltrials.gov. We believe that both patients 
and healthcare providers can benefit from knowledge of clinical trials 
that are open for enrollment, and our policy is intended to provide 
this information to consumers in a manner that is as clear and easy to 
access as possible. In the period from September 2005 to July 2006, 
more than 24,000 visitors browsed Johnson & Johnson sponsored studies 
on http://www.clinicaltrials.gov. Of these about 250 patients expressed 
interest in participating in one of our studies and were subsequently 
referred to investigators in their geographic region.
    Our policy also addresses disclosure of trial results. For marketed 
medicines, we publish the results of all confirmatory clinical studies 
regardless of outcome. With respect to all other clinical studies of 
marketed medicines, we assess the medical importance of trial results 
and publish those results that are material and relevant to the 
clinical use of the medicine or to the care and safety of patients. 
These trial results appear either in peer-reviewed medical literature 
or in the form of a clin-
ical study report synopsis in the ICH-E3 format. At present, our 
clinical study results are posted as links from the protocols we have 
registered on http://www.clinicaltrials.gov.
    Clearly, there is industry support for organized clinical trial 
registries to inform patients and providers about the opportunities for 
enrollment in relevant clinical trials. Like our colleagues in 
industry, we also recognize the importance of sharing with regulators, 
with medical professionals, and with the general public the results of 
clinical trials, regardless of outcome.
    S. 3807 establishes a comprehensive framework for both trial 
registration and reporting of trial results that should provide a clear 
roadmap for industry with respect to both activities. If properly 
implemented, the trial registry and results database will give industry 
clear guidance regarding which trials are covered, when, where, and 
what information must be posted, and last the consequences for failure 
to comply. Hopefully, the result will be convenient and understandable 
web-based destinations where patients and providers, as well as 
regulators, can readily access timely information about the 
availability of clinical trials and the results of trials, regardless 
of outcome.
    While we are generally supportive of the legislation's clinical 
trial provisions, we are concerned about two matters: the requirement 
for registration and disclosure of results coming from exploratory 
clinical trials because they are not designed or powered to provide 
firm answers to questions regarding the safety and efficacy of 
medicines. These trials are designed to generate hypotheses about 
medicine--not to confirm findings. As such, these results could be 
confusing or misleading to patients and to physicians.
    We are also concerned that the requirement to register trials 
within 14 days of the first patient enrollment may be an unreasonably 
short timeline. We would recommend that the legislation provide for 
registration within 21 days of the first patient enrollment in order to 
be consistent with the terms of Sec. 113 of the Food and Drug 
Administration Modernization Act, with which we and many other 
pharmaceutical companies currently comply.
    S. 3807 is commendable in its specificity, but its provisions are 
not necessarily self-executing, and many questions will undoubtedly 
arise in the course of implementation. For this reason, consultation 
with industry as well as with patients, providers and other interested 
parties, is essential. In that connection, we note that the legislation 
contains several references to rulemaking or promulgation of 
regulations, as well as a requirement for a Guidance document to 
clarify what clinical trials are ``applicable'' for purposes of the 
trial registry. We believe that virtually all aspects of the systems 
for clinical trial registries and for a trial results database would 
benefit from the opportunity for public comment through rulemaking, and 
therefore we recommend prior publication in the Federal Register. While 
rulemaking might delay somewhat the implementation of these important 
policies, the trial registry and trial database are complex 
undertakings, and it is more important to get them right than to get 
them quickly.

                    TITLE IV--CONFLICTS OF INTEREST

    FDA cannot possibly provide, solely from the ranks of its 
employees, the expertise necessary to evaluate the broad array of new 
medical interventions being brought to patients today. Therefore, 
advisory committees and other panels of outside experts are critical 
for the competent review of new drugs, biologics, devices and 
diagnostics. S. 3807 makes important changes to FDA's current practices 
to enhance the integrity of the advisory process through greater 
transparency in initial selection and in management of potential 
conflicts of interest for advisory committee members.
    Public confidence in the FDA review process requires that members 
of advisory committees be as free as possible of financial 
entanglements or other possible conflicts such as positions of prestige 
or long-time investments in scientific positions or ideas. Such 
conflicts could theoretically influence a committee member's judgment. 
On the other hand, it is important that advisory committees include 
individuals with the highest qualifications and undoubted expertise to 
ensure that FDA decisions are guided by the best medical and scientific 
advice. Frequently, it is not feasible to exclude those with one or 
another type of conflict, as the resulting pool of expertise would be 
too small for a meaningful selection process. Thus, it is vital that 
restrictions on participation for reasons of conflicts be balanced and 
moderate, with sufficient flexibility to address the demand for 
expertise from what may be a limited supply of potential advisors.
    It is important that S. 3807 seek an appropriate balance by 
measuring the magnitude of the potential advisor's financial 
involvement or other conflict against the necessity of access to his or 
her expertise. The legislation should also set forth a process, with 
applicable timelines, for identifying and assessing a range of 
potential conflicts, determining the appropriate remedy and 
communicating the agency's determination of approval for service, 
waiver, limited waiver or recusal. Greater transparency of the FDA 
decisionmaking process will enhance public confidence and reassure all 
stakeholders.
    Unavailability of sufficient numbers of qualified experts to serve 
on advisory committees, however, could pose a serious obstacle to the 
efficiency as well as the competency of product review at FDA. It is 
therefore critical that conflict of interest provisions be applied in a 
fair and balanced manner so as not to unduly limit participation. While 
it is important that FDA have the tools to improve the current system 
for managing potential conflicts, attention must also be given to 
recruiting more qualified potential members of advisory committees. We 
support creation of a mechanism for nominating qualified academics and 
practitioners for potential advisory committee service and the 
publication of Guidance in the Federal Register establishing this 
mechanism. The need for sufficient numbers of qualified experts for 
service on FDA committees is an issue of concern for FDA, industry 
sponsors, patients and providers.

                   ANALYSIS OF IOM DRUG SAFETY REPORT

    While we agree with many aspects of the IOM report, we disagree 
with the recommendation to incorporate specific safety-related 
performance goals in the standards for the 2007 version of the 
Prescription Drug User Fee Act (PDUFA). We accept that user fees may be 
applied to safety-related activities at FDA, but we question whether it 
would be appropriate to create new and untested safety-related 
performance goals as a measure of agency compliance with its user fee 
obligations.
    As we discuss below, we are concerned that imbalances in financing 
of FDA activities, with increasing reliance on sponsor user fees as the 
core of agency funding accompanied by additional mandates for agency 
activities, are already a serious problem, which would only be 
exacerbated by this IOM proposal. Related to this, it is important to 
note that safety issues may also emerge in older products that are no 
longer marketed by research pharmaceutical companies. Additionally, we 
feel that the committee needs to consider what specific funding 
mechanism will be implemented for safety activities associated with the 
products of generic manufacturers.

                               CONCLUSION

    S. 3807 reflects a desire that we all share, to enhance drug safety 
and access to new therapies, and Johnson & Johnson greatly appreciates 
the opportunity you have provided to discuss these issues with you 
today. An important consideration for the committee is the potential 
undermining of its efforts to strengthen FDA by increased reliance on 
user fees to fund FDA activities. User fees currently account for more 
than 50 percent of the agency's operating budget. At the same time, 
Congress and the Administration continue to burden FDA with additional 
unfunded responsibilities. We do not believe that FDA dependence on 
user fees creates institutional conflicts of interest. FDA's integrity 
is intact despite its receipt of user fees. Nevertheless, there is a 
perception, fostered by critics of FDA and of industry, that the agency 
is overly reliant on user fees in a way that compromises the integrity 
of its decisionmaking processes.
    To address this inaccurate perception, Congress must increase FDA's 
appropriated funding, to restore balance to the agency's financing and 
to ensure public confidence in its independence. Although we appreciate 
that this committee is not responsible for appropriations for FDA, your 
status as the authorizing committee for FDA allows you to exercise 
considerable influence on your colleagues in the Senate.
    On behalf of my colleagues at Johnson & Johnson, we look forward to 
working with you and your congressional colleagues to address this 
funding issue and to collaborate throughout the 110th Congress to 
refine the terms of this very important legislation on drug safety and 
innovation.
    Thank you once again for the opportunity to speak with you today.

    The Chairman. Thank you.
    Mr. Guest.
    Mr. Guest. Mr. Chairman and members of the committee, I am 
Jim Guest, the President of Consumers Union, publisher of 
Consumer Reports, and I appreciate the opportunity to testify. 
For 70 years Consumers Union has provided consumers with 
independent unbiased information on vital public health issues. 
In the wake of the Vioxx and Paxil disasters, for example, 
where tens of thousands of Americans needlessly suffered, we 
have educated our more than 7 million subscribers, our more 
than 20 million readers, our many thousands, hundreds of 
thousands of citizen activists, on the need for stronger drug 
safety laws, and there is strong, compelling support for 
improvements in the FDA.
    We applaud you, Mr. Chairman and Senator Kennedy, on S. 
3807, which is a good first step towards meeting this need. It 
would bring greater balance to the process, save lives, help 
restore public trust in our Nation's drug safety system. 
Further, it does not impede another shared goal, which is rapid 
approval of safe, effective medications, particularly life-
saving drugs.
    In the interest of protecting consumer safety, we further 
urge that you strengthen the bill in several key areas. We 
endorse the bill's clinical trials registry requirements for 
phase two through phase four trials and indeed we support and 
recommend even stronger provisions in S. 470. Publication of 
trials--however, should be within 1 year, not 2--would be our 
recommendation, and we urge that you require speedy publication 
of any other studies that indicate safety concerns. Too many 
Americans have died because pharmaceutical companies have 
suppressed clinical trials and other studies with crucial 
safety information.
    We urge modifying the bill's GAO study requirements. It 
should be a given that all phase two trial results be public. 
That doesn't need a study. Rather, we urge a requirement that 
the GAO consider what useful phase one trial data might also be 
important to be made public, and we hope the registries, as you 
heard earlier, will be gradually expanded to include trials 
completed before the date of enactment.
    The bill makes clear that once a drug is approved emphasis 
on safety does not end. We support the REMS provisions and urge 
that they be strengthened further, recognizing that the average 
drug adverse event does not show up until nearly 7 years after 
approval. To ensure that these risks are identified once a drug 
has been used by millions of people over time, we suggest the 
bill should approve--should provide for review on a 5-year 
basis and perhaps again on a 10- or 15-year basis as well.
    In addition, advertising new drugs should be subject to 
limits for 3 years, not 2 as is in the bill. The FDA should 
require safety studies of those drugs most widely used off-
label and civil monetary penalties should be strengthened, 
especially for repeat offenders.
    Another area of great concern are the various reports about 
the severe morale and cultural problems at the FDA. These can 
be difficult to address, but we believe that legislation indeed 
can help set a higher ethical standard by requiring that all or 
at a minimum 90 percent of advisory committee members be free 
of conflict of interest.
    Establish a climate of open and honest scientific debate 
and discussion at the FDA by institutionalizing a system of 
transparency, with staff dissenting or additional views on all 
new drug applications being public, along with whistleblower 
protections such as are contained in H.R. 5922.
    Ensure more resources to the agency so it can do its job. 
One option would be to free the FDA from the detailed 
restrictions on how user fees are spent. Another option would 
be to increase user fees to deal with the huge backlog of 
safety issues. The appropriations process you have heard is 
ideal, but it's important one way or another that the FDA be 
sufficiently funded.
    S. 3807 allows user fees to be used for post-market safety 
approval. We suggest it also set standards for the performance 
and safety of the computer modernization goals.
    Finally, Consumers Union hopes that S. 3807 will be 
expanded to include reforming the laws on generic and 
biogeneric drugs and provide resources for the timely approval 
of safe, low-cost generics. Far too many families have suffered 
because the drug safety system is broken. Many victims and 
survivors are working tirelessly for reform so others won't 
have to endure their heartbreak.
    I just want to note that two such extraordinary people are 
in the room today, Mr. Chairman, for this occasion: Eric Swann, 
whose brother-in-law Woody Witzak was casually prescribed an 
anti-
depressant for insomnia and 5 weeks later killed himself; and 
Matthew Downing, whose daughter Candace was put on Zoloft 
because she was anxious taking tests at school and 10 months 
later she took her own life at the age of 21. Neither Eric nor 
Matthew knew about clinical trial results because they had been 
suppressed, that indicated increased risk of suicide for these 
types of anti-depressants.
    For their sake, Mr. Chairman and members of the committee, 
and for others, thank you for the important work you're doing 
and thank you for your consideration of our recommendations. 
Again, we appreciate the chance to testify.
    [The prepared statement of Mr. Guest follows:]

                    Prepared Statement of Jim Guest

    Mr. Chairman and members of the committee, thank you for inviting 
Consumers Union, the nonprofit publisher of Consumer Reports, to 
testify. I request that our full statement appear in the Record.
    For 70 years Consumers Union has provided consumers with 
independent, unbiased information on vital public health issues. In the 
wake of the Vioxx and Paxil disasters, for example, where tens of 
thousands of Americans needlessly suffered, we've educated our more 
than 7 million subscribers, our more than 20 million readers, many 
hundreds of thousands of our citizen activists, on the need for 
stronger State and Federal drug safety laws. They seek action.
    We applaud you, Mr. Chairman and Senator Kennedy, on S. 3807, a 
good first step toward meeting this need. It would bring greater 
balance to the process, save countless lives, and help restore public 
trust in our Nation's drug safety system. Further, it does not impede 
another shared goal--rapid approval of safe, effective medications, 
particularly life-saving drugs.
    We believe the committee would miss a great opportunity for 
protecting consumer safety, however, if you don't strengthen the bill 
in several key areas:

     assuring quicker publication of the results of more 
clinical drug trials;
     enhancing the FDA's power to protect public health;
     restoring the science-based culture and morale of the FDA;
     garnering more resources, especially for postapproval 
safety and information technology; and
     reforming the generic and biogeneric laws to bring lower-
cost medicines to patients.

    We will elaborate on each of these issues below, noting how the 
proposed bill addresses them, what the Institute of Medicine (IOM) and 
other research groups have concluded, and where Consumers Union 
recommends strengthening the bill.

                    1. DISCLOSURE OF CLINICAL TRIALS

Background
    There are several major issues in the clinical trial area: the 
registration and disclosure of trials and studies, and the scientific 
integrity and reasonable patient safety of those trials.
    Registration and Disclosure: The registration and public disclosure 
of clinical trials and other studies is key to determining the safety 
of drugs. Transparency of study results is necessary to understand the 
true safety and efficacy of drugs, to identify further research efforts 
and to ensure appropriate safety warnings. Too often, pharmaceutical 
companies distort, manipulate and conceal results from clinical studies 
in order to guarantee the approval of their drug. Today, there is an 
enormous bias toward reporting favorable results and the hiding or 
minimizing of lackluster and negative results. As one analyst has 
written:

          ``Another problem with the existing system is that 
        nonpublication of negative trials and nonreporting of negative 
        outcomes, coupled with redundant publication of positive 
        findings, has led to systematic publication bias, which can 
        undermine the reliability of medical evidence.'' \1\

    Two such examples are Vioxx and Paxil. Vioxx was removed from the 
market in 2004 after clinical trials revealed an increased risk of 
heart attack and stroke for those taking the drug.\2\ According to 
testimony from Dr. Sandra Kweder, deputy director of the FDA's Office 
of New Drugs (OND), these trial results were not made available to the 
FDA prior to Merck's voluntary withdrawal of the drug.\3\ Similarly, 
GlaxoSmithKline, maker of Paxil, concealed results from clinical trials 
linking the drug to an increased risk in suicidality among adolescents, 
as proven by New York Attorney General Eliot Spitzer's successful 
complaint against GlaxoSmithKline.\4\ These trials also revealed that 
the drug was actually less effective than placebos among 
adolescents.\5\
    These abuses have not ceased. As recently as September 29, 2006, 
the FDA released a Public Health Advisory that Bayer, maker of 
Trasylol, failed to inform the FDA Advisory Committee (which had 
convened 8 days earlier on September 21, 2006 to discuss Trasylol) of a 
new study that revealed an increased risk of death, serious kidney 
damage, congestive heart failure and stroke.\6\ The FDA began 
conducting a review of Trasylol in January, 2006, after two published 
research articles reported serious risks associated with use of the 
drug.\7\ \8\ Such research misconduct has contributed to injuries and 
deaths by consumers who use these potentially dangerous drugs, and USA 
Today reports that the pharmaceutical industry faced more product 
liability lawsuits than any other industry last year.\9\
    Abuses in the registration and reporting of clinical trial and 
study results highlight the need for increased transparency. Such 
transparency would enable the scientific community to better assess the 
true safety and efficacy of drugs. The World Health Organization (WHO) 
has taken steps to standardize trial registration and reporting through 
the International Clinical Trial Registry Platform (ICTRP), identifying 
a 20-item minimal dataset for all clinical trials, which includes 
target sample size and primary and secondary outcomes.\10\ Many medical 
journals have formally supported these steps taken by the WHO and will 
now consider the publication of the results of a clinical trial only if 
it has been registered before the enrollment of the first patient.\11\ 
The Journal of the American Medical Association is responding even more 
aggressively to ensure accuracy in data analysis by requiring all 
submissions of clinical trial results funded by industry to hire an 
independent statistician to analyze the data.\12\ A coalition of over 
100 healthcare stakeholders have signed the Ottawa Statement, making a 
moral case for full disclosure:

          ``When members of the public agree to participate in trials, 
        it is on the understanding that they are contributing to the 
        global body of health-related knowledge. It is thus unethical 
        to conduct human research without ensuring that valid 
        descriptions of the study and its findings are publicly 
        available.'' \13\

    Lack of oversight and reasonable patient safety in clinical trials: 
The need for registration of clinical trials (at all phases) became 
even clearer after this spring's Phase 1 TGN1412 trial in which 6 
healthy UK volunteers suffered catastrophic multiorgan failure after 
taking the drug. Many argue that these events could have been avoided 
had trial information been available for public review.\14\ Although 
pharmaceutical companies argue that disclosing such sensitive 
information would allow competitors to conduct similar trials of their 
own, the WHO and many others in the field find that these concerns are 
not sufficient to delay disclosure.\15\ Given the extraordinarily 
aggressive patenting of all aspects of a new drug, we do not believe 
that these public registrations will cause proprietary commercial 
losses. Disclosure of the TGN1412 trial would have allowed experts to 
determine if the trial was generally appropriate and if the procedures 
that were followed were sound.\16\
    The research community must take more responsibility in protecting 
human volunteers, yet recent reports indicate that the FDA is about to 
loosen regulations in this area. Senator Charles Grassley, in a letter 
to the HHS Office of Inspector General (OIG), asserts that clinical 
trial subjects are not always adequately warned of potential risks, and 
are sometimes endangered and harmed as a direct result of participating 
in such trials.\17\ Bloomberg News investigative reporting has found 
that safety oversight of clinical trials is often left in the hand of 
pharmaceutical companies and their contractors and that the quality of 
these experiments is often suspect and certainly dangerous to the 
participants.\18\ The consequences are clear: the Center for Drug 
Evaluation and Research (CDER) recommended official action against 6 
percent of the 319 clinical investigators it inspected in 2006 for 
noncompliance of regulations.\19\ CDER requested voluntary corrections 
for an additional 42 percent of clinical investigators whose deviations 
from the regulations were considered to be ``minor.'' Senator Grassley 
asserts that a fundamental concern regarding the participation of human 
subjects is the ``lack of protections and respect for research 
participants who place their health and their lives in the hands of 
clinical investigators and the entities that are expected to monitor 
and oversee the studies.'' \20\
    In addition to the lack of safety for individuals enrolled in some 
trials, there is the safety problem created by fraud in the 
falsification of data used to justify a drug's approval. In the recent 
case of Ketek, the FDA found multiple instances of fraud in the 
company's clinical trial of about 24,000 patients, some cases of which 
the maker Sanofi already knew about yet failed to notify the 
agency.\21\
    In light of the various abuses that may potentially occur while 
conducting clinical trials, the FDA must do more to ensure scientific 
integrity and patient safety in clinical trials. We comment on this 
problem further in the ``Additional FDA Resources Needed'' section.
Discussion of Solutions in S. 3807 and Further Recommendations
    S. 3807 addresses the issues regarding transparency in research by 
establishing (1) a Clinical Trial Registry Database and (2) a Clinical 
Trial Results Database, both of which would be made public. These 
databases conform to the WHO ICTRP described in the previous section. 
If they are seeking journal publication, sponsors may take up to 2 
years after they determine the trial is ended to report Phase 3 and 
Phase 4 trials to the public.
    Consumers Union strongly supports the establishment of the Clinical 
Trial Registry Database and the Clinical Trial Results Database, but 
recommends that sponsors be required to report results, including the 
results of Phase 2 trials, within one (1) year, and that results from 
trials of drugs revealing safety concerns be reported publicly as soon 
as trials are completed. This recommendation follows that of the 
Institute of Medicine (IOM), which requests that trials be registered 
``in a timely manner.'' \22\ Given the history of manipulation and 
concealment of results by pharmaceutical companies, a stricter deadline 
than 2 years for reporting results seems appropriate.
    While the proposed legislation requires the registration of the 
results of Phase 3 and 4 trials, it does not require the registration 
of the results of Phase 2 trials unless the Government Accountability 
Office (GAO) specifically recommends registration, which would then be 
implemented through a further rulemaking process. The Institute of 
Medicine report recommends that, at a minimum, all Phase 2-4 trials be 
registered, including a posting of a ``structured field summary of the 
efficacy and safety results of the studies.\23\ Furthermore, trial 
registration will do nothing to diminish publication bias and 
misreporting if only trials that have been completed and reveal 
favorable results are reported and published.\24\ In order to really 
address the problem of selective reporting--which is clearly an issue 
given recent history--all clinical trials should be registered.
    In addition, some argue that even Phase 1 trials can gather data on 
efficacy in addition to safety, and therefore should also be subject to 
registration.\25\ The data found in a Phase 1 trial can contribute to 
meta-analyses of adverse events and is used by successful safety 
projects such as RADAR.\26\ Finally, there is a strong moral argument 
for such registration: fellow human beings have volunteered to serve 
basically as guinea pigs to test the basics of a new drug idea. If 
there is any adverse side effect from such tests, it seems immoral not 
to report such results and not to warn other companies who may stumble 
down the same research pathway. There may be little merit in the 
concern that a company will lose ``proprietary'' data. A company's 
proprietary and commercial interests are undoubtedly protected by the 
aggressive patenting that occurs in the drug industry. The safety of 
human test subjects should come first.
    Consumers Union supports the public disclosure of as much 
scientific data as possible. S. 3807 should be amended to change the 
GAO study of whether Phase 2 trial results should be disclosed. We 
believe that Phase 2 disclosure should be a given. Instead, the GAO 
study should concentrate on whether all or some of Phase 1 trials 
should be disclosed at the point when a final decision is made on the 
drug subject to the trial (i.e., it is approved, or withdrawn).
    Consumers Union also urges that the legislation extend the registry 
to gradually include all studies completed since at least 1996, and 
hopefully earlier. For example, each year over the next 5 years, 2 
years of pre-enactment of S. 3807 trial results could be publicly 
posted. It would be a great service to the world's scientific community 
to have in one place an expanded, Internet available library of these 
past trials.
    In order to address the potential of trial abuses and 
falsifications, the proposed bill calls for the FDA to ``sample'' 
clinical trials to ensure that the descriptions of results are 
``nonpromotional, and are not false or misleading in any particular . . 
. '' In light of past abuses, Consumers Union recommends that 
pharmaceutical companies that neglect to provide relevant results or 
falsify results should be subject to FDA Civil Monetary Penalties 
(CMPs). In the ``Additional FDA Resources Needed'' section, we urge 
that a higher percentage of trial and study papers be audited for 
scientific integrity and honesty.
    Finally, S. 3807 pre-empts State laws that require clinical trial 
registration. Because of lack of action at the Federal level, Consumers 
Union has been a driving force behind these State debates and laws. We 
accept the idea of pre-emption, but only if there is a strong Federal 
law. If the type of changes we recommend above are not included, we 
oppose State pre-emption. The States should be able to do more to 
protect the safety of their citizens.

                     2. FDA POWER TO ENSURE SAFETY

    The IOM report highlights the fact that PDUFA has done a great deal 
to ensure speed in the drug approval process--perhaps at the neglect of 
safety. The report notes that although the PDUFA laws have established 
performance goals relating to review speed, there are no performance 
goals relating to safety.\27\ Thus the FDA assigns priority to specific 
drug approval performance goals, and in turn (as the recent history of 
withdrawals suggests), lacks resources to act aggressively on safety 
issues which have no such performance goals.
    S. 3807 provides exciting new powers, resources, and enforcement 
tools for the FDA to improve post-market approval safety. But in light 
of recent history, we urge even stronger actions. The following five 
(5) subsections offer recommendations on how to give the FDA clearer 
additional authority to ensure safety without in any way slowing the 
approval of life-saving medicines:

    A. Effective use of adverse event reports
    B. Postapproval management
    C. Direct-To-Consumer (DTC) advertising
    D. Off-label use
    E. Enforcement

               A. Effective use of Adverse Event Reports

Background
    An estimated 700,000 people required emergency department attention 
due to Adverse Drug Reactions (ADRs) in 2004 and 2005.\28\ ADRs are 
responsible for as many as 100,000 deaths annually.\29\ Although these 
numbers indicate that ADRs are an enormous problem, no effective 
mechanisms for reporting and analyzing potentially serious ADRs exist 
today.\30\ Spontaneous reporting systems such as MEDWATCH, while 
sometimes useful, are incapable of reliably or quickly detecting many 
long-range ADRs.\31\
Discussion of Solutions in S. 3807 and Further Recommendations
    S. 3807 establishes a key principle: that drug safety issues do not 
stop with the approval of the drug. Instead a drug must be looked at 
over its ``life cycle''--drugs need to be monitored and studied over 
many years. The bill establishes a system of Risk Evaluation and 
Mitigation Strategies (REMS). In addition, in title II it creates the 
Reagan-Udall Institute, in consultation with the National Institutes of 
Health (NIH) and other research programs, to explore ways to improve 
adverse event reporting and analysis and improve the science of drug 
development and safety.
    The IOM report specifically calls for an improved Adverse Event 
Reporting System (AERS), and asks that the Center for Drug Evaluation 
and Research (CDER) conduct a scientific review of AERS to identify and 
implement improvements, and, ``systematically implement statistical-
surveillance methods on a regular and routine basis for the automated 
generation of new safety signals.'' \32\ While spontaneous reporting 
methods, such as MEDWATCH, may contribute to AERS, these methods are 
not the only tool to track and evaluate ADRs. Consumers Union 
recommends the incorporation of a temporary demo whereby the FDA 
devotes resources (including user fees) to support NIH funding of a 
program like the Research on Adverse Drug Events and Reports (RADAR) 
project in which medical scientists proactively search ADRs for 
patterns.\33\ The RADAR project is funded entirely by peer-reviewed 
grants from the NIH, the Veterans Administration (VA), and the American 
Cancer Society (ACS). Summary safety information from the project is 
synthesized into reports for medical journals, revised package inserts, 
and ``Dear Doctor'' letters. The information is presented to 
physicians, the FDA and relevant sponsors. The RADAR project may 
provide important answers as to how more ADRs can be reported and 
evaluated in a meaningful way.
    Today, it is estimated that only 1 to 10 percent of all adverse 
events are reported. But with the coming age of health information 
technology and personal health records (PHRs) where patients can be 
electronically warned of dangers and asked to report reactions to new 
drugs, we will soon have access to a huge amount of new data. The FDA 
is to be commended for contracting with a number of large patient 
encounter databases. The use of these large databases can eventually 
permit the FDA to detect patterns of ADRs that are invisible when only 
smaller populations are examined. But it is not yet clear when and how 
they will be able to use the extraordinarily rich data that will be 
available from Medicare Parts A, B and D. We urge the committee to lay 
the groundwork in S. 3807 for FDA to use the Medicare databases and PHR 
systems to establish a truly effective AERS that will be able to detect 
many more kinds of drug interactions. Further, such a system will help 
us compare drug effectiveness to determine which medicines and courses 
of treatment are most effective in fighting life's diseases. Of course, 
using large databases to aggressively search out adverse drug events 
will take significant new resources (which we discuss below).

