[Senate Hearing 112-858]
[From the U.S. Government Publishing Office]







                                                        S. Hrg. 112-858

                 FDA USER FEES: ADVANCING PUBLIC HEALTH

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

                                HEARING

                                 OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                      ONE HUNDRED TWELFTH CONGRESS

                             FIRST SESSION

                                   ON

  EXAMINING FOOD AND DRUG ADMINISTRATION (FDA) USER FEES, FOCUSING ON 
                        ADVANCING PUBLIC HEALTH

                               __________

                             JULY 28, 2011

                               __________

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





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          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                       TOM HARKIN, Iowa, Chairman

BARBARA A. MIKULSKI, Maryland       MICHAEL B. ENZI, Wyoming
JEFF BINGAMAN, New Mexico           LAMAR ALEXANDER, Tennessee
PATTY MURRAY, Washington            RICHARD BURR, North Carolina
BERNARD SANDERS (I), Vermont        JOHNNY ISAKSON, Georgia
ROBERT P. CASEY, JR., Pennsylvania  RAND PAUL, Kentucky
KAY R. HAGAN, North Carolina        ORRIN G. HATCH, Utah
JEFF MERKLEY, Oregon                JOHN McCAIN, Arizona
AL FRANKEN, Minnesota               PAT ROBERTS, Kansas
MICHAEL F. BENNET, Colorado         LISA MURKOWSKI, Alaska
SHELDON WHITEHOUSE, Rhode Island    MARK KIRK, Illinois
RICHARD BLUMENTHAL, Connecticut     

                    Daniel E. Smith, Staff Director
                  Pamela Smith, Deputy Staff Director
     Frank Macchiarola, Republican Staff Director and Chief Counsel

                                  (ii)











                            C O N T E N T S

                               __________

                               STATEMENTS

                        THURSDAY, JULY 28, 2011

                                                                   Page

                           Committee Members

Harkin, Hon. Tom, Chairman, Committee on Health, Education, 
  Labor, and Pensions, opening statement.........................     1
Enzi, Hon. Michael B., a U.S. Senator from the State of Wyoming, 
  opening statement..............................................     2
Franken, Hon. Al, a U.S. Senator from the State of Minnesota.....    23
Burr, Hon. Richard, a U.S. Senator from the State of North 
  Carolina.......................................................    24
Hagan, Hon. Kay R., a U.S. Senator from the State of North 
  Carolina.......................................................    26
Murray, Hon. Patty, a U.S. Senator from the State of Washington..    28
Mikulski, Hon. Barbara A., a U.S. Senator from the State of 
  Maryland.......................................................    29
Hatch, Hon. Orrin G., a U.S. Senator from the State of Utah......    32
Merkley, Hon. Jeff, a U.S. Senator from the State of Oregon......    34
Bennet, Hon. Michael F., a U.S. Senator from the State of 
  Colorado.......................................................    35

                                Witness

Hamburg, Margaret, M.D., Commissioner, Food and Drug 
  Administration, U.S. Department of Health and Human Services, 
  Silver Spring, MD..............................................     3
    Prepared statement...........................................     5

                          ADDITIONAL MATERIAL

Study of Medical Device Rules Is Attacked, Unseen, The New York 
  Times, article.................................................    53
Response of the Food and Drug Administration (FDA) to questions 
  of:
    Senator Enzi.................................................    55
    Senator Alexander............................................    58
    Senator Burr.................................................    70
    Senator Hatch................................................    84

                                 (iii)



 
                 FDA USER FEES: ADVANCING PUBLIC HEALTH

                        THURSDAY, JULY 28, 2011

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The committee met, pursuant to notice, at 9:50 a.m. in Room 
430, Dirksen Senate Office Building, Hon. Tom Harkin, chairman 
of the committee, presiding.
    Present: Senators Harkin, Mikulski, Murray, Hagan, Merkley, 
Franken, Bennet, Enzi, Alexander, Burr, Isakson, and Hatch.

                  Opening Statement of Senator Harkin

    The Chairman. The Committee on Health, Education, Labor, 
and Pensions will come to order. We've convened this hearing 
today to kick off the FDA user fee reauthorization process. We 
will discuss the history and purpose of the user fee agreements 
between the FDA and the industries it regulates, and we will 
learn more about the importance of user fees to ensuring that 
new medical products get to the American patients as quickly 
and safely as possible.
    Since 1992, the Prescription Drug User Fee Agreement has 
paved the way for quicker and more thorough reviews of 
applications for prescription drug products. Ten years later, 
beginning in 2002, the Medical Device User Fee Agreement has 
similarly facilitated getting medical devices onto the market. 
Currently, the drug and device user fees collectively make up 
34 percent of FDA's overall budget. They are a significant 
source of the funds that FDA needs to get its job done.
    Both the Prescription Drug User Fee Agreement and the 
Medical Device User Fee Agreement expire at the end of the next 
fiscal year. Failing to reauthorize them would have significant 
consequences for FDA, which would have to let staff go and 
substantially slow its approval process; and even more 
importantly, failing to pass the reauthorization legislation 
would have devastating consequences for the patients, whose 
health and lives depend on new medical treatments. We can't let 
that happen. For the health of the agency, the medical products 
industry and, most importantly, the patients who rely on new 
medical technologies, we need to reauthorize the user fee 
agreements before they expire.
    I know that this legislation is likely to attract attention 
from everyone here who is interested in policy related to the 
FDA. I have policy priorities of my own, including helping to 
ensure the integrity of our global pharmaceutical supply chain 
at a time when our drug products and their ingredients are 
increasingly being brought to the United States from around the 
world.
    This fall, we hope and expect to convene hearings to 
explore some of these policy issues. Today, however, we begin 
the process with a focus on user fees themselves.
    We welcome Dr. Peggy Hamburg, the Commissioner of the FDA, 
and look forward to her description of the history and 
importance of the user fee program, and explanation of the 
impact user fees have on FDA's ability to get medical products 
to American consumers.
    We look forward to hearing Commissioner Hamburg's views on 
this important subject, and I look forward to working with my 
colleague and Ranking Member, Senator Enzi, to continue the 
tradition of bipartisan cooperation on these user fee efforts.
    Now I'll yield to Senator Enzi.

                       Statement of Senator Enzi

    Senator Enzi. Thank you, Mr. Chairman, and thank you for 
having this hearing.
    The Prescription Drug and Medical Device User Fee programs 
have been a success, originally decreasing product review 
times, stabilizing funding for FDA's Drug and Medical Device 
Centers, and decreasing the burden on taxpayers. I do believe, 
however, that the FDA can do better. On the metric most 
important for patients, the total time to market, FDA's 
performance regarding medical devices has declined sharply. 
According to a study by Boston Consulting Group, by the 
California Health Care Institute, overall 510(k) review times 
have increased 43 percent, and PMA review times have increased 
by 75 percent over the past 4 years. These findings have been 
widely corroborated. Numerous studies have identified serious 
problems with the Device Center's performance.
    The Device Center's performance is not a partisan issue. 
Democrats and Republicans, patient and consumer groups, 
industry, academics, and nonprofits alike have all raised 
serious concerns about the Device Center's performance. FDA 
itself has engaged in extensive self-scrutiny, and the 
Institute of Medicine is expected to report on several 
controversial problems tomorrow.
    In this Congress, I look forward to working with Chairman 
Harkin to reauthorize these user fee agreements. We have a 
couple of challenges as we try to move this legislation. First 
is timing. We plan to front-load as much of the work as 
possible to conclude the HELP Committee markup by the spring of 
2012. Second, the Federal debt is about $14 trillion and 
rising, and FDA is close to a tipping point. In the past few 
years, Congress has imposed several challenging new mandates on 
the agency. The Government Accountability Office has put FDA on 
its high-risk list because the FDA is overwhelmed by its many 
diverse public health responsibilities. We need to be practical 
and strategic about what FDA can and cannot do.
    I do want to salute Commissioner Hamburg for recognizing 
and starting to address these strategic challenges, and I'll 
have some questions for the record concerning the agency's 
recent reorganization.
    And last, we have a firm deadline. If we don't authorize 
new user fee programs before the old one expires, FDA will need 
to lay off approximately 20 percent of the Device Center and 60 
percent of the Drug Center's full-time employees. This would 
create a severe personnel shortage and disrupt important public 
health programs.
    Having said all that, I'm an optimist, and I believe all of 
us, Congress and the outside stakeholders alike, can work 
together to enact a good user fee bill. The last time we did it 
in the 110th Congress, we got a good bill through the Senate 
unanimously and on time because we all worked together. I 
believe the way to do that is something called the 80 percent 
rule. I've learned over the years that for just about any given 
problem, reasonable people can agree on 80 percent of the 
solution. If we go ahead and get that done, the American people 
are very happy.
    The problem is that the process of finding common ground is 
hard, slow work, and not always very exciting. The 20 percent 
where people strongly disagree is much more dramatic. The media 
love to cover the 20 percent and make it the story, but my hope 
is that we'll focus on the areas of broad agreement.
    This committee has had great success on FDA legislation 
when we work together. In 2007 the New England Journal of 
Medicine said we passed the biggest drug bill in 50 years. We 
also gave FDA new authority to regulate tobacco and create new 
biosimilar pathways, and just last year Chairman Harkin and I 
and the many other members of the HELP Committee worked hard to 
give FDA new food safety authorities. We're going to need this 
kind of bipartisan inclusion and cooperation to get this done, 
and I hope today's hearing kicks off a constructive discussion 
on these serious problems.
    The Chairman. Thank you very much, Senator Enzi.
    And now we'll turn to our only witness today, Commissioner 
Hamburg. I'd like to welcome Dr. Hamburg back again to this 
committee. Commissioner Hamburg has an impressive background as 
a doctor, an NIH scientist, and significant administrative 
experience in protecting and promoting the public health from 
her previous post at New York's Department of Health and Mental 
Hygiene, and here in Washington at the Department of Health and 
Human Services.
    Commissioner Hamburg is expertly positioned to lead the 
agency and to protect the public health as we work to 
reauthorize the user fee agreements in this Congress.
    Thank you very much, Commissioner, for being here today. 
Your statement, which I tried to get through last night, is a 
long and very involved statement and very good statement, and 
it will be made a part of the record in its entirety, and I'd 
ask you to proceed as you so desire. You can ignore the 5-
minute thing there, and if you need to take 10 minutes, please 
go ahead and take whatever time. If you start going over 10, I 
might start getting a little nervous about that time, but 
please proceed as you so desire.

  STATEMENT OF MARGARET HAMBURG, M.D., COMMISSIONER, FOOD AND 
   DRUG ADMINISTRATION, U.S. DEPARTMENT OF HEALTH AND HUMAN 
                  SERVICES, SILVER SPRING, MD

    Commissioner Hamburg. Thank you, Mr. Chairman and members 
of the committee. I promise that I will be shorter than the 
length of my written testimony.
    I'm very, very pleased to have the opportunity to be here 
and to testify about the Prescription Drug User Fee Act, the 
PDUFA, and the Medical Device User Fee Act, or MDUFA.
    The enactment of PDUFA back in 1992 was prompted by 
concerns that patients in the United States were waiting longer 
than patients in other countries for critical therapies, 
sometimes with tragic consequences. Through user fees paid by 
the drug industry, PDUFA provided FDA with a source of stable, 
consistent funding to hire additional reviewers, upgrade IT 
systems, and strengthen programs.
    At the same time, FDA committed to complete reviews in a 
predictable timeframe, to meet more often with industry, and to 
provide more guidance.
    These changes revolutionized the drug approval process in 
the United States and enabled FDA to speed its reviews without 
compromising the agency's high standards for safety and 
effectiveness, and our commitment to promote and protect the 
health of the public.
    The time required for FDA approval has been cut by 60 
percent since the enactment of PDUFA, and the United States now 
leads the world in the first introduction of new active drug 
substances. And so far this year, with the assistance of PDUFA 
user fees, FDA has approved 21 new ground-breaking medicines, 
including treatments for hepatitis C, late-stage prostate 
cancer, and lupus. In fact, this is the same number of novel 
drugs approved in all of 2010, and we're only in July. So that 
is very positive news.
    But despite this positive news, we face a severe 
productivity problem worldwide in drug development in which an 
ever-increasing research and development investment is 
producing fewer new drugs. And at the same time, the scientific 
opportunities have never been greater due to new biomedical 
discoveries. And, of course, this is a complex ecosystem. FDA 
represents one important player in addressing this challenge, 
but the proposed PDUFA enhancements discussed in my written 
testimony include new steps to incorporate scientific advances 
into regulations so that we can modernize and streamline our 
processes to the benefit of both patients and industry.
    The enactment of MDUFA in 2002 was prompted by similar 
concerns about the speed of the FDA review process for devices. 
User fees paid by the device industry under MDUFA have helped 
FDA expand available expertise and staffing, modernize IT 
systems, and provide additional guidance to industry. While FDA 
is meeting the vast majority of its goals under MDUFA, we know 
that the overall time to a decision, FDA time plus the time the 
manufacturer spends responding to FDA questions, has increased, 
as Senator Enzi noted. FDA and industry share responsibility 
for that increase, and FDA has been instituting management 
changes to address our role.
    As a result, for 2010, total time for lower-risk devices 
appears to have stabilized, and preliminary data suggest that 
total time for higher-risk devices is improving. We appreciate 
that AdvaMed is also working to address the part that poor-
quality applications play in delaying approval by offering 
training for its companies regarding FDA standards.
    Beyond review times alone, we recognize that significant 
concerns have been raised about how well the device review 
program is meeting its two goals, ensuring that medical devices 
are safe and effective, and fostering medical device 
innovation.
    In response to these concerns, the agency conducted an 
assessment of the 510(k) review program. What we found was that 
insufficient predictability in our premarket review programs 
was contributing to inconsistent decisions and longer times to 
market. The causes included unnecessary or inconsistent data 
requirements, insufficient guidance for industry, insufficient 
interactions with industry, high reviewer and manager turnover, 
insufficient reviewer training, insufficient managerial 
oversight, and a rapidly growing workload.
    After soliciting public comment on these reports, we 
announced this past January 25 specific actions that we will 
take in 2011 to improve the predictability, consistency, and 
transparency of our pre-market review programs and have since 
announced additional actions.
    For example, we've committed to developing updated and new 
guidances to clarify FDA requirements, and several have been 
released in recent days and weeks. We're enhancing the 
interactive review process and streamlining the review program 
for low to moderate-risk novel medical devices, called the ``de 
novo'' process.
    We have established a new Center Science Council to help 
ensure consistency in our scientific decisionmaking and are 
developing a network of experts to help us to resolve complex 
scientific issues.
    We're instituting a certification program and a pilot 
experiential learning program to provide review staff with 
necessary training and real-world experiences.
    These and other efforts signify our commitment to improving 
our pre-market review programs to ensure that patients have 
timely access to safe and effective devices and that the U.S. 
device industry remains innovative and strong.
    PDUFA IV and MDUFA II expire on September 30, 2012, and 
we're eager to work with you to achieve their timely 
reauthorization. These are critical programs and make possible 
the resources and tools that are so vitally needed if we are to 
provide the American people with the medical products they need 
and the safety and effectiveness they count on.
    Thank you for your contributions to the continued success 
of PDUFA and MDUFA and to the mission of the Food and Drug 
Administration.
    And I'm now happy to answer any questions that you may 
have.
    [The prepared statement of Commissioner Hamburg follows:]
            Prepared Statement of Margaret A. Hamburg, M.D.
                              introduction
    Mr. Chairman and members of the committee, I am Dr. Margaret 
Hamburg, Commissioner of Food and Drugs at the Food and Drug 
Administration (FDA or the Agency). I am pleased to be here today to 
discuss the fifth reauthorization of the Prescription Drug User Fee Act 
(PDUFA), also referred to as ``PDUFA V,'' and the third reauthorization 
of the Medical Device User Fee Act (MDUFA), also referred to as ``MDUFA 
III.'' I will also talk about FDA's efforts to promote the science and 
innovation necessary to ensure that we are fully equipped to address 
the public health issues of the 21st century and to address the 
continuing challenges of a global marketplace.
Background on PDUFA
    FDA considers the timely review of the safety and effectiveness of 
New Drug Applications (NDAs) and Biologics License Applications (BLAs) 
to be central to the Agency's mission to protect and promote the public 
health. Prior to enactment of PDUFA in 1992, FDA's review process was 
understaffed, unpredictable, and slow. FDA lacked sufficient staff to 
perform timely reviews, or develop procedures and standards to make the 
process more rigorous, consistent and predictable. Access to new 
medicines for U.S. patients lagged behind other countries. As a result 
of concerns expressed by both industry and patients, Congress enacted 
PDUFA, which provided the added funds, through user fees, that enabled 
FDA to hire additional reviewers and support staff and upgrade its 
information technology systems. At the same time, FDA committed to 
complete reviews in a predictable timeframe. These changes 
revolutionized the drug approval process in the United States and 
enabled FDA to speed the application review process for new drugs 
without compromising the Agency's high standards for demonstration of 
safety, efficacy, and quality of new drugs prior to approval.
    Three fees are collected under PDUFA: application fees, 
establishment fees, and product fees. An application fee must be 
submitted when certain NDAs or BLAs are submitted. Product and 
establishment fees are due annually. The total revenue amounts derived 
from each of the categories--application fees, establishment fees, and 
product fees--are set by the statute for each fiscal year. PDUFA 
permits waivers under certain circumstances, including a waiver of the 
application fee for small businesses.
    Of the total $931,845,581 obligated in support of the process for 
the review of human drug applications in fiscal year 2010, PDUFA fees 
funded 62 percent, with the remainder funded through appropriations.
PDUFA Achievements
    PDUFA has produced significant benefits for public health, 
providing patients faster access to over 1,500 new drugs and biologics, 
since enactment in 1992, including treatments for cancer, infectious 
diseases, neurological and psychiatric disorders, and cardiovascular 
diseases. Importantly, PDUFA has led to the reversal of the ``drug 
lag'' that prompted its creation. According to a study published in 
Health Affairs in June 2011, of the 35 cancer drugs approved over the 
last 7 years in either the United States or Europe, FDA approved 32, in 
an average time of 261 days. The European Medicines Agency (EMA) 
approved only 26 in an average time of 373 days. All 23 cancer drugs 
approved by both agencies during this period were marketed first in the 
United States.
    As shown in Figure 1, the United States now leads the world in the 
first introduction of new active drug substances. According to 
researchers at the Tufts Center for the Study of Drug Development, the 
time required for the FDA approval phase of new drug development (i.e. 
time from submission until approval) has been cut by 60 percent since 
the enactment of PDUFA,\1\ from an average of 2.0 years for the 
approval phase at the start of PDUFA to an average of 1.1 years today. 
So far this year, FDA has approved 21 new, groundbreaking medicines, 
including treatments for hepatitis C, late-stage prostate cancer, and 
lupus. This is the same number of novel drugs approved in all of 2010.
---------------------------------------------------------------------------
    \1\ Milne, Christopher-Paul (2010). PDUFA and the Mission to Both 
Protect and Promote Public Health [PowerPoint slides]. Presentation at 
the FDA PDUFA Public Meeting, Rockville, MD.


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    Increased resources provided by user fees have enabled FDA to 
provide a large body of technical guidance to industry that clarified 
the drug development pathway for many diseases and meet with companies 
during drug development to provide critical advice on specific 
development programs. In the past 5 years alone, FDA has held over 
7,000 meetings within a short time after a sponsor's request. 
Innovations in drug development are being advanced by many new 
companies as well as more established ones, and new sponsors may need, 
and often seek, more regulatory guidance during development. In fiscal 
year 2009, more than half of the meetings FDA held with companies at 
the early investigational stage and midway through the clinical trial 
process were with companies that had no approved product on the U.S. 
market.
    PDUFA provides FDA with a source of stable, consistent funding that 
has made possible our efforts to focus on promoting innovative 
therapies and help bring to market critical products for patients. FDA 
aims to review priority new molecular entities (NME) more quickly--6 
months vs. 10 months for standard drugs. Priority NMEs represent the 
truly innovative medicines generally targeted at severe illnesses with 
few or no available therapeutic options. FDA reviewers give these drugs 
priority attention throughout development, working with sponsors to 
determine the most efficient way to collect the data needed to provide 
evidence of safety and effectiveness.
    Improvements in the efficiency of the drug review process and the 
quality of new drug applications is evident in the trends toward 
greater first-cycle approvals for priority NMEs. A first-cycle approval 
means that the product application is approved after the initial, 
complete FDA review, rather than entering another cycle of FDA 
questions. Importantly, first-cycle approvals bring innovative drugs 
with new benefits to patients sooner. When FDA is presented with high-
quality applications that are based on strong science, we can approve 
these products quickly and efficiently. The average first-cycle 
approval rate for priority NMEs increased from 46 percent in PDUFA I to 
68 percent to date in PDUFA IV, as shown in Figure 2. And I am pleased 
to report that we are on track for approving a historically high 
percentage of priority NMEs for 2011. First-cycle approval rates have 
also increased for standard NMEs from an average of 30 percent in PDUFA 
I to 38 percent to date in PDUFA IV.


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    It should be noted that FDA assesses the benefit-risk of new drugs 
on a case-by-case basis, considering the degree of unmet medical need 
and the severity and morbidity of the condition the drug is intended to 
treat. This approach has been critical to increasing patient access to 
new drugs for cancer and rare and other serious diseases, where 
existing therapies have been few and limited in their effectiveness. 
Some of these products have serious side effects but they were approved 
because the benefit outweighed the risk. For example, in March of this 
year, FDA approved Yervoy (ipilimumab) for the treatment of 
unresectable or metastatic melanoma. Yervoy also poses a risk of 
serious side effects, including severe to fatal autoimmune reactions, 
in 12.9 percent of patients treated with Yervoy. FDA decided that the 
benefits of Yervoy outweighed its risk, especially considering that no 
other melanoma treatment has been shown to prolong a patient's life.
    PDUFA funds help support the use of existing mechanisms in place to 
expedite the approval of certain promising investigational drugs, and 
also to make them available to the very ill as early in the development 
process as possible, without unduly jeopardizing the patients' safety. 
One such program is accelerated approval. In 1992, FDA instituted the 
accelerated approval process, which allows earlier approval of drugs 
that treat serious diseases and that fill an unmet medical need based 
on a surrogate endpoint that is reasonably likely to predict clinical 
benefit, but is not fully validated to do so. A surrogate endpoint is a 
marker--a laboratory measurement, or physical sign--that is used in 
clinical trials as an indirect or substitute measurement for a 
clinically meaningful outcome, such as survival or symptom improvement. 
The use of a surrogate endpoint can considerably shorten the time to 
approval. Approval of a drug based on an unvalidated surrogate endpoint 
is given on the condition that post-marketing clinical trials verify 
the anticipated clinical benefit. Over 60 critical products have been 
approved under accelerated approval since the program was established.
    While the best means of providing access to useful medical 
treatments for all Americans is to approve drugs proven to be safe and 
effective, FDA also recognizes circumstances in which there is public 
health value in making products available prior to marketing approval. 
A promising but not yet fully evaluated treatment may sometimes 
represent the best choice for individuals with serious or life-
threatening diseases who lack a satisfactory therapy.
    FDA allows for access to investigational products through multiple 
mechanisms. Clinical trials are the best mechanism for a patient to 
receive an investigational drug, because they provide a range of 
patient protections and benefits and they maximize the gathering of 
useful information about the product, which benefits the entire patient 
population. However, there are times when an individual cannot enroll 
in a clinical trial. In these cases, the patient may gain access to an 
investigational therapy through one of the alternative mechanisms, and 
FDA's Office of Special Health Issues assists patients and their 
doctors in this endeavor.
Drug Safety Activities
    In parallel with improvements in the drug review process, FDA has 
increased its focus on safety, including implementing the Food and Drug 
Administration Amendments Act of 2007 (FDAAA). In FDAAA, Congress 
authorized additional user fees totaling $225 million for the 5 years 
of PDUFA IV reauthorization to enhance drug safety activities. FDAAA 
also provided FDA with important post-market safety authorities. Under 
FDAAA, FDA was given the ability to require post-marketing studies and 
clinical trials to address important drug safety questions. Between the 
enactment of FDAAA on September 27, 2007, and June 1, 2011, FDA has 
required sponsors to conduct approximately 375 post-marketing studies 
or trials to address important drug safety questions that could not be 
addressed before the drug was approved. FDAAA also gave FDA the 
authority to require safety labeling changes based on new safety 
information identified after a drug is on the market. FDA has used its 
new authority to require sponsors to place important new safety 
information onto their drug labels quickly, in some cases using this 
authority to require changes to the labeling of all members of a class 
of drugs. FDAAA also provided FDA with authority to manage risks 
associated with marketed drug products through required Risk Evaluation 
and Mitigation Strategies (REMS). FDA has been using this new authority 
judiciously to ensure that drugs that could not otherwise be approved 
because the risks without a REMS would outweigh the benefits, are 
available to patients.
Challenges for the Current Drug Program
    Although we can report many important successes with the current 
program, new challenges have also emerged that offer an opportunity for 
further enhancement. While new FDAAA process requirements have 
strengthened drug safety, they have put strains on FDA's ability to 
meet pre-market review performance goals and address post-market review 
activities. In addition, there has been a significant increase in the 
number of foreign sites included in clinical trials to test drug safety 
and effectiveness, and an increase in the number of foreign facilities 
used in manufacturing new drugs for the U.S. market. While foreign 
sites can play an important role in enabling access to new drugs, the 
need to travel much farther to conduct pre-approval inspections for 
clinical trials and manufacturing sites overseas has created additional 
challenges for completion of FDA's review within the existing PDUFA 
review performance goals, while at the same time trying to communicate 
with sponsors to see if identified issues can be resolved before the 
review performance goal date.
    Despite these challenges, FDA has maintained strong performance in 
meeting the PDUFA application review goals, with the exception of a dip 
in fiscal year 2008-9, when staff resources were shifted to ensure 
timely implementation of all the new FDAAA provisions that affected 
activities in the new drug review process. This is shown in Figure 3.


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    However, FDA wants to meet not only the letter (i.e., PDUFA goal 
dates), but also the spirit of the PDUFA program--speeding patient 
access to drugs shown to be safe and effective for the indicated uses.
    Although the NDA/BLA approval phase of drug development (the phase 
in which FDA plays the biggest role) is reported to have the highest 
success rate of any phase of drug development, it is critical to our 
public health mission that we work with industry and other stakeholders 
to take steps to reduce uncertainty and increase the success of all 
phases of drug development. We must leverage advances in science and 
technology to make sure that we have the knowledge and tools we need to 
rapidly and meaningfully evaluate medical products. The science of 
developing new tools, standards, and approaches to assess the safety, 
efficacy, quality, and performance of FDA-regulated products--known as 
``regulatory science''--is not exclusively about helping drug 
development to speed it along before it gets to FDA for review and 
approval. It also gives us the scientific tools to modernize and 
streamline our regulatory process. With so much at stake for public 
health, FDA has made advances in regulatory science a top priority. The 
Agency is both supporting mission-critical science at FDA and exploring 
a range of new partnerships with the National Institutes of Health and 
academic institutions to develop the science needed to maximize 
advances in biomedical research and bring the development and 
assessment of promising new therapies and devices into the 21st 
century. With this effort, FDA is poised to support a wave of 
innovation to transform medicine and save lives.
    For example, FDA is working to improve the science behind certain 
clinical trial designs. Recent advances in two clinical trial designs--
called non-inferiority and adaptive designs--have required FDA to 
conduct more complex reviews of clinical trial protocols and new 
marketing applications. Improving the scientific bases of these trial 
designs should add efficiency to the drug review process, encourage the 
development of novel products, and speed new therapies to patients.
    FDA has also taken steps to facilitate the development and approval 
of safe and effective drugs for Americans with rare diseases. Therapies 
for rare diseases--those affecting fewer than 200,000 people in the 
United States--represent the most rapidly expanding area of drug 
development. Although each disease affects a relatively small 
population, collectively, rare diseases affect about 25 million 
Americans. Approximately one-third of the NMEs and new biological 
products approved in the last 5 years have been drugs for rare 
diseases. Because of the small numbers of patients who suffer from each 
disease, FDA often allows non-traditional approaches to establishing 
safety and effectiveness. For example, FDA recently approved Carbaglu 
(carglumic acid) for the treatment of N-acetylglutamate synthase (NAGS) 
deficiency, a rare disorder of the urea cycle, caused by a genetic 
deficiency or absence of the NAGS enzyme that results in severe 
elevations in plasma ammonia levels and can rapidly result in injury to 
the brain or death. There have only been approximately 50 known cases 
reported in the literature worldwide to date. The disease can be 
diagnosed throughout life, but in infants, the disease can be rapidly 
fatal due to severe hyperammonemia that can result in cerebral edema, 
seizures, and death. FDA approved this drug in March 2010, based on the 
results of a single, non-concurrently controlled, retrospective review 
of the clinical course of 23 patients with NAGS deficiency treated with 
Carbaglu over a 21-year period.
                          background on mdufa
    Similar to the PDUFA program, the enactment of the Medical Device 
User Fee and Modernization Act in 2002 (MDUFMA I) was prompted by 
growing concerns about the medical device review program's capacity and 
performance. MDUFMA I and the Medical Device User Fee Act of 2007 
(MDUFA II) authorized user fees for the review of medical device pre-
market applications, reports, supplements, and pre-market notification 
submissions. These additional resources enabled FDA to make its reviews 
more timely, predictable, and transparent to applicants. MDUFA fees and 
mandated appropriations for the medical device program helped FDA 
expand available expertise, modernize its information management 
systems, provide new review options, and provide more guidance to 
prospective applicants.
    MDUFA authorizes FDA to collect user fees for certain medical 
device applications, the registration of certain medical device 
establishments, and certain other purposes. Small businesses may 
qualify for a waiver or a reduced fee on certain submissions to FDA.
    Of the total $292,707,540 obligated in support of the process for 
the review of medical device submissions in fiscal year 2010, MDUFA 
fees currently fund about 20 percent. The remainder of the funding is 
through appropriations.
                           mdufa achievements
    FDA has consistently met or exceeded goals agreed to by FDA and 
industry under MDUFA II for approximately 95 percent of the submissions 
we review each year. FDA consistently completes at least 90 percent of 
pre-market notification, or 510(k), reviews within 90 days or less, 
which meets the applicable goal. In the limited areas where FDA is not 
yet meeting its MDUFA II goals, the Agency's performance has been 
steadily improving, despite growing device complexity and an increased 
workload, and without a commensurate increase in user fees. And FDA is 
committed to continued improvements in the device approval process to 
address legitimate concerns raised by industry and other stakeholders, 
which I will discuss later in this testimony.
    MDUFA II metrics reflect FDA time only; they do not reflect the 
time taken by industry to respond to requests from FDA for additional 
information. As Figure 4 and 5 illustrate, while the time FDA spends 
reviewing an application has improved for both low- and high-risk 
devices, overall time to decision--the time that FDA has the 
application, plus the time the manufacturer spends answering any 
questions FDA may have--has increased. FDA and industry share 
responsibility for the increase in overall time to final decision, and 
FDA has been instituting management changes to address this. As a 
result, in 2010, total time for 510(k)s appears to have stabilized and 
preliminary data suggest that the total time for pre-market approval 
(PMA) decisions is improving.


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    FDA is committed to working on ways to streamline the regulatory 
review process. Success will require that we continue to focus on our 
own internal process, but industry also bears responsibility for the 
increase in overall time to a decision. Poor-quality submissions that 
need to be addressed are significant contributors to delays in pre-
market reviews. These include submissions that do not adhere to current 
guidance documents and existing standards that contain inadequate 
clinical data (e.g., missing data, or data that fail to meet 
endpoints), or that deviate from the study protocol agreed upon.
    Figure 6 shows the steep and prolonged increase, since fiscal year 
2002, in the percentage of 510(k) submissions requiring an Additional 
Information (AI) letter after the first review cycle. The increasing 
number of AI letters has contributed to the increasing total time from 
submission to decision. Over 80 percent of AI letters were sent because 
of problems with the quality of the submission. These submission 
quality problems waste FDA and sponsor time and resources and divert 
FDA resources from pending, higher-quality applications.


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    We are pleased that, in response to FDA calls for improving the 
quality of pre-market submissions, AdvaMed has made available training 
courses for its companies to help them develop 510(k) and PMA 
submissions that meet FDA standards.
Medical Device Safety
    The Food and Drug Administration Amendments Act of 2007 (FDAAA) 
authorized appropriations of $39,231,982 in MDUFA user fees for fiscal 
year 2008-fiscal year 2012 for the collecting, developing, reviewing, 
and evaluating of post-market safety information on medical devices. 
This includes activities such as the Post-Approval Studies Program 
(Program) at the Agency's Center for Devices and Radiological Health 
(CDRH), which encompasses the design, tracking, oversight, and review 
of studies mandated as a condition of approval of pre-market 
applications. This Program guides industry in the design of 
scientifically sound and feasible post-market studies that address 
relevant safety questions and ultimately provide valuable data for 
ongoing device evaluations. CDRH has also established a Center 
Electronic Submissions (CeSub) system that provides for electronic 
submission of adverse event reports and an efficient method for staff 
to perform analyses that bridge pre-market and post-market device 
safety data in support of the device review process. In addition, CDRH 
scientific investigations provide in-depth analyses of the underlying 
causes of post-market device safety issues, which increase reviewer 
understanding of issues that occur in marketed products. Findings from 
these scientific investigations are provided to industry to facilitate 
the redesign of existing devices and guide device development along 
paths that allow for the most efficient determination of device safety 
and effectiveness.
Challenges for the Medical Device Program
    FDA recognizes that concerns have been raised about how well CDRH's 
pre-market review program is meeting its two goals of ensuring that 
medical devices are safe and effective and fostering medical device 
innovation. Some stakeholders--particularly in industry--have argued 
that a lack of predictability, consistency, and transparency in the 
510(k) program is stifling medical device innovation in the United 
States and driving companies (and jobs) overseas. Other groups, 
including health care professional, patient, and third-party payer 
organizations, have argued that the 510(k) program allows devices to 
enter the market without sufficient evidence of safety and 
effectiveness, thereby putting patients at unnecessary risk and failing 
to provide practitioners with the necessary information to make well-
informed treatment and diagnostic decisions.
    In response to these concerns--and because FDA is continually 
looking for ways to improve its performance in helping to bring safe 
and effective devices to market--the Agency conducted an assessment of 
the 510(k) review program and an assessment of how it uses science in 
regulatory decisionmaking, which addressed aspects of its other pre-
market review programs.
    The two reports we released publicly in August 2010, with our 
analyses and recommendations, showed that we have not done as good a 
job managing our pre-market review programs as we should and that we 
needed to take several critical actions to improve the predictability, 
consistency, and transparency of these programs.
    For example, we have new reviewers who need better training. We 
need to improve management oversight and standard operating procedures. 
We need to provide greater clarity for our staff and for industry 
through guidance about key parts of our pre-market review and clinical 
trial programs and how we make benefit-risk determinations. We need to 
provide greater clarity for industry through guidance and expanded 
interactions about what we need from them to facilitate more efficient, 
predictable reviews. We need to make greater use of outside experts who 
understand cutting-edge technologies. And we need to find the means to 
handle the ever-increasing workload and reduce staff and manager 
turnover, which is almost double that of the FDA's drugs and biologics 
centers. We are making progress in these areas.
    The Agency solicited public comment on the recommendations 
identified in the studies and received a range of perspectives from 
stakeholders throughout the process at two public meetings and three 
town hall meetings, through three open public dockets and via many 
meetings with stakeholders. FDA received seventy-six (76) comments from 
medical device companies, industry representatives, venture 
capitalists, health care professional organizations, third-party 
payers, patient and consumer advocacy groups, foreign regulatory 
bodies, and others.
    After considering the public input, in January 2011 FDA announced 
25 specific actions that the Agency will take this year to improve the 
predictability, consistency, and transparency of our pre-market review 
programs. Since then, FDA has announced additional efforts, including 
actions to improve its program for clinical trials and the 
Investigational Device Exemptions (IDE) program. These are based on an 
analysis of this program that the Agency committed to as part of its 
January 2011 announcement.
    These actions, many of which were supported by industry, include:

     Developing a range of updated and new guidances to clarify 
CDRH requirements for timely and consistent product review, including 
device-specific guidance in several areas such as mobile applications 
(released in July 2011) and artificial pancreas systems (to be 
completed by the end of 2011), and draft guidance that clarifies the 
kinds of changes that trigger the need for a new submission (released 
July 27, 2011);
     Revamping the guidance development process through a new 
tracking system and core staff to oversee the timely drafting and 
clearance of documents (to be completed by the end of 2011);
     Improving communication between FDA and industry through 
enhancements to interactive review (some of these enhancements will be 
in place by the end of 2011);
     Streamlining the de novo review process, to provide a more 
efficient pathway to market for novel devices that are low to moderate 
risk. This new structure will be described in draft guidance for 
industry that is expected to be available for public comment by 
September 30, 2011;
     Streamlining the clinical trial and IDE processes by 
providing industry with specific guidance on how to improve the quality 
and performance of clinical trials. (IDEs are required before device 
testing in humans may begin, and they ensure that the rights and 
welfare of human subjects are protected while gathering data on the 
safety and efficacy of medical products.) We are also developing 
guidance to clarify the criteria for approving clinical trials, and 
criteria for when a first-inhuman study can be conducted earlier during 
device development (to be issued by October 31, 2011);
     Establishment of an internal Center Science Council to 
actively monitor the quality and performance of the Center's scientific 
programs and ensure consistency and predictability in CDRH scientific 
decisionmaking (already completed);
     Creating a network of experts to help the Center resolve 
complex scientific issues, which will ultimately result in more timely 
reviews. This network will be especially helpful as FDA confronts new 
technologies (expected in place by the end of 2011);
     Instituting a mandatory Reviewer Certification Program for 
new reviewers (to be completed by September 2011); and,
     Instituting a pilot Experiential Learning Program to 
provide review staff with real-world training experiences as they 
participate in visits to manufacturers, research and health care 
facilities, and academia (to begin in early 2012).
    For manufacturers and FDA, ``not substantially equivalent'' (NSE) 
determinations often represent an inefficient use of time and 
resources. NSE determinations require significant Agency resources and 
time, yet fail to result in the marketing of a new product. The 
following chart shows a spike in the percentage of 510(k) decisions 
that were NSE in 2010. Among the reasons that 510(k) submissions result 
in NSE determinations are: lack of a suitable predicate device; 
intended use of the new device is not the same as the intended use of 
the predicate; technological characteristics are different from those 
of the predicate and raise new questions of safety and effectiveness; 
and/or performance data failed to demonstrate that the device is as 
safe and effective as the predicate. The vast majority of NSE decisions 
are due to the absence of adequate performance data, sometimes despite 
repeated FDA requests.
    I'm pleased to report that, consistent with our many improvements 
to the 510(k) program, the recent increase in the NSE rate appears to 
be turning around. From a peak of 8 percent in 2010, the NSE rate has 
decreased to 5 percent through the first 8 months of 2011. Just as 
important, we also may be seeing a reversal in the trend of declining 
rate in Substantially Equivalent (SE) decisions that clear a 510(k) 
submission for marketing. After several years of declining percentages, 
reaching a low of 73 percent in 2010, we are seeing an increase of 4 
percent through the first 8 months of 2011, as shown in Figure 7.


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    Facilitating medical device innovation is a top priority for FDA. 
As part of its 2010 and 2011 Strategic Plans, FDA's medical device 
center has set goals to proactively facilitate innovation to address 
unmet public health needs. FDA's Innovation Initiative seeks to 
accelerate the development and regulatory evaluation of innovative 
medical devices, strengthen the Nation's research infrastructure for 
developing breakthrough technologies, and advance quality regulatory 
science. As part of this initiative, CDRH proposed additional actions 
to encourage innovation, streamline regulatory and scientific device 
evaluation, and expedite the delivery of novel, important, safe and 
effective innovative medical devices to patients, including:

     Establishing the Innovation Pathway, a priority review 
program to expedite development, assessment, and review of important 
technologies;
     Advancing regulatory science through public-private 
partnerships;
     Facilitating the creation of a publicly available core 
curriculum for medical device development and testing to train the next 
generation of innovators; and
     Engaging in formal horizon scanning--the systematic 
monitoring of medical literature and scientific funding to predict 
where technology is heading, in order to prepare for and respond to 
transformative, innovative technologies and scientific breakthroughs.

    A public docket has been set up to solicit public comment on the 
Innovation Initiative proposals, and a public meeting on the topic took 
place on March 15, 2011 In the near future, FDA will announce actions 
it plans to take under the Initiative.
PDUFA/MDUFA Reauthorization
    With the reauthorization of PDUFA and MDUFA in 2007, Congress 
directed FDA to take additional steps to ensure that public 
stakeholders would have adequate opportunity to provide input to any 
program enhancements for PDUFA and MDUFA. In addition to receiving 
input from an initial public meeting, Congress directed the Agency to 
meet with public stakeholders every month while conducting negotiations 
with regulated industry, to hold discussions on their views on the 
reauthorization and hear their suggestions for changes to the PDUFA and 
MDUFA performance goals. After negotiations with regulated industry 
have concluded, PDUFA and MDUFA require that FDA present 
recommendations to congressional committees relating to reauthorization 
of those programs, publish such recommendations in the Federal Register 
for public comment, and hold a public meeting. Final PDUFA and MDUFA 
recommendations must be submitted to Congress no later than January 15, 
2012. Below I will summarize the status of our PDUFA and MDUFA 
negotiations.
PDUFA Negotiations
    Based on a public meeting held in April 2010, input from a public 
docket, and the Agency's own internal analyses of program challenge 
areas, FDA developed a set of potential proposed enhancements for PDUFA 
V. In July 2010, FDA began negotiations with industry and parallel 
discussions with public stakeholders. These discussions were concluded 
in May 2011, and the enhancements are under internal review.
    We are very pleased to report that seven categories of enhancements 
for PDUFA V are under consideration. These enhancements address many of 
the top priorities identified by public stakeholders, the top concerns 
identified by industry, and the most important challenges identified 
within FDA. I will briefly summarize the enhancements under 
consideration.