                       B. Postapproval Management

Background
    As noted in the previous subsection, ADRs pose serious safety 
concerns. According to a study by the General Accounting Office (GAO), 
over 50 percent of all approved drugs had serious postapproval 
risks.\34\ These ADRs are often detected years after the drug has been 
on the market. One study indicates that only 50 percent of ADRs are 
discovered within 7 years after approval.\35\ This delay in detecting 
drugs with serious risks is apparent in the withdrawal process as well; 
one report documents the median time on the market, before a drug is 
withdrawn, to be 5.4 years.\36\
    These figures highlight the importance of postmarketing 
surveillance, but in the current system the FDA focuses almost 
exclusively on pre-approval indicators. This strategy has proven to be 
inadequate and dangerous. Although pre-approval trials may assess 
efficacy, they cannot assess safety due to the fact that they are 
conducted in small, selected populations (often disproportionately 
males who are younger and healthier than the population which will 
actually use the drug) for very limited periods of time. In general, 
Phase 1 trials are conducted on several dozen healthy humans to 
determine safe dosages and generally evaluate safety. Phase 2 trials 
are conducted on a slightly larger population--perhaps several hundred 
people--to test effectiveness and further evaluate safety. Phase 3 
trials are conducted on large populations of several thousand to 
confirm effectiveness, monitor side effects, and gather additional 
information that will allow the drug to be used safely. An abbreviated 
trial may be conducted for as little as 6 months. Finally, Phase 4 
trials are conducted after a drug has been marketed to evaluate long-
term safety. FDA regulations allow for the approval of a drug with 
evidence from a single clinical trial.\37\ Clearly, clinical trials are 
simply incapable of portraying an accurate picture of how a drug will 
behave in the general population or the older patient population over 
many years. Thus, the need for reviewing drugs once they are on the 
market is essential.\38\ \39\
    Although the FDA has the authority to recommend Phase 4 
postapproval studies, sponsors of drugs often fail to complete such 
studies. For example, Sanofi-Aventis failed to complete a postapproval 
study on the arthritis drug, Arava, after the FDA questioned its long-
term safety at the time of its approval in 1998.\40\ Arava has been on 
the market for 8 years and fatal liver complications have been reported 
in those using the drug.\41\ Bloomberg News reports that 860 
postapproval studies requested by the FDA have yet to be completed, 260 
of which are on drugs that were approved at least 5 years ago.\42\ It 
appears that many of these trials have not even been started and the 
commitments given to the FDA are often ignored.
    Not only is there a problem with getting companies to fulfill their 
post-market study commitments, but lack of FDA resources has led to 
poor enforcement of this program. In June 2006 the HHS Inspector 
General reported that:

          FDA cannot readily identify whether or how timely post-
        marketing study commitments are progressing toward completion. 
        About one-third of ASRs [Annual Status Reports on these 
        studies] were missing or incomplete, . . . ASRs contain 
        information of limited utility . . . FDA lacks an effective 
        management information system for monitoring post-marketing 
        study commitments. . . . Monitoring post-marketing study 
        commitments is not a top priority at FDA. . . . Our analysis 
        showed that FDA validated only 30 percent of ASRs submitted in 
        fiscal year 2004. . . . 

    The OIG called on FDA to instruct companies to provide 
``additional, meaningful information in their ASRs, improve the 
management information system for monitoring post-marketing study 
commitments so that it provides timely, accurate, and useful 
information, and ensure that post-marketing study commitments are being 
monitored and that ASRs are being validated.'' \43\
Discussion of Solutions in S. 3807 and Further Recommendations
    This year's GAO report on the FDA comments on the agency's 
inability to ensure the completion of postapproval studies, asserting 
that ``FDA needs greater authority to require such studies.'' \44\ The 
report goes on to further document cases where the FDA has been unable 
to negotiate with sponsors to ensure that postapproval studies are 
conducted. Since sponsors voluntarily agree to conduct such studies, 
the FDA has no authority to ensure their completion.
    As part of REMS, S. 3807 gives the FDA authority to require safety 
trials and tools to enforce the requirement. Consumers Union strongly 
supports this provision: it is one of the most important in the bill.
    In addition, required REMS call for 3 years of review, and 
additional review may be required ``at a frequency determined by the 
Secretary for subsequent years.'' The IOM repeatedly highlights the 
need to perform postmarketing surveillance throughout the entire life 
cycle of a drug. In particular, the IOM recommends that the evaluation 
of a new drug's total safety profile occur after 5 years. Consumers 
Union strongly supports the IOM's recommendation and asks that the 
review time cycle for a drug be increased from S. 3807's 3 years to 5 
years. This review should be institutionalized, and not left to the 
total discretion of the Commissioner. Given the history of ADRs and 
drug withdrawals that occur many years after a drug is first on the 
market, this kind of extended postmarketing surveillance is necessary. 
Because of the history of problems detected many years and even decades 
after a drug's approval, we also support the institutionalization of 
another focused review of the literature, ADERs, etc., at some later 
interval, perhaps at the 10th or 15th year a drug has been on the 
market.
    With respect to industry conducted post-approval safety studies, 
HHS OIG recommended that the FDA instruct sponsors to provide 
``additional, meaningful information'' in their annual status reports 
in order to determine how timely post-marketing study commitments are 
progressing toward completion.\45\ According to the OIG, the FDA 
disagreed with this recommendation, stating that the implementation of 
such a recommendation would require additional regulations. The OIG 
concludes that the FDA cannot identify the progress of post-marketing 
study commitments, and that regulatory changes may need to be enacted 
in order to address these issues. Consumers Union supports the OIG's 
recommendation that sponsors include progress reports on post-approval 
safety issues in their annual status reports. S. 3807's annual REMS 
review process is a major step in this direction.

                C. Direct-To-Consumer (DTC) Advertising

Background
    Although full safety risks are often unknown for years after 
approval, pharmaceutical companies invest a great deal of money in the 
immediate promotion of approved drugs, including billions of dollars in 
Direct-To-Consumer (DTC) advertising. We have seen, too many times, the 
devastating effects of such DTC advertising. At least one study has 
commented on how DTC advertising contributed to the overuse and misuse 
of Vioxx by both consumers and physicians, which led to an unnecessary 
increase in the number of people at risk of heart attack and 
stroke.\46\ In addition to the safety concerns, DTC advertising of 
Vioxx increased costs to consumers and health plans alike, which were 
paying significantly more for a new drug that added little or no 
benefit.\47\
    Some defend the use of DTC advertising, asserting that it promotes 
patient-physician dialogue and increases awareness of diseases and 
treatments. One study shows, however, that these ads are rarely 
educational; while many advertisements gave the name of the drug and 
the condition being treated, very few provide any additional health 
information on alternative treatment of the condition.\48\ The study 
reports that out of a possible 11 educational codes (specific 
educational points), the average number of codes present in 
advertisements was 3.2. Despite the lack of truly educational 
information in DTC advertising, consumers tend to believe the 
pharmaceutical industry's message that only the safest and most 
effective drugs appear in advertisements.\49\ This is particularly 
dangerous given the fact that the goal of this advertising is to sell a 
costly product that can potentially have serious safety risks. 
Consumers Union believes that if we need to increase awareness or 
dialogue about certain medical problems, the industry could contribute 
to scientifically-based Public Service Announcements approved or 
managed by an impartial, expert group, such as the FDA, CDC, or 
NIH.\50\
Discussion of Solutions in S. 3807 and Further Recommendations
    As a part of REMS, the proposed bill gives the FDA authority to 
require the pre-clearance of advertisement to ensure disclosure of a 
serious risk listed in the labeling of the drug. In light of the 
promotional nature of DTC advertising and the long history of abuses in 
DTC advertising, and given that such advertising strongly influences 
consumers, Consumers Union recommends a requirement that ALL 
advertisements be pre-cleared by the FDA for accuracy and honesty, 
including the growing use of ads in the Internet and other 
nontraditional sites.
    In addition, the FDA may impose a 2-year moratorium on DTC 
advertising for drugs showing more serious safety concerns. Given the 
amount of influence this type of advertising has on consumers, and 
given the potential serious ADRs that may occur years after approval, 
Consumers Union recommends a moratorium on DTC advertising of 3 or more 
years for all new drugs. The history of ADRs and withdrawals shows that 
drugs cannot be assumed safe after just 2 years. Adding a possible 
third year to the moratorium authorities in S. 3807 would be prudent 
and constitutional.\51\

                            D. Off-Label Use

Background
    The FDA currently approves drugs for specific indications based on 
scientific evidence and clinical trials. Off-label uses of these drugs 
(in which physicians prescribe medicines for indications other than the 
ones for which a drug is approved) lack the same kind of scientific 
scrutiny. In an analysis of 160 commonly prescribed drugs from 2001, 
off-label uses accounted for 21 percent of overall use, and most uses 
had little or no scientific support for such use.\52\ In some classes 
of drugs, off-label use accounts for up to 75 percent of 
prescriptions.\53\
    Often, drug companies inappropriately and illegally influence 
doctors to prescribe medications for off-label uses. In the case of 
gabapentin, pharmaceutical company Parke-Davis used teleconferences, 
consultant meetings, selective research, as well as other tactics to 
encourage doctors to use the drug for off-label uses.\54\
    Despite the high occurrence of off-label uses, the scientific 
efficacy of such drugs for unapproved indications is not 
established.\55\ \56\ Many off-label uses are often helpful and 
probably have little adverse consequences, but since off-label uses are 
not subject to FDA approval, it is difficult to determine what 
scientific evidence exists to prove clinical effectiveness. Off-label 
use of prescription drugs also generally raises concerns regarding 
potential risks to patients as well as issues about the reimbursement 
and coverage of these drugs.\57\ Adverse drug events may also occur 
more commonly in off-label settings than in on-label settings, since 
clinical trial information is often unavailable.\58\ The Wall Street 
Journal recently reported on the off-label use of Actiq, a potent 
narcotic that is indicated for use in cancer patients who experience 
intense pain.\59\ According to the article, Actiq is 80 times as potent 
as morphine and is in a group of drugs that has the highest risk of 
fatal overdose. In fact, 47 deaths due to overdose were associated with 
the use of Actiq. Despite the safety risks, data suggest that 80 
percent of patients use the drug not for cancer pain, but for off-label 
uses such as headache and back pain.
Discussion of Solutions in S. 3807 and Further Recommendations
    S. 3807 is silent on the issue of off-label use. Given the 
potential for off-label uses to create serious safety problems, 
Consumers Union recommends that the FDA develop a program to 
scientifically study drugs widely used in off-label settings. We are 
not advocating a ban on such use. We are simply asking that some 
scientific study be brought to this area, so that the labels on these 
drugs may be expanded and improved in the cases where the scientific 
evidence is supportive.

                             E. Enforcement

Background
    As described above, the FDA has limited authority to effectively 
enforce postapproval safety. As this year's GAO report highlights, the 
``FDA has little leverage to ensure that these [commitments for post-
approval safety studies are carried out . . . by imposing 
administrative penalties.'' \60\ The IOM also reports that lack of 
clear regulatory authority is a serious problem at the FDA.
    In addition to the lack of clear authority in some areas, there is 
the issue of failing to use existing authorities. Rep. Henry Waxman has 
reported that the level of enforcement actions has been declining and 
the recommendations of FDA field staff for corrective actions are often 
disregarded:

          ``Internal agency documents show that in at least 138 cases 
        over the last 5 years involving drugs and biological products, 
        FDA failed to take enforcement actions despite receiving 
        recommendations from agency field inspectors describing 
        violations of FDA requirements.''

    The House Government Reform Committee report noted a 50-percent 
decline in warning letters in recent years.\61\
Discussion of Solutions in S. 3807 and Further Recommendations
    In addition to existing authorities (some of which like drug 
withdrawals or seizures are so serious and disruptive they are not 
creditable and almost never used), the bill allows the FDA to issue 
Civil Monetary Penalties (CMPs) of between $15,000 to $250,000. CMPs 
may not add up to more than $1,000,000 for all violations ``in a single 
proceeding.'' While this CMP authority is a major improvement, given 
the large profits that pharmaceutical companies can enjoy every day a 
drug is on the market, Consumers Union recommends that CMP authority be 
increased to more than $1,000,000, especially when companies are 
repeated offenders.
    S. 3807 also gives the FDA more authority to order changes in drug 
labels and to control the dispensing of drugs so to ensure that 
particularly vulnerable populations (such as pregnant women) are better 
protected from unnecessarily dangerous forms of treatment. Consumers 
Union strongly endorses these labeling and dispensing provisions in S. 
3807. As the Office of New Drugs Director Dr. John Jenkins said,

          ``There's no doubt that there are situations where we 
        internally feel frustrated that the discussions about label 
        changes are taking longer than we would like. Remember that 
        labeling is the primary way we have to communicate to 
        practitioners and health providers about the safety and 
        effectiveness of the drug. So everything keys off the 
        labeling.'' \62\

    The language in S. 3807 should prevent a recurrence of the 22 
months of FDA-Merck ``negotiating'' on the Vioxx label while millions 
of patients continued to take an unnecessarily dangerous drug.

                        3. RESOURCES AT THE FDA

Background
    The FDA needs more resources if it is to truly be the world's Gold 
Standard in prescription drug approval and safety.
    We agree with the IOM report that the FDA suffers from serious 
resource limitations. The IOM notes that although user fees have 
greatly increased the resources for new drug review, FDA's other 
functions--such as post-approval drug safety monitoring--are seriously 
under funded. As the IOM notes, PDUFA not only sets performance goals, 
but also tightly restricts CDER's use of its funds: ``each round of 
PDUFA negotiations has led to more demands on CDER and continued 
restrictions on CDER's flexibility.'' \63\
    The lack of resources for safety is appalling. The public would be 
truly shocked if they realized how huge the FDA's jurisdiction is and 
how little the agency can really manage to do with its limited budget. 
Unfortunately, the public is periodically reminded of those limitations 
by outbursts of fatalities--such as the recent E. coli spinach deaths.
    According to the 2006 GAO report on post-market drug safety, the 
FDA has currently allocated $1.1 million per year for its contracts 
with researchers outside of FDA to conduct postapproval studies. Yet 
the GAO also reports that just one clinical trial designed to study 
long-term drug safety could cost between $3 million and $7 million.\64\ 
The IOM report also highlights the need for increased resources to 
support new staff devoted to post-market safety work. PDUFA funding has 
supported the surge of new drug review staff, whereas ODS has not 
experienced such a dramatic increase in staff: between 1996 and 2004, 
new drug review staff increased by 125 percent (from 600 to 1320) but 
ODS staff increased by only 75 percent (from 52 to 90).\65\ While the 
drug companies flood the airwaves and Internet with ads, the FDA is 
only able to review about 24 percent of these for accuracy.\66\ And 
while generic drugs can save consumers billions of dollars, this fall 
there is a backlog of 394 generic drugs awaiting approval because of 
FDA bottlenecks.\67\
    The IOM highlights the need for resources to support Information 
Technology (IT) at the FDA, and concluded that CDER's IT systems are 
antiquated. Consumers Union staff has been told that half the FDA's 
computer systems are so old that they will no longer be served by 
vendors after this year. It is worth quoting at length Dr. Scott 
Gottlieb, writing before his appointment to the FDA:

          ``Although it is impossible to calculate exactly how much the 
        agency's review programs spend on IT-related infrastructure 
        (because it is embedded in many different programs), consider 
        that total spending on IT-related activities at the FDA was cut 
        $29.1 million in 2004 from what the agency had requested so 
        that the FDA could find savings to stay inside its 
        congressional budget allocation. That exceeds the entire $23.8 
        million budget of the FDA's Office of Drug Safety for 2004.''
          ``All of this leaves little doubt that even the most basic IT 
        improvements have been slow in coming, hobbled by a lack of 
        budget and vision. As a result, information is made available 
        to the FDA slowly and takes even longer to analyze by the FDA's 
        trained personnel. Subtle side effects--especially medical 
        problems that occur naturally in a large population or as a 
        consequence of the condition that a drug aims to treat (the 
        side effects at issue with Vioxx and the SSRIs met these 
        criteria) could be easily dismissed as normal or ``background'' 
        events as a result of inadequate sample sizes and the inability 
        to easily aggregate and analyze population-based data on actual 
        drug use.'' \68\

    Yet IT resources are essential for making post-market surveillance 
work, improving AERS, and--in the long run--making comparative 
effectiveness analyses that will save the Nation tens of billions of 
dollars by identifying what courses of treatment work and don't work. 
In addition to modern systems, the FDA needs the resources to develop 
electronic data submission formats; today, all too many applications 
are submitted as expensive-to-process reams of paper, because the FDA 
says it doesn't have the resources to develop regulations for 
electronic submission formats.
Discussion of Solutions in S. 3807 and Further Recommendations
    S. 3807 allows PDUFA user fees to be available for REMS work to 
improve postapproval safety. Many are concerned, however, that the FDA 
is too closely tied with the industries it regulates. User fees may 
contribute to the pharmaceutical industry's ``capture'' of the FDA.\69\ 
The IOM recommends that Congress approve a substantial increase in both 
funds and personnel for FDA safety activities in order to counteract 
PDUFA's restrictions on how the FDA can use its funds. The IOM 
discusses the ideal option of general Treasury revenues to adequately 
fund the FDA. Importantly, however, the IOM notes that if user fees are 
required, Congress should greatly reduce current restrictions on how 
the FDA can use those funds.
    Consumers Union strongly supports the IOM's recommendations for 
more resources with no ``strings attached.'' This could be achieved, as 
Rep. Maurice Hinchey's bill (H.R. 2090) does, by depositing user fees 
into the Treasury, then entitling the FDA to an amount of money from 
the Treasury equal to the amount currently raised by user fees, but 
freeing the agency from detailed restrictions on how such moneys are 
spent. As noted in section 5 below, freeing the FDA from dependence on 
the industry is probably the single major thing we can do to improve 
the morale and culture within the FDA on behalf of consumers.
    Another option would be to increase user fees to deal with a huge 
backlog of safety issues. Consumers Union echoes the IOM's words that 
regardless of the funding source, ``the functioning of a drug safety 
system that assesses a drug's risks and benefits throughout its 
lifecycle is too important a public health need to continue to be under 
funded.'' \70\
    If a user fee system is continued, we urge that S. 3807's section 
104 be strengthened to spell out adequate levels of resources and 
performance goals for safety. Just as the industry has goals for rapid 
drug approvals, consumers and patients should have goals for rapid 
resolution of safety concerns.
    Attachment #1 is a list of the kind of safety goals that should be 
funded, ideally by the general Treasury, but if the user fee program is 
continued, then by user fees. This list is illustrative. Of course, 
your committee would need to provide details on the exact performance 
levels and the realistic rate of increase in safety quality after 
consultation with the FDA, OMB, and after studying the President's 
fiscal year 2008 budget and the FDA's actual safety budget deficiencies 
in the middle of fiscal year 2007.
    While all these safety standards are important, we particularly 
appreciate S. 3807's study of the FDA's IT needs. But another IT study, 
without funding, is meaningless. We urge you to give a priority to 
funding these crucial IT building blocks.

                4. ADVISORY COMMITTEES (ACS) AT THE FDA

Background
    Advisory committee meetings are a very important resource for the 
FDA. Such meetings are public and provide an opportunity for the 
agency's scientific experts, consumer advocates, and industry 
representatives to contribute to the regulatory process. Recently, 
however, there have been serious concerns about the process.
    Although AC meetings provide a valuable contribution to the FDA's 
efforts to regulate drugs, the frequency with which they convene has 
been declining. The OIG reported that the number of AC meetings 
decreased from 40 in 1998 to 23 in 2001.\71\ The OIG also reported that 
FDA managers believed that they had little time to hold these meetings. 
In addition, only 21 percent (5/24) of approved New Molecular Entities 
(NMEs) were preceded by an advisory committee meeting. NMEs are drugs 
that contain an active ingredient that has never before been approved, 
and may be more likely to carry safety risks.\72\
    In addition to the recent reduction of meetings, important 
information regarding drug safety is sometimes purposefully excluded. 
For example, a senior epidemiologist at the FDA, Dr. Andrew Mosholder's 
concerns that Paxil increased suicidal behavior in children were 
dismissed by higher FDA authorities.\73\ Dr. Mosholder was not allowed 
to present his analysis at the February 2004 joint meeting of the 
Psychopharmacologic Drugs Advisory and the Pediatric Subcommittee of 
the Anti-Infective Drugs Advisory Committee because it was believed to 
be too preliminary.\74\ In later interviews with the GAO, the Directors 
of CDER and the Office of New Drugs (OND) said that in retrospect they 
felt it was a mistake for the FDA to have restricted Dr. Mosholder from 
presenting his safety information.\75\
    The GAO report on post-market drug safety notes that the role of 
the Office of Drug Safety (ODS) in AC meetings is unclear. The report 
cites another case (in addition to the one above) in which ODS staff 
was not allowed to present their analysis: the OND did not allow the 
ODS to present their review of Arava at the Arthritis Advisory 
committee meeting in March 2003 because the OND division believed that 
ODS's review lacked scientific merit. ODS found the use of Arava to be 
associated with acute liver failure. GAO reports that after the 
meeting, ODS epidemiologists and safety evaluators requested 
clarification of ODS's role in advisory committee hearings, but that 
there was no written response to this request.
    Although certain FDA experts have been refused permission to 
testify at AC meetings, many outside scientific experts are free to 
participate in such meetings despite having outstanding conflicts of 
interest. For example, at the February 2005 joint meeting of the 
Arthritis Advisory Committee and the Drug Safety and Risk Management 
Advisory Committee to discuss the safety of cyclooxygenase-2 (COX-2) 
inhibitors, 10 of the 32 voting panel members had financial 
associations with the manufacturers of these drugs (such as consulting 
fees or research support).\76\ All 10 members were issued general 
waivers that allowed them to participate in the meeting. Twenty-eight 
out of the thirty votes cast by these 10 members favored marketing of 
Bextra, Celebrex and Vioxx, whereas only 37 out of the 66 votes cast by 
the remaining 22 members favored marketing of these drugs.\77\ If the 
10 panel members with conflicts of interest had not participated in the 
meeting, the committee would have voted to remove Bextra from the 
market, and to keep Vioxx from returning to the market (Merck 
voluntarily withdrew Vioxx from the market in 2004). Instead, due to 
the inclusion of the votes from the 10 conflicted panel members, the 
committee voted to keep these drugs on the market. The FDA consequently 
announced that it had asked Pfizer to voluntarily withdraw Bextra from 
the market, which it did in April 2005, 2 months after the advisory 
committee meeting.

Discussion of Solutions in S. 3807 and Further Recommendations
    Frequency of Meetings: Title IV of S. 3807 recommends a series of 
clarifying efforts to reduce or disclose conflicts of interest. The IOM 
recommends that FDA advisory committees review all NMEs either prior to 
approval or soon after approval. The IOM notes that although it might 
be impossible to convene AC meetings for all NMEs prior to approval, 
the FDA should have the authority to require such meetings after 
approval. Since advisory committees provide valuable scientific 
expertise, it is important that the FDA capitalize on such a resource. 
Consumers Union supports the IOM's recommendation that all NMEs be 
reviewed by FDA advisory committees and be part of the REMS process.
    ODS involvement in ACs: In addition to encouraging participation of 
outside scientific experts through AC meetings, it is important that 
FDA's own scientific experts also be heard. ODS staff has recommended 
that as a matter of policy, they present post-market safety data at 
these meetings.\78\ Consumers Union recommends that ODS always have the 
right to testify before ACs. If ODS chooses not to testify, Consumers 
Union strongly recommends that ACs be granted the authority to request 
such testimony or a statement from ODS that they have no safety 
concerns to raise.
    The IOM highlights the fact that the FDA must undergo cultural 
changes if postapproval safety is to be improved. Consumers Union 
encourages language in S. 3807 that would speak to this issue and 
assure the right of FDA scientists to dissent or provide ``additional 
views'' to the majority view. The right to dissent must be especially 
acknowledged at AC meetings.
    Also, a recent report by the National Resource Center for Women and 
Families \79\ shows that while ACs often raise safety questions, they 
very seldom reject a drug. There appears to be a clear bias toward 
approval and a suppression of safety concerns (which is another reason 
to seek more conflict-free experts). The study also shows that even 
when an AC rejects a drug, the FDA frequently ignores the 
recommendation. We believe that if the FDA overrules an AC 
recommendation, it should provide a detailed public statement of why it 
disagrees and why it believes the science supports the FDA's disregard 
of the expert outside panel.
    Ending Conflict of Interest: AC meetings must be conducted in such 
a way that scientific integrity is promoted. Recent history suggests 
that committee members are given voting rights despite significant 
financial associations with the pharmaceutical companies affected by 
the committee's review. The New England Journal of Medicine reports 
that, according to Dr. J. J. Wood, the chair of the joint meeting that 
reviewed the COX-2 inhibitors, the FDA made a ``judgment error'' when 
it decided to issue a general waiver and not to disclose specific 
information regarding the conflicts of interests of committee 
members.\80\ The IOM recommends that a ``substantial majority'' (and 
suggests 60 percent) of the members of each advisory committee be 
``free of significant financial involvement'' with the pharmaceutical 
companies that would be affected by the committee's review. In 
addition, the IOM recommends that the FDA issue waivers to committee 
members ``very sparingly.''
    Consumers Unions recommends that no advisory committee meeting be 
convened unless a substantial majority of the committee is free of 
significant financial involvement. We think it is important for 
restoring public confidence in the agency and creating a culture of the 
highest public service that no less than 90 percent, and ideally 100 
percent, of advisory committee members be free of conflict.
    The public has lost confidence in the FDA. The Wall Street Journal 
reported on a May 24, 2006 WSJ Online/Harris Interactive poll that 58 
percent of the public feels the FDA does a fair or poor job on ensuring 
the safety and efficacy of new drugs, and 80 percent said they are 
somewhat or very concerned about the agency's ability to make 
``independent'' decisions. Clearly, this is a time to bend over 
backwards to ensure integrity and public interest in all aspects of the 
FDA, including the integrity of its Advisory Committees.
    It is argued that the best experts in a field are those who have 
been working with drug companies on the research and development of 
specific drugs and that it would be impossible to staff conflict-of-
interest-free committees with qualified experts. We argue that when one 
looks at the recent FDA's reports to the Congress on advisory 
committees, it is clear there is no one person at the FDA charged with 
coordinating the recruitment of advisors to all the various FDA 
Centers. We urge the Congress to support a major outreach effort by the 
FDA to find nonconflicted advisory committee members. Until one 
actively recruits, how can one know that AC's that would inspire public 
confidence cannot be created?