     Drug Review Process: Increase the number of meetings 
between FDA and sponsors during FDA's review of NME NDAs and original 
BLAs, including pre-submission meetings, mid-cycle communications, and 
late-cycle meetings. To accommodate this increased interaction during 
regulatory review, FDA's review clock would begin after the 60-day 
administrative filing review period, rather than immediately upon 
filing. The impact of these modifications on the efficiency of drug 
review for this subset of applications would be assessed during PDUFA 
V.
     Regulatory science: Regulatory science is the science of 
developing and applying new tools, standards and approaches to assess 
the safety, effectiveness, quality and performance of FDA-regulated 
products. Under consideration for PDUFA V are:

          Promoting innovation by establishing a dedicated drug 
        development communication and training staff. This staff will 
        be responsible for identifying best practices for communication 
        between the Agency and sponsors, training review staff, and 
        disseminating best practices through published guidance.
          Developing a dedicated staff to evaluate best 
        practices and limitations in meta-analysis methods. A meta-
        analysis typically attempts to combine the data or findings 
        from multiple completed studies to explore drug benefits and 
        risks and, in some cases, uncover what might be a potential 
        safety signal in a pre-market or post-market context.
          Augmenting the Agency's clinical, clinical 
        pharmacology, and statistical capacity to adequately address 
        submissions that propose to utilize biomarkers or 
        pharmacogenomic markers. Pharmacogenomics and the application 
        of qualified biomarkers have the potential to decrease drug 
        development time by helping to demonstrate benefits, establish 
        unmet medical needs, and identify patients who are pre-disposed 
        to adverse events.
          Improving FDA's clinical and statistical capacity to 
        address submissions involving patient-reported outcomes (PROs) 
        and other endpoint assessment tools, including providing 
        consultation during the early stages of drug development. PROs 
        measure treatment benefit or risk in medical product clinical 
        trials from the patients' points of view. They are critical in 
        understanding the drug benefits and harm from the patients' 
        perspectives.
          Facilitating rare disease drug development by issuing 
        relevant guidance, increasing the Agency's outreach efforts to 
        the rare disease patient community, and providing specialized 
        training in rare disease drug development for sponsors and FDA 
        staff.

     Enhancing Benefit-Risk Assessment: Part of FDA's 
decisionmaking lies in understanding the condition treated and the 
unmet medical need. Patients who live with a disease have a direct 
stake in the outcome of the drug review process. The FDA drug review 
process could benefit from a more systematic and expansive approach to 
obtaining the patient perspective on disease severity and the potential 
gaps or limitations in available treatments in a therapeutic area. 
PDUFA V enhancements include expanded implementation of FDA's benefit-
risk framework in the drug review process, including holding public 
workshops to discuss the application of frameworks for considering 
benefits and risks that are most appropriate for the regulatory 
setting. FDA will also conduct a series of public meetings between its 
review divisions and the relevant patient advocacy communities to 
review treatments available for specific indications or disease states.
     Enhancement and Modernization of the FDA Drug Safety 
System: Two post-market, safety-focused initiatives are being 
considered. First, PDUFA V enhancements would initiate a public process 
to standardize REMS with the goal of reducing burden on practitioners, 
patients, and others in the health care setting; additionally, FDA 
would conduct public workshops and develop guidance on methods for 
assessing the effectiveness of REMS and the impact on patient access 
and burden on the health care system. Second, FDA would use user fee 
funds to conduct a series of activities to determine the feasibility of 
using Sentinel, a long-term program designed to build and implement a 
national electronic system for monitoring the safety of FDA-approved 
medical products, to evaluate drug safety issues that may require 
regulatory action, e.g., labeling changes, post-marketing requirements, 
or post-marketing commitments. This may shorten the time it takes to 
better understand new or emerging drug safety issues, and may reduce 
the Agency's reliance on required post-marketing studies and clinical 
trials.
     Required Electronic Submissions and Standardization of 
Electronic 
Application Data: PDUFA V enhancements being considered include a 
phased-in requirement for standardized, fully electronic submissions 
for all marketing and investigational applications; this would 
facilitate a more timely and efficient rigorous review within PDUFA 
goal timeframes. The Agency would also conduct a public process to 
develop standardized terminology for clinical and nonclinical data 
submitted in marketing and investigational applications. Standardized 
data would translate into a more standardized approach to risk-benefit 
assessment and would be helpful in safety analyses that inform FDA 
decisions related to post-marketing requirements.
     User Fee Increase for PDUFA V: Implementing these PDUFA 
enhancements being considered would add $40.4 million to the estimated 
PDUFA user fee revenue amount in fiscal year 2012. This translates to a 
modest 6 percent increase, and a total estimated base of $712.8 million 
in fiscal year 2013.\2\
---------------------------------------------------------------------------
    \2\ The fiscal year 2012 estimated user fee amount is $672.4 
million. The exact amount will be determined when we have the final-
year workload data for PDUFA IV. That number would be used to calculate 
the exact fee amounts for fiscal year 2013, the first year of PDUFA V.
---------------------------------------------------------------------------
     Modified Inflation Adjuster and Additional Evaluations of 
the Workload Adjuster: PDUFA V enhancements being considered include a 
modification to the inflation adjuster to accurately account for 
changes in its costs related to payroll compensation and benefits as 
well as changes in non-payroll costs. FDA would continue evaluating the 
workload adjuster that was developed during the PDUFA IV negotiations 
to ensure that it continues to adequately capture changes in FDA's 
workload.
MDUFA Negotiations
    In September 2010, prior to beginning negotiations with the 
regulated industry, FDA held a public meeting attended by a variety of 
stakeholders, including regulated industry, scientific and academic 
experts, health care professionals, and representatives of patient and 
consumer advocacy groups. FDA heard stakeholders' views on medical 
device user fee reauthorization, including the public's assessment of 
the overall performance of the MDUFA program and opinions as to which 
aspects of the program should be retained, changed, or discontinued in 
order to further strengthen and improve the program.
    Since January 2011, FDA has been holding discussions with regulated 
industry in an effort to develop a package of proposed recommendations 
for MDUFA reauthorization. Upon completion of these negotiations and 
discussions, FDA intends to develop a package of proposed 
recommendations for reauthorization of the MDUFA program. The public 
will have an opportunity to comment on these proposals prior to FDA's 
submission of MDUFA recommendations to Congress in January 2012.
Biosimilar User Fees
    The Affordable Care Act directed FDA to develop a user fee program 
for review of biosimilar and interchangeable biological products. On 
May 9, 2011, FDA published a Federal Register notice to seek public 
comment on a proposed stakeholder meeting process and proposed 
principles for developing a user fee for biosimilar review. This 
summer, FDA is conducting a series of meetings and will develop a set 
of proposed recommendations. This fall, we plan to brief Congress on 
the recommendations, publishing them in the Federal Register for 
comment, and presenting them at a public meeting. After the public 
meeting, the proposed recommendations would be revised as necessary 
before transmittal to Congress by January 15, 2012. FDA expects to 
publish general guidance on biosimilar drug development by the end of 
2011. FDA is currently actively meeting with sponsors interested in 
developing biosimilar drugs and providing advice specific to their 
individual development programs.
Generic Drug User Fees
    The Administration supports legislation authorizing generic drug 
user fees. We have made significant progress in our current generic 
user fee negotiations and believe we can reach a final agreement with 
industry and submit recommendations to Congress as soon as possible. We 
expect such fees would reduce the currently pending application queue 
(the so-called ``backlog'') and permit FDA to process generic drug 
applications on a more timely basis.
The Challenges Posed by Globalization
    In addition to reauthorizing PDUFA and MDUFA, FDA is also committed 
to meeting challenges posed by increased globalization. When President 
Franklin Delano Roosevelt established the modern FDA in 1938, the 
percentage of food and medical products imported into the United States 
was minimal. Today, approximately half of all medical devices used and 
40 percent of the drugs Americans take are manufactured outside our 
borders, and up to 80 percent of the active pharmaceutical ingredients 
in those drugs comes from foreign sources. Last month, FDA published a 
special report, ``Pathway to Global Product Safety and Quality,'' our 
global strategy and action plan that will allow us to more effectively 
oversee the safety of all products that reach U.S. consumers in the 
future. Over the next decade, FDA will transform itself from a domestic 
Agency, operating in a globalized world, to a truly global Agency fully 
prepared for a regulatory environment in which product safety and 
quality know no borders. To achieve this transformation, the Agency is 
developing a new, more international operating model that relies on 
strengthened collaboration, improved information sharing and gathering, 
data-driven risk analytics, and the smart allocation of resources 
through partnerships with counterpart regulatory agencies, other 
government entities, international organizations, and other key 
stakeholders, including industry.
    Toward this goal, I recently created a directorate focused on 
grappling with the truly global nature of today's world--food and drug 
production and supply, as well as the science that undergirds the 
products we regulate--so that FDA can move from being a regulator of 
domestic products to one overseeing a worldwide enterprise. I have 
appointed a Deputy Commissioner for Global Regulatory Operations and 
Policy to provide broad direction and support to FDA's Office of 
Regulatory Affairs and Office of International Programs, with a mandate 
from me to make response to the challenges of globalization and import 
safety a top priority in the years to come and to ensure that we fully 
integrate our domestic and international programs to best promote and 
protect the health of the public.
    New regulatory authorities may help ensure that we can hold 
industry accountable for the security and integrity of their supply 
chains and the quality control systems they use to produce medical 
products for the American people. In our increasingly complex and 
globalized world, additional authorities could be important tools to 
help support FDA's efforts to protect the safety of imports and the 
health of our citizens.
                               conclusion
    PDUFA IV and MDUFA II expire on September 30, 2012, and FDA is 
ready to work with you to ensure timely reauthorization of these 
critical programs. If we are to sustain and build on our record of 
accomplishment, it is critical that these reauthorizations occur 
seamlessly, without any gap between the expiration of the old law and 
the enactment of PDUFA V and MDUFA III. Thank you for your 
contributions to the continued success of PDUFA and MDUFA and to the 
mission of FDA. I am happy to answer questions you may have.

    The Chairman. Dr. Hamburg, thank you very much. We'll start 
a round of 5-minute questions.
    First of all, let me compliment you and your leadership of 
the agency. It's not very often--I think it's very rare--that 
we get the administrator of any agency here before this 
committee or any other committee on which I serve. That, quite 
frankly, says that some of the things they were doing weren't 
quite right and they've taken action to correct them. I 
compliment you both for your investigation and your overview of 
that and for what you did in January to make the necessary 
changes. I think that is exemplary, so I really appreciate what 
you've done in that regard on the premarket approval and the 
510(k).
    Let me ask a general question. If we did not reauthorize 
user fees or didn't do so on time, what repercussions would 
that have for patients? Now, I know what it does to industry. I 
want to think about the patients. Can you give us some thought 
on that?
    Commissioner Hamburg. Of course, I worry that it would have 
enormous negative implications for patients because we would 
see significant delays in our ability to review and approve 
applications of promising medical products that could make a 
difference in treating, preventing, diagnosing and potentially 
curing medical conditions from which they suffer.
    These user fee programs represent a very important 
component of our medical product review capabilities. They help 
to ensure, especially at a time of tightening budget 
constraints, a source of stable, reliable funding for our 
critical activities, for activities that, of course, involve 
our premarket review of candidate products, as well as our 
ability to provide management and oversight throughout the 
whole life cycle of a product and ensure the safety and 
effectiveness that Americans do so rely on.
    The Chairman. Thank you, Dr. Hamburg. You mentioned in your 
testimony the importance of regulatory science. I never thought 
of it as being a science. But can you explain what that is and 
how it helps to facilitate innovation, and what are you doing 
to further this regulatory science?
    Commissioner Hamburg. Yes. This is an area of science that 
I have become deeply passionate about since becoming FDA 
commissioner, because as I've looked out over the landscape and 
looked inward in terms of our capacities, it is clear that we 
are not adequately harnessing advances in science and 
technology to really promote the development of new medical 
products and the knowledge and tools to enable their swift and 
meaningful review and approval.
    When I talk about regulatory science from the perspective 
of FDA, it's the knowledge and tools that we need to 
effectively and efficiently review for safety, efficacy, 
quality and performance, and it really is a gap in our overall 
scientific enterprise, and I think it's increasingly recognized 
within the scientific community as a critical gap.
    And certainly academia, industry, and government, NIH, FDA, 
and other scientific agencies within government need to come 
together to really build this area of science to give us the 
ability, for example, to usher in the era of personalized 
medicine so that we can really identify the genetic traits and 
biomarkers that will enable us to target therapies in sub-
populations of responders; to develop innovative new clinical 
trial models that will give us robust scientific answers, but 
in a more timely and cost-effective way; to enable us to really 
mine the available sources of data both to inform us about 
important aspects of the effectiveness of products, including 
this issue of sub-populations of responders, but also to enable 
us to look in the postapproval, postmarket period to really 
monitor for emerging safety signals.
    There are a host of ways that targeted investments in the 
area of regulatory science can really enable us to bridge that 
gap between investments in biomedical research and the 
opportunities and discoveries that exist today, and the 
translation of those discoveries into real-world products, and 
that's what we're really focusing on, and in partnership with 
the other key stakeholders--patients, industry, academia, and 
particularly the National Institutes of Health, our sister 
scientific agency within HHS.
    The Chairman. Thank you very much, Dr. Hamburg. My time has 
expired.
    Senator Enzi.
    Senator Enzi. Thank you, Mr. Chairman.
    A Wall Street Journal opinion piece yesterday talked about 
genomic sequencing and other new technologies that are going to 
usher in this era of personalized medicine. Last year the FDA 
approved 20 new drugs, but in the future it may be necessary to 
target hundreds or maybe thousands of drugs for specific 
patients. I know you've thought a lot about personalized 
medicine. How is the FDA's pre-market approval system preparing 
for that future?
    Commissioner Hamburg. I think, as I was just describing, 
this expansion of knowledge through investments in regulatory 
science and partnership is going to be very, very important. 
The models for drug development are certainly changing, and we 
are recognizing that the future, to really serve patients, is 
to try to better understand what therapies really work for what 
patients and why, and to better understand not just 
effectiveness but also safety, because we are increasingly 
realizing that there are subgroups of patients that may develop 
serious adverse events in response to a treatment, and others 
will not, and the more we can understand and target those 
therapies, the better we can serve patients and consumers.
    So it is, on the part of industry and the part of FDA, a 
new world. We are trying to really clarify the regulatory 
expectations for these new kinds of products, often products 
that involve combining a device, a diagnostic with a 
therapeutic intervention, and so it requires more teamwork 
within FDA. It also requires new ways for companies to develop 
and present products to us. We are trying to clarify our 
regulatory pathways, as well as to develop the underlying 
science to enable those pathways to be as modern and 
streamlined as possible.
    And just within recent weeks, we did release a new guidance 
on combination--on companion diagnostics to help us move into 
this era of personalized medicine, and to help industry 
understand our expectations and standards.
    Senator Enzi. I appreciate the thought that you've given 
it.
    The Institute of Medicine is expected to make their 
recommendations tomorrow, I think, on how the FDA should change 
the 510(k) process. What process will the FDA use to evaluate 
and act on those recommendations, and will you have a notice 
and comment period?
    Commissioner Hamburg. We will welcome, of course, the IOM 
report and its recommendations, but they are just 
recommendations, and we will review them internally and engage 
with stakeholders to get their perspectives on the 
recommendations. Any actions that we would take in terms of 
program or policy change that would emerge from the 
recommendations of the IOM report would be done in an open and 
transparent process with lots of opportunity for discussion, 
for notice and comment and feedback as we go forward.
    Senator Enzi. Thank you. And the last PDUFA reauthorization 
contained some new rules on conflicts of interest for the 
advisory committees. Are these rules making it harder for the 
FDA to get qualified experts on the advisory committees, 
especially for the rare diseases?
    Commissioner Hamburg. This is a very important question 
and, frankly, something that comes up in many contexts. 
Whatever groups I'm meeting with, whether it's patients and 
consumers, scientific societies and organizations, academic 
organizations, industry, we do hear the concern about are you 
able to get the experts that you need on your advisory 
committees.
    We work very hard to get the appropriate experts, and in 
rare instances we can waive conflict of interest requirements 
in order to get the experts that we need. But I think it's 
something we need to--it's a dynamic process. We need to keep 
looking at it, especially, as you note, when you're talking 
about rare, unusual diseases, getting the people with true 
expertise is more challenging, and they're often ones that have 
been involved in some aspect of the development of new drugs or 
products for that disease condition.
    And so we are certainly talking with our various 
stakeholders, happy to explore this issue further with you as 
well, because at the end of the day, we depend on the best 
possible science to make our decisions, and getting that 
external expertise is very, very critical.
    Senator Enzi. Thank you. My time has expired.
    Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Enzi.
    In order of appearance, then, it would be the following. It 
would be Senator Franken, Senator Burr, Senator Hagan, Senator 
Isakson, Senator Bennet, Senator Alexander, Senator Murray, 
Senator Mikulski, and Senator Merkley.
    And we'll recognize Senator Franken.

                      Statement of Senator Franken

    Senator Franken. Thank you, Mr. Chairman.
    Dr. Hamburg, I think we can all agree that patient safety 
is a priority of Congress and a priority of the FDA, and it is 
my job and the job of the entire HELP Committee to help you to 
protect patient safety to the best of our ability.
    When I talk to patients in Minnesota, they also tell me 
that they want to be able to access medical devices that have 
been developed, and their doctors want to provide them with the 
best devices for their conditions, but too often these devices 
haven't been approved by the FDA.
    And when I talk to the medical device manufacturers in 
Minnesota, they tell me how frustrated they are that they're 
developing innovative and potentially life-saving devices, but 
they can't get them to their patients because the FDA is taking 
so long to approve the devices.
    You and I both know that it takes time and effort for the 
FDA to thoroughly review devices for safety and effectiveness, 
but I believe that we can make the FDA processes more 
efficient, more predictable, and better support and reward 
biomedical innovation.
    I really want to get into three areas here, and I just want 
to use my time wisely. But I just want to summarize them before 
I ask questions.
    No. 1, is improving coordination between the FDA and the 
medical device industry and how we can do that.
    No. 2, speaking to what Senator Enzi spoke to--dealing with 
FDA rules on conflict of interest, and so how you can avail 
yourself of expertise outside the agency when the review staff 
is confronted with novel technologies.
    And I want to ask a bit about humanitarian use devices and 
how it has worked in banning profits or limiting profits on the 
sale of these devices.
    Given those three areas, let me ask some questions and try 
to get through maybe three questions, if we can. And I 
apologize for taking half your time with the set-up here.
    How can the FDA do a better job of working with the 
industry to answer questions, make the review process more 
predictable, and restore trust between the FDA and the 
industry, because we know that's been a problem?
    Commissioner Hamburg. It's so important, and it's something 
that we are very actively engaged in. And, of course, the MDUFA 
negotiations give us a chance to work with industry to lay out 
a set of critical issues and concerns and priorities for 
action.
    Certainly, Dr. Jeff Shuren, who is with me and who is the 
director of the Center for Devices and Radiologic Health, and 
myself and other leaders of the FDA are trying very hard to 
reach out, to listen to, learn from and work with members of 
industry. In the last 10 days, I've actually been in Boston, 
California, and Cleveland meeting with leadership, CEOs of the 
device companies and entrepreneurs involved in the device 
industry. I haven't yet been to your State to do that, but I'll 
put that on my list.
    Senator Franken. We're the home of medical----
    Commissioner Hamburg. I know. But Dr. Shuren, I know, has 
spent a lot of time, and----
    Senator Franken. And I appreciate that, by the way.
    Commissioner Hamburg [continuing]. We've organized both 
formal and informal town hall meetings in order to facilitate 
these kinds of exchanges. And as we were developing, doing our 
internal review of the 510(k) process, also a lot of outreach 
to get feedback on our recommendations before we came out with 
our action steps.
    There are some critical areas that will make a difference 
that we are working on and want to strengthen, communication in 
terms of both formal and informal mechanisms for sponsors to 
come in and meet with us, to ask questions, to get feedback in 
an ongoing way, because we know that early engagement, 
continuing engagement helps to smooth the process toward a 
successful outcome.
    Being able to provide more guidance is really key, and it 
makes a difference, adding clarity to what our expectations are 
and giving industry the opportunity, as the guidances are being 
shaped, because we always start with draft guidances, to have 
input in the process as well.
    I think that we have just recently put out some critical 
guidances in that regard.
    The ability for us to really make sure also that our own 
staff are adequately trained and that we are as explicit as 
possible about our standards is another important aspect of 
what we're working on with new training, certification 
programs, and we're eager to work with AdvaMed and others 
representing the device industry, and companies on what is 
expected and how they can improve their ability to comply with 
our standards.
    Senator Franken. Submissions.
    Commissioner Hamburg. And we're really trying to reach out 
to small business as well, because we recognize that, 
especially in the device industry, so many of the companies are 
small. Many, many of the companies, a very high percentage, 
have never put forward an application to the FDA before, and we 
recognize that it's a complex landscape to navigate, and we're 
trying to build in some new points of contact and some new 
programs to make FDA more transparent in that regard.
    Senator Franken. Thank you. My time is up. I'll submit some 
questions for the record.
    Mr. Chairman, going forward, I plan to work on the three 
policy issues that I touched on in my questions, communication 
between the FDA and the industry, unnecessarily restrictive 
conflict of interest rules, and the profit cap on humanitarian 
use devices, and I hope we can work together to address these 
issues.
    The Chairman. I assure you, Senator Franken, I appreciate 
your leadership on these issues, and I'll be pleased to work 
with you to move this forward.
    Senator Franken. Thank you so much. Thank you, Mr. 
Chairman.
    The Chairman. Thank you.
    Senator Burr.

                       Statement of Senator Burr

    Senator Burr. Dr. Hamburg, welcome.
    Commissioner Hamburg. Thank you.
    Senator Burr. Thank you for what you do, and thank you for 
being here with us today.
    Do you have any idea how many drugs and devices bypass the 
American market now and seek approvals in Europe, Asia, and 
South America because of time delays or the cost of approval in 
the United States?
    Commissioner Hamburg. Actually, on the drug side, we are--
--
    Senator Burr. You're still the 800-pound gorilla in the 
room, but does it concern you that manufacturers make decisions 
not to seek approval in the United States for ground-breaking 
therapeutics?
    Commissioner Hamburg. I'm very concerned about the strength 
of the U.S. industry, the ability of American companies to 
deliver the products, drugs and devices that the American 
people need, and that we have a strong----
    Senator Burr. Is it alarming to you that American companies 
would choose not to seek American approval for breakthroughs 
that they have?
    Commissioner Hamburg. It is important to step back and look 
at where we are and to strengthen the programs to make sure 
that we maintain our pre-eminence. On the drug side, as I said, 
we are the first to approve drugs in more than 50 percent of 
the cases. So Americans are getting those new products sooner.
    Senator Burr. Tell me why we should reauthorize user fees 
for pharmaceuticals and devices when, in the case of devices, 
the length of time has gone up since we instituted user fees?
    Commissioner Hamburg. This chart, back on your other 
question, does speak to the success of the user fee program on 
drugs. And really the increase in terms of the new active 
substances first launched on the world market really came after 
the introduction of PDUFA, and it's very striking, and it's 
very, very important, and it matters to patients.
    Senator Burr. Well, you had a very long----
    Commissioner Hamburg. But there's another chart I was going 
to show which gets to your question on medical devices. This is 
the average time to decision for the 510(k) process, and the 
blue line represents the FDA, and the red line represents the 
submitter, and the black line the overall time to decision.
    Senator Burr. And charts have a tendency of flipping back 
and forth between real days and FDA days. That's something 
we've all got to get into to figure it out, but let me move, if 
I can, because you were talking about----
    Commissioner Hamburg. And I apologize. You were asking both 
questions in terms of our comparison with other countries and 
the times to review, and I was trying to answer both.
    Senator Burr. And I think you've alluded to FDAMA as sort 
of the statutory guidelines. It's the blueprint out there right 
now. And FDAMA required FDA to eliminate unnecessary burdens 
that caused delays. The sections of the statute that capture 
that is the least burdensome language. For years, FDA included 
least burdensome in the guidance and the letters. Yet in 2009, 
least burdensome disappeared, no notification. Least burdensome 
just went away. An internal document from the FDA dated 
November 23, 2009 called for the removal of the least 
burdensome language to avoid confusion and inconsistency in its 
application.
    Now, doesn't this memo basically say that the FDA applied 
these provisions in an unpredictable and inconsistent manner?
    Commissioner Hamburg. I think we are trying very hard on 
both the drug side and the device side to make our regulatory 
pathways as transparent, as predictable, and as consistent as 
possible. If you look at what we're trying to do on the device 
side, the 25 recommendations following our internal review of 
the 510(k) process----
    Senator Burr. But is it the agency's policy to ignore the 
statute in the law?
    Commissioner Hamburg. Pardon me?
    Senator Burr. Is it the agency's policy to ignore the 
statute in the law?
    Commissioner Hamburg. We are striving to be as least 
burdensome as possible and really trying to look hard at our 
business processes.
    Senator Burr. But if it's in the law, why would you take it 
out of the process? Why would you take it out of the guidance?
    Commissioner Hamburg. You know, I'm not sure what document 
you're looking at.
    Senator Burr. It's a document dated November 23d.
    Commissioner Hamburg. But we absolutely adhere to the least 
burdensome context for what we do, and as I said, we're trying 
very hard to----
    Senator Burr. Let me read from the document, if I can.

          ``The approach the Center has followed in including 
        least burdensome language in guidance documents is not 
        consistent with either the 2002 guidance or the GGP 
        Manual. To avoid further confusion and inconsistency, 
        from the date of this memorandum forward, draft and 
        final guidance should no longer include standard least 
        burdensome paragraphs,''

which is the statute of the law that we follow least 
burdensome.
    Commissioner Hamburg. My sense is that it was a removal of 
certain boilerplate language, but that it is a fundamental 
concept and commitment that we have, and in the work that we're 
doing on both the device side and the drug side, we are 
striving to achieve that. We're trying to achieve it in both 
looking at our business processes and----
    Senator Burr. But your own internal document states that 
there was inconsistency and confusion is the reason that the 
language is no longer there, yet least burdensome was put into 
the statute of the law to try to make sure that we didn't move 
the goalposts on applicants that were in the process for 
approval.
    Now, my time has run out. Mr. Chairman, I'll stick around 
for as long as Dr. Hamburg will. Thank you.
    The Chairman. Thank you, Senator Burr.
    Now we go to Senator Hagan.

                       Statement of Senator Hagan

    Senator Hagan. Dr. Hamburg, thank you for being here today 
and for your work at the FDA.
    Just to follow up a little bit on the medical device, we 
are hearing that companies are taking research overseas, and 
taking jobs and closing down companies in North Carolina 
because of some of the unpredictability. And in particular, I'm 
hearing from medical device companies about the review of the 
510(k) products. It's become particularly burdensome, causing 
product approval delays and the frustration for the 
manufacturers, providers, and obviously the patients. That's 
what we're most concerned about. And so anything that would 
delay the review process really concerns me at this time of 
economic job losses, of losing any jobs overseas, and then the 
inability to innovate.
    The industry plays an important part in our economic 
recovery, and I want to support their growth. I also continue 
to hear from constituent companies that the FDA's medical 
device review process is pretty unpredictable.
    How can we improve the situation? I think you talked about 
that in your opening remarks. And what I'm particularly 
interested in is that I've heard concerns that the FDA is 
stopping the clock. The clock stops when questions about more 
data are brought forward. And I certainly understand that the 
FDA is not responsible for how long it takes a company to 
respond, but I think the FDA does share responsibility in the 
delay when the agency requests additional data that warrants 
significant and additional financial and time burdens.
    I know you can't speak about confidential negotiations, but 
can you discuss whether the agency has thought about providing 
early feedback to companies prior to application submissions or 
adjusting how the FDA measures time in relation to the user fee 
goals?
    Commissioner Hamburg. You have a lot of important questions 
embedded there. We are very committed to trying to streamline 
the review process and make it easier to navigate for 
companies, and importantly for patients, get products to them 
as quickly and efficiently as possible while, of course, 
safeguarding the important standards for safety and 
effectiveness.
    I do think that in the MDUFA process we have an opportunity 
to really act in some key areas that will provide us with the 
necessary tools and resources to make significant strides 
forward in key areas, whether it's in terms of the review 
teams, their training, their management oversight, the ability 
to provide guidances in critical areas to industry, the ability 
to ensure consistency of decisionmaking with the creation and 
support of our Center Scientific Council, a number of things 
that I think we clearly agree with industry are very, very 
important to the effectiveness and performance of the program, 
and we're embarked on many of them. We need to strengthen and 
extend, and I think we have an opportunity if we can clarify 
some of the needs and priorities, and the sources of stable 
funding as well.
    That said, I think it is important to look at that at the 
present time we are meeting most of the agreed-on goals with 
industry. Ninety percent of the 510(k) applications that come 
before us are reviewed within 90 days, 98 percent within 150 
days. That was the agreed-on targets in terms of the FDA time 
with industry.
    But what really matters, as you point out, is the time it 
takes to get that product to market, and that is longer. I had 
a chart that I was showing earlier that shows an upward trend 
in terms of the time of the submitter as part of the 
contribution to the overall trend.
    We're committed to working on our part. We're also 
committed to working with industry to reduce the time of their 
contribution to the overall time to decision. AdvaMed is moving 
forward in working with industry to train them to FDA standards 
so that some of the issues with poor quality submissions can be 
addressed. Earlier communication, more frequent communication 
can also help to bring that line down.
    Senator Hagan. When the clock stops, that's when we're 
hearing so much concern.
    Commissioner Hamburg. And I think the better the 
communication and the more clarity in terms of guidance and 
communication, the less frequently we'll have to stop the 
clock.
    We also took a very serious look at whether or not our 
reviewers were asking for data that was appropriate to do the 
responsible review.
    Senator Hagan. That's what we're hearing a lot.
    Commissioner Hamburg. And we found that in some instances 
they were not. It wasn't a huge amount of the time, but more 
often than is acceptable, and that's why we're implementing 
these reviewer certification programs and training programs, 
and the oversight of the Center Scientific Council that will 
review and sign off on data requests and the scientific issues 
in terms of an application and its adequacy.
    I think we are moving forward in some key ways that will 
make a difference, and I hope that as we move into the next 
stage of MDUFA we can really strengthen these programs and 
activities that will make a difference.
    Senator Hagan. My time is out. But just one thing--and I 
would like to submit some questions for the record.
    And that is that I'm concerned that there's a proposal to 
regulate laboratory diagnostic tests as medical devices, and 
they're already regulated under CLIA, and I worry about the 
impact of the additional and duplicated requirements that the 
industry would have to meet under a second regulatory regime. 
So that's another huge concern out there, and maybe if we have 
time to come back around for a second round, we can go over 
that issue. Thank you.
    The Chairman. Thank you, Senator Hagan.
    Senator Bennet is gone.
    Senator Murray.

                      Statement of Senator Murray

    Senator Murray. Thank you very much, Mr. Chairman.
    Dr. Hamburg, welcome. I appreciate you coming and all of 
the work that you and your agency are doing. It is always 
challenging to balance getting everything approved in a timely 
manner while making sure that the public is safe. I appreciate 
the job you do.
    One issue that I wanted to raise this morning that is of 
concern to me is the safety and effectiveness of drugs used in 
children.
    We have passed two laws, the Best Pharmaceuticals for 
Children Act and the Pediatric Research Equity Act, championed 
by Senator Dodd and Senator Clinton. They have both 
dramatically increased the amount of information that we now 
have available on drugs for children. Studies conducted under 
those two laws have led to almost 400 pediatric label changes, 
and those two laws have historically been reauthorized along 
with the Prescription Drug User Fee Act. I hope we can further 
strengthen these laws in 2012.
    Additionally, I wanted to direct you to a GAO report 
published in May which found that 130 additional products have 
been studied in children since these laws were last 
reauthorized in 2007, and as a result, all 130 products were 
revised with important pediatric information.
    Can you just take a few minutes and tell us about the 
importance of these laws and whether you support 
reauthorization?
    Commissioner Hamburg. These laws, as you point out, have 
been very, very important and have really in many ways changed 
the landscape in terms of deepening our understanding about the 
appropriate use of products, drugs in pediatric populations and 
recognizing that children are not just small adults but there 
are differences in how they respond to various treatments, and 
we need to understand them, and we need to make it clear to 
patients and their health care providers about that appropriate 
use through labeling changes.
    Senator Murray. So would you support their reauthorization?
    Commissioner Hamburg. We strongly support, we're very 
enthusiastic about what has been accomplished since these laws 
were enacted, want to work with you to make sure they are 
reauthorized and can remain vibrant and active going forward.
    Senator Murray. OK, very good. I appreciate that response.
    Mr. Chairman, I look forward to working with you to make 
sure those bills are reauthorized as we move forward, too. I 
think that's really important.
    I do have several other questions I'm going to have to 
submit for the record.
    I have to get to another hearing. But, Dr. Hamburg, thank 
you for your work. I appreciate it.
    Commissioner Hamburg. Thank you.
    The Chairman. Thank you, Senator Murray.
    Senator Mikulski.

                     Statement of Senator Mikulski

    Senator Mikulski. Thank you very much, Mr. Chairman.
    Good morning, Dr. Hamburg.
    Commissioner Hamburg. Good morning.
    Senator Mikulski. I'm so glad to see you, and I welcome you 
with the same enthusiasm that I feel with pride that the FDA is 
located in my State, all the wonderful people, thousands, over 
3,000 who get up every single day to think about how they can 
help with our drug and medical devices to make sure that we're 
saving lives, improving lives, and creating jobs.
    I really would like to welcome the committee to go out to 
FDA, that we actually take a field walk-around where we go to 
see what FDA actually does and the wonderful people who work 
there, and the talent that we have that we have to keep, that 
we have to motivate, energize and so on. So often blaming the 
Federal employees for the problems of Federal policy I think is 
a lesson we should learn.
    I want to thank you for your self-evaluation of the agency 
that you presented here today. But I want our colleagues to 
realize who works at FDA--M.D.s, Ph.D.s. If you just take the 
word ``bio,'' bioengineering, biostatisticians, computational 
biology, these are people who, if they left FDA, could go to 
Wall Street and make three to five times as much money managing 
money rather than managing this process.
    We need to get real. We need to have the right policies, 
the right user fees, and the right way so that we can work, 
because for we in Maryland and we in America, life science is 
our jobs. It is our jobs, the medical devices we implement and 
the drugs that we do.
    When I think of my own mother, who passed away in 1996 from 
the ravages of diabetes, she had the best that medicine, 
Medicare could offer. And now, what would she have now that she 
didn't have then? Better home testing medical devices to be 
able to provide her with the biofeedback to better monitor 
herself. She had three drugs to pick from. There are now 300 
drugs to pick from. Her life would have been better, it would 
have been longer, and we would have created jobs to do that.
    This is why I'm so passionate about FDA and what we need to 
do.
    Having said that, let me go to your very meaty testimony. 
You raised the issues related to innovation. You have a series 
of recommendations. As you can see here today, there is an 
inherent tension between innovation and regulation, and we 
shouldn't have to pick one side or the other, regulation for 
safety first, efficacy as crucial for getting value for our 
dollar.
    What can you see that we need to do in PDUFA to make sure 
we promote adequate regulation but we don't stifle innovation? 
So this is the underpinnings of some of the questions. Could 
you elaborate on that, and what do you need us to seriously 
think about?
    Commissioner Hamburg. I think you're absolutely right. We 
need to marry safety and innovation. We need to make sure that 
we are really capturing all the advances in science and 
technology today into real-world products for people. I think 
there are a number of things that are underway and a number of 
elements in the PDUFA V negotiation package that will help us 
to strengthen those activities.
    One is critically building out some of these scientific 
capabilities so that we can really use science to target our 
therapies, to identify where are the critical opportunities in 
terms of the patterns of disease, how can we do clinical trials 
that are meaningful but shorter and more cost-effective, how 
can we look out across the whole life cycle of a drug to ensure 
safety and effectiveness by using data mining and monitoring 
available information in the real world.
    Senator Mikulski. Dr. Hamburg, if you could withhold a 
minute. In your written testimony, you talk about how you want 
to streamline the regulatory process but make sure we ensure 
safety.
    Commissioner Hamburg. Right.
    Senator Mikulski. It's an obsession with us and I think 
what separates Western democracies from those who just want to 
make products. You have several recommendations here. Were they 
supported by the private sector, and have you begun to 
implement them?
    I'm talking about the innovation, pathway to public-private 
partnerships.
    Commissioner Hamburg. The innovation pathway--yes, very 
much so.
    Senator Mikulski. Scanning.
    Commissioner Hamburg. I think one of the areas that's been 
very exciting is the opportunity through public-private 
partnerships to really address these critical issues in terms 
of the gaps in science and how to build on them to really spur 
innovation, and I met recently with R&D directors from some of 
the major pharmaceutical companies, and they really see this as 
a critical need from their perspective, and we see it as a 
critical need from our perspective in terms of having the tools 
to apply to the process.
    I think that in terms of the device program, it's very, 
very important that we have a flexible regulatory process that 
recognizes that innovation is so dynamic in that area, and we 
need to be able to really support industry as it develops an 
idea and tests it and puts it into the marketplace, and 
continuing to monitor it.
    As innovation occurs going forward, it requires that we 
have adequate support for science within FDA in terms of 
reviewers who understand the complexity of the products that 
are coming before us and have the access to external experts 
that they need to help enable the review process that will 
support these innovative products from----
    Senator Mikulski. That's very helpful, and I don't mean to 
interrupt. My time is up because I wanted to get in my comments 
about FDA.
    Also, you share with us the private sector's views and 
recommendations on just how to improve the process, from drug 
review to regulatory science to others, benefit/risk 
assessment. Have you incorporated these in the recommendations 
for the committee for reform and refreshing?
    There's no doubt when we look at PDUFA, we've got to 
refresh it, reform it, re-energize it, but also keep on the 
right track for the balance between innovation and industry. So 
where are you on these private sector regs?
    Commissioner Hamburg. These are the elements, the seven 
categories of enhancements that were agreed to with industry as 
part of the PDUFA V negotiations. There was enormous enthusiasm 
and support for these activities. I would say that that 
negotiation process was very constructive and forward leaning, 
and we do think that these elements will really strengthen our 
programs and activities and our ability to deliver.
    Senator Mikulski. Senator Harkin is giving me the tap. I 
got it.
    Senator Harkin, I really am serious about my invitation to 
the committee to come out and really see FDA, because when you 
look at who is around the table, our economies in our State 
really rest on it, sir. Baltimore, our largest employer was 
Bethlehem Steel. Now our largest employer is Johns Hopkins. And 
one of which is because of NIH, but also the new products for 
FDA. Let's go out and actually see what they do, and let's work 
together. Our economy and our people depend on it.
    Commissioner Hamburg. We would welcome you, and we did host 
an event for congressional staff. I think it was very 
successful and useful, and I look forward to hosting all of 
you.
    The Chairman. Senator Mikulski, I'll take you up on that 
sometime this fall if we can find a good day to do it on.
    Senator Hatch.

                       Statement of Senator Hatch

    Senator Hatch. Thank you, Mr. Chairman. I want to 
compliment my colleague from Maryland. We've worked together 
very strongly on these issues.
    I think a great deal of her, and I also think a great deal 
of you, Dr. Hamburg.
    Commissioner Hamburg. Thank you.
    Senator Hatch. In fact, I even like the people in the first 
row.
    [Laughter.]
    I just wish you'd be a little less risk-averse, because I 
think I would like to see our medical device regulator start to 
match what Europe does. I think we're way behind as far as I 
can see. Now, I'd be happy to be convinced otherwise.
    This is a great agency. It handles a tremendous amount of 
commerce in this country. In fact, it's almost impossible to 
handle all that you've been called upon to do, but you can do 
it. And I think you should call on us to help where we can.
    It's clear that in the area of medical devices, we're 
losing ground to other countries, in part due to the increasing 
difficulty in getting new products approved by the FDA in a 
timely and efficient way. For complex and innovative devices, a 
whole series of studies have shown a device lag, and every 
device executive I talk to is saying that they are moving 
clinical trials for first product introductions overseas 
because of the challenges they face with FDA.
    I've had some medical device manufacturers show me how the 
approvals in Europe are so much faster than here and, frankly, 
people have benefited from those approvals and those devices in 
ways that Americans have not, and I would like to see that 
change.
    In fact, I read in a recent article in the Cleveland Plain 
Dealer that you acknowledge that FDA has played a role in the 
national decline in medical product innovation, adding that you 
felt much of the criticism of the agency was ``deserved.''
    Let me just ask you this. What are you doing to get us at 
least back to where we were several years ago in terms of speed 
and consistency of review? And how are you attracting 
manufacturers to come to and remain in the United States? I 
think we're losing a number of them because of some of these 
difficulties that I've been raising.
    Commissioner Hamburg. Let me first thank you, Senator 
Hatch, for all your support over so many years and, of course, 
the great work that you and Senator Mikulski have done to 
support the White Oak facility and other important aspects of 
our work.
    Let me then address the question about U.S. approvals 
versus Europe, because I think it is important to clarify.
    A recent industry study that has been cited already did 
show that for lower-risk devices that don't require clinical 
data, which represents about 80 percent of the devices we 
review, that the United States is, in fact, as fast or faster 
than Europe in bringing those products to market. For the 
higher-risk--and this chart does speak to that. For the higher-
risk devices, we are slower than Europe, but it's important to 
recognize that we have a different standard, a different 
regulatory framework, and in Europe they don't require safety 
and effectiveness like we do. They require safety and 
performance.
    And what that means in the real world is that, for example, 
for a condition like atrial fibrillation, which is an irregular 
beating of the heart that can be associated with serious 
medical complications, including stroke, that for a technique 
called ablation that tries to disrupt abnormal electrical 
pathways that cause the irregular beating, you can use a tool 
to basically cut or burn the tissue. And in the United States, 
we have to show that the device actually has a benefit for 
patients in terms of a positive impact on this underlying 
condition. In Europe they just have to show that it affects the 
heart tissue.
    That is a different standard, and I think----
    Senator Hatch. I understand that. Would it be better for us 
to switch to the European performance language?
    Commissioner Hamburg. I think it is very, very important. I 
think the American people really count on----
    Senator Hatch. Let's get some answers.
    Commissioner Hamburg [continuing]. The fact that a medical 
device that they will use or a family member will use that may 
be implanted into them for a very long period of time, that not 
only will it be safe and effective, they count on that and that 
it will actually benefit them in terms of the intended use, and 
the European requirement is different.
    I think it's a very different model where the sponsor pays 
a private entity, a so-called notified body, to review the 
product. These are not bodies that are under the oversight of 
any authority. They have different expertise and 
qualifications, and the information and data that goes into the 
decisionmaking is not made available to the public.
    So, I think, the device industry leadership agrees that we 
should not change the standards for medical device approval in 
this country. AdvaMed recently put out a press release speaking 
to that. But I think what we can and must do is work together 
to make sure that we have the most streamlined and modern 
regulatory systems possible. At the end of the day, absolute 
speed is probably not the only and ultimate criteria to ensure 
safe and effective products.
    Senator Hatch. I'd be the first to agree with that. Just 
the latter part of that question about attracting business to 
this country, could you elaborate on that for a minute?
    Commissioner Hamburg. That is a very, very important----
    Senator Hatch. It really is.
    Commissioner Hamburg [continuing]. Issue, and we are----
    Senator Hatch. I'm on your side.
    Commissioner Hamburg [continuing]. Working very hard. No, 
and I think----
    Senator Hatch. I'd like to help you. But I really think 
we're pretty slow. But go ahead, attracting----
    Commissioner Hamburg. I think we have a contribution to 
make in achieving that goal that's very, very real. It's also a 
more complex ecosystem with economic policies and issues around 
the costs of labor in other countries versus the United States.
    But in terms of the FDA component, that is why we are so 
committed to making our regulatory pathways as clear, 
consistent, and predictable as possible, as streamlined and 
modern as possible, trying to develop guidances to address some 
of the key areas of concern for American manufacturers such as 
clinical trials, which are often cheaper and easier to do 
overseas. We're soon going to be putting out new guidance to 
encourage earlier in-human study of medical devices that will, 
I think, provide an important incentive to doing those studies 
here in the United States.
    And I think that through the MDUFA process, we have the 
opportunity to really focus and act on some of the key areas 
that will help to make our medical device review systems as 
timely and efficient and responsive to the needs of patients 
and innovation as possible.
    Senator Hatch. I want you to know I'm interested in all the 
UFA processes, not just MDUFA.
    But I want to thank the Chairman for his leadership in 
these areas and, of course, the Ranking Member as well, both 
are terrific as far as I'm concerned. And I want to thank you, 
doctor.
    Commissioner Hamburg. Thank you.
    Senator Hatch. Appreciate you.
    The Chairman. Thank you very much, Senator Hatch.
    Senator Hatch. I'll submit my questions, further questions.
    The Chairman. OK. Thank you, Senator Hatch.
    Senator Merkley.