                 5. IMPROVING CULTURE AND MORALE AT FDA

Background
    Some of the conflict of interest problems that plague FDA's 
advisory committees appear to affect other aspects of life at the FDA 
as well. The fact that many career FDA scientific staff members believe 
their voices are silenced speaks of larger, extremely serious troubles 
relating to culture and morale at the agency.
    In August 2006, the Union of Concerned Scientists (UCS) and Public 
Employees for Environmental Responsibility (PPER) released their survey 
of FDA staff. The findings echoed those reported by the Office of 
Inspector General (OIG) in 2003.\81\ For example, in response to the 
question: ``Have you ever been pressured to approve or recommend 
approval for an NDA despite reservations about the safety, efficacy, or 
quality of the drug?'' Forty-one respondents out of 217 Center for Drug 
Evaluation and Research (CDER) staff (nearly 19 percent) answered 
``yes.'' \82\ These types of responses raise concerns regarding the 
extent to which these experts are capable of practicing their right to 
dissent on issues of drug safety.
    These poll findings support the IOM report's finding that the 
organizational culture at the FDA is partially responsible for the 
marginalization of dissenting voices.\83\ The IOM says that the 
polarization between the pre-marketing and post-marketing review staff 
contributes to a negative culture at the FDA. This polarization is 
evidenced in advisory committee meetings as described in the previous 
section, where the OND has prohibited the ODS from presenting pertinent 
safety information. In addition, the resource gap resulting from the 
introduction of user fees has further divided the two offices and 
increased tension.\84\ The IOM notes that ODS staff have been 
considered marginal players compared with OND staff, and that the ODS 
is perceived to have a lower status compared to the OND. According to 
the IOM, various concerns relating to culture at the FDA have resulted 
in a ``persisting problem with retention, turnover, and morale in 
CDER.'' \85\ Key relevant staff members are sometimes excluded from 
discussion and decisionmaking about the agency and the work they 
perform daily.

Discussion of Solutions in S. 3807 and Further Recommendations
    In order to address the culture and morale challenges facing the 
FDA, it is imperative that the agency establish a climate of open 
scientific debate. Consumers Union recommends institutionalizing a 
system of public staff dissent and additional views on all new drug 
applications, accompanied by ``whistleblower'' type staff protections. 
Representative Ed Markey (D-MA) has a bill (H.R. 5922) with 
whistleblower language.
    Just as Congress or the Courts have institutionalized a system 
where Members can and are expected to offer additional or dissenting 
views, we believe a similar, institutionalized system within the FDA 
would improve culture and morale, and contribute to a healthier 
scientific debate. Some say that this kind of dissent would confuse the 
public, make practitioners uncertain about whether a drug was good or 
not, and make people too cautious to use new, important new drugs. We 
believe that consumer empowerment is good, and that by making it clear 
where the scientific questions and uncertainty are, it will help 
researchers around the world concentrate on answering those questions 
as quickly as possible. The public would understand that while a 
majority of the FDA found a drug to be effective and safe, dangers were 
not swept under the rug as part of some pro-drug company conspiracy. 
The public will support dissent and debate--suppression of dissent will 
destroy confidence in the system.

            6. SPEEDING APPROVAL OF GENERICS AND BIOGENERICS

Background
    Healthcare costs continue to surge at double or triple the rate of 
general inflation, in part due to the high cost and rate of inflation 
of brand-name prescription drugs. Generic and biogeneric drugs, can 
dampen health inflation by providing equally safe and effective 
medicine at a far lower price--often prices only 70 percent or less of 
the brand name drug. Generics and biogenerics save consumers billions 
of dollars. For example, according to one study by the Pharmaceutical 
Care Management Association (PCMA), generic drugs could save consumers 
over $23 billion over the next 5 years if optimal use is made of the 14 
generic drugs scheduled to enter the market during this time.\86\ These 
savings could also significantly help reduce Medicare and Medicaid 
costs, since many of these 14 generic drugs are commonly used by senior 
citizens.
    Despite the enormous savings available from generics, the FDA has 
been unable to ensure that these drugs are approved for the market in a 
timely manner. In a memo to Consumers Union this autumn, the FDA 
reported that an unduplicated count of pending generic applications 
showed a backlog of 394 drugs pending more than 180 days--drugs which 
could help lower costs to consumers if they were approved. An article 
in the Washington Post \87\ explains that part of the problem is the 
lack of staff to review these applications: the Office of Generic Drugs 
only has 200 employees. This is in stark contrast with the OND, which 
has more than 2,500 employees to review about 150 (admittedly more 
complex) applications.
    There is no clear law providing for the development of generic 
versions of more complex molecular biologic medicines. These new 
products are the most expensive medicines on the market--some costing 
as much as $100,000 to $250,000 for a course of treatment. Some 
criticize the notion that biogenerics could bring cost-
saving benefits, saying that these drugs are far more complex than 
other drugs because they are made from living organisms, and therefore 
cannot be copied as easily, as inexpensively, or as safely as other 
drugs.\88\ Nevertheless, the European Medicines Agency is creating a 
framework for biogenerics to be approved.\89\ Consumers Union joins 
most other observers in believing that biogenerics could provide some 
savings and can be provided safely, thus helping some of our most 
severely ill patients.\90\ The law should be clarified to allow us to 
do what the Europeans are doing: bringing some relief to consumers.
    In addition to backlogs in the approval of generics and legal 
uncertainty and stalemate on the issue of biogenerics, there are a 
series of legal loopholes in the law that have allowed drug companies, 
often in collusion with generic companies themselves, to block the 
entry of lower-cost generics--sometimes for years. These loopholes 
range from abuse of the pediatric exclusivity provision to payment 
arrangements to keep a generic from entering the market. In recent 
years, the use of phony citizens petitions has cost consumers millions 
of dollars by delaying the entry of generics. According to the FDA, 
only 3 of 42 petitions answered between 2001 and 2005 raised issues 
that merited changes in the agency's policies about a drug. For 
example, Flonase, a commonly used prescription allergy medication, went 
off patent in May 2004. But GlaxoSmithKline stretched its monopoly 
window by almost 2 years with petitions and a legal challenge to the 
use of generics.\91\

Discussion of Solutions in S. 3807 and Further Recommendations
    The current legislation is silent on issues surrounding generics 
and biogenerics.
    Consumers Union urges that a major new title be added to S. 3807 to 
correct the full range of generic and biogeneric problems, or that the 
committee address these issues in separate legislation early in 2007.
    Specifically, Consumers Union asks that language be added to S. 
3807 to:

     increase funds and staff at the Office of Generic Drugs, 
and to set goals to ensure that application backlogs do not occur. 
Given the significant savings that are associated with the marketing of 
generic drugs, this language will help moderate rising healthcare 
costs; and
     establish a path for the approval of biogenerics. We 
strongly endorse H.R. 6257, a bill by Rep. Henry Waxman and others, 
that provides legal direction to the FDA to approve biogenerics. 
Consumers Union hopes that Congress, learning from the European Union 
experience, will soon create a framework for biogenerics to enter the 
market.
    We hope that the committee will hold hearings on the abuse of the 
citizen petition and patent and exclusivity laws to keep generics from 
the market. Senators Kohl and Leahy (S. 3981) and Stabenow and Lott (S. 
2300) and Rep. Waxman and others (H.R. 6022) have bills to close these 
loopholes that are worth exploring in hearings and adopting as part of 
FDA reform legislation or as stand-alone proposals.

      7. IMPROVING SCIENCE AT THE FDA: THE REAGAN-UDALL INSTITUTE

Background
    The FDA's ability to make sound decisions and to regulate the 
pharmaceutical industry depends on the quality of scientific data that 
it receives. Recently, many experts have raised concerns regarding the 
quality of reports submitted to the FDA and the quality of the science 
used at the FDA. In particular, questions have been raised about 
noninferiority trials and the use of surrogate endpoints.
    Often, drug company sponsors conducting clinical trials use 
``surrogate endpoints'' rather than final outcomes. These endpoints are 
relatively easily and quickly obtainable physical markers that are used 
to reflect what is believed to be a clinically meaningful outcome. 
Clinically meaningful outcomes are often difficult and costly to obtain 
directly because they often require very large and long clinical 
trials. Although the use of surrogate endpoints is sometimes 
appropriate, this methodology is often abused and clinical trials which 
use surrogate endpoints often exaggerate the benefits. One recent 
article in Health Affairs reports that this methodology resulted in the 
overestimation of the benefits of Natrecor, a drug used to treat acute 
exacerbations of congestive heart failure.\92\ The authors of the 
article note that 
higher rates of kidney impairment and mortality are found in those 
using the drug.
    The use of the noninferiority design has also created a great deal 
of controversy. Non-inferiority trials are intended to show that the 
effect of a new treatment is not worse than that of a currently 
marketed treatment. But as FDA experts have pointed out, it is possible 
over time that the use of noninferiority trials could lead to the 
approval of drugs that are actually less effective and/or harmful 
compared to a placebo. A number of Members of Congress have requested 
that the GAO investigate the FDA's acceptance of noninferiority 
studies, and Rep. Markey's bill, H.R. 5922, calls for reports on the 
use of this method of approving drugs.\93\ This congressional concern 
has been heightened by the FDA's approval of Ketek, which was based on 
noninferiority trials. Ketek, which is indicated for pneumonia, throat 
and sinus infections, and chronic bronchitis, has caused serious liver 
toxicity in some patients.\94\

Discussion of Solutions in S. 3807 and Further Recommendations
    S. 3807 proposes the establishment of the Reagan-Udall Institute to 
``modernize medical product development, accelerate innovation, and 
enhance product safety by initiating, sponsoring, and organizing 
collaborative and multidisciplinary research.'' The Institute appears 
to be part of the Critical Path Initiative to increase the level of 
FDA's scientific research and to find faster, cheaper, and more 
effective ways to develop drugs. It appears that the Institute's 
responsibilities are in line with some of the science recommendations 
of the IOM's report.
    We strongly support increased high quality scientific work at the 
FDA, and research on how to solve problems like those that can occur 
with surrogate endpoints, noninferiority, and determining the 
comparative effectiveness of drugs and classes of drugs. Nevertheless, 
we hope the committee will hold further hearings on the idea of this 
Institute. It is not clear why these functions could not be placed 
within the FDA directly, rather than conducted through a quasi-private 
institute. It is important that any actions in this area are not just 
another industry-dominated effort to speed the development of drugs 
without adequate regard to their safety. \95\ We commend you for 
including many references to drug safety in the Reagan-Udall Institute 
language. But the governing board of the Institute is tilted toward 
industry and lacks the guarantee of governance by nonconflicted public, 
consumer board members. The language calls for the acceptance of funds 
from private entities, which raises the same independence issues as we 
have seen in PDUFA fees. To repeat, we hope you will spend more time on 
this issue and refine some of the language to ensure that whatever is 
done serves the public in a balanced way.
    We note that one way to improve science at the FDA is to reduce the 
level of staff turnover of experienced, trained personnel, which is 
higher at the FDA than many other Federal science agencies. Improving 
the FDA's culture and morale, as discussed earlier, and allowing FDA 
scientists more freedom to publish academically (as provided in Rep. 
Markey's bill H.R. 5922) are all keys to creating a better scientific 
climate.

                               CONCLUSION

    Finally, I would be remiss not to acknowledge the countless 
families who have suffered because of our broken drug safety system. 
They are the reason we are here today. And many of them have worked 
tirelessly on this issue so others won't have to endure their 
heartbreak.
    Two of these fine people are here today--Eric Swann, whose brother-
in-law, Woody Witzak was casually prescribed an antidepressant for 
insomnia, and 5 weeks later killed himself. And Mathy Downing, whose 
daughter, Candace, was put on Zoloft because she was anxious taking 
tests at school. Ten months later, she took her own life at the age of 
12. Neither Eric nor Mathy knew about clinical trial results that 
indicated increased risk of suicide from these types of 
antidepressants.
    Senators, I deeply appreciate your time, and I thank you for your 
consideration of these ideas--and for the good work you have begun.

                                Endnotes

    1. ``Publishing Clinical Trial Results: The Future Beckons,'' by 
Elizabeth Wager, www.plosclinicaltrials.org, Oct., 2006 e31.
    2. Curfman, et al. Expression of Concern: Bombardier et al., 
``Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and 
Naproxen in Patients with Rheumatoid Arthritis,'' N Engl J Med. 
2000;343:1520-8. New England Journal of Medicine. 2005; 353: 2813-2814.
    3. U.S. Congress. Senate. Committee on Finance. Hearing on ``FDA, 
Merck and Vioxx: Putting Patient Safety First?'' Testimony of Sandra 
Kweder, M.D. (November 18, 2004).
    4. People of the State of New York v. GlaxoSmithKline and 
SmithKline Beecham Corporation.
    5. Ibid.
    6. FDA Public Health Advisory: Aprotinin Injection (marketed as 
Trasylol). (September 29, 2006).
    7. FDA Public Health Advisory: Aprotinin Injection (marketed as 
Trasylol). (February 8, 2006).
    8. Mangano DT, Tudor IC, and Dietzel C. The Risk Associated With 
Aprotinin in Cardiac Surgery. N Engl J Med. 2006; 354:353-365.
    9. Schmit, Julie. ``More Drugs Get Slapped With Lawsuits.'' USA 
Today. August 23, 2006.
    10. World Health Organization. World Health Organization 
International Clinical Trials Registry Platform: Unique ID Assignment. 
Geneva: World Health Organization; 2005.
    11. DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, et al. 
Clinical Trial Registration: A statement from the International 
Committee of Medical Journal Editors. JAMA. 2004; 292: 1363-1364.
    12. Fontanarosa PB, Flanagin A, DeAngelis CD. Reporting Conflicts 
of Interest, Financial Aspects of Research, and Role of Sponsors in 
Funded Studies. JAMA. 2005; 294: 110-111.
    13. Ottawa Statement on Trial Registration, http://
ottawagroup.ohri.ca/statement.html.
    14. Kenter MJH and Cohen AF. Establishing Risk of Human 
Experimentation With Drugs: Lessons from TGN1412. The Lancet. 2006; 
368: 1387-1391.
    15. Establishing Transparency to Restore Trust in Clinical Trials. 
The Lancet Neurology. 2006; 5: 551.
    16. Goodyear M. Learning From the TGN1412 Trial. BMJ. 2006; 332: 
677-678.
    17. Grassley, Charles. Letter to the Department of Health and Human 
Services Office of Inspector General. November 8, 2005.
    18. Evans, David. ``Human Guinea Pigs Pay for Lax FDA Rules.'' 
Bloomberg News. November 6, 2005.
    19. Gidron, Martin. ``Six Percent of Clinical Investigators 
Violated Regulations, FDA Says.'' Washington Drug Letter. October 2, 
2006.
    20. Grassley, Charles. Letter to the Department of Health and Human 
Services Office of Inspector General. November 8, 2005.
    21. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM Report, 
November, 2006. It is equally disturbing that the FDA did not disclose 
this known fraud to the Advisory Committee members who met to review 
Ketek.
    22. IOM, 2006.
    23. Ibid.
    24. Ibid.
    25. Rennie D. Trial Registration; A Great Idea Switches From 
Ignored to Irresistible. JAMA. 2004; 292: 1359-62.
    26. Bennett, C.L., et al., The Research on Adverse Drug Events and 
Reports (RADAR) Project, JAMA, May 4, 2005, Vol. 293, No. 17.
    27. Institute of Medicine (IOM), 2006.
    28. Budnitz DS, et al. National Surveillance of Emergency 
Department Visits for Outpatient Adverse Drug Events. JAMA. 2006; 296: 
1858-1866.
    29. Lazarou J, Pomeranz BH, Corey PN. Incidence of Adverse Drug 
Reactions in Hospitalized Patients: A Meta-analysis of Prospective 
Studies. JAMA. 1998; 279: 1200-1204.
    30. Bennet CL, et al. The Research on Adverse Drug Events and 
Reports (RADAR) Project. JAMA. 2005; 293: 2131-2139.
    31. Brewer T, Colditz GA. Postmarketing Surveillance and Adverse 
Drug Reactions: Current Perspectives and Future Needs. JAMA. 1999; 281: 
824-829.
    32. IOM, 2006.
    33. Bennet CL, et al, 2005.
    34. U.S. General Accounting Office. FDA Drug Review: Postapproval 
Risks, 1976-1985. Washington, DC.: U.S. General Accounting Office; 
April 26, 1990. GAO/PEMD 90-15.
    35. Lasser, KE et al. Timing of New Black Box Warnings and 
Withdrawals for Prescription Medications. JAMA. 2002; 287: 2215-2220.
    36. Man, F et al. Evaluation of the Characteristics of Safety 
Withdrawal of Prescription Drugs From Worldwide Pharmaceutical 
Markets--1960-1999. Drug Information Journal. 2001.
    37. 505(d) Federal Food Drug and Cosmetic Act.
    38. IOM, 2006.
    39. Furberg, CD et al. The FDA and Drug Safety: A Proposal for 
Sweeping Changes. Arch Intern Med. 2006; 169: 1938-1942.
    40. Blum, Justin. ``Sanofi, Drugmakers Fail on Promise to Study 
Medicines' Effect.'' Bloomberg: June 9, 2006.
    41. U.S. Government Accountability Office. FDA Postmarket Drug 
Safety. Washington, DC.: U.S. Government Accountability Office; March, 
2006. GAO-06-402.
    42. Blum, 2006.
    43. ``FDA's Monitoring of Postmarketing Study Commitments,'' HHS 
OEI-01-00390, June, 2006.
    44. GAO-06-402.
    45. Office of Inspector General. FDA's Monitoring of Postmarketing 
Study Commitments. June, 2006.
    46. Dai C, Stafford RS, Caleb GC. National Trends in 
Cyclooxygenase-2 Inhibitor Use Since Market Release: Nonselective 
Diffusion of a Selectively Cost-effective Innovation. Arch Intern Med. 
2005; 165: 171-177.
    47. Ibid.
    48. Bell RA, Wilkes MS, Kravitz RL. The Educational Value of 
Consumer-targeted Prescription Drug Print Advertising. J Fam Pract 
2000; 49: 1092-1098.
    49. Bell RA, Kravitz RL, Wilkes MS. Direct-to-consumer Prescription 
Drug Advertising and the Public. J Gen Intern Med 1999; 14: 651-657.
    50. Wolfe, SM. Direct-to-Consumer Advertising--Education or Emotion 
Promotion? N Engl J Med. 2002; 346: 1424.
    51. ``The Court has developed a four-pronged test to measure the 
validity of restraints upon commercial expression. Under the first 
prong of the test as originally formulated, certain commercial speech 
is not entitled to protection; the informational function of 
advertising is the first amendment concern and if it does not 
accurately inform the public about lawful activity, it can be 
suppressed. Second, if the speech is protected, the interest of the 
government in regulating and limiting it must be assessed. The State 
must assert a substantial interest to be achieved by restrictions on 
commercial speech. Third, the restriction cannot be sustained if it 
provides only ineffective or remote support for the asserted purpose. 
Instead, the regulation must `directly advance' the governmental 
interest. The Court resolves this issue with reference to aggregate 
effects, and does not limit its consideration to effects on the 
challenging litigant. Fourth, if the governmental interest could be 
served as well by a more limited restriction on commercial speech, the 
excessive restriction cannot survive. The Court has rejected the idea 
that a `least restrictive means' test is required. Instead, what is now 
required is a `reasonable fit' between means and ends, with the means 
`narrowly tailored to achieve the desired objective.' '' Central Hudson 
Gas & Electric Co. v. Public Service Comm'n, 447 U.S. 557 (1980). Quote 
from http://caselaw.lp.findlaw.com/data/constitution/amendment01/
17.html.
    52. Radley, et al. Off-label Prescribing Among Office-Based 
Physicians. Archives of Internal Medicine. 2006; 166: 1021-1026.
    53. Young, Alison and Adams, Chris. ``Off-label Drugs Take Their 
Toll,'' Knight Ridder Newspapers, November 2, 2003.
    54. Steinman MA, Bero LA, Chren M, Landefeld CS. Narrative review: 
The Promotion of Gabapentin: An Analysis of Internal Industry 
Documents. Annals of Internal Medicine. 2006; 145: 284-93.
    55. Radley, et al., 2006.
    56. Henney, JE. Safeguarding Patient Welfare: Who's in Charge? 
Annals of Internal Medicine. 2006; 145: 305-307.
    57. Nightingale, SL. Off-label Use of Prescription Drugs. American 
Family Physician. 2003; 68: 425-427.
    58. Bennet CL., et al., 2005.
    59. Carreyrou, John. ``Narcotic Lollipop'' Becomes Big Seller 
Despite FDA Curbs. Wall Street Journal. November 3, 2006.
    60. GAO, 2006.
    61. FDA Week, November 10, 2006, ``Waxman May Investigate FDA on a 
Broad Range of Issues.''
    62. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM Report, 
November 2006.
    63. IOM, 2006.
    64. GAO-06-402.
    65. FDA. Center for Drug Evaluation and Research-Activities and 
Level of Effort Devoted to Drug Safety. 2005.
    66. FDA, ``White Paper: Prescription Drug User Fee Act (PDUFA),'' 
p. 34. As the FDA says, ``In 2004, [FDA] reviewed 142 proposed 
broadcast ads, with the 4 full-time staff available to perform these 
reviews. Although FDA review of all materials would ensure alignment 
with the approved labeling and a fair balance of information on 
benefits and risks, current FDA resourcing for this work would probably 
result in delayed reviews if all companies were to submit their ads. 
Such delays would likely affect companies' ability to meet their 
marketing timelines, and discourage them from submitting the materials 
for prior FDA review.''
    67. FDA e-mail memo to Consumers Union.
    68. Gottlieb, in ``Opening Pandora's Pillbox: Using Modern 
Information Tools to Improve Drug Safety,'' Health Affairs, July/August 
2005, p. 938ff.
    69. IOM, 2006.
    70. IOM, 2006.
    71. Department of Health and Human Services. Office of Inspector 
General, Report No. OEI-01-01-00590, FDA's Review Process for New Drug 
Applications: A Management Review 42 (2003).
    72. IOM, 2006.
    73. Ibid.
    74. GAO-06-402.
    75. Ibid. The exclusion of information at advisory committee 
meetings has been documented with devices as well: the European 
experience with anti-wrinkle device ArteColl was not part of the 
discussion at the February 2003 Medical Devices Advisory Committee for 
ArteFill (same product under a different brand name), despite the fact 
that the device caused serious disfigurations years after implantation. 
(Rundle, Rhonda. ``Antiwrinkle Shots Spark Debate.'' The Wall Street 
Journal D3, October 31, 2006.)
    76. Center for Science in the Public Interest. Conflicts of 
interest on COX-2 panel. February 25, 2005. (Accessed October 30, 2006, 
at http://cspinet.org/new/200502251_print.html.)
    77. Harris G, Berenson A. 10 Voters on panel backing pain pills had 
industry ties. New York Times. February 25, 2005.
    78. GAO-06-402.
    79. NRCWF, ``FDA Advisory Committee: Does Approval Mean Safety?'' 
August 28, 2006.
    80. Steinbrook, R. Financial Conflicts of Interest and the Food and 
Drug Administration's Advisory Committees. N Engl J of Med. 2005; 353: 
116-118.
    81. Union of Concerned Scientists (UCS) and Public Employees for 
Environmental Responsibility (PEER). UCS 2006 Food and Drug 
Administration Survey Compared to the 2002 Health and Human Services 
Inspector General Survey.
    82. Ibid.
    83. IOM, 2006.
    84. Ibid.
    85. Ibid.
    86. Pharmaceutical Care Management Association (PCMA). ``Potential 
Savings to Medicare from New Generic Drugs Becoming Available.'' 
Accessed November 7, 2006 available at: http://www.pcmanet.org/
newsroom/2006/Pr_4_06/Medicare%
20Savings%20from%20Generics.pdf.
    87. Kaufman, Marc. ``Generic Drugs Hit Backlog at FDA--No New Plans 
to Expand Review Capabilities,'' The Washington Post, February 4, 2006.
    88. Pharmaceutical Business Review. ``Biogenerics: the battle is 
only just beginning,'' January 18, 2006.
    89. Ibid.
    90. Tsao, Amy. ``Seeking a Prescription for Biogenerics.'' Business 
Week. October 24, 2003.
    91. Consumer Reports, November, 2006, p. 58.
    92. Kesselheim AS, Fischer MA, and Avorn J. The Rise and Fall of 
Natrecor for Congestive Heart Failure: Implications for Drug Policy. 
Health Affairs. 2006; 25: 1095-1102.
    93. Letter to the GAO. 09-06-06 Letter to GAO.pdf.
    94. Letter to the GAO, 2006.
    95. There is certainly no evidence that approval times are a 
problem. The United States leads the world in the first introduction of 
new drugs. In 2006, standard reviews are averaging 12.7 months, half 
the 25.4 months it took to review applications in 2005. Priority review 
times in 2006 average 9.4 months, down 16 percent from 2005 and 33 
percent from 2004. ``Designer Labeling,'' by Ramsey Baghdadi, The RPM 
Report, November, 2006.
                                 ______
                                 

                             Attachment #1

                PROPOSAL FOR SAFETY RESOURCES AMENDMENT

    Idea for amendment to S. 3807 to ensure adequate resources for 
needed FDA safety improvements and to set performance goals for the use 
of such resources. The percentage increases are just illustrative: the 
exact increases would have to be determined in consultation with the 
FDA and in light of the fiscal year 2007 appropriations and the 
President's budget proposals for fiscal year 2008.
    On page 34, line 19, insert the following before the quotation 
mark:
    ``Such estimate shall provide enough increased revenue to achieve 
the following safety improvement goals on a phased-in basis between the 
date of enactment and the end of fiscal year 2012:

    (A) ensure the pre-clearance of all electronic media (including 
Internet) advertisements and informationals\1\;
---------------------------------------------------------------------------
    \1\ It would be good to define ``advertisements'' so as to pick up 
the many forms of promotions used to promote drugs and frequently to 
promote off-label use.
---------------------------------------------------------------------------
    (B) increase by 100 percent (that is, double) the percent of 
clinical trial data and investigational review board applications 
audited to ensure the ethical treatment of enrollees, and the 
experiments integrity and compliance with good scientific practice\2\;
---------------------------------------------------------------------------
    \2\ It is reported that the FDA is revising regulations allowing 
drugs used in a Phase 1 trial to be exempt from quality control 
manufacturing requirements. If this is accurate, there should be some 
system of sampling a certain percentage of these drugs for purity and 
safety. See Triangle Business Journal, Nov. 3, 2006, ``Triangle 
scientists reticent about FDA shift.''
---------------------------------------------------------------------------
    (C) ensure the electronic filing of all applications, amendments, 
petitions, adverse event reports, and other data required by FDCA laws 
relating to drugs;
    (D) investigate all serious adverse event reports within 15 days, 
and conduct at least XX investigations per year into patterns or 
clusters of adverse event reports to determine if REMS action should be 
taken;
    (E) increase by 100 percent the inspection of manufacturing 
(including compounding) facilities for compliance with FDCA laws;
    (F) through active outreach and recruitment, develop and maintain a 
list of potential advisory committee specific experts who have no 
conflicts of interest and who have indicated a willingness to be 
appointed to future relevant advisory committee vacancies, and such 
advisory committee specific list shall equal 50 percent of the number 
of individuals serving on each such advisory committee;
    (G) between the completion of the strategic plan for information 
technology provided for by subsection (c) of this section and the year 
2012, collect and apply the resources described by subparagraph (4) of 
such subsection (c) to the implementation of the strategic plan;
    (H) in addition to the clinical trial registry and results 
databases established by title III of this act for drug applications 
received after the enactment of this act, develop over a phased-in 4-
year period ending in 2012 a similar registry of clinical trials and 
clinical trial results for those trials initiated or completed after 
1997 and before the effective date of this act.
    (I) take action, which may include the levying and collection of 
civil monetary penalties provided under section 502(f)(3) (as added by 
this Act) against at least 50 percent of the applicants who have failed 
to complete follow-up safety studies or trials as provided under 
section 505(o)(4)(D) and (E) (as added by this Act).