                      Statement of Senator Merkley

    Senator Merkley. Thank you very much, Mr. Chair.
    It's a pleasure to have you here, Dr. Hamburg. I wanted to 
start with an article that came out yesterday regarding a 
report that's anticipated tomorrow. This is a report from the 
Institute of Medicine that was charged with analyzing 
regulatory proposals related to medical equipment like hip 
implants, hospital pumps and defibrillators.
    And apparently, even before it's out, it's becoming quite a 
controversial study. Would you mind commenting on what are the 
issues here? Is there a problem with the balance of the panel? 
Is it already known what the report will say and people simply 
disagree with it, so on and so forth? What's going on here?
    Commissioner Hamburg. The Institute of Medicine is a branch 
of the National Academy of Sciences, and of course the National 
Academy of Sciences was actually begun by Abraham Lincoln many, 
many years ago to help provide scientific consultation and 
expertise to government as important decisions are made.
    We actually asked the Institute of Medicine to put together 
a committee and do a study about important issues involving the 
510(k) regulatory process, which is the largest component of 
our medical device review activities and so important.
    They put together a committee, as they always do. We as the 
requesting agency have no input into the committee composition, 
but they have standards and practices about diversity and 
conflict of interest on their committees. They will be putting 
out a report. That report, as I mentioned earlier, will provide 
us with recommendations, which will only be recommendations, 
and we will review them and we will get feedback in terms of if 
we want to pursue aspects of those recommendations.
    Senator Merkley. But just cutting to the chase, is there 
something anticipated that is really quite controversial?
    Commissioner Hamburg. I think there was concern expressed 
by some components of the device industry about whether their 
perspective was adequately represented on the committee. I 
think that various lawyers have looked at that and feel that 
the composition of the committee is sufficiently diverse and 
containing----
    Senator Merkley. My impression is that people are upset 
because they are disagreeing with what they think is going to 
be in the report tomorrow. I don't know if there was a pre-
announcement or a draft announcement, but what is the heart of 
the actual policy issue that is being wrestled with here?
    Commissioner Hamburg. I think the heart of the policy issue 
is the adequacy and appropriateness of the 510(k) process, 
whether it achieves its dual goals of assuring safety and 
efficacy of products and the timely introduction of innovative 
products into the marketplace. I have been briefed but have not 
had a chance to actually read the report, which is embargoed 
until tomorrow.
    But I think that it obviously will be speaking to very 
important issues, and I think that the concerns reflected in 
that newspaper article have to do with whether the committee 
was properly constituted.
    Senator Merkley. OK. Let me switch gears here, then. Thank 
you.
    Sometimes problems develop after a product is introduced 
that weren't caught in the clinical trials. Can you address how 
well the MedWatch system is publicized and being used by 
consumers? Is it providing valuable feedback? Could it be 
improved?
    Commissioner Hamburg. I think we need to strengthen many 
components of our postmarket surveillance activities, as you 
suggest. We often learn about safety concerns in much greater 
detail once the products are out in the marketplace being used, 
not just by a limited number of patients who are involved in 
the early clinical studies but by thousands, hundreds of 
thousands, millions of patients and individuals who may have 
other underlying medical conditions or are taking other drugs 
that may also affect the safety and safe use of those products.
    So we do need to continue to strengthen the systems for 
adverse event reporting. We also, in large part due to efforts 
by Congress, through FDAA in 2007, are strengthening our 
broader activities and programs in the postmarket period, 
including our ability to really target in on emerging safety 
concerns through changes in labeling, changes in data 
collection to further drill down and understand those problems, 
and in mining existing databases and creating new databases to 
inform our decisionmaking.
    Senator Merkley. A last brief question, or at least I'll 
need a brief response.
    Commissioner Hamburg. Sorry.
    Senator Merkley. And that is, given new forms of 
advertising, Internet and social media and so forth, and the 
types of cautions that are normally embedded in prescription 
drug and medical device advertising, are those presenting new 
issues that you're having to wrestle with?
    Commissioner Hamburg. Certainly the age of the Internet has 
created vast new challenges for us in terms of monitoring what 
information is out there about products in terms of advertising 
and its accuracy; and also products that are, in fact, being 
advertised for sale that are fraudulent or counterfeit. And we 
are working very hard--it's a domestic issue; it's also an 
international issue, because many of these Web sites are based 
overseas--to try to get a better handle on the scope of the 
problem and to identify solutions that will really work. But 
it's a huge, huge challenge.
    Senator Merkley. Thank you very much.
    Commissioner Hamburg. Thank you.
    The Chairman. Thank you, Senator Merkley.
    Senator Bennet.

                      Statement of Senator Bennet

    Senator Bennet. Thank you, Mr. Chairman. Thanks for letting 
me go and come back.
    And, Dr. Hamburg, thank you so much for being here today.
    Commissioner Hamburg. Thank you.
    Senator Bennet. I heard the questions at the beginning, the 
answers at the beginning, missed some in the middle. But I 
wanted to make one observation about the tension that I think 
exists around some of these issues.
    The mission statement of the FDA is pretty clear that it's 
both about the public safety, public health, and also about 
driving innovation in our medical device industry, or 
supporting innovation maybe is a better way of saying it. The 
tension that the folks in my State feel that are in this, doing 
this work, this incredibly important work of developing medical 
devices, I think is rising as a reflection of the globalization 
of the industry, and the concern that a lot of us have is that 
we may not own this industry in the 21st century, or that we 
may lose it.
    One thought that I have is whether we want to consider 
changing the mission statement to recognize the global economy 
that we're in and the importance to the United States of being 
able to drive this, or maybe that's not the right place to do 
it, maybe it's somewhere else. But I wonder whether just more 
broadly--your efforts are commendable, but are we moving at a 
rate of speed that's going to get us to a place where we're 
going to be able to compete in real time with the rest of the 
world, or not lose the advantage that we have?
    Commissioner Hamburg. I certainly share your concerns, and 
certainly in terms of my leadership at the FDA and the 
orientation of all the extraordinary staff that work with me at 
the FDA, we see our mission as doing our very, very best to 
assure the safety and effectiveness and quality of the products 
that we regulate, but also to help support and facilitate the 
translation of opportunities in biomedical research and science 
into products that people need, and also to try to provide some 
sort of recognition of the need to match unmet public health 
needs with opportunities that exist in terms of available 
science and technology. And so we are committed to all of those 
things.
    I have actually created within my office in recent months a 
special focus on innovation, trying to support all of the good 
ideas, programs and policies that are spread throughout FDA 
with a focus on advancing innovation. I've also been trying 
very hard to work with my colleagues in government and outside 
to really look at what can we, as a nation, do to strengthen 
our programs and policies to support innovation, because FDA 
plays a critical role, but it also has to do with patents and 
IP. It has to do with economic policies and taxes and 
incentives. It has to do with reimbursement issues, and it has 
to do with making sure that FDA takes a very hard, serious 
look, which we are doing, at how can we streamline and 
modernize our regulatory systems to make it easier for 
companies to work with us and to make sure that those exciting 
and promising candidate medical products actually make their 
way into the marketplace.
    Senator Bennet. I think that's well said, and I think 
everything that you said is true. What concerns me when I have 
the people come in is because they're the life science 
manufacturers or the inventors or entrepreneurs, because their 
interaction with the Federal Government generally is the FDA, 
they're looking for the FDA to help solve this problem on 
competitiveness, or to at least not compromise their ability to 
be competitive and stay here in the United States and do the 
work, and I feel like I'm having the same conversation year 
after year, with respect, because I know you are doing a lot of 
this work, having the same conversation year after year, and it 
sometimes feels to me as though it's no one's day job, and you 
just said it is some people's day job, it's no one's day job to 
say how do we hold onto the competitive advantage that we have, 
or create more competitive advantage going forward.
    And it's not just an FDA issue, as you said, patent issues, 
all kinds of things. Whose job is it to think about and to 
really implement policies that are going to drive innovation in 
the country?
    I want you to know that I look forward to working with you 
on this to try to support these efforts on behalf of Colorado 
and on behalf of the country.
    And before my time runs out, we're now at a point where, 
just to shift gears for a second, 80 percent of the active 
ingredients in our drug supply chain is coming to us from 
offshore, and you have acknowledged that as an issue and I 
think stated the need for us to work with international 
regulatory agencies to make sure that we can stay ahead of the 
problem of a compromised drug supply and other issues.
    I wonder if you could talk a little bit about what that 
will look like and whether we are doing everything we can to 
try to inspire international cooperation around that issue.
    It's a big surprise to people in Colorado when I tell them 
that 80 percent of the active ingredients in their drugs come 
from overseas and that we actually have very little in the way 
of inspection of those plants, especially in China and other 
places, and that we can't always be sure of what's in our 
pharmaceuticals.
    Commissioner Hamburg. It's such an important problem. 
Globalization has really changed the world, and it really 
requires that FDA changes the way that we do business. You're 
absolutely correct. Today, 80 percent of the active 
pharmaceutical ingredients in drugs taken here actually come 
from other countries. About 40 percent of the finished drugs 
taken here come from other countries. And we need to recognize 
that the supply chain for these products has gotten very 
complex and much more complicated, with many points along the 
way for potential unintentional or intentional contamination, 
adulteration, or impacts on quality.
    And so we need to really transform. When our agency was 
first created, the world looked very different. We need to 
transform and we need to move beyond the borders in terms of 
how we inspect and ensure quality in products coming into this 
country. We need to work much more closely with sister 
regulatory authorities to share information, to try to 
harmonize standards and approaches, and to actually in some 
instances share the workload in terms of inspections. There are 
way too many facilities out there for any regulatory authority 
to get in and inspect them with the frequency that we would 
like. And so we're really developing those kinds of 
relationships.
    We also have to work in much closer partnership with 
industry, who clearly needs to be accountable for the supply 
chain of their products, and at the end of the day, through 
working together, we need to be able to assure the integrity of 
the supply chain and the trust and confidence of the American 
people in these products.
    We've also now set up offices in many countries around the 
world that provide a regional presence for inspections and 
activities, working with industry and other stakeholders and 
our counterpart regulatory authorities to ensure that our 
standards are understood and being met. We're also trying to 
work hard with many countries that have less sophisticated 
regulatory capabilities than we do to help raise their 
standards, which will serve us all.
    There's an enormous amount to be done. I know that you've 
been taking a very serious look at this, and we welcome the 
opportunity to work with you as you examine what kinds of 
additional authorities might be needed.
    Senator Bennet. I appreciate that, and my time is long 
expired. But I want to thank the Chairman and the Ranking 
Member for letting me go over for a second.
    The authorizing statute for the FDA, as you know, was 
written I think in 1938. It was in the 1930s, sometime when the 
entire supply chain was domestic, and now I think it's high 
time for us to take a look at that.
    I also want to let you know that I've asked the biotech and 
device guys in Colorado to give me the 9 or 10 pain points that 
they really have, and we will get those to you, in an effort to 
not have the same conversation next year that we had this year. 
And I hope it will be useful to you as you think about this.
    Commissioner Hamburg. Yes. I appreciate that. It is very 
useful to hear directly from people on the ground what are 
their critical issues and perceived barriers and concerns.
    Senator Bennet. Thank you, Mr. Chairman.
    The Chairman. Thank you, Senator Bennet.
    Let's start a second round here.
    I just want to say to Senator Bennet, looking at the supply 
chain, I had mentioned in my opening remarks that we wanted to 
focus today on PDUFA and MDUFA and the reauthorization in that 
area, and I said I'm going to have some hearings this fall on 
that very subject of the supply chain. I look forward to 
working with you.
    Senator Bennet. Good. Thank you. I will as well. Thank you.
    The Chairman. You know, we all want better devices. We all 
want innovation. We all want to know that if we have an injury 
or something like that, that there are devices out there that 
will permit us to live life to the fullest, and we've made 
great strides in that area in this country, in innovation in 
devices. I've followed them for years with my work on 
disability issues, for example.
    But, you know, let's face it, there's a lot of money to be 
made in devices. People have gotten immensely rich in this 
country because they've innovated, they've invented, they made 
a device and got out there, and people have gotten immensely 
wealthy in this area. I don't deny that. That's fine. That's 
part of the American dream.
    But I do want to make sure that we have an agency that is 
independent and that is able to withstand the tremendous fire 
power of an industry that has a lot of money and obviously 
wants the least amount of regulatory oversight. I understand 
that. I mean, that is, again, part of the give and take of our 
society.
    I think it is a gross disservice to many of us who have 
been supportive of the industry, as I have been in the past, as 
I said, through my work with disability issues over most of my 
adult lifetime. I've seen the tremendous help that devices have 
provided for people so that they could have a better life. It 
does a great disservice to us when an article like this appears 
in the New York Times this morning outlining how--I'll just 
read the first sentence.

          ``Allies of the medical device industry are waging an 
        extraordinary campaign in Washington to discredit a 
        coming report by one of the country's pre-eminent 
        scientific groups that examines possible new 
        regulations on the industry. The scientific group 
        being''--of course--``the Institute of Medicine, is 
        scheduled to release a report on Friday that could,''--
        that could, I don't know, I haven't seen the report 
        yet--``that could propose a tougher approval process 
        for a wide range of devices like hip implants, hospital 
        pumps external heart defibrillators.''
          ``The report, commissioned by the Food and Drug 
        Administration, comes after several well-publicized 
        recalls in recent years of devices that have failed in 
        thousands of patients, causing numerous injuries. But a 
        business group and others have taken the highly unusual 
        step of making a pre-emptive strike, arguing that the 
        report is biased. That attack began even before the 
        study panel finished its review and has intensified in 
        recent weeks.''
          ``The challenge to the panel has been led by a Ralph 
        F. Hall,''--who I don't know--``a professor of law at 
        the University of Minnesota and a device industry 
        lawyer. . . . `I could have waited until the report 
        came out,' Mr. Hall said in an interview. `That seems 
        intellectually less than satisfactory with me.' ''