    The Chairman. Thank you.
    Mr. Simon.
    Mr. Simon. Thank you, Mr. Chairman. It's an honor to be at 
this hearing today and to serve on this panel with these 
distinguished witnesses. FasterCures is dedicated to saving 
lives by saving time in the way we research and discover new 
cures for diseases. We are independent and nonpartisan. We do 
not take funds from pharmaceutical companies, biotech 
companies, or medical device companies. We have one mission and 
that is to save patients' lives as quickly as possible, and we 
approach every problem from the patient's point of view.
    This committee is asking a very important question, not 
just about the details of how the FDA should run, but how do we 
create an FDA for the 21st century? In the 20th century we saw 
the greatest extension of life expectancy in the history of 
humankind, 50 percent in the United States and a doubling of 
life expectancy globally. In the 21st century it is our 
challenge to make sure that those extra lives and extra years 
are quality years, free from debilitating pain and disease.
    That raises the central question at this moment in our 
history as a Nation concerned about our people's safety and 
wellbeing: Do we believe that we can cure any of the diseases 
in this generation that are taking the lives of our friends and 
loved ones long before they otherwise would die? If you believe 
that we can do that and that we must do that, then creating an 
effective FDA for the 21st century is of the greatest 
importance.
    But there is no defending the fact that the FDA budget for 
providing 300 million people and the global population 
confidence in the food supply and the medicine supply is the 
same in real dollars as it was in 1996. The superintendent of 
the Montgomery County School Board has a budget equal to the 
commissioner of the FDA. Now, that's great for Montgomery 
County's children. It doesn't speak well of our commitment as a 
Nation to food and drug safety.
    Many of the recommendations contained in the IOM report and 
the Enzi-Kennedy bill would go a long way toward building the 
proper FDA for the 21st century. FasterCures believes that the 
FDA needs to be able to assess a drug's impact post-approval, 
and to do that it needs stronger authority to regulate the way 
drugs enter the market, and to do that we have to have 
increased appropriations, not user fees that are restricted 
from being applied to post-market approval surveillance. To do 
any of this, we need strong leadership, and we support the 
confirmation of Dr. Andy von Eschenbach to be the commissioner 
of the FDA.
    And the FDA, if it is trying to communicate risks to the 
public, has never hit the mark. We need to engage the patient 
community to help the FDA learn how to communicate risks and 
benefits to the patients. People with terminal diseases or 
debilitating diseases have a very different viewpoint about 
risks and benefits than those of us who are well. If the post-
approval system is neglected, then the pre-approval system 
becomes too cautious because approval is the whole ballgame. 
That is why we support a strong approval system after a drug is 
marketed, so that we can move more expeditiously and quickly to 
get drugs to the market knowing that we're taking the life 
cycle approach, as was suggested by Sheila Burke.
    Every one of us is touched every day by the FDA. Its 
mission in my opinion is the best example of the core function 
of government to protect the health and safety of people who 
could not do what the FDA does for themselves. We need to 
empower the FDA to do that for us and we need to show our 
commitment to the FDA by valuing its work at the same level 
that we value our health and the health of our families and our 
neighbors.
    Thank you for having this hearing today.
    [The prepared statement of Mr. Simon follows:]

                    Prepared Statement of Greg Simon

                            I. INTRODUCTION

    I want to thank the committee for the opportunity to present 
testimony today. My name is Greg Simon, and I am the President of 
FasterCures/The Center for Accelerating Medical Solutions, based in 
Washington, DC.\1\
---------------------------------------------------------------------------
    \1\ Before joining FasterCures, I served as the Chief Domestic 
Policy Advisor to Vice President Al Gore from 1993 to 1997, 
specifically on economic, science and technology issues. In that role, 
I oversaw a number of initiatives, including the programs of the 
National Institutes of Health, the National Cancer Institute, the Food 
and Drug Administration (FDA), the Human Genome Project, and the 
development of the regulatory framework for biotechnology products. 
From 1991-1993, I served as Legislative Director for then-Senator Al 
Gore. From 1985 to 1991, I was Staff Director of the Investigations and 
Oversight Subcommittee of the House of Representatives Committee on 
Science, Space and Technology.
---------------------------------------------------------------------------
    FasterCures is dedicated to saving lives by saving time in the 
discovery and development of new therapies for the treatment of deadly 
and debilitating diseases both in the United States and around the 
globe. The organization was founded in 2003 under the auspices of the 
Milken Institute to catalyze systemic change in cure research and to 
make the complex machinery that drives breakthroughs in medicine work 
for all of us faster and more efficiently. During our relatively brief 
history, FasterCures has worked with a broad range of individuals and 
organizations to eliminate barriers to efficiency and effectiveness in 
our systems of disease prevention, treatment, research and development.
    FasterCures is independent and nonpartisan. We do not accept 
funding from companies that develop pharmaceuticals, biotechnology 
drugs, or therapeutic medical devices. Our primary mission is to 
improve the lives of patients by improving the research environment, 
research resources, and research organizations.
    I am honored to appear before this committee, which has a long 
history of spearheading efforts to protect and promote the health of 
the public by improving our Nation's process of drug discovery and 
evaluation. I want to commend Chairman Enzi, Senator Kennedy, and other 
members on this committee who have introduced and supported bipartisan 
legislation to strengthen the FDA's oversight of drug safety. I commend 
you for focusing this hearing on the broader issue of how to ensure 
that the FDA is truly prepared to meet the challenges and reap the 
benefits of 21st Century medicine.
    Earlier this year, FasterCures provided detailed comments to 
Chairman Enzi and Senator Kennedy regarding the specific provisions of 
the ``Enhancing Drug Safety and Innovation Act of 2006.'' I will touch 
on some of the major points covered in those comments that we believe 
deserve continued focus. However, I primarily want to discuss today the 
broader principles that FasterCures believes should guide any effort to 
strengthen the FDA so that the agency can continue to play a vital role 
in advancing 21st Century cures.
    These principles are as follows:

    1. The FDA needs to be able to assess a drug's impact postapproval, 
weigh both benefits and risks and take appropriate action to protect 
the public;
    2. To do that the FDA needs much stronger authority to regulate and 
enforce how an approved drug enters the market, how it is advertised, 
what claims are made for it and how labels are updated to reflect 
growing knowledge of a product;
    3. To do those things the FDA needs increased appropriations from 
Congress and should not be forced to rely on industry user fees which 
the FDA is largely restricted from using on postapproval activities;
    4. To do any of this, the FDA needs a confirmed Commissioner to 
provide strong, effective and professional leadership with a long-term 
focus and vision; and
    5. And for all of this to work, the FDA needs a better 
understanding of how to communicate its scientific findings to the 
public to make them better informed participants in our healthcare 
system.

              II. THE FDA AT THE DAWN OF THE 21ST CENTURY

    In the past 10 years, we have witnessed dramatic advances in 
science that impact the practice of medicine, including the mapping of 
the human genome, and advances in computational tools and broadband 
communications. Electronic health records and personalized medicine 
will likely change the practice of medicine and clinical research in 
the coming decade, and offer substantial benefits to monitoring adverse 
events.
    Yet, while the personalized medicine era is leaping forward into 
the 21st Century, the FDA remains tethered to 20th Century technology, 
regulations and practices as if the Information Age had never happened. 
Worst of all, it remains mired there because we the people, and our 
elected government have deprived the FDA of the financial and human 
resources it needs to do the job we have asked it to do in the 90 laws 
Congress has passed since 1907 setting the FDA's goals and 
responsibilities.
    There is simply no defending the fact that the FDA budget for 
providing 300 million Americans a safe food supply and safe and 
effective medical treatments is the same in real dollars as it was in 
1996. The Superintendent of Schools for Montgomery County, Maryland has 
a budget equal to that of the FDA. This speaks well of Montgomery 
County's commitment to education but calls for questions of our 
national commitment to food and drug safety and the approval of new 
cures for diseases.
    Each year, the FDA receives minimal new dollars and yet its costs 
increase, missions evolve, the scope of science expands, and inflation 
erodes the budget. In addition, innovative, future focused programs of 
the FDA such as the Critical Path Initiative that would bring the 
agency into the 21st century have not been given full financial 
support, and the impact of new technologies such as nanotechnology 
cannot be measured and evaluated. The budget is holding the FDA back 
and preventing the agency from maximizing the benefits of these 
historical advances in science for the American public. The staff of 
the FDA are dedicated public servants who are ready to tackle these 
problems.
    The FDA plays a central role in American medicine. It has an 
incredibly challenging role to protect and promote the public's health. 
The agency must ensure that products are safe, but also effective. It 
must help speed lifesaving drugs to patients, yet ensure that those 
same patients have the safest drugs possible. We expect the FDA to be 
committed to protecting our health and well-being. But we have not been 
committed to giving the agency the tools and resources it needs to meet 
our expectations.
    So how do the Institute of Medicine (IOM) report The Future of Drug 
Safety and the Enzi-Kennedy bill address this gap between where we 
would like the agency to be and where it is?
    The recommendations contained in the IOM report would go a long way 
toward helping the FDA meet the goal of speeding to patients innovative 
cures that are both safe and effective. Last month, shortly after the 
IOM report was released, FasterCures and the National Health Council 
hosted a forum for patients and medical research advocates to consider 
and debate the report's findings and recommendations. Sheila Burke, who 
chaired the IOM committee, as well as IOM Study Director Kathleen 
Stratton, participated in the meeting. The conference was our attempt 
to help focus involved members of the patient and research communities 
on the implications of the proposed policy changes. We believe the 
meeting was an important first step in ensuring that the perspectives 
of patients and researchers have a prominent place in any future debate 
on drug safety. A brief summary report on that meeting will be 
submitted for the hearing record later this week.
    We urge the Congress to put the work of the IOM Committee front and 
center in its deliberations. As Ms. Burke stated at our meeting on the 
report,

           ``We've revolutionized how we care and manage people with 
        illness, but the FDA has not been able to keep up with that 
        complexity. Delaying approval until certainty is reached is not 
        always a good option. Patients depend on these drugs and yet 
        there is an all or nothing environment.''

    We appreciated the opportunity to provide comments on your proposed 
legislation prior to introduction, and we look forward to continuing to 
draw on our experience to be a resource to the members of this 
committee as you consider any policy that will strengthen the FDA. Some 
specific comments are as follows:

     On the Risk Evaluation and Mitigation Strategies (REMS) 
process, we are concerned that this process has the potential to slow 
down product reviews if not constructed correctly and with precision. 
We believe scarce FDA resources should be concentrated on activities 
that actually mitigate safety risks for designated products rather than 
be focused on reviewing risk mitigation plans for all products and 
label changes.
     We welcome the draft bill's focus on using 
www.clinicaltrials.gov to support mandatory reporting of clinical trial 
data in a manner that is useful to both medical professionals and 
patients.
     The Reagan-Udall Institute for Applied Sciences concept 
for advancing the Critical Path Institute is an exciting development. 
We are pleased that the bill recognizes the importance of Federal 
funding and the importance of having representatives of the National 
Institutes of Health in this partnership.
     Finally, we believe strengthening the FDA Advisory 
Committee process is a very important goal, however we do not believe 
the bill goes far enough. Extricating all potentially perceived 
conflicts of interest will in fact ``dumb down'' these committees 
through overly broad definitions of conflict of interest. Conflicts can 
never be eliminated from panels of experts, but they can be disclosed 
and balanced.

               III. FASTERCURES' PRESCRIPTION FOR CHANGE

    I want to elaborate on our key principles that FasterCures believes 
are essential to strengthening the FDA and ensuring that our Federal 
drug approval and oversight processes are fully prepared to harness the 
promise of 21st century medical progress.

    1. The FDA needs to be able to assess a drug's impact postapproval 
and take appropriate action to protect the public. The IOM report cited 
the need for a ``lifecycle'' approach to drug oversight. FDA's 
regulatory authority should not end with a drug's approval, because 
that is just the beginning of what we can learn about a medical 
treatment in the marketplace. Rather, we believe that FDA should have a 
greater role working with industry, doctors, and others to communicate 
what is learned about products once they have been introduced into real 
medical practice. As a drug moves from controlled trials in several 
hundreds or thousands of people to a potential market of millions, both 
its benefits and risks may be magnified. This will require more 
resources for the FDA. If the postapproval authority is exercised 
properly, we believe it will help speed the approval process because 
the agency, policymakers, and the public would have greater confidence 
that safety issues that are not apparent during the pre-approval 
phase--or that cannot be detected in pre-approval clinical trials--
would be detected and addressed quickly postapproval. This knowledge 
should be captured and analyzed in a way that doctors can better 
communicate treatment benefits and risks to their patients so more 
informed decisions on options can be made.
    2. To do proper postmarket surveillance, the FDA needs much 
stronger authority to regulate and enforce how an approved drug enters 
the market, how it is advertised, what claims are made for it and how 
labels are updated to reflect growing knowledge of a product. As the 
IOM report recognizes, safety and efficacy are the yin and yang of 
every drug and are best weighed together. We need a flexible system of 
approval and postapproval that helps consumers, physicians, and 
patients more appropriately weigh and respond to those risks and 
benefits. We specifically commend to the committee the important role 
highlighted by the IOM for nonprofit research organizations and the 
patient advocacy community in helping to bridge the gap between FDA and 
the public when discussing the benefits and risks of new medicines.
    3. To do any of this, the FDA needs a confirmed Commissioner to 
provide strong, effective and professional leadership with a long-term 
focus and vision. FasterCures supports the confirmation of Dr. Andrew 
von Eschenbach to be the Commissioner of the FDA and urges he be 
confirmed as soon as possible.
    4. And for all of this to work, the FDA needs a better 
understanding of how to communicate its work to the public to make them 
better informed participants in our healthcare system. Patients and 
consumers need timely information to help them make informed decisions. 
Toward this end, the FDA should take more aggressive steps to ensure 
that labeling information and supplemental safety and efficacy 
information are more patient-centered. Moreover, FasterCures supports 
proposals found in legislation before this committee and embraced by 
the IOM to give the FDA more authority to require sponsors to register 
data at a centralized independent Website, www.clinicaltrials.gov. We 
believe that posting appropriate information at a single, credible, 
widely available source will go a long way toward providing consumers, 
patients, providers, scientists and researchers with data they need to 
help analyze safety and efficacy information and make more informed 
decisions.
    5. To do all these things the FDA needs increased appropriations 
from Congress and should not be forced to rely on industry user fees 
which the FDA is largely restricted from using on postapproval 
activities. The FDA needs greater resources to carry out its mission. 
Many of the improvements recommended by the IOM and included in several 
legislative proposals will simply not be possible without additional 
resources. The IOM recommended that Congress approve a substantial 
increase in both FDA funding and personnel. FasterCures strongly 
believes that any additional funding should come from appropriated 
funds, rather than user fees. Because FasterCures believes this is 
critical, we are actively participating in two coalitions that are 
aggressively advocating for additional funding for the agency: The FDA 
Alliance and the Coalition for a Stronger FDA.

                             IV. CONCLUSION

    There is no agency or aspect of our government that touches more 
lives everyday than the FDA. Its mission is the highest and best 
example of the government's core mission--to protect the health and 
safety of the American people. Historically, the FDA has done its work 
so well that it represents the gold standard all other countries rely 
upon and seek to emulate. There can be no resting on our laurels. 
Either we provide the FDA the tools and resources it needs to thrive in 
the 21st Century or it will begin to atrophy and our Nations' health 
will begin to atrophy with it. Many of the proposals contained in both 
the IOM report and the Enzi-Kennedy legislation will help position the 
FDA to meet the medical challenges of the 21st Century. But those 
proposals will not succeed if we are not committed as a Nation to 
valuing the health of our people far greater than is now the case and 
to acting accordingly.
    Thank you for the opportunity to testify. FasterCures looks forward 
to continuing to be a resource to the members of the HELP Committee and 
to Congress as you address these important issues.

    The Chairman. Thank you very much, and I want to commend 
all of you for your ability to stay close to the time that was 
allotted. That's extremely helpful. And I've got to say your 
testimony, the written as well as what you've just presented, 
was outstanding and extremely helpful. I do have a few 
questions. Actually, I've got a lot of questions. Some are of a 
fairly technical nature. Those I'll submit to you in writing so 
that I can get some fairly technical answers that won't put 
anybody to sleep, but will aid in the production of good 
legislation.
    But in the line of some questions, Ms. Thompson, are you 
worried that asking the FDA to take on new responsibilities is 
going to result in a slowing down of drug approvals?
    Ms. Thompson. We're obviously of the position that patients 
shouldn't have to choose between speed and safety, and that it 
is particularly important that as this committee looks to 
asking the FDA to take on new responsibilities or to improve 
the way that it performs existing responsibilities that that 
request, that mandate, be coupled with resources adequate to do 
the job. It can't be an either/or situation.
    The Chairman. Thank you.
    Dr. Nissen, as a practicing doctor doing these clinical 
trials, do you think that the restrictions on distribution and 
use interfere with the practice of medicine and prevent doctors 
from using their best judgment about how to treat patients?
    Dr. Nissen. I'm not sure I understand your question. What 
do you mean by ``distribution and use?''
    The Chairman. Well, I'll phrase it more broadly than that. 
The restrictions that are now being placed on drugs and the 
potential under this bill to place some requirements on it, do 
you think that will interfere with the practice of medicine and 
prevent the doctors from using their best judgment? Do you 
think it's open enough that we're not going to be constricting 
your practice?
    Dr. Nissen. I don't think that from the point of view of 
physicians that anything in this bill would restrict our 
ability to care for patients. It's important to understand 
that, in fact, physicians do retain a great deal of discretion 
in what we do and how we do it. But we can only make good 
decisions when we have access to all the information, and I 
would argue that you really are enhancing the ability of 
physicians to make good decisions, because you're providing for 
the disclosure of all the information on safety and efficacy 
that we need to make good choices, and that's why the increased 
transparency that's required in this bill, if anything, will 
enhance the ability of physicians to make good decisions.
    The Chairman. Thank you.
    Dr. Thomas, the legislation that we're proposing gives the 
FDA the authority to impose restrictions on drugs. Recently the 
iPLEDGE program for the acne drug Accutane has come under fire 
because, while it seems to be meeting the goal of reducing 
pregnancy exposures, it's also reducing the number of people 
who get the drug. We believe that we have taken steps in the 
pill to assure that patients get the drugs they need even if 
those drugs have restrictions on their use. Your comments?
    Dr. Thomas. Thank you, Chairman Enzi. I think the issue of 
restriction on distribution or supply is an interesting one and 
it's certainly true that there are many situations where the 
risk of inadvertent exposure may require agreements about how 
products are accessed. I come from a kind of large country with 
not many people and I have worked as a flying doctor, and I was 
probably one of the only flying vascular surgeons or physicians 
around and patients' ability to get from isolated areas, to get 
to a specialist was difficult. So I can also foresee that one 
unintended outcome of distribution restrictions is, in fact, 
restrictions of access by a supplier.
    So I think those things need to be carefully thought out. 
Without discounting the importance that one needs to place on 
the legitimate use of it, unintended consequences may follow.
    The Chairman. Thank you.
    Mr. Guest, in your testimony you recommended across the 
board restrictions on the direct-to-consumer advertising for 3 
years as opposed to the 2 years that's in the bill. Banning all 
direct-to-consumer advertising is kind of a blunt authority. 
The bill that we've introduced tries to get away from that 
strict of an approach. Since every drug represents a unique 
profile of benefits and risks, would it make sense to give the 
FDA some discretion in this area?
    Mr. Guest. The bill does give the FDA restriction and 
that's okay. We would just say it should be for a longer period 
of time, because obviously a lot of the adverse consequences or 
events that can occur will occur after a pill is on the market, 
when there are then millions, hundreds of thousands and 
millions of people. That's the real clinical trial on a drug.
    Our concern about direct-to-consumer advertising generally 
is that's not a good way for consumers or physicians or medical 
providers to be informed. At Consumer Reports our whole history 
is that consumers should be given full information, unbiased, 
independent, research-based information, about both the 
positive qualities and the negative qualities of products or 
services, whatever they may be.
    The problem with direct-to-consumer advertising is that's a 

poor way to give comparative information to consumers so they 
can make informed choices. There was a conversation earlier 
with Sheila Burke that what's needed is a way for consumers to 
have full information about the range of choices that they have 
in a fashion that they can understand and not just a particular 
hype.
    I mean, direct-to-consumer advertising is not a good way to 
convey really good information about pharmaceuticals. It's 
really--clinical trials should not be a marketing tool. They 
should be a tool for consumers to make informed choices and 
providers to make informed choices.
    The Chairman. Thank you.
    My time has expired.
    Senator Reed.
    Senator Reed. Thank you very much, Mr. Chairman, and thank 
you, ladies and gentlemen, for your testimony.
    I have just one major question. I think it's a threshold 
question for us. I'll start with Mr. Simon. Everyone 
understands that the FDA culture has to change and that's a 
function of funding, it's a function of other legislation we've 
created, PDUFA, the way we collaborate with the industry. But I 
presume, and I don't want to have it unstated, that you feel 
that the legislation that's being discussed today, both 
versions, are important; we have to do something legislatively, 
that we just can't rely upon a little more money and some 
spontaneous cultural change will happen at FDA. Mr. Simon, do 
you want to comment? And you can use this as a broader 
springboard to discuss, and I'll go down the line.
    Mr. Simon.
    Mr. Simon. Thank you. First, Senator, with regard to 
resources, there is no amount of leadership or organizational 
change that can trump a lack of resources. So you have to have 
a balance.
    Secondly, the greatest asset of the FDA is its people and 
they have too few assets. They need far more people to do this. 
We spend as a Nation $100 billion a year researching new drugs 
and treatments for diseases as a government, as industry, and 
as nonprofits, and then we ask the FDA on a budget of $1 
billion on the drug side to review the product of this enormous 
pipeline, and then we wonder why they don't do it fast enough 
and well enough. So they need more people.
    But they also need organizational change. You can't have 
people wait until the end to start asking safety questions. You 
need people to see all the information through the entire 
process. I totally agree with Sheila Burke that we should not 
separate these functions. They need to be integrated. And when 
you have the money and you have the leadership and you have the 
organizational structure, then you need political independence 
to be able to take the science where the science goes and be 
able to tell the American people, this is where the science is 
and now you as the patient with your provider can make a 
decision about how to treat your condition.
    Senator Reed. Please.
    Mr. Guest. Just briefly, I think this legislation, and 
hopefully with the changes we recommend, will help restore 
trust in the FDA and help the FDA actually earn that trust, 
because there's a real skepticism right now among the American 
public, are our drugs safe and is this agency that's supposed 
to be protecting our safety really doing it in an independent 
scientific, unbiased way.
    That's why, among other things, we think it's really 
important that the other scientists who do the research at the 
FDA, that their information also be public, because these 
decisions are not all black or all white. There are subtleties 
and the public and consumers and members of the medical 
community ought to know where there are reservations or 
concerns so they can take that into effect when they're making 
their decisions.
    Senator Reed. Dr. Nissen.
    Dr. Nissen. Yes. I must tell you that the staff at the FDA 
are demoralized. I know them very well and I've worked with 
them 5 years on their advisory panel. Some of the best people 
have left the agency. There's a flight going on now. It will 
take us years to recover from what's happened already. That 
flight has occurred because of underfunding. There is a lot of 
concern expressed, not publicly but privately, about the 
politicization of the agency. It's very discouraging when you 
want to do the right thing and you feel like you're not free to 
do so, and I have heard this from staffers at the FDA.
    I believe that also, that the entire PDUFA principle has 
undermined the FDA. It's created dual loyalty, and we need to 
have one loyalty and the loyalty is to the American public. 
That's what we've got to get back to. We're not asking for the 
Congress to fund this agency with tens of billions of dollars, 
just somewhat modest increases, and we could get away from the 
user fee principle and we could go to recruiting back into the 
agency the kind of quality people that we need to get the job 
done.
    Senator Reed. Thank you, doctor.
    Ms. Thompson, do you have a comment?
    Ms. Thompson. Yes. I would certainly like to echo the 
comments made about the importance and professionalism of the 
FDA and its staff. Clearly the people at that agency are its 
most precious resource and in order for them to do the best 
that they can they must have effective leadership, they must 
have the resources they need to do the job, and there must be a 
transparent system that will enable all of us to participate in 
rebuilding the sort of support for the FDA that traditionally 
has existed.
    You know, the ability of a mom and two of her friends 
sitting around the table to engage in the drug review process, 
as Elizabeth Glaser and her friends in the foundation were able 
to do, is enormously important to the public credibility for 
this agency. So clearly leadership, resources, and transparency 
are key components to re-establishing that credibility.
    Senator Reed. Before I call on Dr. Thomas, I think we all 
agree with that, but I don't want to assume that people would 
be suggesting that we don't need to do this legislation. I 
think this legislation's an important part of the ingredients 
for that accountability, resources, and structural changes 
within the organization, and we have your advice on changes to 
that and there's two very good models that have been proposed 
by my colleagues. But simply to sit back and maybe put a little 
more money into the till is not going to fix the problem.
    Ms. Thompson. Well, Senator, if I may.
    Senator Reed. Yes, ma'am.
    Ms. Thompson. Thank you for that. That's absolutely right. 
In resources I would include the tools that the agency needs, 
the enforcement tools, informatics infrastructure. There's a 
whole range of elements that come under resources, but of 
course the ability to keep those key staff as well.
    But this legislation and many of the recommendations that 
have been made will be key elements to providing--will provide 
those key elements in terms of authority, structure, emphasis, 
priorities, that will be critical to moving this drug safety 
system forward.
    Senator Reed. Dr. Thomas, I'd appreciate your comments very 
much.
    Dr. Thomas. Thank you, Senator Reed. Broadly speaking, this 
piece of legislation, this bill, is a very important piece of 
work towards enhancing patient safety, and I want to say that 
up front. However, I agree with the rest of the panel, you need 
to have both the resources and leadership to enable the agency 
to meet what is fundamentally a very important and very 
significant role within this country, not just this country, 
but as someone who works broadly around the world, the U.S. FDA 
is today a very respected and strong provider of scientific 
leadership in regulatory matters.
    So we should not diminish the role they play today. But 
without the appropriate leadership, without the appropriate 
resources--and industry is not averse to increases in PDUFA 
fees. But when the increases lead to industry funding more than 
50 percent of the agency's activities, that's a legitimate 
matter for public concern. So I think the agency needs all the 
things the panel has discussed and we in the industry agree 
fully that the first responsibility of the agency and its 
accountability is to the American public.
    Senator Reed. Thank you very much. Thank you, gentlemen. 
Thank you, Ms. Thompson.
    Thank you.
    The Chairman. Senator Clinton.
    Senator Clinton. Thank you, Mr. Chairman.
    I want to really thank and compliment this panel. I'm sorry 
that I had to step out to tend to some other business, but I am 
very grateful to each of you. Dr. Thomas, thank you for your 
last comments. I think that that's very helpful. Ms. Thompson, 
Elizabeth Glaser was a friend of mine and I'm very pleased that 
you're here representing the foundation and that the foundation 
continues to play such an important role in public policy. Dr. 
Nissen, thank you not only for your testimony but for your 
courage. I appreciate you being on the end of the spear, as you 
say in your testimony, because we need you there and your 
stepping forward and lending your expertise to this debate is 
absolutely essential. I also want to thank my friend Greg Simon 
for his continuing public service, and this FasterCures 
approach is one that I hope we can really see as a tremendous 
partner as we move forward in this.
    I particularly want to thank Jim Guest for being here. I'm 
proud that Consumers Union is based in Yonkers, New York, and I 
was delighted to go to their facilities and see all of the 
great work that is being done there. Jim, it's terrific that 
you're here. I want to also thank the families that you 
mentioned in your testimony for joining us today.
    As Jim noted, the problems of our drug safety system are 
not just abstract questions of studies and trials. Really, the 
failure to place concerns about safety above ideological or 
economic concerns has had an impact on the lives of Americans. 
As we continue to work on drug safety and broader FDA 
legislation next year, I think it will be important to give 
those impacted, such as the families you reference, a voice in 
this debate, because we need to put a human face on it. We 
often get caught up in the statistics and the dollars and all 
of the complexity of legislative language, but this comes down 
to people's lives, to their well-being.
    Jim, in your written testimony you talk about the need for 
legislation that would establish a path for the approval of 
biogeneric drugs. I think we have to look both at what we do 
with respect to biologics from pharma as well as biogeneric. 
We're not doing a very good job on the former yet. We don't 
have a good partnership. I visited a plant in my State that is 
one of the great leaders in biologics right in Syracuse, New 
York, Bristol-Myers-Squibb, and they have concerns about where 
the expertise is going to come from inside the FDA to help them 
work on biologics. So we've got to simultaneously work on 
biologics and biogenerics and try to understand what we have to 
do going forward.
    I've introduced along with Senator Schumer and Congressman 
Waxman the Access to Life-Saving Medicine Act, a bill that 
would improve the FDA's ability to quickly bring safe 
biogeneric products to the market. But I just want to say a 
word of caution. I don't think we've done a very good job on 
biologics yet.
    But would you elaborate on the ways in which you think 
increasing access to biogenerics could improve access to safe 
and appropriate treatments for patients?
    Mr. Guest. Well, let me first say I agree with you, it's 
both biologics and biogenerics which are really complicated, 
and to break through a process for responsible and timely 
review on both counts I think is important. I certainly hope 
that there'll be hearings and really serious consideration of 
your proposals on it. That's a whole new hearing almost and a 
whole new set of things to do it.
    But I mean, clearly the future of people's health is going 
to be significantly affected by biologics and biogenerics. 
Again, as an organization that's interested in consumer safety 
and consumer opportunity, I think that it's--I think the 
emphasis that you're giving it is absolutely well placed and 
would hope that the Congress would move forward on that front 
as well.
    Senator Clinton. I thank you for that, and I think that in 
addition to what is clearly a complicated area, there are very 
few of us--there are some, but I think there are few of us in 
the Congress who really have the background in this complex, 
fast-moving area. We need quite a bit of discussion. I would 
throw on the table another issue which I am increasingly having 
questions about and that's the whole area of nanotechnology and 
the creation of these nanodevices and nanoelements. They are 
clearly part of the whole biologics effort. We don't really 
understand the impact on our health or our environment of them.
    We are truly on a new frontier, Mr. Chairman. I hope that 
as we go forward we will take the time to educate ourselves 
thought-
fully about this range of issues. But the bottom line is we 
need, as Dr. Thomas said, to make sure that the FDA remains the 
gold standard. We've got to give it the resources, the morale, 
and the authority it needs, because we're on the brink of 
extraordinary, breathtaking changes and we're not even 
particularly well equipped for what's already on the table.
    So I thank you, Mr. Chairman, for holding this important 
hearing.
    The Chairman. Thank you very much.
    I want to thank the witnesses for their time that it took 
to prepare the testimony, the time to give it, the time to 
answer the questions that we've had here. And of course I am 
hoping that obligates you to also answer the questions that 
we'll provide in writing. Around here there are a lot of things 
going on at the same time, so there are a lot of conflicts with 
different committees. So members of our committee will have to 
educate themselves on what has been said and they'll do that 
through staff that's been attending, and we'll undoubtedly have 
some questions for you, too. But that will all play a vital 
role in us getting it right, which is what we want to do. This 
has been a fantastic panel because it's a wide spectrum of 
stakeholders and it's been very helpful.
    The record will stay open for 10 days and members of the 
committee can submit their questions. I would also mention that 
I do have a number of comments from other colleagues, some of 
whom are not on the committee, and I would ask unanimous 
consent that the number of outside groups as well as 
colleagues' comments be entered in the record. Without 
objection.
    Thank you very much. This hearing is adjourned.
    [Additional material follows.]