    Say again? I attack something before it comes out rather 
than waiting until it comes out to read it, to analyze it, to 
see what the input was? But I attack it before that, and that's 
more intellectually satisfactory?
    I'm going to ask that this article be made a part of the 
record here, since I quoted from it.
    [The article referred to may be found in Additional 
Material.]
    The Chairman. Look, there have been times in the past when 
I've seen studies from the Institute of Medicine that I didn't 
like because it went against my preconceived beliefs. Well, 
then it made me really question my preconceived beliefs.
    I say to the device industry, the kind of story that 
appeared in the New York Times this morning, and the statements 
by Mr. Hall and others do a disservice to your industry, 
because the FDA is charged, as you said, Dr. Hamburg, quite 
frankly, not only with making sure that products are safe, but 
that they are effective, different than what they do in Europe. 
I want the FDA to continue that, and I want it to continue to 
be an independent agency.
    From my standpoint and having been here for so many years, 
on both this committee and the Appropriations Committee, 
perhaps one of the most unbiased scientifically oriented groups 
in this country is the Institute of Medicine. I hope you will 
continue to rely upon them, and don't let this kind of stuff 
that's coming out here today and other days dissuade you from 
that.
    I want you to continue to be independent, use the best 
science. I know you're going to get pulled from one way and 
pulled from the other way. I understand that. This industry is 
so important to our country. We don't want it to go overseas. 
We want it to stay here. But to take this kind of attitude that 
they will not even listen to a report from the IOM and engage 
in a reasonable conversation about it but they just attack it 
before it comes out, as I said again, not only it does a 
disservice to the industry, it does a disservice I think to the 
patients and our country.
    So having said that, I've used up my time. I didn't even 
get to ask a question. But I just wanted to respond on that 
issue with the difference between here and Europe. I'll just 
take a couple of more seconds.
    In Europe, you're right, they just want to know if it 
performs as they say, without deciding whether it is effective. 
But that's covered later on in their reimbursement systems in 
Europe, which is quite different than ours. And since we are 
not really changing our form of reimbursement system to be like 
Europe's, then we rely upon the FDA to make that decision, is 
it effective, does it really lead to good clinical outcomes.
    As I said, that's not part of the European system. It's 
part of their system later on in the reimbursement side of it. 
So that's why our system is different than Europe's.
    Thank you very much, Dr. Hamburg, and I'll yield to Senator 
Enzi.
    Senator Enzi. Thank you, Mr. Chairman. I'll follow up a 
little bit on what you said and ask a question.
    The last PDUFA law authorized the risk evaluation and 
mitigation strategies to speed access to drugs with risk 
concerns, but in many cases REMS just ended up slowing down the 
review process. Can you fix that process administratively, or 
could small statutory fixes help you to effectuate legislative 
intent?
    Commissioner Hamburg. As you know, REMS, the authority to 
pursue that strategy, was given to us in 2007 in FDAA, and we 
had to put in place new systems and really sort of develop 
strategies that would enable us to better monitor and assess 
safety in the postmarket period, which is so important, as 
we've talked about.
    As we have implemented it, I think it has put new burdens 
on FDA and on industry, and we are looking now at ways that we 
can really sort of systematize how we do it and look not at a 
product-by-product way of implementing some components of it, 
but really having guidelines for classes of products. It's an 
area where, obviously, the feedback and the exchange with 
industry and their experience is helping us to shape how we 
organize this program.
    And I think that working in that manner, we can move 
forward and improve and strengthen REMS. It does give us a set 
of important tools that actually give us more confidence on the 
front end as we improve promising candidates that may have 
safety concerns, that we can continue to monitor and address 
those as they go into the marketplace and we learn more about 
them.
    So I think we can continue to strengthen and streamline the 
program. At the moment I, at least, am not aware that there is 
any particular need for a legislative fix, but I think we 
recognize that the program has been somewhat cumbersome, and it 
certainly has put a lot of additional demands on us as we 
develop and implement it, and we want to see it really achieve 
the goals but not be as complex in its administration and the 
workload on both companies and on FDA.
    Senator Enzi. Thank you. A June 2011 report from the 
Government Accountability Office found that the Device Center 
is not overseeing recalls effectively. FDA already has a clear 
statutory authority to mandate device recalls, but the average 
time it took for FDA to effectuate a Class I recall, which is 
the highest risk type of recall, was 516 days. There have been 
incidents where individuals were seriously injured or died due 
to continued use of defective devices that were supposed to 
have been recalled. In one instance, a supposedly recalled 
device was re-introduced to the market and patients needed 
surgery to remove them. In addition, GAO found that the FDA 
does not use recall data to identify systemic safety risks.
    What steps are being taken to address those problems?
    Commissioner Hamburg. Very, very crucial concern, and we do 
need to strengthen our programs and reduce our response times. 
There are a number of important activities that are underway, 
including the creation of a unique device identifier that will 
enable us to more effectively track devices, that health care 
providers and the FDA can have much better information about 
who has what products, and working with industry when there is 
a problem, we can move more swiftly to actually address the 
immediate patient needs.
    In addition to that kind of activity that will make a 
difference from a safety perspective, we have to look at our 
systems to make sure that we are responding to emerging 
concerns in as timely a way as possible, both in terms of 
collecting the safety information, analyzing it, responding to 
it and, importantly, acting on it.
    Senator Enzi. Thank you. Also referring to the Government 
Accountability Office, in 1998 they called for FDA to implement 
a series of recommendations to respond to challenges posed by 
the globalization of drug manufacturing.
    What progress has the agency made on the GAO's longstanding 
recommendations on that globalization of drug manufacturing?
    Commissioner Hamburg. As I was discussing with Senator 
Bennet, this is a huge and growing area of focus, concern, and 
activity. We are trying to extend our capabilities in terms of 
our foreign inspections, working with counterpart regulatory 
authorities to try to share information as well about the 
inspections that they are doing and information about supply 
chain integrity and the quality of products.
    Really, working with industry also because, of course, at 
the end of the day their knowledge and accountability around 
the supply chains and the manufacturing practices in these 
overseas sites is critically important and fundamental to our 
shared goal of achieving integrity and safety of the supply 
chain.
    So we are very, very much focused on this as a priority. 
You mentioned I think some interest in the reorganization that 
I recently did, and one of the areas was really to try to bring 
greater integration of our Office of Regulatory Affairs 
activities, which is out in the field doing inspections and 
compliance activities, with our Office of International 
Programs so that we can really use our resources in the most 
coordinated way possible and really focus on strategies that 
take into account risk, risk of certain types of products, risk 
in terms of past history of certain products or manufacturers, 
and really within the realm of possibility enables us to engage 
all of the important partners and really use all the best 
possible information, wherever it comes from, to inform our 
activities.
    Senator Enzi. Thank you. My time is up, but I'll have a 
followup question. I'll send that in writing.
    Commissioner Hamburg. Thank you.
    The Chairman. Thank you, Senator Enzi.
    Senator Burr.
    Senator Burr. Dr. Hamburg, on the question of the IOM 
report, if the IOM report on 510(k)s triggers a change in 
process, do you commit to make sure that that process is a 
notice and comment rulemaking process?
    Commissioner Hamburg. Oh, absolutely. We would view their 
recommendations as just that, recommendations, and we would 
review them internally and seek the perspective of key 
stakeholders on those recommendations, and anything that we 
would do that would be a permanent action coming out of that 
report and those recommendations would be done in an open and 
transparent way in notice and comment.
    Senator Burr. Let me stay on 510(k)s, if I can. I heard you 
say to Senator Merkley that the 510(k) process looks at safety 
and effectiveness. Did I hear that correctly?
    Commissioner Hamburg. Through the 510(k) process we are 
trying to assess safety and effectiveness, yes.
    Senator Burr. In reality, the process for 510(k) is 
substantially equivalent. Now, if FDA has made a shift to an 
assessment of safety and efficacy on 510(k)s, this would be an 
earth-changing move.
    Commissioner Hamburg. It's clearly a different process than 
when you talk about the drug evaluation process and the way 
that we look at data and require information to demonstrate 
safety and effectiveness.
    We're looking at predicates, and we're looking at a 
different model. But at the end of the day, the goal is to 
support the assessment of safety and effectiveness of that 
product.
    Senator Burr. Let me just say the statute that's applicable 
here is substantially equivalent. That is the process for 
510(k) approval. Are you telling me that's not the threshold?
    Commissioner Hamburg. That is the criteria. What I'm saying 
is that the goal is to make sure that devices that are 
reviewed----
    Senator Burr. So if you determine that it's substantially 
equivalent but you feel that it doesn't meet safety and 
efficacy, you're not going to approve the 510(k)s?
    Commissioner Hamburg. It's a different model of regulation, 
as I said, from the drugs, and it does build on track records 
of prior products.
    Senator Burr. I'll certainly follow-up on this with 
additional questions.
    But I would question whether you've got the authority 
without a change in rules to do exactly what you've stated. And 
if it does, then it may explain a lot as to why there has been 
an increase in the time that it takes for device approval.
    Has the increase in fees resulted in fewer review cycles 
per submission compared to previous user fee agreements on 
devices?
    Commissioner Hamburg. On devices, unfortunately, the review 
cycle has increased somewhat over time, and it's something that 
we're focused on and we want to bring down, and we think that 
by working together with industry to try to both address the 
issues within FDA that we've talked about and the issues around 
the quality of applications and response to information 
requests from FDA, that we can continue to move in the 
direction of bringing those review cycles down.
    Senator Burr. Industry says the FDA is moving the goal 
posts. The FDA says that this whole process is the result of 
poor quality 510(k) applications. Do you want to comment on it?
    Commissioner Hamburg. I think that's a very stark view of 
what is the conversation. I think that we recognize that it's a 
combination of factors. FDA has a role to play, and that's why 
we have undertaken this fairly self-critical internal review 
and made recommendations for problems that have been identified 
that we can act on.
    But it is the case that the delays in the time of getting a 
new product to market do also reflect the time taken by the 
submitter, whether it's because the quality of the application 
wasn't adequate and we've had to have a lot of back and forth 
to get the information that we need, or because in some 
instances we have asked for information that, in fact, wasn't 
necessary.
    We need to make the overall time as short as it needs to be 
to achieve the goals of the review, which is to make sure that 
we understand the nature of the product and its risks and 
benefits in terms of its use for a given medical condition.
    Senator Burr. You're in the middle of negotiating the 
device user fees. Would you consider a new structure with the 
device user fees where the industry would pay at different 
intervals based upon FDA performance?
    Commissioner Hamburg. Right now the model does really focus 
on FDA review time. I think what you're saying is would we look 
at it in terms of the overall performance of the system.
    Senator Burr. If the FDA doesn't perform, they don't pay. I 
mean, the whole user fee foundation was built on if you supply 
us this money, we will become more efficient at what we do, 
which one would assume that from all the conversations I heard 
today--increased communication, less confusion, clearer 
guidelines--that that would all be incorporated so that the FDA 
would actually meet and exceed what the expectations were of 
the companies and the industries that were paying the fees.
    Now, were I in the industry, I would be very reluctant to 
come to the table and talk about even reauthorizing the fees 
because of the performance that I've seen. Dr. Coburn and I 
have asked the GAO to examine the performance goals so that 
Congress can fully be informed when we consider the user fee 
reauthorizations, and I look forward to reviewing those GAO 
recommendations because it's an independent assessment of how 
well the industry is meeting the performance goals and the data 
on these numbers. The industry says one thing, the FDA says 
another. GAO can now sort this out so that whether it's Senator 
Harkin or Senator Hagan or Senator Enzi or Senator Burr, that 
we can look at it and determine did you meet the performance 
goals or didn't you.
    Commissioner Hamburg. I can assure you that we track our 
performance on the existing MDUFA goals, and in fact those 
goals were negotiated with industry, as you know. And at the 
present time, we are meeting, in the 510(k) process, 95 percent 
of the goals.
    I think the larger concern, which is one that we share, is 
are we doing an adequate job getting products to market as 
quickly as possible, and that involves both the time taken by 
the submitter during the process and the time taken by FDA.
    The MDUFA goals that were negotiated with industry only do 
focus on that FDA component. I think we have a commitment to 
working with industry, whether it's part of the MDUFA 
negotiations or it's part of our overall work as the regulator 
of medical devices, to doing everything that we can to bring 
down that overall time so that we can deliver important 
products to patients in as timely a way as possible, but with 
adherence to the standards that we all agree really matter.
    Senator Burr. The Chairman has been gracious to me, and I 
will have one more round, Mr. Chairman, just to put you on 
notice. But I want to ask this because it's applicable to the 
conversation we were just on.
    Of the applications counted toward meeting the performance 
goals in your chart, what percentage are either approval or 
denial letters?
    Commissioner Hamburg. Which chart are you referring to?
    Senator Burr. I think it's the one on page 10 of your 
testimony. I think that's one that your staff has diligently 
put up every time we've gotten on devices, but I can't read it 
from here because of the light.
    But of those applications counted toward performance goals 
in the chart, what percentage are actually approval or denial 
letters versus----
    Commissioner Hamburg. First of all, I have to confess, I'm 
not sure what chart you're referring to. But I also think that 
in terms of the level of detail of your question, it would be 
best if we could get back to you.
    Senator Burr. Would you answer that for the record for me?
    Commissioner Hamburg. I absolutely will, sir.
    Senator Burr. Mr. Chairman, you've been gracious, but 
please come back to me.
    The Chairman. But you have very good questions, Senator 
Burr.
    Senator Hagan.
    Senator Hagan. Thank you, Mr. Chairman.
    Once again, Dr. Hamburg, thank you for all of your work and 
service in this job. I really do appreciate all the efforts 
that you're putting forward.
    I did mention about the laboratory diagnostic tests, that I 
would like to go back to that question, and I've heard concerns 
about the FDA's proposal to regulate these tests as medical 
devices.
    As you know, LDTs are already regulated under the CLIA, and 
a lot of the industry is worried about the additional impact of 
duplicating requirements that they would have to meet under a 
second regulatory regime, and I'm concerned once again that 
this added regulatory process would definitely slow innovation, 
which is what we're really looking for here, impeding the 
improvements to patient care, as well as job growth that has 
come with innovation across this industry.
    It is my understanding that the FDA is in the process of 
developing guidance to regulate laboratory-developed tests as 
medical devices. Where is the FDA in the development of this 
guidance?
    Commissioner Hamburg. Laboratory-developed tests clearly 
are devices. They are diagnostic tests that are often used to 
guide clinical treatment of very serious, often life-
threatening diseases. FDA does have the authority to regulate 
them historically because of the nature of how these tests were 
developed and used, which was all in-house. FDA exercised 
enforcement discretion.
    But I think given the realities of the world that we're in 
today and that these laboratory developed tests are being done 
in commercial laboratories and treating patients in facilities 
that are widespread, that it is important that there be a 
common standard of review and approval for those tests, along 
with other comparable diagnostics. We shouldn't have different 
standards depending on where the test was developed. We are 
going to be putting out several guidances to help the 
laboratory-developed test industry understand what will be 
expected of them in terms of regulatory oversight. I think it 
actually will create for industry a level playing field in 
terms of the companies that are involved in LDTs per se, or 
diagnostics more broadly.
    We are very mindful of the fact that the LDTs are subject 
to CLIA regulation. That, of course, looks at very different 
things. They don't look at the actual clinical validity of the 
laboratory-
developed test. They're looking at aspects of the laboratory 
and the credentials of the people that work there, etc. But we 
are going to provide guidance to companies about how they can 
use the materials that they have to do under the CLIA 
regulatory program to support what they need to provide to FDA 
so that we don't--so we try to minimize any duplication of 
effort under that circumstance.
    Senator Hagan. When are these guidance--when will these be 
put forward?
    Commissioner Hamburg. I think I can tell you quite soon. 
They are at somewhat different stages of development and 
review, but they will all be moving forward in a timely way.
    Senator Hagan. With the effective dates being--I mean, once 
you put your guidance forward in the regulatory process, then 
they would have to take effect? Is there a timeframe?
    Commissioner Hamburg. Draft guidance. It would be draft 
guidance. So we'd have the opportunity for----
    Senator Hagan. Public comment.
    Commissioner Hamburg [continuing]. Public comment and 
engagement around the issues as perceived by the various 
stakeholders, and we would obviously take that into 
consideration as we move toward final guidance.
    Senator Hagan. I know we've talked a lot today about the 
drugs and the process there. But in North Carolina, we have 
about 19,000 biopharmaceutical jobs in our State, and it is 
such an important part of our economy, and I want to make sure 
we do all we can to invest in this sector and protect and 
attract even more jobs.
    I've heard from companies that they've experienced, 
obviously, what we've been talking about, the delays in their 
approvals. But the main concern has been the FDA's issuance of 
a complete response letter and the fact that once the FDA 
issues this complete response letter, the agency is no longer 
bound by any deadline to make the decision on the product. And 
the crux of the problem seems to stem from inadequate 
communication between the agency and the company at all stages 
of the process. So I would just urge you to help improve upon 
the efforts to provide frequent, transparent communication with 
the companies.
    Can you tell me, is the FDA providing early feedback to 
companies to ensure that their application submission contains 
all the necessary data? And what is the FDA doing to provide 
companies with feedback when the agency issues this complete 
response letter or doesn't approve the application?
    Commissioner Hamburg. I think one piece of good news is 
that, as this chart shows, we actually are approving more 
things in the first cycle rather than using the complete 
response. So you can see that from the early days of PDUFA, 
we've gone from 46 percent approval in the first cycle to now 
68 percent. And so that is good news, and it means timely 
review and approval, and that's for priority MMEs, but similar 
trends, not quite as marked, for the non-priority review drugs 
that come before us.
    In the PDUFA V categories of activity, we do include a 
focus on strengthening communication at various stages in the 
cycle because that really does matter to sponsors, and we do 
know that it makes a real difference, but it of course does 
stretch our resources further. So we're very, very happy that 
that is a part of the PDUFA V strategy, and we think that if we 
can move forward on that, in fact, it will make a real 
difference in terms of opportunities to provide more feedback 
and to address questions early and in a continuing way.
    Senator Hagan. My time has run out. Once again, thank you 
very much for your service.
    Commissioner Hamburg. Thank you.
    The Chairman. Thanks, Senator Hagan.
    I have no more questions.
    Senator Enzi.
    Senator Enzi. I appreciate all the time that Dr. Hamburg 
has spent with us. I'll submit some questions in writing and 
relinquish my time to Senator Burr.
    Senator Burr. Thank you. Thank you, Mr. Chairman. I'll try 
to be brief.
    Dr. Hamburg, getting back to a conversation you had with 
Senator Hatch, in PDUFA we created the opportunity for the FDA 
to use outside review for predominantly Class I devices with 
accredited institutions that the FDA could exercise who to 
accreditate, what the accreditation requirements would be, and 
whether it extended out of Class I into some Class II. But the 
objective was to try to move things out of the FDA so that we 
could stay focused within the FDA with the limited number of 
reviewers on the most sensitive and potentially difficult 
devices.
    In addition to that, part of PDUFA gave the authority for 
the FDA to include foreign clinical data in submissions of 
applicants. Now, the first one with the devices was never fully 
fleshed. The second one has never been used. Do you see an 
appropriate use of either one of those options that are current 
authorities given to the FDA?
    Commissioner Hamburg. We do use data from foreign clinical 
trials in our drug review and approval.
    Senator Burr. But not to substitute for the U.S. trials you 
require. You use it to supplement. Is that correct?
    Commissioner Hamburg. We can use them. We often do see a 
situation where there's a U.S.-based trial and an international 
trial, but we can use foreign clinical trials data.
    Senator Burr. I'd love for your staff to highlight any of 
that that is appropriate that they can share with me.
    Commissioner Hamburg. OK. And we do seek outside expertise 
in our device review programs as well, and it's actually one of 
the areas that Dr. Shuren has identified as a priority for 
strengthening as well, because it is so critical. And as the 
world of devices gets so much more complex and scientifically 
and technologically advanced, it is, of course, very hard for 
FDA to have all of the expertise in-house that's needed to 
review products.
    Senator Burr. One has to question whether you can have an 
accredited institution approve a band-aid versus the FDA have 
to be the one to review it and go through it.
    Commissioner Hamburg. We don't spend a lot of time 
reviewing band-aids.
    Senator Burr. Much of your testimony today highlights 
certain data points and performance goals reports. However, the 
time to market is probably the most important metric for 
patients waiting for life-saving products. How would moving 
from FDA days to calendar days help to ensure that the review 
clock is not skewed and the performance goals truly reflect the 
time that it really takes for life-saving products to reach 
patients?
    Commissioner Hamburg. At the end of the day, I think we all 
agree that what really matters, the outcome measure that makes 
the difference, is what American consumers can access in the 
marketplace. That is our overall goal in terms of the mission 
of the agency and what we're trying to accomplish.
    I think that there are different strategies in terms of 
identifying the performance goals and the metrics to get there 
that can be discussed as part of the MDUFA negotiations, and I 
think that we want to see a program where industry and FDA are 
working together with clearly defined, achievable goals, and 
that it has to be a partnership, and that we have to be held 
accountable for what we can do, and I think industry also has a 
critical role to play whether it's in terms of the quality of 
the submissions or the time that they take to respond to our 
questions.
    We are working very hard to make sure that we have the 
proper oversight, the proper review teams, the proper 
scientific management structures, that we're asking only for 
the data that's appropriate and necessary, that we are 
reviewing what comes before us in as timely a way as possible, 
that we are seeking the external expertise that we need to be 
able to make the right decisions in as timely a way as 
possible.
    But we also want to work with industry so that that lag in 
time in terms of the submitter also declines, and I think 
that's very, very important. I think we're committed to doing 
that with industry. I think we agree that there are a set of 
issues that we need to work on together, that there is a 
blueprint for action. We need to really clarify that, and then 
we need to make sure that we have the resources and tools to 
build on it and make that real.
    Senator Burr. Would you be supportive of eliminating FDA 
days and going to calendar days?
    Commissioner Hamburg. You know, I don't think it's 
appropriate for me to step up to the negotiating table. I think 
that that's important----
    Senator Burr. I'm not asking you to negotiate. I'm asking 
you would you be supportive if an initiative, if a legislative 
initiative went to eliminate FDA days and switch to calendar 
days.
    Commissioner Hamburg. I think it is hard for us to be held 
completely accountable. If you're talking about trying to 
achieve a program that really works, we have to have----
    Senator Burr. My intent is not necessarily to hold you 
accountable. My intent is that Members of Congress, 
policymakers understand how dang long it takes to approve 
something, and your charts are all based upon FDA days, and I'd 
be willing to bet that less than 10 percent of the Members up 
here even understand what FDA days are.
    Commissioner Hamburg. But that is what was negotiated with 
industry around our performance goals. So that's why we're 
speaking to that.
    Senator Burr. In defense of my colleagues, we all know what 
calendar days are. So do the American people. And you start 
talking about FDA days to somebody who's got cancer and waiting 
for a therapy to be approved, and this is a very difficult 
thing.
    I'm increasingly concerned that the agency is not striking 
an appropriate risk/benefit balance for patients. The 
California Health Care Institute recently reported that FDA is 
focused, ``less on the benefits of new products than on 
potential risk, and to try to mitigate the risk by demanding 
larger, more expensive, and more costly clinical trials.''
    In 2007, Congress gave the agency postmarketing risk-
evaluation mitigation strategy, REMS, authority to address 
theoretical risk and empower doctors to prescribe the best 
medicine for their patients in an attempt to help the agency 
strike the risk/benefit balance. I'm concerned that this 
authority is not being used appropriately.
    We all want safe and effective drugs. But what are you 
doing to ensure that there's a balanced approach that does not 
create a barrier to new drugs such as drugs to treat diabetes 
or obesity, and has the agency considered the possibility that 
patients and physicians would be willing to tolerate some level 
of risk in order to obtain new alternatives to treat costly 
conditions?
    Commissioner Hamburg. We always do look at the risk/benefit 
balance, and we recognize that patients are willing to take 
very significant risks when they face a very serious life-
threatening or debilitating disease. We certainly approve drugs 
all the time that have known associated risks. We do look at 
what is the risk/benefit balance.
    We recently approved a new drug for malignant melanoma, I 
believe, that has a very high risk, almost 13 percent risk of 
serious autoimmune disorder associated with it, which can, in 
fact, even be life-threatening. But the demonstration of 
benefit in treating a disease that otherwise has so very 
limited treatment options made that risk/benefit equation make 
sense.
    Another drug that was approved a while back for migraine 
headaches comes with a significant set of risks, including 
potential cardiovascular problems. But it is because of the 
migraine sufferer--it's different than cancer, those headaches 
can be so severe and debilitating--that that risk/benefit 
equation was taken.
    I do think that in the PDUFA V plan that's going to come 
before you, we have an opportunity to address risk/benefit in a 
more systematic way. Industry and FDA agreed that this is a 
very important area, and that as we really build out a 
framework for how to systematically look at risk/benefit, we 
also need to make sure that the patient perspective is very 
much engaged.
    One of the categories of focus in PDUFA V is really going 
to strengthen our activities in that area and build out a new 
program. And on the device side, we're going to be putting out 
very soon guidance about how we think about the risk/benefit 
equation and recognizing the complexity of the problem and its 
importance in terms of making sure that we get products to 
people. And you're right that our postmarket surveillance 
authorities also give us different tools as we think about risk 
and benefit across the life cycle of a product.
    Senator Burr. Doctor, let me thank you for being here 
today, allowing me to go through three sessions. I know to 
answer any question in FDA is difficult, especially when we're 
spanning such a timeframe. But I'd like to make one thing 
abundantly clear to you and to the chairman.
    This committee, as well as one in the House, has the policy 
responsibilities for the Food and Drug Administration. No 
matter what you negotiate with an industry on user fees, it's 
got to pass through Congress under a reauthorization. I've 
raised issues today about measurement tools. If in those 
agreements there's not something that addresses to my 
satisfaction the ability to measure, whether it's devices or 
pharmaceuticals, this will be a very slow and laborious 
process.
    I'm somewhat bewildered that both industries even sat down 
and talked about reauthorization given what I looked at and my 
judgments of what they have gotten for the money. It's a 
disturbing day when I think that the argument is, provide us 
more money and we'll do a better job. I don't think that's the 
case.
    I think in many cases, follow the statutes and the law, and 
there's a pathway to either approval or denial. As you know, 
I'm intimately familiar with FDAMA. In 1997, I was one of the 
authors. And it amazes me, Mr. Chairman, how far we have 
strayed from what is the statutory language of the law. I don't 
think that's something I'd suggest the committee undertake, but 
if we don't have measurement tools to determine whether a fee 
system produces a better outcome, then I'm not sure why we 
would sign off on it as policymakers, and I wanted to be very 
candid with you today, as I did with the chairman.
    If we meet the threshold of satisfaction, I'll be the 
biggest fan of the agreement. If not, I will do everything to 
try to change it to make sure that we've got the measures in 
place that are sufficient for me and for others to agree to 
sign off on it.
    I thank the Chair.
    The Chairman. I thank the Senator from North Carolina.
    Commissioner Hamburg. Can I briefly respond?
    The Chairman. Please.
    Commissioner Hamburg. I do feel obliged to respond. I think 
that if you look at the PDUFA program, you can really see 
dramatic changes in our drug review programs that have been 
fostered, enabled by that important legislation and have really 
changed review times and have really enabled us to address what 
was an early concern about Americans not getting access to 
drugs and therapies as early as people in Europe and elsewhere.
    We've seen the dramatic shifts as a result of PDUFA. I 
think industry would agree that it has made a real difference 
having that source of stable and predictable funding and the 
ability to identify together key areas of priority for action. 
We're at an earlier stage with the MDUFA process, but I think 
that we have the opportunity to really transform that review 
process as well and to support the industry in its critical 
goals.
    And so I'm very, very optimistic about what we can achieve 
through this reauthorization process, very, very eager to work 
with you and others to provide all of the information that we 
can.
    I think that it is going to be a very productive and 
meaningful process, and I welcome the opportunity to be here 
today to begin those discussions and to continue to work with 
you to achieve the goals that we share of making sure that the 
American people have access to safe and effective products that 
can make a difference in their lives, in the lives of their 
families, and improving the health of our Nation.
    The Chairman. Thank you, Dr. Hamburg. And I thank the 
Senator from North Carolina.
    I have just three or four statements.
    Time to market I do not believe is the most important 
metric, I say to my friend from North Carolina, who is my 
friend and who is very diligent in his efforts. I don't think 
time to market is the most important metric. I think safety and 
effectiveness is the most important metric, first.
    Second, when we talk about FDA days, I'm quite familiar 
with that I say again to my friend from North Carolina, who 
just had to leave. But why should the clock continue to tick if 
FDA asks for additional information from the industry, and they 
don't give the information, they drag it out? Why should the 
clock continue to run? So again, I understand why we stop the 
clock until we get that information in.
    Third, on the more money and better job, I think if we look 
at the staffing of FDA 20 years ago--well, I'll go before 
PDUFA--if you look at the staffing of FDA and the amount and 
the number of items that they were involved in approving and 
compare to today, when we have MDUFA and PDUFA, and not only 
that, we've asked you to do other things, like how about food 
safety. We just dumped a lot on you 2 years ago on food safety, 
and I can tell you, I want you to do that. I want the FDA to be 
more active in inspecting the food that comes from other 
countries into this country.
    So if you look at all of the things that we've asked FDA to 
do in the last 20 years, and the staffing, I think you will see 
that if we had kept the staffing at that level, we are 
understaffed at FDA right now, quite frankly. We are 
understaffed and underfunded.
    So again, more money, better job, that's true. You need 
more staff to do all the myriad things that we've asked FDA to 
do.
    Last, I'd just say, as we're reauthorizing this, and the 
user fees that came in, which were meant to help FDA do its 
job, and it has. I said that in my opening statement. It helped 
provide a lot of funding to FDA to help speed up the process to 
provide additional personnel. It has done that. I just hope 
that there isn't this mistaken idea somewhere out there that 
somehow that if you provide the money, you get to buy the 
outcome. I don't want the money buying the outcome. I want the 
agency to be as independent as possible. I want it to be 
scientifically based. I want it to use resources that are also 
scientifically independently based.
    Balance? Yes, there should be balance in the input that's 
coming in. But I don't want anyone to get any mistaken idea 
that somehow the money is going to buy the outcome.
    With that, I request to keep the record open for 10 days 
for Senators to submit statements and questions for the record, 
and the hearing will stand adjourned.
    Thank you again very much, Commissioner Hamburg.
    Commissioner Hamburg. Thank you.
    [Additional material follows.]