                          ADDITIONAL MATERIAL

   Prepared Statement of the Advanced Medical Technology Association 
                               (ADVAMED)
    AdvaMed and its member companies thank the committee for holding 
this hearing on improving drug safety and innovation. Although the bill 
under review is not specifically intended to affect medical devices, 
there are two provisions in the bill pertaining to FDA advisory panels 
and critical path which could affect our industry. We respectfully 
submit our comments for your review.
    AdvaMed member companies produce the medical devices, diagnostic 
products and health information systems that are transforming 
healthcare through earlier disease detection, less invasive procedures 
and more effective treatments. Our members produce nearly 90 percent of 
the healthcare technology purchased annually in the United States and 
more than 50 percent of the healthcare technology purchased annually 
around the world. AdvaMed members range from the largest to the 
smallest medical technology innovators and companies.

                          FDA ADVISORY PANELS

    A rational conflict of interest policy for panel members is 
critically important to the effective functioning of panels. It is 
equally important, however, to ensure that highly capable, expert 
physicians and researchers continue to be willing to serve on FDA 
advisory panels, and we are concerned that the current bill language 
may discourage such experts from participating in the FDA panel 
process.
    The pool of experts in the device arena is limited due to the fast-
advancing product developments and diverse product areas where only a 
handful of national experts may exist within literally thousands of 
different product areas. It is important that physicians and 
researchers at the top of their fields be able to provide their 
expertise, insights and perspective to FDA on emerging technologies to 
advance patient care and ensure safe and effective technologies.
    Workable conflict of interest rules and/or guidance can strike a 
healthy balance between ensuring the participation of knowledgeable 
panel members and avoiding bias attributable to self-interest. A more 
measured approach to addressing potential conflicts for panel members 
should include a broad requirement for the FDA to review its guidance 
and rules related to panel member conflicts and to update them to be 
more precise and understandable. Any legislation in this area should 
avoid impinging on the privacy of persons who are performing a public 
service.
    AdvaMed is concerned about provisions to standardize how panel 
members are evaluated and require FDA to publicly disclose the 
financial status of potential panel members over the Internet and via 
guidance documents. Under current law, waivers are published on the 
Internet and financial and other personal information about panel 
members is redacted. The legislation would discourage individuals with 
needed expertise from participating in FDA panels by broadly 
publicizing the details of determinations about advisory panel members 
over the Internet, and by requiring the issuance of guidance that is 
aimed at revealing the financial status, including possibly the net 
worth of individual panel members. For example, the legislation would 
publicly release detailed financial information and ``involvements''--
requirements that will clearly discourage needed panel participation. 
AdvaMed recommends changing the legislation to allow the FDA to 
individually evaluate each panel member for conflict of interest 
status.
    We are also concerned about provisions in the legislation to 
require the HHS Inspector General (OIG) to ``on an ongoing basis'' 
conduct reviews ``of the financial interests of a representative sample 
of individuals who have served on a[n] [FDA] panel . . . ''. As part of 
a semi-annual report, the OIG would also be required to include the 
results of the OIG's review of the financial interests of panel 
members. These measures would discourage the foremost device experts as 
well as experts with no conflicts at all from serving on FDA panels.

                             CRITICAL PATH

    AdvaMed strongly supports the objectives of FDA's Critical Path 
Initiative and the intentions of the proposed Reagan-Udall Institute 
envisioned in S. 3807, particularly regarding the Institute's potential 
role in focusing resources on the unique challenges of medical device 
development and evaluation. Our member companies and the academic 
research community are pioneering new research methods that can speed 
medical product development and more quickly identify and assess 
emerging safety issues.
    AdvaMed urges the Administration and Congress to allocate new funds 
to the FDA device program to ensure that device-related aspects of the 
Critical Path Initiative are able to develop fully. The additive nature 
of user fee programs should not be violated by diverting these funds to 
activities far removed from the product application review function.
    AdvaMed also recommends that programs undertaken through both the 
Critical Path Initiative and the proposed Reagan-Udall Institute be 
implemented to clearly reflect the important differences between drugs 
and devices. We recommend the specific inclusion of device expertise in 
the leadership structure of both programs at all levels.
    The mission of both programs should be adjusted to reflect the 
fundamental differences between the medical device development and drug 
discovery processes; while new drugs stem from discovered molecules, 
new devices are developed through a design and engineering process with 
specific, intended functions in mind. AdvaMed and its member companies 
are committed to working with FDA and the leadership of the Reagan-
Udall Institute to broaden understanding of the unique nature of 
medical device technology development and to working to maximize the 
contributions of the medical device community to the Critical Path 
Initiative.

                               CONCLUSION

    Again, we thank the committee for holding this hearing today. As 
the committee works to create a 21st Century FDA, AdvaMed looks forward 
to working with you to create a balanced approach to expert panels at 
FDA, increase the attention to devices within the Critical Path 
Initiative and Reagan-Udall Institute efforts, and enhance patient 
access to lifesaving and life-enhancing medical technologies.

      Prepared Statement of the American Society of Health-System 
                           Phamacists (ASHP)

    The American Society of Health-System Pharmacists (ASHP) 
respectfully submits the following statement for the record to the 
Senate Health, Education, Labor, and Pensions (HELP) committee hearing 
on ``Building a 21st Century FDA: Proposals to Improve Drug Safety and 
Innovation.''
    ASHP is the 30,000-member national professional and scientific 
association that represents pharmacists who practice in hospitals, 
health maintenance organizations, long-term care facilities, and other 
components of health systems. For more than 60 years, ASHP has helped 
pharmacists who practice in hospitals and health systems improve 
medication use and enhance patient outcomes. This includes working with 
patients to help them access the medications they need and to use them 
safely and effectively.
    The Society has long-standing policies that express support for 
congressional action to provide the Food and Drug Administration (FDA) 
with increased authorities to require post-marketing studies on the 
safety of drugs that are in the public interest. ASHP policy has also 
supported broader authority for the FDA to require additional labeling 
or the withdrawal of certain products on the basis of review of such 
studies.
    ASHP applauds Chairman Enzi and Senator Kennedy for their efforts 
to try and address the difficult challenge of establishing a system of 
drug approval and monitoring that maintains a balance between the 
benefits of an innovative, potentially life-saving drug and the risks 
associated with its widespread use in the population. The current drug 
safety system can be improved through increased regulation, but it is 
important to realize that no system will succeed without the commitment 
and proper training of healthcare professionals and the understanding 
of patients of medication risks and benefits.
    As you move forward with legislation to address drug safety, we 
would urge you to continue to evaluate the essential role that 
healthcare professionals and especially pharmacists play in ongoing 
post-marketing surveillance and in managing known risks. As medication-
use experts and frontline providers of medication management services, 
pharmacists are necessary and fundamental to the drug safety system, 
with a responsibility to assist patients, physicians, and other 
healthcare professionals.
    As the committee pursues its legislative strategy, we would ask 
that you consider several points in key areas:

        POST-MARKETING SURVEILLANCE STRATEGY & RESTRICTED DRUG 
                          DISTRIBUTION SYSTEMS

    The ``Enhancing Drug Safety and Innovation Act'' (S. 3807) does 
permit the establishment of new Restricted Drug Distribution Systems 
(RDDS) in some limited circumstances. While ASHP values and 
acknowledges the critical role that an RDDS plays in managing drug 
safety, the use of such systems should not compromise timely and 
appropriate patient care and should not be overly burdensome to 
healthcare practitioners who are attempting to meet patient needs. This 
is especially of concern in hospital settings where pharmacists are 
trying to deliver medications and manage the therapy for high-risk 
patients.
    While we understand that new RDDS programs will only occur in 
limited circumstances, they do have a cumulative effect on health-
system pharmacy practice and patients directly. Many ASHP members have 
reported that RDDS programs are burdensome and confusing for 
practitioners and that they at times result in delayed care and 
inconvenience for patients and disrupt the continuity of care.
    In order to simplify these programs while maintaining their intent, 
we urge the committee to work with ASHP and other stakeholders to 
develop legislation that would standardize RDDS programs, require 
pharmacist input into each program's development, and improve access to 
information for clinicians and patients about the types of restricted 
distribution systems.

                     DIRECT-TO-CONSUMER ADVERTISING

    ASHP policy supports direct-to-consumer advertising of drug 
products only when the following requirements are met: (1) such 
advertising is delayed until post-marketing surveillance data are 
collected and assessed, (2) the benefits and risks of therapy are 
presented in an understandable format at an accepted literacy level for 
the intended population, (3) that such advertising promotes medication 
safety and allows informed decisions, and (4) that a clear relationship 
between the medication and the disease state is presented.
    While ASHP is pleased to see that S. 3807 permits FDA to place 
certain requirements on manufacturers' drug advertising efforts, we 
would recommend that the committee permit the FDA to extend any 
moratorium period over 2 years should additional delays be required to 
collect and assess essential post-marketing surveillance data.

     CLINICAL TRIALS REGISTRY AND CLINICAL TRIALS RESULTS DATABASE

    ASHP policy supports the disclosure of the most complete 
information possible on the safety and efficacy of drug products and 
has recommended the establishment of a mandatory results registry for 
all Phase II, III and IV clinical trials that are conducted on drugs 
intended for use in the United States. All clinical trials undertaken, 
but not yet completed, should be added to the registry and, upon 
completion, the results should be posted electronically with 
unrestricted access as quickly as possible after FDA approval but 
before marketing commences. Strong enforcement mechanisms are necessary 
to ensure compliance.

     ADDITIONAL FDA FUNDING NEEDED FOR POST-MARKETING SURVEILLANCE

    While we acknowledge funding is not in the jurisdiction of this 
committee, we cannot discuss enhancing FDA's ability to meet its public 
health mission without expressing support for increased resources for 
the agency. It is startling that the resources designated for all food 
and drug regulatory activities in the United States are equivalent to 
the budget of the Montgomery County, Maryland, public school system 
($1.85 billion for 2007), which is the county where the agency is 
located. ASHP is a member of the FDA Alliance and supports funding 
increases for the agency for the 2008 fiscal year.

          BETTER UTILIZATION OF PHARMACISTS SHOULD BE FOSTERED

    Increased Federal regulations of drug approval and marketing alone 
will not result in an improved drug safety system. We urge the 
committee to look carefully at methods to better prepare healthcare 
professionals for playing a larger role in post-marketing surveillance 
and in managing known risks. ASHP believes pharmacists have a crucial 
role in fostering improved medication-use safety. Postgraduate pharmacy 
residency training is especially designed to prepare pharmacists for 
this role. Unfortunately, there are an insufficient number of such 
accredited programs to meet the Nation's needs. Additional Federal 
support for pharmacy residency training would have a major effect on 
improving the outcomes from medication use, especially in high-risk 
patients.
    As medication-use experts and frontline providers of medication 
management services, pharmacists are necessary and fundamental to the 
drug safety system. All medications have associated risks, and 
pharmacists have a responsibility to assist patients, physicians, and 
other healthcare professionals in managing medicines with risk profiles 
that require careful patient selection and monitoring. Products that 
are safe and effective only in certain patients, but not in others, 
have been withdrawn from the market due to inappropriate management of 
well-known risks and a lack of ability to differentiate appropriately 
among patients. If a pharmacist, as part of the healthcare team, had 
monitored and adjusted the therapy to minimize or eliminate risks, a 
subset of patients could have continued to receive benefits from the 
withdrawn medications.

                               CONCLUSION

    We appreciate the opportunity to share our views on how to improve 
the drug safety system in this country. It is essential that the 
American public have confidence in our Nation's ability to maintain the 
integrity of our drug supply and protect patient health through 
appropriate drug approval and monitoring systems. ASHP and its members 
are committed to working with the Congress, FDA and other stakeholders 
to achieve this goal.

        Prepared Statement of the National Association of Chain 
                          Drug Stores (NACDS)

    Chairman Enzi, Ranking Member Kennedy, and Members of the Health, 
Education, Labor, and Pensions Committee. The National Association of 
Chain Drug Stores (NACDS) appreciates this opportunity to provide the 
committee with a statement for your hearing, ``Building a 21st Century 
FDA: Proposals to Improve Drug Safety and Innovation.''
    NACDS represents the Nation's leading retail chain pharmacies and 
suppliers, helping them to better meet the changing needs of their 
patients and customers. Chain pharmacies operate more than 37,000 
pharmacies, employ 114,000 pharmacists, fill more than 2.3 billion 
prescriptions yearly, and have annual sales of nearly $700 billion.
    The chain pharmacy industry agrees with the need to enhance the 
safety of medication use in the United States, and shares the 
committee's goal of improving public safety and helping patients and 
healthcare providers make informed decisions about healthcare. Because 
the methods in which community pharmacies protect the safety of their 
patients would be directly impacted by drug safety legislative changes, 
we are providing comments to you on two specific elements of drug 
safety proposals: Medication Guides and restricted distribution 
systems.

                           MEDICATION GUIDES

    Over the past 2 years, the Food and Drug Administration (FDA) has 
significantly increased the number of pharmaceutical products which 
require a Medication Guide (``MedGuide'') to be dispensed with each new 
and refilled prescription. Currently, there are over 1,500 
individually-manufactured products with different National Drug Codes 
(NDCs) that require the dispensing of a MedGuide.
    With over 1,500 individual products needing to be dispensed with 
MedGuides, we are concerned about proposals that could lead to the 
unnecessary approval of MedGuides outside the scope of the FDA's 
original intention to require them only for a few products which pose a 
``serious or significant concern.'' Requiring the use of a MedGuide as 
part of all Risk Evaluation and Mitigation Strategies (REMS) may result 
in overuse of MedGuides.
    All pharmacies already provide patients with comprehensive written 
information on their medications. This information, which is updated 
continuously, is provided to pharmacies electronically by database 
companies and then printed by pharmacies. To enhance the distribution 
of MedGuides, we suggest a similar procedure be developed for 
MedGuides, in which pharmacies are permitted to print MedGuides through 
their computer systems. This will enhance the percentage of patients 
that receive Medguides that are consumer friendly and easy to read.
    NACDS supports educating patients on their medications. However, 
the use of MedGuides may not be the most effective way to educate 
patients for all medications. MedGuides should remain a resource only 
for medications which pose a serious or significant concern. It is 
important to note that while the FDA has significantly increased the 
number of MedGuides recently, there is no evidence which demonstrates 
that MedGuides enhance patients' understanding of medication risks.
    Although manufacturers are required to provide MedGuides in 
``sufficient quantities'' to pharmacies, there is no standard method of 
distribution used throughout the industry. Instead, each manufacturer 
of a product with a required MedGuide can choose from an unlimited 
number of methods. Most commonly, manufacturers provide pharmacies with 
small MedGuide documents which are difficult to handle for pharmacists 
and even more difficult to read for patients. In most cases, this 
results in a MedGuide which does not achieve its intended goal of 
educating patients on their medications.
    We suggest that drug safety proposals enhance the process by which 
MedGuides are provided by manufacturers and dispensed to patients. FDA 
should use its authority to require manufacturers to use identical 
procedures for producing MedGuides and distributing them to pharmacies.
    In order to determine whether or not MedGuides are meeting the 
goals of educating patients on their medications, we suggest that the 
FDA assess the benefits of different types of written information, 
including MedGuides. This information will be very helpful in 
determining how to best educate patients on their medications so they 
can use them safely and effectively.

                    RESTRICTED DISTRIBUTION PROGRAMS

    NACDS and the community pharmacy industry believe there is a need 
for significant changes to the manner in which restricted distribution 
programs are developed, approved, and monitored. We support proposals 
to provide the FDA with more authority over the development of these 
programs so that they are effectively and efficiently implemented by 
healthcare providers.
    Community pharmacies have extensive experience with many restricted 
distribution programs, including one of the largest programs, the 
iPledge program for isotretinoin (Accutane). As a result, we have 
several recommendations for drug safety legislation as it relates to 
restricted distribution programs.
    As evidenced through the challenges with the recently implemented 
iPledge risk management program for isotretinoin, if restricted 
distribution programs are not developed properly, patient access can be 
hindered significantly. As a result, a delay in patient access to 
medications in restricted distribution programs can have negative 
consequences on health outcomes.
    To help limit burdens on patients, NACDS suggests that drug 
manufacturers and the FDA obtain the input of stakeholders, including 
patients, pharmacies, and physicians that will ultimately implement the 
restricted distribution program. This will result in a more effective 
program which builds upon the risk management strategies already put 
into place in the private sector. Programs developed using industry 
capabilities will also result in enhanced compliance by all 
participants with fewer interruptions in patient care.
    Although NACDS recognizes the necessity of training practitioners, 
pharmacists, and other healthcare providers as part of restricted 
distribution programs, it is important to note that there are already 
rigorous requirements on pharmacists and pharmacies in order to be 
licensed by States to dispense medications. We believe pharmacists and 
pharmacies should not be subject to certification requirements to 
participate in restricted distribution programs.
    NACDS also urges restricted distribution programs to provide all 
dispensing locations, including community pharmacies, with the 
opportunity to participate. There are some medications that are only 
appropriately dispensed in the institutional setting because of 
specific monitoring necessities, but these prescription drugs are the 
exception. Many patients prefer to use their local community pharmacy 
for their prescription needs. Also, having patients fill all of their 
prescriptions at one location helps assure that their pharmacy is able 
to identify and prevent any potential adverse drug reactions (ADRs) or 
complications between the restricted distribution medication and the 
other medications the patient is taking. Participation by pharmacies or 
other healthcare providers in a restricted distribution program should 
only be limited if a dispensing location cannot meet the program 
requirements.

                               CONCLUSION

    Thank you for the opportunity to provide this statement to the 
hearing record. We look forward to working with the committee on 
advancing legislation that improves drug safety and public health.

       Response to Questions of Senators Enzi, Kennedy, Murray, 
                      and Clinton by Sheila Burke

                       QUESTIONS OF SENATOR ENZI

    Question 1. Do you believe that comparative effectiveness studies 
for drugs should be done by the FDA or by payers?
    Answer 1. Such studies can be done by FDA, by payers, or by both 
working collaboratively on some or all aspects of study design and 
execution.

    Question 2. Do you think that user fees affect product approval 
decisions by FDA?
    Answer 2. The committee did not attempt to conduct a systematic 
analysis of the impact of user fees on product approval decisions by 
FDA. However, the committee recognizes that a perception exists that 
user fees influence approval decisions. Also, in its information 
gathering, the committee has learned that the time pressures associated 
with the user fees program requirements may contribute to an inability 
to examine pre-approval safety issues as closely or thoroughly as a 
reviewer may believe is necessary. The committee also noted that the 
attention and resources devoted to the pre-approval (review) process 
are substantially greater than those available to monitor and 
effectively react to a drug's post-approval performance.

    Question 3. The IOM report addresses some communication issues 
within FDA and their impacts on drug safety. Are communications between 
FDA and other agencies on drug safety issues effective? If not, how 
might they be improved?
    Answer 3. The committee was not asked specifically to consider 
interagency communication on drug issues, but the committee did comment 
on the existing and increasing data available from publicly funded 
healthcare programs (those of CMS and VA), and the need for better 
communication and especially greater resources to support collaborative 
efforts among FDA and other agencies. For example, collecting and 
analyzing relevant Medicare part D data for FDA drug safety 
surveillance purposes requires funds for staff, information technology, 
etc.

    Question 4. I agree with you and with some of the other witnesses 
that, absent increased appropriations, we should expand what activities 
may be covered by user fees. However, approximately half of CDER's 
budget is currently derived from user fees. If we increase this figure, 
do we run the risk of undermining the perceived independence of the 
agency?
    Answer 4. That is a legitimate concern. In acknowledgement of the 
high likelihood of PDUFA reauthorization, the committee has called for 
removing the restrictions on how user fee funds are used, in the belief 
that these not only create hardships for certain CDER programs 
important to drug safety, but also reinforce the perception that the 
sponsors unduly influence the process. It is also incumbent on the 
Commissioner and center director to clearly explain the science based 
behind the decisions that are made in order to dispel any inaccurate 
assumptions or interpretations of what motivated certain regulatory 
decisions. In other words, it is important that agency leadership ``go 
the extra mile'' in the area of transparency.

                      QUESTION OF SENATOR KENNEDY

    Question. There has been a lot of debate on whether to establish a 
safety center at FDA that is separate from the office that approves new 
drugs, but your report rejected this idea. Why did you conclude that 
this was not the right approach?
    Answer. There are two reasons for the committee's discomfort with 
the idea of a separate safety center. First, the committee believes 
strongly that safety and efficacy must be considered together during a 
drug's lifecycle by professionals who can work collaboratively to piece 
together a complex and evolving puzzle--what was known before approval, 
and what is learned about a drug's risks and benefits after it has been 
on the market for some time. Staff in the Office of New Drugs and those 
in the Office of Surveillance and Epidemiology (formerly Office of Drug 
Safety) each possess information and skills that are important to the 
process. For example, reviewers of new drugs know a lot about (classes 
of) drugs that never make it to market. Separating post-marketing 
safety staff from review staff would break down and complicate the 
lines of communication and it could compromise the institutional memory 
about drugs reviewed in the past and those that were actually approved. 
Second, the reasons that have been given for creating a separate safety 
center have included the claim that the staff who were responsible for 
approving a drug have a built-in bias against overturning their 
previous decision once safety problems arise. There have not been in-
depth studies to support this theory, but the committee in its 
information gathering activities found no reason to suspect this would 
be the case. In fact, the committee found that drug reviewers are 
deeply aware of and sensitive to the reality that the risk-benefit 
analysis that leads to a drug approval is frequently based on limited 
information, and that only more extensive and prolonged experience with 
a drug in a real-life setting will either solidify the earlier position 
on a drug, or lead to identifying and then confirming serious safety 
problems with the drug.

                       QUESTION OF SENATOR MURRAY

    Question. I know that the IOM did not look at the over-the-counter 
application and review process. However, we know that the recent 
experience on the Plan B OTC application did impact morale and that 
reviewers who supported this application were silenced. Dr. Susan Wood 
is probably the most visible casualty of this process and I truly hope 
that no one else ever feels that they must resign in protest at the 
FDA. How can we legislate a better culture and improve morale at FDA as 
is proposed by the IOM? How can we create a structure to allow for 
scientific disagreement without undermining the agency?
    Answer. This is an enormously difficult question to answer. 
Unfortunately, it seems difficult if not impossible to legislate a 
better culture. However, the committee believes that it is possible to 
put in place some of the elements management literature has shown may 
help support organizational change and lead to good morale and a 
healthy organization. The committee believes that stability at the top 
may help contribute to this, as well as a group of experienced 
leadership advisors to help support agency and center leadership, 
systematic management efforts to facilitate communication and 
collaboration, and addressing some of the imbalances that may 
exacerbate polarization among offices and disciplines. The committee is 
aware of the recent efforts at CDER to establish mechanisms for dispute 
resolution, but it believes that management must make such issues a 
priority and consistently demonstrate that they are not simply empty 
words on paper, but evidence of support for a true spirit of open-
minded scientific inquiry. Finally, and most importantly, the 
Commissioner and the center director need to make it clear to all staff 
that a healthy organizational culture is a high priority, and that 
specific actions will be implemented to facilitate and maintain an 
atmosphere of transparency, inclusion, optimal communication, and 
mutual trust.