                          ADDITIONAL MATERIAL

                  [The New York Times, July 27, 2011]

         Study of Medical Device Rules Is Attacked Sight Unseen

                            (By Barry Meier)

    Allies of the medical device industry are waging an extraordinary 
campaign in Washington to discredit a coming report by one of the 
country's pre-eminent scientific groups that examines possible new 
regulations on the industry.
    The scientific group, the Institute of Medicine, is scheduled to 
release a report on Friday that could propose a tougher approval 
process for a wide range of devices like hip implants, hospital pumps 
and external heart defibrillators. The report, commissioned by the Food 
and Drug Administration, comes after several well-publicized recalls in 
recent years of devices that have failed in thousands of patients, 
causing numerous injuries.
    But a business group and others have taken the highly unusual step 
of making a pre-emptive strike, arguing that the report is biased. That 
attack began even before the study panel finished its review, and has 
intensified in recent weeks.
    Device producers have also released a series of their own reports 
that say more regulation would slow innovation, harm patients and cost 
jobs. An official of a group that represents surgeons who implant hips 
and other artificial joints has also voiced support for a recent filing 
by a pro-business organization that challenged the scientific report's 
credibility and argued that the F.D.A. was statutorily required to 
ignore it.
    Christine Stencel, a spokeswoman for the Institute of Medicine, 
which is part of the National Academy of Sciences, said the group was 
unaware of a previous instance in which one of its reports, sight 
unseen, was the target of a similar effort to invalidate it.
    Dr. Sheldon Greenfield of the University of California, Irvine, who 
has served on several Institute of Medicine panels, said he was 
surprised by the campaign's intensity. ``It is pretty audacious,'' he 
said.
    The challenge to the panel has been led by Ralph F. Hall, a 
professor of law at the University of Minnesota and a device industry 
lawyer, who said the criticism was not an attempt tofront-run the 
report's conclusions but rather to air legitimate concerns about how 
the review had been conducted.
    ``I could have waited until the report came out,'' Mr. Hall said in 
an interview. ``That seems intellectually less than satisfactory with 
me.''
    Medical experts said the institute's study, regardless of how it 
falls, was likely to have a significant impact on patient safety, 
device effectiveness and the speed at which new products reached the 
market.
    With millions of dollars of product sales at stake, the experts 
said, it is not surprising that the device industry and others would 
want to avert what they see as potentially restrictive new rules. 
Still, the lobbying has taken on a tone akin to Washington infighting 
over an issue like bank regulation, rather than patient health, they 
said.
    ``We are trying to get to good policies, and the spin game doesn't 
help us,'' said Dr. Harlan M. Krumholz, a professor of medicine at Yale 
who has served on a different Institute of Medicine panel.
    The Institute of Medicine is a widely respected organization that 
assembles experts to study a range of health-related issues, often at 
the request of government agencies. In 2009, the F.D.A. contracted with 
the group to review the adequacy of one of the two regulatory pathways 
though which it approves medical devices, a process known as 510K.
    Some devices, like implanted heart defibrillators, undergo clinical 
trials in patients before they can be sold. But most medical devices, 
including implanted hips, go through the 510K route. Under that 
pathway, a producer need show only that a new product is 
``substantially equivalent'' to one already sold to gain approval.
    For example, so-called metal-on-metal artificial hips, which are 
currently the subject of scrutiny and lawsuits, appeared to work well 
when tested only on mechanical simulators but then failed disastrously 
when implanted in patients.
    The 12-member review panel assembled by the Institute of Medicine 
included physicians, academics and two lawyers who had worked for 
device makers on regulatory issues. Another lawyer on the panel, Brian 
Wolfman, who once worked for Public Citizen, a consumer advocacy group, 
has come under particular attack by business-affiliated groups.
    Mr. Wolfman and several other panel members declined to be 
interviewed for this article or did not respond to telephone calls or 
e-mails.
    Last month, the Washington Legal Foundation, a pro-business group, 
filed a petition with the F.D.A. arguing that the agency was 
statutorily barred from adopting any of the report's recommendations 
because of what it claimed was the panel's bias. The legal foundation 
argued that the Institute of Medicine had failed to balance the panel 
by including officials from industry, the investment community or 
patients who had benefited from devices.
    ``We wanted to let F.D.A. know that there are significant concerns 
with the composition of the committee,'' said Richard A. Samp, a lawyer 
for the legal foundation.
    Mr. Samp said his organization took action after the issue was 
brought to its attention by a lawyer who works at a firm that 
represents device makers. Shortly after filing its petition, the legal 
foundation was contacted by an official of the American Academy of 
Orthopaedic Surgeons, which represents doctors who perform joint 
replacements, who congratulated it for ``taking the bull by the 
horns,'' Mr. Samp said.
    A spokeswoman for the doctors' group confirmed that one of its 
officials had called Mr. Samp, adding that it was concerned that the 
Institute of Medicine panel did not include a practicing surgeon.
    William Skane, a spokesman for the National Academy of Sciences, 
said the group worked hard to balance its committees and barred people 
from serving on a panel if they had a financial conflict of interest or 
a clear bias on an issue.
    Dr. William Maisel, the chief scientist of the F.D.A. division that 
oversees medical devices, said the agency was satisfied with the 
panel's makeup.
    ``I think it would be difficult to find a more reputable scientific 
organization than the Institute of Medicine,'' Dr. Maisel said. He 
added that the F.D.A. was not bound to accept the report's 
recommendations.
    Over the last year, the panel charged with reviewing device 
approvals has also held hearings to gather feedback and data from all 
interested parties, including device producers and investors.
    Earlier this year, Mr. Hall, the lawyer and Minnesota professor, 
wrote an article with a colleague, arguing that the Institute of 
Medicine, in selecting its panel, had violated a little-known rule, the 
Federal Advisory Committee Act, which requires balance on such 
committees.
    In the interview, Mr. Hall acknowledged that he had worked either 
directly or in the same law firm with the two lawyers on the panel who 
had advised device makers on F.D.A matters.
    At a Congressional hearing this month, the editors of two medical 
journals--The Journal of the American Medical Association, The New 
England Journal of Medicine and the Archives of Internal Medicine--
questioned the value of two industry-backed studies that claimed that 
new regulations would create hardships for patients and producers, 
describing them as methodologically flawed.
                                 ______
                                 
             Department of Health & Human Services,
                      Food and Drug Administration,
                                   Silver Spring, MD 20993,
                                                 November 10, 2011.
Hon. Tom Harkin, Chairman,
Committee on Health, Education. Labor, and Pensions,
U.S. Senate,
Washington, DC 20510.

    Dear Mr. Chairman: Thank you for providing the opportunity for the 
Food and Drug Administration (FDA or the Agency) to testify at the July 
28, 2011 hearing, before the Committee on Health, Education, Labor, and 
Pensions, entitled ``FDA User Fees: Advancing Public Health.'' This 
letter provides responses for the record to questions posed by certain 
members of the committee, which we received on August 12, 2011.
    We have addressed our responses to each member. We have re-stated 
each question below in bold type, followed by FDA's responses.
    Thank you, again, for contacting us concerning this matter. If you 
have further questions, please let us know.
            Sincerely,
                          Karen Meister for Jeanne Ireland,
                            Assistant Commissioner for Legislation.
                                 ______
                                 
  Response by the Food and Drug Administration (FDA) to Questions of 
    Senator Enzi, Senator Alexander, Senator Burr, and Senator Hatch
                              senator enzi
    Question 1. Beginning in 1998, the Government Accountability Office 
has called for FDA to implement a series of recommendations to respond 
to the challenges posed by the globalization of drug manufacturing. 
What progress has the agency made on GAO's longstanding 
recommendations? How will your recent reorganization help you make 
additional progress? Please be as specific as you can in answering 
these two questions.
    Answer 1. FDA takes recommendations from the Government 
Accountability Office (GAO) very seriously. Below are several specific 
GAO recommendations related to responding to the challenges posed by 
the globalization of drug manufacturing, followed by the Agency's 
activities in response to these recommendations.
                           gao recommendation
    FDA should, ``[c]onduct more inspections to ensure that foreign 
establishments manufacturing drugs currently marketed in the United 
States are inspected at a frequency comparable to domestic 
establishments with similar characteristics.''\1\
---------------------------------------------------------------------------
    \1\ GAO, Drug Safety: Better Data Management and More Inspections 
Are Needed to Strengthen FDA's Foreign Drug Inspection Program, GAO-08-
970, September 2008, p. 8.
---------------------------------------------------------------------------
                            agency response
    In recent years, FDA has taken measures that have resulted in an 
increased number of foreign inspections, a more sophisticated approach 
to identifying facilities for inspection, and a more streamlined 
approach to conducting inspections. For example, we have implemented 
collaborative efforts with our foreign counterparts, and we have issued 
a new compliance program within the Compliance Program Guidance Manual 
(CPGM) for pre-approval inspections that strengthens the criteria for 
determining when a pre-approval inspection is necessary. We also have 
established a cadre of dedicated foreign investigators, managed from 
headquarters with employees located in FDA districts whose work is 
dedicated to conducting foreign inspection assignments. It is important 
to note, however, that inspections are necessary but not sufficient to 
ensure quality.
    In large part as a result of these initiatives, FDA has increased 
the frequency of its foreign Current Good Manufacturing Practice (CGMP) 
surveillance inspections from 347 in Fiscal Year 2007 to 443 in fiscal 
year 2010 and the Agency is better positioned to conduct enforcement 
followup after the issuance of a Warning Letter (WL). The number of WLs 
issued to foreign facilities also has increased significantly. For 
example, in calendar year 2008 the Agency issued four WLs to foreign 
facilities (two to sites in China and two to sites in India), and in 
2010, the Agency issued 19 WLs to foreign facilities, also including 
sites in China and India.
                           gao recommendation
    FDA should ``[c]onduct timely inspections of foreign establishments 
that have received warning letters to determine continued compliance.'' 
\2\
---------------------------------------------------------------------------
    \2\ Ibid. page 43.
---------------------------------------------------------------------------
    During 2010, FDA issued 19 WLs to foreign establishments. Of the 19 
establishments that received WLs during 2010, six have been re-
inspected. Of the 13 foreign firms to which the Agency issued WLs in 
2009, the Agency has already re-inspected 11. The remaining firms are 
either implementing corrective action plans or will be re-inspected in 
the near future. Once re-inspected, FDA will determine if they are in 
compliance with GMPs and evaluate whether or not they can be removed 
from import alert status.
                           gao recommendation
    FDA should ``enforce the requirements that establishments 
manufacturing drugs for the U.S. market update their registration 
annually.'' \3\
---------------------------------------------------------------------------
    \3\ Ibid. page 43.
---------------------------------------------------------------------------
                            agency response
    Under the Federal Food, Drug, and Cosmetic Act (FD&C Act or the 
Act) most foreign drug establishments shipping drugs to the United 
States must register with FDA electronically. Registration is completed 
through FDA's electronic drug registration and listing system (eDRLS) 
and must be resubmitted on or before December 31 of each calendar year. 
The implementation of eDRLS helps FDA to identify foreign 
establishments that have not satisfied their statutory registration 
obligations and helps the Agency to assemble more reliable information 
about drug establishments.
    Revising FDA's statutory provisions to modernize drug registration 
and listing may improve the timeliness, completeness, and accuracy of 
FDA's current database, making sure that FDA has accurate and up-to-
date information about foreign and domestic parties involved in medical 
product manufacture.
                           gao recommendation
    FDA should ``[e]stablish mechanisms for verifying information 
provided by the establishment at the time of registration.'' \4\
---------------------------------------------------------------------------
    \4\ Ibid. page 43.
---------------------------------------------------------------------------
                            agency response
    FDA recently hired a contractor to verify registrations of foreign 
fines. A total of 373 site visits were conducted over a 3-year period. 
Of the 373 visits, 142 sites were drug firms. Two-hundred and thirty 
sites were food firms, and one site was a medical device firm. The 
contract ended in August 2011 and FDA is also continuing to explore 
additional avenues for verifying the registration information submitted 
by foreign facilities.
    FDA, working with Dun and Bradstreet (D&B), has established a pilot 
project to verify foreign establishments in the drug GMP inventory for 
whom FDA's records are incomplete or dated. The U.S. Customs and Border 
Protection identified for the pilot nearly 160 establishments who have 
shipped drugs to the United States from these countries in recent 
years. D&B employees located in India and China are using phone calls, 
email, site visits or a combination of these methods to engage to 
attempt to acquire complete and accurate registration information. 
About two-thirds of the verifications are complete.
    FDA is also working towards use of a unique facility identifier, 
such as the D&B DUNS number, which would allow the Agency to verify the 
accuracy of registration information using robust, established 
databases. Section 510(e) of the FD&C Act states that the Secretary may 
assign a registration number to any establishment registered in 
accordance with section 510. However, FDA does not currently have 
explicit statutory authority to require the submission of a unique 
identifier, such as a DUNS number, as a condition of drug establishment 
registration and drug import. Current FDA guidance states that DUNS 
numbers serve as the registration numbers for drug establishments in 
the electronic system, and thus recommends, but does not require, that 
industry provide DUNS numbers during the registration and listing 
process.
                           gao recommendation
    FDA should ``[e]nsure that information on the classification of 
inspections with serious deficiencies is accurate in all FDA 
databases.'' \5\
---------------------------------------------------------------------------
    \5\ Ibid, page 43.
---------------------------------------------------------------------------
                            agency response
    In 2008, GAO identified discrepancies between the Office of 
Regulatory Affairs' (ORA's) Field Accomplishments and Compliance 
Tracking System (FACTS) database and the Center for Drug Evaluation and 
Research's (CDER's) Office of Compliance Foreign Inspection Tracking 
System (OCFITS) database, with regard to the types of action indicated 
in following a foreign inspection. Since GAO's report, FDA has 
identified the cause of these discrepancies and has implemented 
measures to prevent them in the future.
    CDER's Office of Compliance has now replaced OCFITS with a new 
information management system referred to as Compliance Management 
Services. The new system links directly to FACTS for some critical 
information and the information about sites and inspection events is 
more accurate than the earlier system, OCFITS.
                           gao recommendation
    FDA should [c]onduct more inspections to ensure that foreign 
establishments manufacturing drugs currently marketed in the United 
States are inspected at a frequency comparable to domestic 
establishments with similar characteristics.'' \6\
---------------------------------------------------------------------------
    \6\ Ibid, page 43.
---------------------------------------------------------------------------
                            agency response
    FDA has committed to conducting more foreign inspections to achieve 
the Agency's goal of addressing the risks posed by the global supply 
chain. The Agency increased foreign inspections by 27 percent from 2007 
to 2010 as stated above and it continues to identify opportunities for 
increasing our surveillance and knowledge about foreign drug 
manufacturers whose drugs are consumed in the United States.
    The statute directs FDA to inspect domestic manufacturers every 2 
years. However, an overall risk-based approach to foreign and domestic 
inspections would be a far better approach than a mandatory inspection 
frequency. There are a number of obstacles that make conducting foreign 
inspections challenging, including:

     Cost of conducting foreign inspections--it is 
exponentially more expensive to conduct a foreign inspection than a 
domestic inspection.
     Sovereignty issues--FDA must obtain a visa to enter a 
foreign country in order to conduct an inspection, and a firm does not 
have to let FDA in, although the product would not be approved if a 
pre-approval inspection is necessary.
     Cooperation with the foreign firm--FDA must notify foreign 
firms of the Agency's intent to conduct an inspection and rely upon 
foreign firms to facilitate the inspection. While foreign firms that 
refuse to permit FDA inspection present a challenge to achieving a 2-
year inspection frequency, it does not impede FDA's ability to protect 
the safety of the drug supply. FDA may refuse entry of goods from 
foreign firms that refuse to permit FDA inspection and may withhold 
approval of pending new drug applications submitted by firms that 
refuse to permit an FDA inspection.