                      QUESTIONS OF SENATOR CLINTON

    Question 1. The IOM report recommends giving the FDA increased 
authority to revise labels, require conditions on distribution, and 
changes in promotional materials. It also recommends increasing the 
range of tools available to ensure that this new authority can be 
effectively enforced. Yet we know that the agency relies heavily upon 
drug agency user fees, and have seen examples of when scientists were 
pressured to lessen their criticism of products. How can we change the 
culture at FDA to ensure that new enforcement authority is used? What 
kinds of enforcement mechanisms would be most effective in combating 
these cultural issues and helping to improve consumer safety?
    Answer 1. It is difficult to make a direct link between culture and 
authority. However, the committee believes that agency leadership can 
play an absolutely essential role in organizational culture change. The 
Commissioner and center director must send a clear message that agency 
leadership expects (and will support) staff in exercising authorities 
available to them when the scientific evidence calls for certain 
regulatory decisions. However, in order to be able to base decisions on 
the best science, staff require the funding, skills, information 
technology, and institutional relationships to access and analyze the 
necessary data which then justifies use of specific authorities. 
Adequate resources (preferably from appropriations) are key. The 
committee believes that the heavy workloads and tight review timelines 
(linked to user fees) of drug reviewers make it difficult for them to 
thoroughly attend to safety issues, and their counterparts in the 
Office of Surveillance and Epidemiology are so few in number and so 
severely underfunded that safety concerns may slip through the cracks.

    Question 2. In recent years, the agency's employees have been 
suffering a crisis of morale. Career scientists report being pressured 
to change their findings by senior level officials. Ideological 
concerns, not scientific data, delayed the decision on the over-the-
counter application for Plan B. We have seen multiple examples where 
political and commercial interests were given higher priority than 
consumer safety.
    The IOM report recommends establishing a fixed 6-year term for the 
Commissioner, to isolate him or her from political pressures. Could you 
comment on the ways in which this fixed term will help address the 
concerns over the current FDA culture? What other reforms might be 
necessary to address the concerns expressed about senior-level 
management, in addition to the Commissioner's post?
    Answer 2. The fixed-term appointment of a thoroughly qualified 
individual may help to set the tone for the organizational culture. A 
commissioner who is ``here to stay'' for several years would have the 
opportunity to support center directors and other agency leaders and to 
ensure that his or her leadership philosophy and priorities are 
implemented.
    Some of the management literature cited in the report refers to 
past leaders of government agencies who were effective in bringing 
about profound cultural changes through their vision and their 
leadership style (participatory, encouraging of transparent and 
frequent communication among all levels of the agency, respectful of 
the diversity of disciplines and viewpoints in the organization, etc.). 
The report states,

          ``Assessments of government agency performance and examples 
        from the management literature have shown repeatedly that 
        organizational cultures that stifle dissent, exclude staff from 
        decisions about the organization's vision, and allow cultural 
        problems to linger unaddressed are not healthy cultures, and 
        those problems interfere with their ability to achieve their 
        goals (Weick and Sutcliffe, 2001; O'Leary R, 2006; Return to 
        Flight Task Group, 2005; Heifetz and Laurie, 1998; Khademian, 
        2002; Kotter, 2005).''

    Question 3. The Drug Safety Oversight Board (DSOB) currently has no 
patient or provider representatives. Patient input into this process 
could help to improve public oversight on issues that will have 
significant impact on patients and to restore public trust in the drug 
safety system. What recommendations does the IOM have for improving 
public input into the FDA's drug safety oversight process?
    Answer 3. The committee believes that FDA did not communicate 
clearly about the nature of the DSOB and its role. Although the board 
seemed to be ``offered'' as a solution to the drug safety problems of 
the several years, one of its functions is to provide internal 
oversight of how safety issues are handled within the agency (tracking 
of issues, resolution, etc.)--a function that needs to be performed by 
an internal group. Obviously, this is not the type of group that could 
be expected to address public concerns and tackle the difficult issues 
of external communication (although the DSOB's job description does 
include the latter, the committee finds this to be inappropriate--see 
Chapter 3).
    The Drug Safety and Risk Management Advisory Committee is the 
external body that could (and already does to some extent) advise CDER 
on drug safety issues. DSaRM, not the DSOB, may be the type of group 
that could demonstrate agency commitment to receiving and acting on 
public input. Furthermore, in Chapter 6 of its report, the committee 
recommended the creation of a new advisory committee to focus on 
patient and consumer communication issues. Such a group, representing 
patient and consumer views and relevant professional expertise, could 
play a dramatic role in improving the quantity, quality, and timeliness 
of agency communication to and with the public.

    Question 4. The IOM report recommends that civil monetary penalties 
be available to FDA as an enforcement tool for various forms of non-
compliance. The report also recommends that industry sponsors be 
required to register and submit clinical trial data. What kind of 
enforcement mechanisms would the IOM consider appropriate to ensure 
that industry sponsors comply with such submission and registry 
requirements?
    Answer 4. The committee did not describe the enforcement mechanisms 
that could be used, other than civil monetary penalties (and offered no 
specifics in this regard). However, such mechanisms are clearly 
needed--the agency's enforcement authorities are extremely limited.

 Response to Questions of Senators Enzi, Kennedy, Murray, and Clinton 
                          by Diane E. Thompson

                       QUESTIONS OF SENATOR ENZI

    Question 1. Some have suggested that the drug safety system is 
broken. Do you agree? Are we seeing drugs being approved that truly 
shouldn't have been?
    Answer 1. Several recent high profile drug safety incidents have 
highlighted the need for a stronger drug safety system. However, as 
Institute of Medicine (IOM) has pointed out, the fact that these 
instances uncovered safety risks after a drug was already on the market 
doesn't mean FDA shouldn't have approved it. Most new drugs are studied 
in fewer than 3,000 patients. And, most often those patients are far 
from a representative sample of the U.S. population. Consequently, 
adverse events that occur even as often as 1 in 10,000 patients are not 
likely to be discovered until the product is on the market. The answer 
to improving drug safety is not to return to the days of significant 
delays in access to new therapies for life-threatening illnesses. 
Instead, we need to continue to study drugs in real life situations in 
larger groups of people in phase IV trails and after FDA approval. It 
is clear that our current drug safety paradigm poses considerable, 
avoidable danger, where the flow of risk-benefit information between 
drug manufacturers and the FDA occurs pre-approval and is extremely 
limited post-approval. This is one of the unintended consequences of 
the Prescription Drug User Fee Act (PDUFA). As the IOM report notes, 
continuing formal evaluations after a drug is approved is necessary. We 
have a historic opportunity to correct the current imbalance in our 
Nation's drug safety system. A reformed drug safety system that, as the 
IOM suggests, takes a life-cycle approach to assessing drug risks and 
benefits is in the best interest of all stakeholders.

    Question 2. Your testimony calls for giving FDA the authority to 
require studies of ``significant'' off-label uses. I expect these post-
market trials of off-label uses would be rather expensive. I worry 
about the impact on patients if companies start discouraging off-label 
uses to avoid having to conduct a set of new and expensive trials. You 
also noted that there are existing incentives to encourage pediatric 
studies of off-label uses. These incentives were created through the 
Best Pharmaceuticals for Children Act, which is due to be reauthorized 
next year. Have you considered ways we could amend that law to create 
better incentives for conducting studies of off-label uses in children?
    Answer 2. Since off-label prescriptions are such a large proportion 
of medicines being prescribed by doctors, granting FDA authority to 
require studies of off-label uses is a necessary safety requirement. It 
is especially critical to children, who already are being placed at 
considerable risk because \3/4\ of pediatric prescribing is off-label. 
The expense of such studies needs to be balanced against the expense of 
treating patients with medicines that have not been proved to be safe 
or effective for the prescribed use.
    Currently, companies cannot advertise or encourage off-label use, 
since these uses are not included on the label nor included during 
label negotiations between FDA and drug companies. It may actually be 
of significant benefit for companies to conduct off-label studies, 
because if studies confirm safety and efficacy for the off-label use, 
companies could then have an opportunity to advertise and market the 
drug for the new use once it is negotiated onto the label. Overall, 
patients stand to benefit greatly from new safety and efficacy 
information, where the public health impact of the off-label use was 
unknown before.
    The reauthorizations of the Best Pharmaceuticals for Children Act 
(BPCA) and the Pediatric Research Equity Act (PREA), both of which 
expire next year, are extremely important to children's health. 
Although BPCA creates incentives to encourage manufacturers to study 
their products for children, these incentives are voluntary. We're 
seeing that manufacturers are increasingly opting not to conduct the 
studies FDA requests. Unambiguous authority to require such studies 
when the off-label use is significant will help ensure that children 
too can reap the benefits of an improved drug safety system. In both 
BPCA and PREA, the balance between incentive and mandate needs careful 
review to ensure that we accomplish the objective of the statute and 
fairly compensate the company for their investment. We look forward to 
working with the committee to further explore this.

    Question 3. Do you think the timeframes for FDA action proposed in 
S. 3807 are reasonable?
    Answer 3. It is very important that when new safety issues arise, 
there be quick and decisive action to address these concerns. Patients 
should not have to choose between safety and access. Safety assessments 
must be incorporated into the approval process so as not to slow the 
process down. This can only happen if FDA has adequate resources to 
address safety issues. Through the Risk Evaluation and Mitigation 
Strategy (REMS) plan, S. 3807 proposes that when new safety information 
demonstrates significant risk, FDA reassess REMS and enter into 
discussions with the manufacturer. We support the requirement that 
action on new safety information be completed in a timely way.
    S. 3807 also establishes a dispute resolution process for resolving 
disagreements between FDA and drug companies related to REMS, referring 
such disputes to the closed-door Drug Safety Oversight Board (DSOB), 
which would review cases swiftly. In our view, transparency and patient 
input into this process is critical, both to ensure that there is 
public oversight on issues that will have significant impact on 
patients and to restore public trust in the drug safety system. We 
recommend that patient and consumer representatives be included on any 
such boards.

    Question 4. Do you believe mandatory reporting of clinical trial 
results would compromise proprietary company information?
    Answer 4. The release of proprietary information is not required in 
order to establish a clinical trials and results database. It's 
important to note that while drug manufacturers invest their resources 
and expertise into the clinical trial process, patients make an 
investment of their own, of their health and their lives. In that 
sense, they also ``own'' the data. Understanding the results of 
clinical trails is of critical importance to participants who, in some 
cases, have heard about trial results via the media rather than the 
trial sponsor. In addition, community members who may not have been 
eligible for a trial but might benefit from the therapy in development 
are also invested in trial outcomes. A clinical trial results registry 
would provide a central, credible source for information, much of which 
currently is widely shared within patient communities. These informal 
communication mechanisms that have developed out of necessity must be 
replaced with a credible, comprehensive, and reliable registry. Access 
to reliable information about drug trials should not be dependent on 
whether a patient has the right contacts.
    To the extent a manufacturer can make the case that the release of 
some piece of data would severely compromise their research efforts, 
the release of such information could be examined on a case-by-case 
basis. If the information is provided to each study patient on the 
trial it should be considered in the public domain for all intents and 
purposes. We should start from the premise that all parties benefit if 
we can restore trust in the clinical trials system, which will only 
come from more transparency in the process. Moreover, the availability 
of clinical trials information will serve to accrue more patients into 
studies more quickly, resulting in faster trial results and FDA 
approval forthcoming sooner. This provides a clear benefit to both 
sponsors and patients.

                      QUESTION OF SENATOR KENNEDY

    Question. Outcomes of studies that are negative or that suggest 
toxicity in patients are often not published. The legislation I 
introduced with Senator Enzi requires publishing clinical trial 
results, both positive and negative, in a public database. What impact 
do you think this would have for patients, healthcare providers, and 
the research community?
    Answer. Several events over the past few years involving selective 
reporting of clinical trials data and more specifically, the 
suppression of negative research have generated concern over whether 
enough is being done to ensure that important information about ongoing 
and completed scientific studies of drugs and devices is easily 
accessible to patients, healthcare providers, and researchers. While 
the NIH currently operates a clinical trials database, it was designed 
solely to help patients find ongoing trials and does not contain trial 
results.
    Creating a mandatory and publicly accessible registry of clinical 
trials and their results is important, to not only provide the public 
with access to critical information affecting their health, but also 
for improving patients' trust in the clinical trial process. As IOM 
notes, the results of trials of not yet approved products is also of 
value to patients and researchers. For example, a drug may be a new 
member of a class of products already on the market and safety signals 
from the trial can help to highlight potential concerns with the 
already approved products. Information from trials on new uses of 
existing products can also be valuable, particularly if the new use is 
one that is already in practice. Furthermore, in our view, for the 
database to be of greatest use to patients, researchers, and healthcare 
providers, it will be critical that it be as comprehensive as possible, 
and that it include trials completed prior to enactment of the proposed 
S. 3807 legislation as well as medical device trials.

                      QUESTIONS OF SENATOR MURRAY

    Question 1. One of my goals for FDA has always been trying to find 
the right balance between getting new drugs to patients without delay 
while ensuring safety and effectiveness. I know it's a tough balance 
and we always have to be concerned about unintended consequences for 
any actions we take legislatively. I also think we need to be concerned 
about making sure that patients get good information--not conflicting 
information or even information that simply focuses on risks and not 
benefits. We have to be sure not to scare patients away from 
potentially beneficial treatments. There are risks with any drug or 
device, and we could raise safety flags on any new treatment, but this 
could also deter access. How can we achieve this balance and do you 
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
    Answer 1. In our view, patients should not have to choose between 
safety and access. There should be equal focus on speedy access to new 
lifesaving drugs and safer, more effective medicines. As the AIDS 
epidemic has shown, patients are thirsty for greater access to 
information that affects their health and are both very capable of 
absorbing this information and better informed to make decisions 
regarding their health because of it. For example, access to 
information in a clinical trials and results database goes a long way 
toward ensuring that patients have access to unbiased information and 
to a full body of trial results for a condition or drug--a vast 
improvement over the fragmented, promotional sources too frequently 
relied on now. In addition, patients aren't alone in the decisionmaking 
process. As always when the decision involves the prescribing of a new 
course of treatment, providers will have a role in navigating new 
information.

    Question 2. As the IOM report noted, 21 percent of prescriptions in 
2001 were for off-label uses, meaning of course that these uses were 
never reviewed or approved by FDA. Many patients often are not even 
aware of off-label use. However, as you pointed out, off-label use is 
extremely important for pediatric patients as well as patients with 
rare diseases. I agree that additional safety data is warranted for 
off-label use, but are you concerned about efforts to discourage off-
label use? Once again is there a way we can encourage greater safety 
data on off-label use without jeopardizing access or impeding the 
practice of medicine?
    Answer 2. As you mentioned above, a substantial number of 
prescriptions are written for off-label uses. Any effort to reform the 
drug safety system that fails to address \1/5\ of the use of drugs in 
real-world settings would create a significant safety gap. Requiring 
that companies conduct clinical trials of off-label uses would not 
jeopardize or impede access or the practice of medicine. Instead, it 
would inform medical practice by providing the necessary safety and 
efficacy information to better assess the impact on public health in an 
area where both efficacy and safety have heretofore been unaddressed.

    Question 3. It has become very clear that we need a more uniform 
mechanism for collecting safety data. Currently the process for 
reporting adverse events is fragmented and there is little role for the 
patient. In fact, FDA does not even have a database of reported adverse 
events.
    As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a 
national poison control center hotline that provides real time, 
accurate information to parents and providers in response to accidental 
poison exposure, I know how difficult it is to create a national 
database of real time information. But, we did succeed. We now have a 
national poison control database that can provide information to any 
caller across the country regarding accidental exposure to poisons. 
Using the data mined from this database we can also find information on 
increases in exposure to certain poisons and even local trends that 
could indicate widespread problems.
    I think we need to consider a national reporting structure for 
adverse events associated to all medications. Many patients don't even 
know what an adverse event is and when a side effect may or may not be 
a concern. This kind of database could provide a great early warning 
system as well.
    What steps can we take to improve the collection of adverse events 
and how can we be sure that patients are included in this process?
    Answer 3. S. 3807 creates a Risk Evaluations and Management 
Strategy (REMS) system that would allow FDA and manufacturers to 
develop a plan to adapt and integrate new safety information about a 
drug, including regular review of adverse events reports by FDA. 
Because adverse events are not likely to be discovered until the 
product is on the market, it is critical that they be addressed post-
approval. IOM recommends improving the current adverse event reporting 
system, through systemic review, to increase its usefulness in post-
market surveillance, which we support. This approach is in-line with 
the idea of taking an overall ``life-cycle'' approach to drug safety, 
allowing for periodic reassessment of the risk-benefit of a drug over 
time. We also recommend that the process be amended to include patient 
representation in the dispute resolution process.

                      QUESTION OF SENATOR CLINTON

    Question. Ms. Thompson, in your testimony, you discuss the ways in 
which the protections in Pediatric Research Equity Act and the Best 
Pharmaceuticals for Children Act have resulted in safer drugs for our 
children.
    With these protections, we can ensure that drugs that are labeled 
for use by children have first been tested to determine effects in 
pediatric populations.
    However, you note that there is significant off-label use of 
medications among pediatric populations, meaning that many children are 
still exposed to unknown risks at the very moments when we are trying 
to improve their health.
    Could you please elaborate on the ways in which giving FDA the 
authority to require studies for off-label utilization of drugs would 
improve children's health? What impact would this authority have on 
adult health outcomes?
    Answer. As the IOM report notes, a recent study found that 21 
percent of prescriptions written in 2001 were for off-label uses. 
Children are placed at particular risk, since as much as \3/4\ of 
pediatric prescribing is off-label and children are prescribed drugs 
for uses different than the adult use. Any safety and efficacy 
information for off-label uses would be extremely useful for children's 
health. Thanks to your efforts and those of Senators Dodd and DeWine, 
there are incentives available to encourage manufacturers to study 
their products for children. However, they are voluntary--and we're 
seeing that manufacturers are increasingly opting not to conduct the 
studies FDA requests. Unambiguous authority to require such studies 
when the off-label use is significant will help ensure that children 
too can reap the benefits of an improved drug safety system. Whether 
focusing on children or adults, the effect of off-label studies is the 
same. Health outcomes are improved when prescribing is guided by safety 
and efficacy for any use of a drug. There would also be an added 
benefit for adult populations who would know with much more certainty 
the benefits and risks of medicine they may be now taking without such 
vital information.
    As valuable as comprehensive drug safety reform improvements would 
be in improving FDA's ability to monitor and act on safety signal once 
drugs are on the market, they don't obviate the need for renewal of 
BPCA and PREA--both of which expire next year. Most importantly, PREA 
creates the presumption that drugs to treat conditions that occur in 
children will be tested in children before approval or soon thereafter. 
This critical authority is not addressed by the proposed general drug 
safety reforms and should not be allowed to expire. In addition, both 
BPCA and PREA extend beyond simply a focus on safety data. Because 
children are not small adults and their bodies can respond very 
differently to a drug than adults, FDA can use the carrot and stick 
combination of PREA and BPCA to also generate critical data on dosing 
and efficacy.

 Responses to Questions of Senators Enzi, Kennedy, Murray, and Clinton 
                        by Steve E. Nissen, M.D.

                       QUESTIONS OF SENATOR ENZI

    Question 1. Can you comment on the feasibility of the Enhancing 
Drug Safety and Innovation Act (S. 3807) to simultaneously shorten the 
time to bring new medications to patients, while improving the safety 
of drugs?
    Answer 1. I remain strongly convinced that the Enhancing Drug 
Safety and Innovation Act (S. 3807) can simultaneously shorten the time 
to develop new medications, while improving drug safety. Because the 
current regulatory environment does not facilitate robust post-
marketing surveillance, the FDA and its Advisory Committees must 
necessarily be cautious in approving new medications. This caution is 
warranted because we lack confidence that emerging drug safety problems 
will be promptly identified and addressed. The Enzi-Kennedy bill 
strengthens the post-marketing risk mitigation, which will increase 
confidence that the Agency can rapidly identify any unforeseen drug 
safety problems. This enhanced confidence will allow more rapid 
approval of innovative new therapies, while protecting against 
unexpected post-marketing risks.
    In addition, the requirement for transparency in reporting the 
results of late stage clinical trials can also help to speed new drug 
development. Currently, enormous resources are expended in the 
development of agents that are often similar to failed compounds. 
Because companies developing these therapies are unaware of the 
problems that led to failure of similar agents, enormous resources are 
wasted exploring failed or nonproductive pathways. The increased 
transparency afforded by S. 3807 will help companies to focus their 
development efforts on truly innovative approaches, while avoiding 
pathways likely to lead to failure. This concentration of resources on 
the most promising therapies should serve to speed drug development.

    Question 2. You suggest a new type of new drug approval that you 
describe as ``provisional.'' Some have suggested that a provisional or 
conditional approval could have very negative market effects, but you 
suggest that it might in fact improve innovation and drug safety. Could 
you elaborate?
    Answer 2. Making provisional approval work in the current market 
environment is possible with creative regulatory strategies. 
Provisional approval would be appropriate for important potentially 
life-saving therapies for which there is inadequate data, particularly 
with respect to long-term benefits vs. risks. For lethal disorders such 
as AIDS or cancer, permitting more rapid access to potentially 
breakthrough medications makes good sense, even if there are remaining 
safety and efficacy concerns. It would be necessary to provide 
legislative support empowering the FDA to mandate that certain Phase IV 
trials must be completed by the end of the provisional approval period. 
If the studies were not performed, approval would automatically be 
rescinded.
    To compensate companies for the shortened period of exclusivity 
that would likely result from provisional approval, legislation could 
adjust the exclusivity period to provide an economic incentive to seek 
provisional approval. This would be similar to the additional 6 months 
of exclusivity that is provided for companies that study therapies in 
pediatric populations. With the proper incentives, new therapies could 
be made available to the public without compromising safety or 
resulting in economic disincentives for industry to seek provisional 
approval.

    Question 3. Do you believe mandatory reporting of clinical trial 
results would compromise proprietary company information?
    Answer 3. In my view, when patients are asked to participate in 
randomized clinical trials, there is a moral and ethical obligation to 
translate their participation into the advancement of scientific 
knowledge. We owe this obligation to our patients who selflessly 
consent to participate in clinical trials. Therefore, I strongly 
disagree with the contention that mandatory reporting of clinical trial 
results would compromise proprietary company information. Most of the 
studies that go unreported are clinical trials in which the agent 
either failed to show benefit or exhibited unacceptable toxicity. In 
either case, there is little or no proprietary information involved. 
The results of clinical trials affect the health and even the survival 
of many of our citizens. It is just simply unacceptable to withhold 
such knowledge under the guise of proprietary interest.
    If a drug fails during Phase II or Phase III due to toxicity, it is 
essential that the scientific community be informed of the nature of 
that toxicity, so that patients treated with related agents can be 
appropriately protected. Similarly, if toxicity is experienced in Phase 
IV trials, physicians must be provided with such information to 
optimally protect their patients from the hazards of such therapies. 
Interestingly, there is dissociation between release of information for 
studies that are reviewed by FDA Advisory Panels and those that are 
not. Currently, the FDA posts the briefing documents for advisory 
panels on the ``worldwide web'' the night before advisory committee 
meetings. But if studies never come to an advisory committee, the 
information is withheld. Since both types of trials contribute to 
knowledge and release of the results always serves the public interest.

    Question 4. Can professional medical societies play a greater role 
in communicating the benefits and risks of drugs to their physician 
members and to the general public? If so, how?
    Answer 4. I believe that professional societies have been under-
utilized as a contributing source for information on the benefits and 
risks of drugs. Professional societies can serve as impartial sources 
of information independent of both the FDA and the pharmaceutical 
industry. Members and leaders of these professional societies include 
individuals with great expertise on the clinical application of 
pharmaco-
therapy. They provide a source for objective information and balanced 
recommendations for practitioners and the public at large.
    In addition, many professional societies operate databases that 
include unique information about outcomes for patients treated with 
pharmacological agents. I am currently President of the American 
College of Cardiology, an organization with 33,000 members that 
includes more than 90 percent of the cardiovascular practitioners in 
the United States. We operate a database known as the National 
Cardiovascular Database Registry (NCDR) that has information on several 
million patients who have undergone various interventional procedures, 
including cardiac catheterization, intervention, carotid stenting and 
implantation of cardioverter-defibrillators (ICDs). This information 
provides vital opportunities for post-marketing surveillance of safety, 
but is currently not generally utilized by regulatory agencies as a 
source for unbiased information. Rather than have the Federal 
Government recreate such databases through the FDA, partnership 
opportunities with professional societies can enable access to this 
information to enhance quality and patient safety.

    Question 5. You conduct large safety trials. Could you give us a 
sense of what is involved in tracking down a safety issue that occurs 
in, say, 1 in 10,000 people who take a drug?
    Answer 5. Evaluating serious or potentially lethal risks that have 
a low frequency of occurrence represents the single greatest challenge 
in post-marketing surveillance. Such risks can virtually never be 
determined prior to drug approval, since most approval packages involve 
treatment of substantially less than 10,000 patients.
    Several strategies have been employed in the past to assess these 
low frequency risks. For example, in the case of rare liver failure 
events, certain biochemical markers can be used to predict which drugs 
will likely have a risk and can estimate with reasonable precision the 
likely rates of occurrence of fatal outcomes. However, for many 
idiosyncratic drug reactions, there exist no predictive biochemical 
markers.
    Ultimately, detection of these low frequency events requires a very 
robust post-marketing surveillance system. The best sources of 
information are patient databases that record clinical outcomes and 
adverse events for larger populations. Several health maintenance 
organizations such as Kaiser Permanente maintain such large databases, 
which have been used successfully in the past to detect low frequency 
risks. I also believe that partnership with professional societies can 
be very helpful since many of these societies maintain ongoing 
databases for monitoring quality and health outcomes.
    Other innovations, available in the near future, may be helpful. 
For example, electronic medical records (EMR's) allow rapid and 
reliable assessment of patient outcomes. EMR's are much easier and less 
expensive to evaluate than abstraction of outcomes information from 
paper records. Current legislative initiatives designed to enhance the 
electronic medical record have the potential to greatly enhance drug 
safety. EMR's make possible nearly automated reporting of outcomes, a 
potentially powerful approach to identification of unanticipated risks.
    Finally, the current Adverse Event Reporting System (AERS) has 
proven inadequate for assessing low frequency events even when they are 
serious or fatal. There are considerable burdens upon the practicing 
physicians to report these rare events. Currently, there exists no 
incentive for voluntary reporting. Perhaps there is an opportunity to 
create incentives for physicians to take the time to report unusual 
events to the FDA. Perhaps, a provision of Continuing Medical Education 
(CME) credits might encourage reporting.

                      QUESTION OF SENATOR KENNEDY

    Question. Outcomes of studies that are negative or that suggest 
toxicity in patients are often not published. The legislation I 
introduced with Senator Enzi requires publishing clinical trial 
results, both positive and negative, in a public database. What impact 
do you think this would have for patients, healthcare providers, and 
the research community?
    Answer. The requirement in S. 3807 for mandatory registration 
reporting of clinical trial results represents one of the most 
important and valuable provisions of this bill. During the past several 
decades, there has been an enormous proliferation of clinical trials 
throughout most medical disciplines. Increasingly, these trials are 
directed by pharmaceutical companies, often working in conjunction with 
independent operators known as contract research organizations (CRO's). 
It is also becoming increasingly clear that such trials are promptly 
published when they show benefits for a pharmacological therapy, but 
are often never published if the study shows no benefits or serious 
toxicity. This practice, known as negative publication bias, has a 
catastrophic effect on the practice of medicine. For example, if 10 
clinical trials are conducted to study a class of medications and 9 of 
the 10 studies show either lack of efficacy or toxicity, it is highly 
likely that the therapy is not beneficial. Yet, if a 10th study is 
conducted and it shows a marginal, but statistically significant 
evidence of benefit, this may be the only study of the therapy that is 
ever published. Physicians unaware of the 9 failed studies may 
prescribe this ineffective or potentially risky therapy because they 
have no knowledge of the studies that failed to show benefit or showed 
toxicity.
    Negative publication bias also has major negative effects on drug 
development. Many companies are unaware that a competitor has studied a 
drug and found it ineffective or showed unacceptable toxicity. As a 
result, they may proceed with clinical trials of a very similar 
compound. This exposes patients to risky drugs, when such exposure 
could have been avoided had the company developing the drug been aware 
of poor outcomes for similar drugs in the class. I strongly believe 
that when we ask patients to consent to participate in a clinical 
trial, there is a moral and ethical obligation to ensure that their 
participation results in the advancement of science. Science cannot 
advance if the results of this study are never published. Accordingly, 
I strongly support the provision of bill S. 3807 requiring registration 
and publication of all late stage clinical trials. This provision is 
essential to restoring an adequate balance between safety and efficacy 
in drug development.

                      QUESTIONS OF SENATOR MURRAY

    Question 1. One of my goals for FDA has always been trying to find 
the right balance between getting new drugs to patients without delay 
while ensuring safety and effectiveness. I know it's a tough balance 
and we always have to be concerned about unintended consequences for 
any actions we take legislatively. I also think we need to be concerned 
about making sure that patients get good information--not conflicting 
information or even information that simply focuses on risks and not 
benefits. We have to be sure not to scare patients away from 
potentially beneficial treatments. There are risks with any drug or 
device, and we could raise safety flags on any new treatment, but this 
could also deter access. How can we achieve this balance and do you 
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
    Answer 1. I understand and share your concerns about achieving the 
right balance between bringing new medicines forward and ensuring 
public safety. I am very comfortable that S. 3807 will achieve both 
goals in a balanced fashion. There is nothing in the bill that directly 
affects patients' perception about the safety of beneficial therapies. 
We have seen a series of drugs withdrawn from the market or come under 
serious scrutiny because of drug safety problems. This has seriously 
undermined public confidence in the safety of medications. As a 
consequence of this series of safety revelations, many patients are 
reluctant to accept life saving therapies. Improving drug safety has 
the potential to improve public confidence and access to innovative 
therapies. If we can improve the approval process and post-marketing 
surveillance, we will avoid the kind of public attention that has 
undermined confidence in drug safety.
    In addition, I believe the FDA has a great opportunity to do a 
better job of communicating the issues of benefit versus risk. In 
several recent FDA advisory panels, I recommended the development of 
``Patient Guides.'' These are mandatory brochures provided to patients 
at the time of dispensing certain risky medications. These Guides 
explain to patients both the benefits and risks of these drugs. The 
Guides are written in language easily understood by the general public 
and carefully explain to patients what side effects to look for and how 
to report these adverse effects to their physicians. I believe that an 
informed public is much more likely to accept the benefits of 
therapies. A public that is suspicious about the relative benefits and 
risks may not comply with therapy. The enhanced transparency of the 
Enzi-Kennedy bill in making certain that we have all the information 
necessary within the public domain can help to improve, rather than 
undermine public confidence.

    Question 2. As the IOM report noted, 21 percent of prescriptions in 
2001 were for off-label uses, meaning of course that these uses were 
never reviewed or approved by FDA. Many patients often are not even 
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as 
patients with rare diseases. I agree that additional safety data is 
warranted for off-label use, but are you concerned about efforts to 
discourage off-label use? Once again is there a way we can encourage 
greater safety data on off-label use without jeopardizing access or 
impeding the practice of medicine?
    Answer 2. Off label use of medications is an important issue and 
must be addressed in a thoughtful fashion. Nothing in the Enzi-Kennedy 
bill restricts the rights of physicians to make individual choices 
about which therapies would be beneficial for their patients. I 
strongly support the notion of physician and patient choice. There are 
many examples where so called ``off label'' therapies have become the 
treatments of choice for important medical conditions. Examples include 
the use of b-blocking agents for angina and clopidigrel to prevent 
thromboses following coronary stent placement.
    However, it is important to distinguish between physician choice 
and active commercial promotion of off-label treatments. Therefore, I 
strongly support the current approach that precludes marketing drugs 
for off-label indications. If a medical therapy is effective, it should 
be demonstrated in an appropriate clinical trial.
    With respect to rare diseases, I also favor ``lowering the bar'' 
for development of therapies for these indications. I served on the FDA 
Advisory Board that approved a drug therapy for a rare fatal disease 
known as pulmonary arterial hypertension. I and other members of this 
panel strongly supported approval of this drug despite a clinical trial 
that provided less statistically robust demonstration of efficacy than 
would ordinarily be required. This adjustment to the standards for 
approval represents good regulatory policy and should be encouraged in 
selected circumstances. This is particularly advisable when the disease 
is potentially lethal and there are few, if any, accepted therapies.

    Question 3. It has become very clear that we need a more uniform 
mechanism for collecting safety data. Currently the process for 
reporting adverse events is fragmented and there is little role for the 
patient. In fact, FDA does not even have a database of reported adverse 
events.
    As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a 
national poison control center hotline that provides real time, 
accurate information to parents and providers in response to accidental 
poison exposure, I know how difficult it is to create a national 
database of real time information. But, we did succeed. We now have a 
national poison control database that can provide information to any 
caller across the country regarding accidental exposure to poisons. 
Using the data mined from this database we can also find information on 
increases in exposure to certain poisons and even local trends that 
could indicate widespread problems.
    I think we need to consider a national reporting structure for 
adverse events associated to all medications. Many patients don't even 
know what an adverse event is and when a side effect may or may not be 
a concern. This kind of database could provide a great early warning 
system as well.
    What steps can we take to improve the collection of adverse events 
and how can we be sure that patients are included in this process?
    Answer 3. The current AERS is ineffective. Reporting of adverse 
events is voluntary which limits effective analysis. We need to find 
creative approaches to the collection and evaluation of adverse event 
data. I am convinced that the electronic medical record can help 
substantially. If patient outcomes are recorded electronically, it 
becomes much easier to collect and report outcomes data, including 
adverse effects for a wide range of therapies. My own institution, the 
Cleveland Clinic, has very effectively used our EMR in this way. 
Similarly, many professional medical societies maintain large 
prospective databases that record outcomes for quality initiatives. 
Providing support for the FDA to partner with medical societies 
represents a truly innovative opportunity. Similar opportunities exist 
for large health maintenance organizations, such as Kaiser Permanente, 
which has played an important role providing independent data during 
several recent drug safety discussions.
    Finally, I support your concept of involving the patient in adverse 
event reporting. We must recognize that such reporting may not have the 
scientific quality of physician reporting, but it is very useful 
nonetheless. There may be an opportunity to provide a vehicle for 
patients to express their observations and have the opportunity for the 
FDA to evaluate such reports.

                      QUESTION OF SENATOR CLINTON

    Question. The IOM report notes that direct-to-consumer (DTC) 
advertising has been shown to have an impact on physician prescribing 
practices, and you stated in your testimony that such advertising 
should be more heavily regulated, with companies required to 
demonstrate a compelling public health benefit for this communication.
    However, we also face challenges from advertising targeted to 
physicians, such as conferences or lunches, at which favorable studies 
and journal articles can be highlighted.
    As a doctor yourself, what are your recommendations for addressing 
pharmaceutical marketing efforts that target physicians? How do we 
ensure that such efforts do not also result in the over-prescription of 
therapies that may be more expensive without being more effective?
    Answer. I share your concerns about the effect of very aggressive 
advertising directed at physicians and other healthcare providers by 
the pharmaceutical industry. Through voluntary restrictions, there has 
been some improvement in these practices in recent years. However, in 
my opinion, these reforms have not gone far enough. Pharmaceutical 
companies now dominate medical education. For example, in smaller 
hospitals ``Grand Rounds'' is typically a weekly conference in which 
emerging educational topics are discussed. In most cases, 
pharmaceutical companies sponsor such Grand Rounds and provide the 
speakers. Often such lecturers are scientifically unbalanced, 
presenting highly promotional material under the guise of medical 
education.
    In addition, there has been a proliferation of so-called ``medical 
education companies.'' Although these entities are loosely regulated by 
the Accreditation Council for Continuing Medical Education, such 
voluntary regulation is largely ineffective. ``Scientific'' symposia 
sponsored by most medical education companies often consist of 
promotional material in which speakers favorable to a particular 
therapy dominate the activity.
    In many hospitals with post-graduate training programs, 
pharmaceutical companies provide lunches and other perquisites for the 
physicians in training, along with a variety of ``educational 
materials'' that are largely promotional. As a consequence of these 
practices, newer and expensive therapies are often favored over older, 
generically available treatments. In some cases, the earlier treatments 
are actually better, but in most cases they are simply more cost-
effective.
    Determining how to regulate physician-targeted advertising is a 
challenging problem. Obviously, we must respect the principles of the 
first amendment in which ``commercial speech'' is traditionally 
considered privileged. Nonetheless, I think we will need to consider 
creative strategies for curtailing inappropriate physician targeted 
advertising. Drugs are not ``widgets'' and the manner in which they are 
marketed affects the health of all 300 million Americans. The standards 
for promotion of drugs should be higher than any other industry. 
Currently, they are not.

      Response to Questions of Senators Enzi, Kennedy, and Murray 
                         by Adrian Thomas, M.D.

                       QUESTIONS OF SENATOR ENZI

    Question 1a. I would like to ask you some questions about clinical 
trials, particularly clinical trial registries and results databases. 
What is an ``adequately designed and well-controlled clinical trial?''
    Answer 1a. An adequately designed and well-controlled clinical 
trial is a clinical study that has the following characteristics:

     Clear objectives and a measurable hypothesis;
     Study design that distinguishes treatment effects from 
other influences;
     Enrolls patients that have evidence of the disease under 
study or of susceptibility;
     Uses methods for assessing patient outcomes that are 
reproducible and valid;
     Has an appropriate control;
     Is adequately powered to achieve the objective of the 
study;
     Has adequate measures to minimize bias such as blinding of 
patients, investigators and data analysts;
     Has random assignment to the test therapy or control 
group; and
     Produces an analysis of the results of the study that is 
adequate to assess the effects of the drug.

    Adequately designed and well-controlled clinical trials are the 
primary basis upon which the FDA determines whether there is 
substantial evidence of effectiveness for a new drug. (Reference: 21 
CFR 314.126 adequate and well-controlled studies)

    Question 1b. What clinical studies does Johnson & Johnson register 
with ClinicalTrials.gov?
    Answer 1b. We publicly register all adequate and well-controlled 
studies of both marketed and investigational drugs regardless of 
location. For studies related to serious and life threatening diseases, 
we register all that include efficacy endpoints, regardless of trial 
design or location. Registration is made to the National Library of 
Medicine's Website, http://www.clinicaltrials.gov.
    We believe that both patients and healthcare providers can benefit 
from knowledge of clinical trials that are open for enrollment, and our 
policy is intended to provide this information to consumers in a manner 
that is as clear and easy to access as possible.

    Question 1c. What clinical study results does Johnson & Johnson 
currently disclose?
    Answer 1c. For marketed medicines, we publish the results of all 
adequate and well-controlled studies regardless of outcome. We also 
publish results of any other clinical studies of our marketed medicines 
that are material and relevant to the clinical use of the medicine or 
to the care and safety of patients.

    Question 1d. How are these results disclosed?
    Answer 1d. These trial results appear either in peer-reviewed 
medical literature or in the form of a clinical study report synopsis 
in the ICH-E3 format, which is designed to present data for a 
standardized scientific regulatory review. At present, our clinical 
study results are posted as links from the protocols we have registered 
on http://www.clinicaltrials.gov.

    Question 2. Do you think the timeframes for FDA action proposed in 
S. 3807 are reasonable?
    Answer 2. Yes, as long as we understand that these are minimum 
timelines and companies should engage with FDA and relevant 
stakeholders earlier if possible.

    Question 3. S. 3807 requires generic drugs to have REMS that are 
identical to the REMS for the innovator product. However, some very 
stringent RiskMAPS are based on patents. I would hope that in such 
cases the patent holder would be amenable to licensing, but that may 
not always be possible. How might this requirement be filled for 
generic versions of these products, without compulsory licensure of the 
patent?
    Answer 3. This is a difficult situation that may not be able to be 
addressed simply. Innovation necessary to address safety concerns 
should not be undervalued, and incentives for this innovation must be 
maintained. There are elements of RiskMAPS such as the ``STEPS'' 
program for thalidomide, which has been patented, and thus a product or 
molecule patent may not be what is at issue, but rather the risk 
management plan itself. It may not even be the company marketing the 
drug that owns a REMS-related patent, but a contract research 
organization, commercial vendor or other third party. This issue is 
complex and we recommend that the committee engage other interested 
stakeholders in this debate.

    Question 4. In your testimony you suggest that the Reagan-Udall 
Institute should not be associated with the FDA and should report 
directly to the HHS Secretary and that intense interaction with the 
pharmaceutical industry is needed for success. Finding the right place 
for the Institute has been a challenge. Could you discuss the benefits 
of placing the Institute outside of the FDA, and if it were placed 
outside the FDA, how would you ensure that what is learned at the 
Institute is integrated into FDA safety reviews?
    Answer 4. The Reagan-Udall Institute could contribute much more 
broadly than to FDA and its output should be optimized by placing it at 
the correct level within the framework of HHS. This would allow it to 
pursue valuable areas of research, for example into effectiveness and 
outcomes areas that are not directly the focus of FDA. In addition, one 
potentially exciting output of this institute could be research into 
methodologies for improving the approval processes. Such research could 
be conflicted if the Institute were placed within the FDA as the 
current process reflects the regulatory tools now used by the agency in 
its activities. Placing this institute at the level of reporting to the 
Secretary of HHS would give this organization appropriate independence 
from FDA, visibility and stature and does not undermine the agency's 
ability to implement output from the institute. Also, industry funding 
partners would be able to distance themselves from the regulatory 
approval process and potential for criticisms that would result if the 
organization were placed within the FDA.

                      QUESTION OF SENATOR KENNEDY

    Question. Outcomes of studies that are negative or that suggest 
toxicity in patients are often not published. The legislation I 
introduced with Senator Enzi requires publishing clinical trial 
results, both positive and negative, in a public database. What impact 
do you think this would have for patients, healthcare providers, and 
the research community?
    Answer. We believe that physicians, patients and the research 
community have a legitimate interest in clinical trial results 
regardless of whether the results show an advantage for an intervention 
or not.
    In recent months, the traffic to clinicaltrials.gov has grown 
illustrating an interest in the availability of trial information, but 
not necessarily reflecting the utility of the information. A patient or 
treating physician needs to know how to interpret the information 
(either positive or negative) in order for it to be useful.

     During the period from May until October 2005 there was a 
73 percent increase in the number of trials registered to 
www.clinicaltrials.gov--from 13,153 to 22,714 (see graph).
     During the period from September 2005 until November 2006 
there was a more than a hundred-fold increase in the number of browsers 
to Johnson & Johnson's postings on www.clinicaltrials.gov from 37 to 
more than 4,000 in November of this year (see graph).

    In order for patients and physicians to effectively use the 
information they learn from clinicaltrials.gov, it is important to 
understand the strength of the clinical evidence. The strength of the 
clinical evidence is related to the scientific method that was used to 
produce the results. In the case of a consumer encountering postings of 
negative information, there could be unintended consequences in terms 
of misinterpretation, or cessation of use of a needed medicine. A 
consumer must know how to interpret the information they read and this 
should be through the assistance of a learned intermediary who can 
evaluate the relevance of the information to a specific situation and 
guide the decisions on the course of treatment. The importance of the 
contribution of the learned intermediary in this context should not be 
underestimated.
    When apparently similar studies, with similar populations and 
ostensibly the same intervention, give apparently conflicting results, 
physicians and even other researchers may not be in a position to 
reconcile and integrate the findings in such a way that meaningful 
conclusions can be drawn.
    There is genuine scientific benefit in having results from all 
studies available to members of the scientific research community, who 
can bring sophisticated skill to evaluating complex and often 
preliminary and exploratory data from early clinical trials. These 
experts often specialize within specific therapeutics areas, use 
sophisticated statistical methods, and apply experience and judgment of 
the principles of evidence-based medicine to weigh the strengths and 
weaknesses of various types of trials and their resulting data. This 
skill is needed to be able to assess varying and sometimes conflicting 
data into an interpretable body of evidence.
    For experts who synthesize research findings, particularly when 
they calculate a quantitative summary of results, the unavailability of 
unpublished results may produce misleading summary evaluations. This 
would be the case if the publication of certain types of results (e.g., 
those not favoring the intervention of interest, or those showing harm 
resulting from an intervention), were systematically suppressed from 
the scientific literature, either through the researchers' failure to 
submit the papers for publication or through the failure of journals to 
publish what editors might view as ``uninteresting'' results (e.g., 
results showing no difference between two treatments).
    At the same time, information from clinical trials may well be 
difficult for patients, and indeed, some healthcare professionals, to 
assess accurately. Significant patient education will be necessary in 
order to avoid unintended and potentially harmful effects to patients. 
Congress should consider how best to ensure patients are educated 
before raw results are made broadly available. Laypersons, as well as 
many healthcare professionals who are not experts in clinical trial 
analysis may misinterpret data in two ways:

     First, by interpreting data from early stages of human 
research as if it were from later stages of research. The research 
methodology of early trials is not robust enough to formally test for 
benefits, but rather is designed to evaluate adverse experiences or 
assess maximum tolerated doses. A related issue is interpreting data 
from a study in one indication as if it is in a different indication. 
It would be unfortunate for patients who are receiving potentially life 
saving treatment for one indication to cease therapy because they 
become aware of toxicity data in another newly tested indication or 
population.
     Second, promising but preliminary data from dose ranging 
studies, or hypotheses-generating studies may be misinterpreted as 
implying benefits that cannot be proved by the study design. Benefit 
cannot be formally evaluated in other than definitive studies, such as, 
for example, mortality studies in cardiovascular disease. By assuming 
benefit that has not been proven, patients could be exposed to 
potentially harmful untested therapies.

    Organizations conducting new drug development studies invest 
significant research time and resources in exploring potentially 
beneficial uses of novel therapies. Typically this involves the 
exploration of multiple indications, populations, dose ranges over 
increasing numbers of patients treated in clinical trials. Much 
negative trial data is to be expected from such research and this 
should be well understood. If early clinical trial data is made broadly 
available, it will be necessary to educate patients so that they can 
better communicate with their physicians about these data.
    One final caution is that there is a major investment in innovation 
associated with investigating novel therapies. This investment could be 
compromised through early release of commercially sensitive data from 
clinical trials. Sufficient protections to support these investments 
must be considered.



                      QUESTIONS OF SENATOR MURRAY

    Question 1. One of my goals for FDA has always been trying to find 
the right balance between getting new drugs to patients without delay 
while ensuring safety and effectiveness. I know it's a tough balance 
and we always have to be concerned about unintended consequences for 
any actions we take legislatively. I also think we need to be concerned 
about making sure that patients get good information--not conflicting 
information or even information that simply focuses on risks and not 
benefits. We have to be sure not to scare patients away from 
potentially beneficial treatments. There are risks with any drug or 
device, and we could raise safety flags on any new treatment, but this 
could also deter access. How can we achieve this balance and do you 
have concerns about the impact of the IOM recommendations or the Enzi-
Kennedy bill as it relates to access?
    Answer 1. Senator Murray raises very real issues about the loss of 
balance potentially resulting from a singular focus on safety, and not 
benefit/risk. The issues at hand are especially pertinent to the 
inherent tension between early approval and availability of products 
for unmet medical needs and the fact that we will always know less 
about risks than is ideal in this situation. The balance needs to be 
achieved through avoiding legislation that may result in inadvertently 
denying access to therapies (i.e., distribution restrictions) but 
focusing more on ensuring the agency has administrative mechanisms for 
evaluating potential risks and negotiating with companies on the 
product and population-specific methods of minimizing those risks. 
Overall, the IOM report and the Enzi-Kennedy bill recognize the need 
for this balance, but Congress should consider carefully before 
legislating periods of restrictions such as fixed moratoriums on DTC, 
distribution restrictions, or REMS that are template in nature. A 
preferable alternative would be for Congress to direct FDA to consider 
these matters through administrative procedures that ensure an 
appropriate risk-based scientific evaluation guides such restrictions.

    Question 2. As the IOM report noted, 21 percent of prescriptions in 
2001 were for off-label uses, meaning of course that these uses were 
never reviewed or approved by FDA. Many patients often are not even 
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as 
patients with rare diseases. I agree that additional safety data is 
warranted for off-label use, but are you concerned about efforts to 
discourage off-label use? Once again is there a way we can encourage 
greater safety data on off-label use without jeopardizing access or 
impeding the practice of medicine?
    Answer 2. In the opinion of treating physicians the use of products 
in unapproved, or off-label, indications may be in the best interest of 
the patient because it is consistent with the best science at the time. 
That said, it may not be a priority for an innovator company focusing 
its limited research resources on areas of larger medical need and 
where more safety data exist to support development programs. The FDA 
can always discuss with companies, as can any scientific organization, 
the potential for areas of research in unapproved indications, and 
these need to be balanced against other research opportunities and 
priorities of the company. With respect to pediatric indications, 
encouraging specific research through offering data exclusivity and 
other programs has been a very useful path forward, and is now also 
being followed in the EU as a way of generating these data. We should 
be very careful not to inadvertently expose patients to unethical or 
unsafe exposure to products in unapproved indications outside the 
protections provided under an IND. The matter of unapproved uses is an 
important area for continued discussion.

    Question 3. It has become very clear that we need a more uniform 
mechanism for collecting safety data. Currently the process for 
reporting adverse events is fragmented and there is little role for the 
patient. In fact, FDA does not even have a database of reported adverse 
events.
    As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a 
national poison control center hotline that provides real time, 
accurate information to parents and providers in response to accidental 
poison exposure, I know how difficult it is to create a national 
database of real time information. But, we did succeed. We now have a 
national poison control database that can provide information to any 
caller across the country regarding accidental exposure to poisons. 
Using the data mined from this database we can also find information on 
increases in exposure to certain poisons and even local trends that 
could indicate widespread problems.
    I think we need to consider a national reporting structure for 
adverse events associated to all medications. Many patients don't even 
know what an adverse event is and when a side effect may or may not be 
a concern. This kind of database could provide a great early warning 
system as well.
    What steps can we take to improve the collection of adverse events 
and how can we be sure that patients are included in this process?
    Answer 3. There are a number of very important steps that can be 
taken to improve the collection and analysis of adverse events. A key 
issue is to collect high quality information and ensure appropriate 
followup. This balance can be achieved, although with the following 
potential considerations:

     The current FDA Adverse Event Reporting System (AERS) 
database needs to be updated and maintained. One option would be to 
streamline this by private/
public partnerships to ensure that cutting edge technologies, validated 
and maintained current with dictionary and database oversight, are 
implemented to allow consistent reproducible searching of data.
     Physicians and healthcare professionals need to be 
encouraged to report adverse events, perhaps through incentives linked 
to performance measures specifically in this area. Considerations such 
as how to streamline this activity are critical as disruption to 
clinical workflow will need to be avoided.
     Opportunities to gather rich clinical data and safety 
information from claims and clinical databases should be accelerated, 
once again through public/private initiatives while protecting patient 
privacy. We need to move away from passive, spontaneous reporting to 
automated systems of surveillance.

    Thank you for the opportunity to provide input on these important 
issues before the Senate HELP Committee. Please let me know if I can 
provide any further information.

       Response to Questions of Senators Enzi, Kennedy, Murray, 
                        and Clinton by Jim Guest

                       QUESTIONS OF SENATOR ENZI

    Question 1. You suggest increasing the opportunity for and 
transparency of scientific dissent within FDA. One of the 
recommendations you make is that dissenters be offered whistleblower 
protections. However, dissent and discussion are an inherent part of 
the scientific enterprise. Rarely is there complete certainty based on 
the data. Do you really think it helps the FDA scientists to equate 
dissent with whistle-blowing?
    Answer 1. Of course dissent and debate should be part of the 
scientific process. However, there is a distinction between an honest, 
competent scientific discussion--including disagreement--and a 
whistleblower who reports on an illegal or improper action which 
threatens the public interest. In a very real sense, in a scientific 
agency like the FDA, allowing and encouraging public scientific dissent 
(and making such dissent public in a timely manner) will eliminate many 
or even most of the need for public servants to become whistleblowers.
    What I am suggesting in the way of additional views and dissent is 
elaborated on in my response to Senator Kennedy's question. Our concern 
is that, for example, a junior staffer might feel that a dissent from 
the opinion held by, say, a section head would destroy future promotion 
opportunities. Assuming that the dissent (or additional views) were 
based on reasonable science, what guarantees can we give to younger 
civil servants that raising red flags is acceptable within the FDA? 
There should be a civil service appeals process in which staffers who 
believe their career path is harmed by speaking out can seek review and 
redress. To ensure objectivity in that appeals system, the office of 
review should have some independence--like a whistleblower/ombudsmen 
office would have. As you indicate, names are important, and perhaps it 
should be called something like ``Office of Scientific Integrity.''
    It is worth noting the December 1, 2006, Wall Street Journal 
article ``Virulent Strain: Inside FDA, a Battle Over Drug to Treat 
`Darth Vader' Bacteria.'' The report describes the issues over the 
approval of the anti-heart valve infection drug Cubicin. It concludes 
with the following paragraph:

          ``An internal e-mail sent out to staffers who worked on the 
        Cubicin application by an FDA administrator said, `this has 
        been a very difficult application,' and promised that 
        dissenting reviewers could note their disagreement for the 
        record, with no retribution. . . .''

    In short, there is precedent for this idea of dissent, but it 
should go without saying that there is ``no retribution,'' and a system 
should be institutionalized to make that promise a guarantee.
    There is language in the FDA regulations that seems ignored, but 
which, if codified and made prominent in the agency's culture, could 
address many of the morale and scientific problems that have plagued 
the FDA in recent years. We urge you to codify and put some teeth into 
compliance with 21 CFR 10.70, which currently reads as follows:

    (1) Appropriate documentation of the basis for the decision, 
including relevant evaluations, reviews, memoranda, letters, opinions 
of consultants, minutes of meetings, and other pertinent written 
documents; and
    (2) The recommendations and decisions of individual employees, 
including supervisory personnel, responsible for handling the matter.

          (i) The recommendations and decisions are to reveal 
        significant controversies or differences of opinion and their 
        resolution.
          (ii) An agency employee working on a matter and, consistent 
        with the prompt completion of other assignments, an agency 
        employee who has worked on a matter may record individual views 
        on that matter in a written memorandum, which is to be placed 
        in the file.

    The type of serious concerns identified by the Union of Concerned 
Scientists (and by the HHS OIG) in their poll of FDA scientists could 
also be addressed by institutionalizing respect for science. S. 1358 
(Senators Durbin and Lautenberg), the ``Restore Scientific Integrity to 
Federal Research and Policymaking Act,'' has language we urge you to 
consider which would prevent political interference with science and 
punish managers who violate such non-interference provisions. One of 
the reasons for the culture/morale problems in the FDA is the 
widespread belief that senior managers regularly have ex parte contacts 
with industry applicants and then use these undocumented contacts to 
overrule line staff. We hope that you could also codify the idea that 
ex parte contacts are prohibited, or if they occur, must be documented.

    Question 2. You suggest that the clinical trial results disclosure 
provisions in the Enzi-Kennedy drug safety proposal allow too much time 
for study sponsors to seek publication of their results. But don't we 
want to encourage publication in peer-
reviewed medical journals?
    Answer 2. We must find a way to move this science into the public 
domain sooner. Certainly, if there are findings of danger, or warnings 
of danger that call for additional research, the findings should be 
posted immediately or within a set period of time, such as 2 working 
days.
    We urge your consideration of an exciting article in 
www.plosclinicaltrials.org, October 2006 e31, by Elizabeth Wager and 
entitled ``Publishing Clinical Trial Results: The Future Beckons.'' The 
article makes a moral case for publication of trial results, points to 
the many problems with the current journal system, and basically 
concludes:

          ``A new model might therefore be for investigators or 
        sponsors to make results available on publicly accessible 
        Websites using standard templates and for journals to add value 
        by publishing peer-reviewed commentary and synthesis.''

    Wager notes that ``it is ironic that medical journals, for so long 
the bastion of publishing research findings, may now prevent or delay 
other, possibly better, forms of publication.''
    A 1-year limit in your bill on the publication of results should 
help force changes in this sector that we believe would be in the 
public interest.

    Question 3. Where is the line between the FDA limiting the 
marketing and use of a new drug and the FDA interfering in the practice 
of medicine?
    Answer 3. Your bill encourages the practice of good medicine. There 
have been repeated studies showing that despite black box warnings and 
other strong guidance to the medical community, very potent drugs are 
repeatedly prescribed inappropriately. Physicians are busy and errors 
happen. For drugs that can be dangerous (e.g., accutane in a pregnant 
woman), your bill systemizes safeguards that will reduce mortality and 
morbidity in the future. We see nothing in your bill that interferes 
with the good practice of medicine, though it does interfere with the 
bad practice of medicine. Physicians should thank you for reducing the 
chance for errors that may harm their patients.

    Question 4. Without advertisements, how would consumers learn about 
drugs that might help them?
    Answer 4. Just as most of us don't need ads to tell us when to eat, 
most of us go to a doctor when we feel sick or something doesn't feel 
right--and that's the best way to get an appropriate prescription. 
Studies have shown that DTC ads prompt people to ask for medicines that 
are often inappropriate, and to keep customers happy, doctors all too 
often comply with the request.
    We are seeing the over-medication of America because of the 
enormous profits that flow from direct-to-consumer advertising. I was 
nervous testifying before the committee--but I don't think that means I 
needed to take a pill, like the television ads keep pushing. In short, 
Americans were doing fine before DTC ads, and we will do fine without 
them. And remember, the proposal is simply to limit for a few years ads 
for drugs which have shown warning signs of trouble.
    In cases where there may be a problem that is hard to talk about, 
or a new vaccine, such as the one for young women to help prevent 
cervical cancer, Public Service Announcements could be run. The PSAs 
could be cleared for objectivity and scientific validity by a group 
within the FDA or NIH and funded through an industry user fee system.

                      QUESTIONS OF SENATOR KENNEDY

    Question 1. The IOM report discusses the need to encourage a 
culture of safety at FDA. Some commentators have argued that FDA needs 
better ways to recognize diverse scientific interpretations of data in 
its review panels, and to create a climate where scientific debate is 
encouraged. What actions need to be taken legislatively to bring about 
this cultural change?
    Answer 1. I would like to offer two different ideas, either of 
which could be legislated and, I believe, would greatly increase the 
morale and culture of scientific vigor at the FDA.
    Proposal #1: Recently Acting Commissioner Dr. von Eschenbach 
responded to a question by Senator Grassley about the need for an 
independent office of safety by describing, in detail, all the ways 
that the Office of Surveillance and Epidemiology (OSE) works with the 
Office of New Drugs (OND), and indicating it would be duplicative and 
wasteful to separate the two offices. But we believe that the FDA's 
morale and culture of scientific vigor could be improved by a variation 
of the separation of offices proposal, and avoid all the problems 
raised by Dr. von Eschenbach. Legislation could state:

     CDER consists of an OND and an OSE, and such other offices 
as the Commissioner may determine necessary.
     The Director of the OSE may, at any time, order a REMS 
process or an amendment to any REMS process (consistent with some 
timeframe for notice to the company, etc.), or order the suspension or 
withdrawal of a drug, and shall provide a written brief as to his/her 
reasons.
     If the Director of the OND disagrees, in whole or part, 
and provides a written brief as to his/her reasons within x days, the 
Commissioner shall decide the issue(s) within y days, and provide a 
written explanation for the decision.
     After the decision has been made, the briefs and final 
decision explanation shall be public documents.

    Nothing else that the OSE does, which Dr. von Eschenbach defends in 
his letter to Senator Grassley as coordinating and working with OND, 
would change. This proposal would not disrupt anything. What it would 
do is make the Director of OSE more responsible for raising questions, 
and forcing an FDA-wide debate and decision within a tight timeframe. 
It would give him/her co-authority with OND to force a decision at the 
Commissioner level. Basically, it would focus more responsibility on 
three people, rather than the very diffuse Drug Safety Oversight Board.
    Proposal #2: (See also our response to Senator Enzi question #1 
relating to codification of current FDA regulations.)

     For every NDA (and other significant approval action) the 
FDA shall develop a memorandum (to be made public at the point of final 
decision) explaining the decision to approve, adjust, or reject an 
application, signed by the members of the team working on the NDA.
     The memorandum shall include a provision for additional 
views, in which any staff member may raise questions, and urge further 
studies and clarifications.
     It shall also include a provision for dissenting views in 
the case of any staff person who believes unresolved questions and 
issues outweigh potential benefits.
     In determining what level of REMS to establish, the 
Commissioner shall give ``weight'' to the additional and/or dissenting 
views.
     There would be Office of Scientific Integrity language 
(see response to Chairman Enzi's first question) to protect those who 
participate in additional or dissenting views.
     Title IV would be amended to provide that any advisory 
committee member can request the presence and participation of any FDA 
staffer who signed a NDA memorandum, either in the majority, additional 
views, or dissenting views. Any FDA staff that conceals relevant 
information from an Advisory Committee should be subject to discipline.

    (In the meantime, we have seen press reports (Inside Health Policy, 
November 14, 2006, ``HHS Seeks to do Away with Incentives, Protections 
for Scientists''), that in on-going labor negotiations between FDA 
management and union representatives, that the Administration is trying 
to weaken protections for workers who dissent. If these press reports 
are true, they take the agency in absolutely the wrong direction, and 
we urge you to contact the FDA as soon as possible in opposition to 
such a negotiating position.)
    There has to be science for there to be scientific dissent, and the 
IOM report makes clear that the FDA needs to do more to promote and 
advance science. We urge you to do more to encourage original 
scientific work within the FDA. The IOM report makes many 
recommendations for increasing the level of science within the agency, 
both for the public good, and as a way to increase morale and build a 
more stable FDA workforce. In addition to resources for continuing 
medical education and participation in scientific conferences, more 
should be done to encourage scientific publication: pre-clearances and 
restrictions on publishing should be dropped (anyone intelligent enough 
to be published in a Journal is smart enough to know what is and is not 
the policy on proprietary information), and managers and staff should 
be measured by and rewarded for the quantity and quality of scientific 
publication that comes out of their Office and Center. We urge you to 
consider the language in H.R. 5922 which provides encouragement for 
scientific publication.

    Question 2. Outcomes of studies that are negative or that suggest 
toxicity in patients are often not published. The legislation I 
introduced with Senator Enzi requires publishing clinical trial 
results, both positive and negative, in a public database. What impact 
do you think this would have for patients, healthcare providers, and 
the research community?
    Answer 2. This is a very important provision that will truly save 
lives, reduce illness, and speed the rate of scientific research and 
knowledge through the world medical community. It is one of the key 
improvements in S. 3807.
    We hope it can be strengthened even more by covering all Phase 2 
results. We hope that you will ask the GAO, or some other appropriate 
body, to report on whether some or all Phase 1 results should be made 
public at the time the drug involved is either approved or withdrawn 
from development. People should not be treated as guinea pigs and then 
have the scientific knowledge gained from their participation in 
sometimes dangerous trials hidden from the world scientific community.
    We urge that the bill also provide for the quicker publication of 
results (especially negative results showing dangers). Finally, we 
think this data is so important, we hope that you will phase in the 
publication in the database of the last 10 years of trial results.

                      QUESTIONS OF SENATOR MURRAY

    Question 1. One of my goals for FDA has always been trying to find 
the right balance between getting new drugs to patients without delay 
while ensuring safety and effectiveness. I know it's a tough balance 
and we always have to be concerned about unintended consequences for 
any actions we take legislatively. I also think we need to be concerned 
about making sure that patients get good information--not conflicting 
information or even information that simply focuses on risks and not 
benefits. We have to be sure not to scare patients away from 
potentially beneficial treatments. There are risks with any drug or 
device, and we could raise safety flags on any new treatment, but this 
could also deter access. How can we achieve this balance and do you 
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
    Answer 1. I do not see any way that the IOM recommendations or the 
Enzi/Kennedy bill denies access.
    I understand your concern that too much negative information may 
deter some from trying a drug. But in general, we always support the 
right of consumers to full information about products--whether it is 
the safety of cars or of prescription drugs. A consumer should have the 
right to decide whether a drug's possible side effects, even though 
unlikely, might not be worth the risk for the condition in question. 
Or, if the consumer has information identifying possible problems with 
one drug, it can help them ask whether there are other drugs in the 
class or in another class that can work without the risk.
    The right of consumers to have full information is particularly 
important in this age where so much is spent on slick direct-to-
consumer ads, and so many researchers, journals, and even physicians 
have become financially conflicted.

    Question 2. As the IOM report noted, 21 percent of prescriptions in 
2001 were for off-label uses, meaning of course that these uses were 
never reviewed or approved by FDA. Many patients often are not even 
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as 
patients with rare diseases. I agree that additional safety data is 
warranted for off-label use, but are you concerned about efforts to 
discourage off-label use? Once again is there a way we can encourage 
greater safety data on off-label use without jeopardizing access or 
impeding the practice of medicine?
    Answer 2. We in no way want to discourage responsible off-label 
use. We are simply asking for the FDA to obtain studies on the most 
commonly prescribed off-label uses to ensure that the science supports 
the safe use of these drugs. Ideally, the studies will lead to label 
amendments so that the drugs are used ``on-label'' and the science of 
pharmaceuticals is expanded and improved. The requirement for studies 
is an obligation on the companies (or the FDA/NIH if their budgets 
permit) and not on the individual physician or pharmacist. The proposal 
does not in any way interfere with the doctor/patient relationship.
    As you know, one recent medical journal article found that of the 
21 percent prescribed off-label, in 73 percent of those cases there was 
no science to support such use. A little more science would be a good 
thing. Also, since the hearing, there are major new reports about the 
safety of drug-coated stents. These stents have been used extensively 
off-label on older, less healthy patients than the FDA approved. The 
result is a high level of heart incidents and deaths--and reminds us 
once again about the importance of applying more science before drugs 
or devices are used widely off-label.

    Question 3. It has become very clear that we need a more uniform 
mechanism for collecting safety data. Currently the process for 
reporting adverse events is fragmented and there is little role for the 
patient. In fact, FDA does not even have a database of reported adverse 
events.
    As an early champion, with Senator DeWine, of 1-800 Mr. Yuck, a 
national poison control center hotline that provides real time, 
accurate information to parents and providers in response to accidental 
poison exposure, I know how difficult it is to create a national 
database of real time information. But, we did succeed. We now have a 
national poison control database that can provide information to any 
caller across the country regarding accidental exposure to poisons. 
Using the data mined from this database we can also find information on 
increases in exposure to certain poisons and even local trends that 
could indicate widespread problems.
    I think we need to consider a national reporting structure for 
adverse events associated to all medications. Many patients don't even 
know what an adverse event is and when a side effect may or may not be 
a concern. This kind of database could provide a great early warning 
system as well.
    What steps can we take to improve the collection of adverse events 
and how can we be sure that patients are included in this process?
    Answer 3. This is an exciting proposal. I believe that within a few 
years, there will be widespread use of electronic Personal Health 
Records (PHR), and we hope that there are strong patient privacy and 
security built-in. We urge you to include a new section in the bill 
which will establish a system that enables a patient (with their 
consent) who gets a prescription (especially a new molecular entity or 
other new, breakthrough drug) to be queried electronically at, say, 2 
weeks, 1 month, 2 months, and at some later dates. The query would ask 
for any adverse events and any major medical events in the patient's 
life, etc., with responses collected in certain electronic fields. The 
electronic response would go to a secure FDA database in a format that 
would allow systematic analysis and the search for short- and long-term 
problems.
    Such a system would be an enormous improvement over today's systems 
which we estimate collect only 1 to 10 percent of all ADRs, and which 
often miss major problems that are buried in the ``background noise'' 
of the medical incidents of an aging society.

                      QUESTIONS OF SENATOR CLINTON

    Question 1. In your written testimony, you talk about the need for 
legislation that would establish a path for the approval of biogeneric 
drugs. Could you elaborate on the ways in which increasing access to 
biogenerics could improve access to safe and appropriate treatments for 
patients?
    Answer 1. Biologics hold much promise for the future, but come with 
awesome price tags. Without generics available at the end of the 
biologics patent/exclusivity life, there will be little or no price 
competition, and some consumers might never be able to afford such 
medicines.
    We know that the development of safe biogenerics will not be easy, 
and it will take time. We hope you will start the process of developing 
a biogeneric pathway in this bill, so that there is hope for financial 
relief in the future.

    Question 2. Consumers Union has been a strong advocate of 
comparative effectiveness studies, which allow us to determine the 
benefits of a range of treatments for a certain disease and ensure that 
providers and patients are making treatment choices that are evidence-
based, and not unduly influenced by direct-to-consumer advertising or 
other marketing efforts.
    These comparative effectiveness studies complement the drug 
approval work of the FDA. The agency's approval process focuses largely 
on ensuring that the drugs that come to market are safe for consumers. 
But newer drugs are not always better drugs, and may not be the 
clinically appropriate choice for all patients with a given condition.
    Comparative effectiveness studies are not a substitute for thorough 
and unbiased safety reviews at the FDA. But the studies completed so 
far highlight the shortcomings that we have faced at the agency and the 
need for reforms in our drug safety system.
    One of the first studies to be carried out under the comparative 
effectiveness studies provision of the Medicare Modernization Act was a 
systematic review of COX-2 drugs, the class of drugs that includes 
Vioxx.
    The results of this study, which were released in September, found 
no difference in the effectiveness of COX-2 painkillers compared with 
over-the-counter pain relieving drugs.
    How can comparative effectiveness studies help us to weigh the 
risks and benefits of the drugs used by consumers?
    Answer 2. We believe one of the long-term hopes for slowing the 
unsustainable inflation in American healthcare is through comparative 
effectiveness research and trials--not just of pharmaceuticals, but of 
medical processes, devices, surgeries, etc. We deeply appreciate your 
leadership in the passage of Section 1013 of the Medicare Modernization 
Act, which establishes a program of comparative effectiveness research 
within the Agency for Healthcare Research and Quality.
    The example you provided on COX-2 Inhibitors is an excellent 
example of the usefulness of comparative effectiveness studies. Another 
example that emerged within weeks of the hearing where I testified was 
the report showing that the expensive new generation of anti-psychotic 
drugs offers little or no advantage over the older drugs in this field. 
For newly diagnosed patients or patients having trouble with one of the 
new generation anti-psychotics, this comparative effectiveness analysis 
shows that other, much lower cost medicines are available that may be 
equally helpful. A third example was illustrated on December 6, 2006, 
at a hearing before the Ways and Means Committee, which identified 
serious danger to the Nation's hundreds of thousands of end stage renal 
disease patients, and hundreds of millions of dollars in excessive 
payments for a drug used in kidney dialysis. There had been warnings 
for years about the over-use of this drug, but no research had been 
undertaken until very lately to determine whether the warnings were 
valid, despite the lives at stake and the enormous cost of the drug.
    For Americans to receive the safest, most effective, and in the 
long run lowest cost medicines (because they work safely), we need to 
greatly increase the funding of section 1013 and use the Medicare Part 
A, B, and D databases to link various drug and treatment options with 
actual successful outcomes. We hope that you will include resources (if 
necessary, through user fees) in S. 3807 to fund an aggressive FDA use 
of the huge new patient de-identified databases now available to us. In 
addition to increased appropriations for section 1013, we hope Congress 
will explore through hearings other ways to provide greatly expanded, 
reliable sources of funding comparative effectiveness trials. For 
example, such funding could be through a very small medical drugs and 
devices profit surtax or ``user free'' at the company level, or a penny 
fee per prescription and device at the customer level. Even at the 
level of a penny per prescription, millions would be raised for section 
1013 research which could quickly save billions of dollars in future 
healthcare costs.

      Response to Questions of Senators Enzi, Kennedy, and Murray 
                             by Greg Simon

    Thank you for the opportunity to answer questions based on my 
testimony before the HELP Committee on November 16.

                       QUESTIONS OF SENATOR ENZI

    Question 1. How can we design and enforce post-approval studies 
that would be early indicators of safety issues to enable earlier 
approval of treatments with proven benefits?
    Answer 1. The actual design of a safety study is intricately tied 
to the nature of the therapy, the intended use, foreseeable off-label 
uses and sectors of the population expected to use the drug or device. 
The FDA needs access to more reviewers and experts who can give careful 
thought to these issues during the pre-approval NDA submissions so that 
in the case FDA approves a product, thoughtful post-
approval studies are designed based on the most up to date, available 
science.
    The FDA's authority to enforce post-approval studies needs to be 
strengthened and its budget increased to permit improved continuous 
safety monitoring and enable the FDA to balance its obligation to bring 
new therapies to the public and to monitor adverse effects that are 
inevitable for any therapy in some segment of the population.
    As stated in our testimony,
     1. The FDA needs to be able to assess a drug's impact 
post-approval, weigh both benefits and risks and take appropriate 
action to protect the public;
     2. To do that the FDA needs much stronger authority to 
regulate and enforce how an approved drug enters the market, how it is 
advertised, what claims are made for it and how labels are updated to 
reflect growing knowledge of a product;
     3. To do those things the FDA needs increased 
appropriations from Congress and should not be forced to rely on 
industry user fees which the FDA is largely restricted from using on 
post-approval activities.

    Question 2. Can you comment on the balance between increasing 
transparency and commercially sensitive information in the context of 
clinical trial results disclosure?
    Answer 2. It is well established that commercial speech is less 
protected under the Constitution than is non-commercial speech. When 
there is a conflict between the public's right to know what happened in 
a clinical trial affecting human health and safety and a company's 
interest in protecting commercial interests, the public should win 
every time barring extraordinary circumstances. FasterCures as an 
organization advocates for positions that save lives by saving time. We 
believe that it is very important to consider and protect patients' 
interests at each step of the process of scientific discovery.
    We believe that patients should be armed with information that will 
help them and their health providers make good treatment decisions for 
the individual. Part of this is making available meaningful information 
during and after the clinical trial process.
    We believe that disclosure of both positive and negative outcomes 
is vital to the progress of medical research and to patient safety. 
While there is a case to be made to disclose all clinical trials data 
starting with Phase 1 trials, FasterCures supports the Enzi-Kennedy 
bill requirement of disclosure of aggregated clinical trial data 
starting with Phase 2 data. We want companies to be able to compete 
adequately in the market place of ideas and to retain proprietary 
information that will motivate them to innovate and improve safety 
profiles of treatments, but we also want this information to inform 
treatment decisionmaking.
    We believe one area of this debate that has not had enough thought 
and energy is finding policies that will help avoid exposing people to 
potential harms that have been shown to have no benefit or to 
unnecessarily repeating trials that worked and that need to move 
forward into therapies.

    Question 3a. I noted in your testimony you expressed support for 
the creation of the Reagan-Udall (RU) Institute. Do you have any 
thoughts about the placement of the Institute and how to maximize its 
chances of it being successful and minimization of conflicts of 
interest?
    Answer 3a. To keep FDA moving forward and preparing for the science 
of tomorrow, we must continue to invest in the infrastructure of 
regulatory science. The RU Institute should be located at the FDA and 
serve as the FDA's research arm to examine the FDA's extensive 
accumulated data of the history of drug development and to identify 
best practices and new promising approaches to therapy development.

    Question 3b. Do you think the timeframes for FDA action proposed in 
S. 3807 are reasonable?
    Answer 3b. FasterCures believes the timeframes are reasonable 
generally but that the committee should be flexible in this area and 
focus more on provisions to strengthen the FDA's authority and budget.

    Question 4. Does our current system of approval and post-approval 
review take into account the very different perspectives people with 
life threatening diseases have about ``risk,'' as compared to the 
concerns of the ``well'' population?
    Answer 4. Finding a way to adequately balance risk tolerance and 
benefit for individual patients is very challenging. Each person 
assesses benefit differently based on his or her life experience. We 
believe the agency should redouble its effort to communicate its 
benefit and risk determinations in the approval process. FasterCures 
believes patients should have access to new and innovative medicines 
even when they have known risks. The challenge is to inform these 
patients and their healthcare providers properly so that they have a 
clear understanding of a product's benefit and risk profile and can 
make good decisions for that individual patient.
    FasterCures believes that properly addressing post-approval safety 
issues should allow the FDA to move more expeditiously to approve 
therapies for terminal illnesses and conditions, knowing that the 
chance of a benefit can outweigh the known threats from the disease or 
condition.
    We believe properly addressing post-approval safety issues will 
help agency reviewers avoid being overly cautious in the pre-approval 
stage out of fear that they have few good options to monitor or affect 
use of the product post-approval.

                      QUESTION OF SENATOR KENNEDY

    Question. Outcomes of studies that are negative or that suggest 
toxicity in patients are often not published. The legislation I 
introduced with Senator Enzi requires publishing clinical trial 
results, both positive and negative, in a public database. What impact 
do you think this would have for patients, healthcare providers, and 
the research community?
    Answer. At FasterCures, we often talk about the need for a Journal 
of Failure. We believe a public database to capture the results of both 
positive and negative clinical trials is vital to pursuing cures. 
Although this will mean culture change in the research community, it is 
the most efficient antidote to the lack of awareness that can exist 
when information is not available about who has done what and what has 
and has not worked.

                      QUESTIONS OF SENATOR MURRAY

    Question 1. One of my goals for FDA has always been trying to find 
the right balance between getting new drugs to patients without delay 
while ensuring safety and effectiveness. I know it's a tough balance 
and we always have to be concerned about unintended consequences for 
any actions we take legislatively. I also think we need to be concerned 
about making sure that patients get good information--not conflicting 
information or even information that simply focuses on risks and not 
benefits. We have to be sure not to scare patients away from 
potentially beneficial treatments. There are risks with any drug or 
device, and we could raise safety flags on any new treatment, but this 
could also deter access. How can we achieve this balance and do you 
have concerns about the impact of the IOM recommendations or the Enzi/
Kennedy bill as it relates to access?
    Answer 1. Both the Institute of Medicine (IOM) report and S. 3807 
will improve access by focusing resources on post-approval safety 
studies, thereby improving the FDA's ability to approve needed drugs 
knowing they are being well monitored for safety post-approval.
    The IOM focus on better labels to communicate with the public is 
vital to increasing the public's understanding of the risks and 
benefits of new therapies.
    Disclosure of clinical trial results is also critical to 
communicating to the public, the medical research community, and 
physicians the risks and benefits of new proposed therapies.

    Question 2. As the IOM report noted, 21 percent of prescriptions in 
2001 were for off-label uses, meaning of course that these uses were 
never reviewed or approved by FDA. Many patients often are not even 
aware of off-label use. However, as Diane Thompson pointed out, off-
label use is extremely important for pediatric patients as well as 
patients with rare diseases. I agree that additional safety data is 
warranted for off-label use, but are you concerned about efforts to 
discourage off-label use? Once again is there a way we can encourage 
greater safety data on off-label use without jeopardizing access or 
impeding the practice of medicine?
    Answer 2. At FasterCures, we believe that off-label use of 
medication remains an important option for health providers and their 
patients. Those patients with the most intractable and serious diseases 
that often have no identified cures need to be able to work with their 
healthcare providers to find the best treatment options. Thus, we are 
concerned with efforts to discourage off-label use.
    With that said, we believe that medical professional societies 
should, and can, do more to ensure that doctors are aware of the 
latest, unbiased treatment options. Physicians should be encouraged to 
share voluntarily their knowledge and experience from off-label usage 
of a drug so that we learn how medications are succeeding and failing 
in various populations.

    Question 3. It has become very clear that we need a more uniform 
mechanism for collecting safety data. Currently the process for 
reporting adverse events is fragmented and there is little role for the 
patient. In fact, FDA does not even have a database of reported adverse 
events.
    As an early champion, with Senator DeWine, of 1-800 Mr. Yuk, a 
national poison control center hotline that provides real time, 
accurate information to parents and providers in response to accidental 
poison exposure, I know how difficult it is to create a national 
database of real time information. However, we did succeed. We now have 
a national poison control database that can provide information to any 
caller across the country regarding accidental exposure to poisons. 
Using the data mined from this database we can also find information on 
increases in exposure to certain poisons and even local trends that 
could indicate widespread problems.
    I think we need to consider a national reporting structure for 
adverse events associated to all medications. Many patients don't even 
know what an adverse event is and when a side effect may or may not be 
a concern. This kind of database could provide a great early warning 
system as well.
    What steps can we take to improve the collection of adverse events 
and how can we be sure that patients are included in this process?
    Answer 3. FasterCures supports improving the adverse event 
reporting system from both the reporting side and the monitoring and 
evaluation side by dedicating significant financial and staff resources 
to overhauling the current system.
    Currently the United States has a voluntary reporting system for 
health professionals. Constraints on physicians' time and a reluctance 
to seek out and report adverse events, have contributed to the system's 
lack of effectiveness.
    We need to identify ways to make reporting more consistent so that 
better data is captured. We also need to invest in an electronic real-
time system that allows computer analysis to spot trends and patterns 
that might elude a human reviewer. We believe an analysis of the pros 
and cons of the ``yellow card'' system in England need to be explored 
and examined.
    Again, thank you for the opportunity to provide answers to these 
questions. Please contact Margaret Anderson at 
[email protected] if you have questions before January 8th, as 
I will be out of the country. Thank you.

    [Whereupon, at 11:53 a.m., the hearing was adjourned.]

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