    Given the challenges in achieving a 2-year inspection frequency 
abroad, FDA has supplemented its use of foreign inspections with other 
reliable sources of compliance information and has instituted risk 
analytics to make best use of this information, including:

     Using the PREDICT import information technology system to 
target the highest-risk entries for further scrutiny, field 
examinations, and/or sample collection analyses.
     Establishing dedicated foreign cadres: FDA has established 
dedicated cadres of foreign investigators for pharmaceutical, device, 
and foreign food inspections.
     Increasing leveraging: FDA continues to increase its 
collaborative efforts with foreign counterparts.
                           gao recommendation
    FDA should ``take steps to enhance strategic planning to ensure 
coordination between overseas and domestic activities and develop a 
workforce plan to help recruit and retain overseas staff.'' \7\
---------------------------------------------------------------------------
    \7\ GAO, Overseas Offices Have Taken Steps to Help Ensure Import 
Safety, but More Long-term Planning is Needed, GAO-10-960, Highlights.
---------------------------------------------------------------------------
                            agency response
    We now have permanent FDA overseas posts in Beijing, Shanghai. and 
Guangzhou, China; New Delhi and Mumbai, India; San Jose, Costa Rica; 
Mexico City, Mexico; Santiago, Chile; Brussels, Belgium; London, 
England; and Parma, Italy. This year, we have opened posts in Amman, 
Jordan and Pretoria, South Africa. These offices enable us to have a 
regional presence around the world and serve as important hubs for 
improved coordination with regulatory authorities and industry in other 
nations. FDA personnel assigned to these posts can also conduct and 
facilitate inspections.
    The Agency is doing strategic and operational planning for its 
foreign offices and has initiated a workforce planning process. As 
noted in the GAO report, FDA recognizes that this process will be 
ongoing and informed by the experience of several cycles of overseas 
staff appointments (deployment and return), and that the Agency will 
benefit from the process.
    We are also supporting our strategic planning efforts by employing 
the FDA-TRACK performance management initiative to identify and track 
performance indicators and milestones for key program activities. The 
transparency of this management process contributes to the coordination 
of our overseas and domestic activities. For more information, please 
visit: http//www.fda.gov/AboutFDA/Transparency/track/default.htm.
                         agency reorganization
    You also asked how our recent reorganization will help us make 
additional progress. On July 13, 2011, we announced that the Office of 
the Commissioner (OC) would be restructured to more accurately reflect 
the Agency's responsibilities, subject matter expertise, and mandates 
in an ever-increasing complex world, where products and services do not 
fit into a single category. OC has been divided into ``directorates'' 
that reflect the core functions and responsibilities of the Agency. 
This new management structure will enable OC to better support the 
Agency's core scientific and regulatory functions, and help tie 
together programs that share regulatory and scientific foundations.
    As part of this reorganization, the Agency created a new position, 
Deputy Commissioner for Global Regulatory Operations and Policy, to 
provide broad direction and support to ORA and to the Office of 
International Programs. The Deputy Commissioner is charged with 
ensuring that FDA responds to the challenges of globalization and 
import safety and ensures that globalization issues are a top priority 
for the Agency in the years to come.

    Question 2. FDA has committed to provide a guidance on the 
artificial pancreas by December of this year. Publication of a draft 
guidance is a very important first step, but it is just that, a first 
step. Can you assure me that the final guidance will reflect the input 
of clinical experts and that FDA will finalize it in a timely way so 
products can be timely tested and moved to market?
    FDA is committed to facilitating and expediting development of the 
artificial pancreas and continues to work diligently with stakeholders. 
The low-glucose suspend system draft guidance, issued on June 22, 2011, 
was developed with considerable input from industry, researchers, and 
the clinical community. The Agency requested additional feedback 
through a 90-day public comment period. FDA is now reviewing and 
addressing the comments received and will finalize that guidance 
document as expeditiously as possible.
    As part of the outreach for the low-glucose suspend draft guidance. 
FDA specifically targeted health care professionals, alerting them to 
the availability of the draft guidance and asking for their comment. 
Provider groups targeted include the Diabetes Technology Society, the 
American Association of Clinical Endocrinologists, the American 
Diabetes Association, the Endocrine Society, the Juvenile Diabetes 
Research Foundation, the National Institutes of Health, the Endocrine 
Nurses Society, and the American Association of Diabetes Educators.
    FDA will continue to collaborate with the medical community and 
other stakeholders and will continue our efforts to prioritize and 
expedite clinical research in this area.
    A critical aspect of a second draft guidance, which is currently 
under development, for the more sophisticated treat-to-target or treat-
to-range systems \8\ is addressing their safety in real-world 
scenarios, i.e., outside of the protection of the clinical or hospital 
setting. That guidance is projected for publication in December 2011.
---------------------------------------------------------------------------
    \8\ A treat-to-range system reduces the likelihood of a 
hypoglycemic event or a hyperglycemic event (when blood glucose is 
dangerously high) by adjusting insulin dosing only if a person's 
glucose level approaches the low or high glucose thresholds. Patients 
using this system will still need to check blood glucose levels with a 
glucose meter and give themselves insulin to maintain control of 
glucose levels. A treat-to-target system sets target glucose levels and 
tries to achieve these levels at all times. It would be fully automated 
and require no interaction from the user, except for calibration of the 
continuous glucose monitoring system.
---------------------------------------------------------------------------
                           senator alexander
    Question 1. I have heard from a start-up device company in my home 
State of Tennessee that, ``Whenever people call us looking for 
employment we tell them we can't hire them, because the Federal 
Government won't let us.'' They went on to cite some of the several 
studies published in recent months that make comparisons between the EU 
and U.S. systems of medical device regulation, which they feel indicate 
that the FDA is over-regulating the U.S. medical device industry, which 
has a negative effect on the industry's ability to raise capital and 
create jobs and doesn't make medical devices safer in the United States 
than they are in Europe.
    My question is, why if a product is available in Europe would that 
product need to go through more pre-clinical testing before beginning a 
U.S. clinical trial? Why isn't an EU CE Mark approval (``European 
Conformity'' meaning it conforms to all required safety and health 
standards) to use in humans enough to allow access for Americans via a 
clinical trial?
    Answer 1. The FD&C Act requires that a Class III medical device 
(i.e., those with the highest risk) be approved on the basis of 
clinical data demonstrating reasonable safety and effectiveness for its 
intended uses. The fact that a device has received the European Union 
(EU) CE mark of approval tells us nothing about the clinical data 
underlying that decision. However, FDA does not require studies to 
support device approvals to be conducted in the United States. We 
accept trials or data from outside the United States as long as the 
studies meet regulatory standards and are applicable to U.S. 
populations.
    Data collected from other countries can be used to support a 
product's safety and effectiveness. Foreign studies performed under an 
Investigational New Drug (IND) application or Investigational Device 
Exemption (IDE) must meet the same requirements of 21 CFR part 312 or 
21 CFR part 812, respectively, that apply to U.S. studies conducted 
under an IND or IDE. The acceptance of foreign clinical studies not 
conducted under an IND or IDE, as support for a marketing application, 
is generally governed by 21 CFR 312.120 and 21 CFR 814.15.
    A marketing application that is based solely on foreign clinical 
data meeting U.S. criteria for marketing approval may be approved if:

     the foreign data are applicable to the U.S. population and 
medical practice;
     the studies have been performed by clinical investigators 
of recognized competence; and
     the data may be considered valid without the need for an 
on-site inspection by FDA or if FDA considers such an inspection to be 
necessary, FDA can validate the data through an on-site inspection or 
other appropriate means.

    Question 2. Is there something about the U.S. device review system 
that is inherently slower than that of the EU? Yes there are different 
standards, but is there something unique about our system that leads to 
delays in patient access?
    Answer 2. A recent industry-sponsored study \9\ compared time to 
market between the United States and the EU. Although the study is 
flawed in some regards, it does show that devices subject to a 510(k) 
without clinical data tend to come on the market first, as often or 
more often in the United States as in the EU. That's approximately 90 
percent of devices marketed in the United States. Higher risk medical 
devices are typically approved faster in the EU than in the United 
States because, unlike the United States, the EU does not require the 
manufacturer to demonstrate that the device actually benefits patients.
---------------------------------------------------------------------------
    \9\ California Healthcare Institute and The Boston Consulting 
Group. ``Competitiveness and Regulation: The FDA and the Future of 
America's Biomedical Industry'' (Feb. 2011), available at http://
www.bdg.com/documents/file72060.pdf.

    Question 3. Could you please define ``reasonable assurance? '' Does 
this term also include some risk?
    Answer 3. Although a manufacturer may submit any form of evidence 
to FDA in an attempt to substantiate the safety and effectiveness of a 
device, by statute the Agency must rely upon valid scientific evidence 
to determine whether there is ``reasonable assurance'' that the device 
is safe and effective. After considering the nature of the device and 
the rules in 21 CFR 860.7, FDA determines whether the evidence 
submitted or otherwise available to FDA is valid scientific evidence 
for the purpose of determining the safety or effectiveness of a 
particular device, and whether the available evidence, when taken as a 
whole, is adequate to support a determination that there is reasonable 
assurance that the device is safe and effective for its conditions of 
use.
    There is reasonable assurance that a device is safe when it can be 
determined, based upon valid scientific evidence, that the probable 
benefits to health from use of the device for its intended uses and 
conditions of use, when accompanied by adequate directions and warnings 
against unsafe use, outweigh any probable risks.
    In order for industry and others to better understand how FDA makes 
these decisions, we recently published for public comment a ``Draft 
Guidance for Industry and Food and Drug Administration Staff--Factors 
to Consider when Making Benefit-Risk Determinations in Medical Device 
Premarket Review,'' which may be viewed at http://www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance/Guidance
Documents/ucm267829.htm.

    Question 4a. I hear from device manufacturers that they are looking 
for more consistency and predictability, which you state in your 
testimony that you have heard for yourself, and the standard in the 
United States is safety and effective while in the EU the standard is 
safety and performance. Is there something about the U.S. standard that 
prevents FDA from providing consistency and predictability in the 
review process? (YES OR NO)
    Answer 4a. No. There is nothing inherent in the U.S. standard that 
prevents consistency and predictability in the review process. However, 
safety and effectiveness is a higher standard than safety and 
performance. For example, in the EU, to clear a laser to cut heart 
tissue to treat heart arrhythmia, it must only be demonstrated that the 
device cuts tissue. In the United States, it must be demonstrated that 
the patient actually benefits from the cutting of the tissue, i.e., 
that the laser treats the arrhythmia.
    Comparisons between the United States and EU systems are not easy 
to make, as the European device review process is less transparent than 
FDA's. There are significant differences between the EU and U.S. device 
review systems. In the EU:

     Manufacturers do not have to demonstrate that their 
products are effective at treating the disease or condition for which 
they are approved;
     Private entities chosen and paid by manufacturers review 
and approve medical devices by giving them a CE mark; these decisions 
are kept confidential and not released to the public or to EU 
regulatory bodies;
     There is not one, centralized regulatory body for review 
of medical devices: instead, each member State has its own system for 
determining reimbursement of medical devices and it is impossible to 
track approvals, adverse events, or recalls; and
     There is little to no publicly accessible, centralized 
system for collecting and monitoring information about device approvals 
or safety problems.

    These differences have recently been highlighted by several 
prestigious European medical journals. Both the British Medical Journal 
\10\ and the European Society of Cardiology \11\ have published reports 
noting that the lack of transparency and clinical data requirements in 
the EU system have led to patient harm.
---------------------------------------------------------------------------
    \10\ Deborah Cohen, ``Europeans Are Left to Their Own Devices,'' 
British Medical Journal 342:d2748 (2011), available at http://
www.bmj.com/content/342/bmj.d2748.full.pdf.
    \11\ Alan G. Fraser, et al., ``Clinical Evaluation of 
Cardiovascular Devices: Principles, Problems, and Proposals for 
European Regulatory Reform: Report of a Policy Conference of the 
European Society of Cardiology,'' European Heart Journal 32 (13): 1673-
86, available at http://eurheartj.oxfordjournals.org/content/32/13/
1673.full.pdf+htm; See also Jacqui Wise, ``Cardiologists Call for a 
Single European System to Oversee Medical Devices,'' British Medical 
Journal 342:d3144 (2011), available at http//www.bmj.com/content/342/
bmj.d3144.full.pdf.
---------------------------------------------------------------------------
    For more information about steps FDA is taking to improve 
consistency and predictability in its review processes, see the answer 
to the following question.

    Question 4b. Why are we seeing this lag? Is it because your 
reviewers are not properly trained? Is it because you are not using 
resources at your disposal such as interactive review? Is it because 
FDA guidance is lacking?
    Answer 4b. As noted in answer to question #2, a recent industry-
sponsored study \12\ compared time to market between the United States 
and the EU. Although the study is flawed in some regards, it does show 
that devices subject to a 510(k) without clinical data tend to come on 
the market first, as often or more often in the United States as in the 
EU. That's approximately 90 percent of devices marketed in the United 
States. Higher-risk medical devices are typically approved faster in 
the EU than in the United States because, unlike the United States, the 
EU does not require the manufacturer to demonstrate that the device 
actually benefits patients.
---------------------------------------------------------------------------
    \12\ California Healthcare Institute and The Boston Consulting 
Group, ``Competitiveness and Regulation: The FDA and the Future of 
America's Biomedical Industry'' (Feb. 2011), available at: http://
www.bdg.com/documents/file72060.pdf.
---------------------------------------------------------------------------
    Although FDA is meeting its 510(k) performance goals under MDUFA, 
overall time to decision (i.e., FDA review time plus industry response 
time) for 510(k) submissions has increased over the past 10 years, due 
primarily to an increase in the number of review cycles and in the 
amount of time companies take to respond to requests for additional 
information.
    We recognize our role in this and are taking steps to address it. 
The two reports we released publicly in August 2010, with our analyses 
and recommendations, showed that we have not done as good a job 
managing our premarket review programs as we should and that we need to 
take several critical actions to improve the predictability, 
consistency, and transparency of these programs.
    For example, we have new reviewers who need better training. We 
need to improve management oversight and standard operating procedures. 
We need to provide greater clarity for our staff and for industry 
through guidance about key parts of our premarket review and clinical 
trial programs and how we make benefit-risk determinations. We need to 
provide greater clarity for industry through guidance and greater 
interactions about what we need from them to facilitate more efficient, 
predictable reviews. We need to make greater use of outside experts who 
understand cutting-edge technologies. And we need to find the means to 
handle the ever-increasing workload and reduce staff and manager 
turnover, which is almost double that of FDA's drugs and biologics 
centers.
    In January 2011, FDA announced a Plan of Action that included 25 
specific actions that we would take this year to improve the 
predictability, consistency, and transparency of our premarket 
programs. The following month, we announced our Innovation Initiative, 
which included several proposals to help maintain the position of the 
United States as the world's leader in medical device innovation, 
including the creation of a new approach for important, new 
technologies called the Innovation Pathway.
    Since then, we have announced additional efforts to improve our 
premarket programs, including actions to improve our program for 
clinical trials and the Investigational Device Exemption (IDE) program. 
The actions we are taking can be grouped into three main areas of 
emphasis:

     Create a culture change toward greater transparency, 
interaction, collaboration, and the appropriate balancing of benefits 
and risks;
     Ensure predictable and consistent recommendations, 
decisionmaking, and application of the least-burdensome principle; and
     Implement efficient processes and use of resources.

    Specific steps that we are taking, many of which are supported by 
industry, include:

     Issuing guidance clarifying the criteria used to make 
benefit-risk determinations a part of device premarket decisions to 
provide greater predictability and consistency and apply a more 
patient-centric approach by considering patients' tolerance for risk in 
appropriate cases (draft guidance issued August 15, 2011);
     Creating standard operating procedures for when a reviewer 
can request additional information regarding a premarket submission and 
at what management level the decision must be made to provide greater 
predictability, consistency, and the appropriate application of the 
least-burdensome principle by reducing the number of inappropriate 
information requests (Standard Operating Procedures issued November 
2011);
     Developing a range of updated and new guidances to clarify 
CDRH requirements for predictable, timely, and consistent product 
review, including device-specific guidance in several areas such as 
mobile applications (draft guidance released July 19, 2011) and 
artificial pancreas systems (to be completed by the end of 2011);
     Revamping the guidance development process through a new 
tracking system and, to the extent resources permit, core staff to 
oversee the timely drafting and clearance of documents (to be completed 
by the end of 2011);
     Improving communication between FDA and industry through 
enhancements to interactive review (some of these enhancements will be 
in place by the end of 2011);
     Streamlining the clinical trial and IDE processes by 
providing industry with guidance to clarify the criteria for approving 
clinical trials, and criteria for when a first-in-human study can be 
conducted earlier during device development to create incentives to 
bring new technologies to the United States first (guidance to be 
issued November 2011) (IDEs are required before device testing in 
humans that involve significant risks may begin, and they ensure that 
the rights of human subjects are protected while gathering data on the 
safety and efficacy of medical devices);
     Implementing internal business process improvements to 
ensure that decisions are made by the appropriate level of management, 
that decisions are made consistently and efficiently, and that we 
appropriately apply the least-burdensome principle. For example, CDRH 
created the internal Center Science Council (Council) to actively 
monitor the quality and performance of the Center's scientific programs 
and ensure consistency and predictability in CDRH scientific 
decisionmaking (Council established March 31, 2011);
     Creating a network of experts to help CDRH resolve complex 
scientific issues, which will ultimately result in more timely reviews. 
This network will be especially helpful as FDA confronts new 
technologies (Standard Operating Procedures issued September 30, 2011);
     Instituting a mandatory Reviewer Certification Program for 
new reviewers (program launched September 2011);
     Instituting a pilot Experiential Learning Program to 
provide review staff with real-world training experiences as they 
participate in visits to manufacturers, research, and health care 
facilities, and academia (to begin in early 2012);
     Providing industry with specific guidance on how to ensure 
the quality and performance of clinical trials while applying the 
least-burdensome principle, and thereby conduct studies that are more 
likely to support the approval of their products (guidance released 
August 15, 2011); and
     Streamlining the de novo review process, the pathway by 
which novel, lower-risk devices without a predicate can come to market 
(draft guidance released September 30, 2011).
    A recent FDA analysis \13\ shows that poor submission quality is a 
major contributor to the increase in total review times. The most 
common deficiencies included:
---------------------------------------------------------------------------
    \13\ CDRH, ``Analysis of Premarket Review Times Under the 510(k) 
Program'' (July 2011), available at http://www.fda.gov/AboutFDA/
CentersOffices/CDRH/CDRHReports/ucm263385.htm
#5.

     Inadequate device descriptions;
     Discrepancies throughout the submission;
     Failure to address necessary information as outlined in 
guidance documents;
     Problems with the proposed indications for use;
     Completely missing performance testing; and
     Completely missing clinical data.

    In addition, sponsors' failure to address deficiencies identified 
in first-round Additional Information (AI) Letters is a major 
contributor to the increase in total review times. For example, 65 
percent of the time, FDA sent a second-round AI Letter because the 
sponsor failed to submit information requested in the first AI Letter.
    FDA has already taken steps to address some of the issues 
identified in this analysis. We are working to provide greater 
predictability for industry by communicating justified changes in data 
requirements more quickly and transparently. We recently issued draft 
Standard Operating Procedures for Notice to Industry Letters,\14\ which 
provides a format for communicating changes more quickly within the 
existing Good Guidance Practices framework. FDA is also enhancing 
training for staff and industry, which is aimed at reducing 
inappropriate requests for additional information and helping sponsors 
understand when they are required to submit data. We will continue to 
work with industry to identify additional actions to reduce the average 
number of review cycles and the percent of 510(k) submissions for which 
an AI Letter is sent.
---------------------------------------------------------------------------
    \14\ CDRH, ``Standard Operating Procedure for `Notice to Industry' 
Letters'' (August 2011), available at http://www.fda.gov/downloads/
MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/
UCM259172.pdf.
---------------------------------------------------------------------------
    Through these and other steps we are taking to address weaknesses 
in the 510(k) program, FDA aims to reduce the total time to clearance 
for 510(k) devices, while assuring that we maintain the same levels of 
safety and effectiveness. It is our hope that taking actions to 
increase submission quality and avoid inappropriate requests for 
additional information will prevent avoidable delays and reduce total 
time to decision, which will, in turn, get safe and effective devices 
to market faster.
    With regard to PMA applications, FDA's internal analysis found 
that, for those PMAs that were not reviewed within the performance 
goals, the main reasons for the longer review times were:

     Poor quality clinical studies, such as clinical trial 
execution issues and problematic data analyses;
     Reviewer turnover, especially changing medical officers 
and branch chiefs; and
     Taking a PMA to an FDA advisory committee. (In general, 
all PMAs for the first-of-a-kind device are taken before the 
appropriate advisory panel for review and recommendations. The 
preparation for an FDA advisory committee involves significant calendar 
time and review team resources.)

    Question 4c. While I appreciate that you have taken steps to 
address some of these issues, what else are you doing right now in the 
short term to manage and increase consistency and predictability in the 
review process?
    Answer 4c. Our most recent activities aimed at increasing 
consistency and predictability in the medical device review process 
include the following:

     On September 6, 2011, CDRH announced that our new Reviewer 
Certification Program, which began as a pilot in April 2010 with 
participants from CDRH's Division of Anesthesia, General Hospital, and 
Infection Control and Dental Devices, would launch that month and is 
intended to include all new device reviewers. The program includes up 
to 18 months of training, aimed at complementing the skills and 
knowledge that new reviewers bring to CDRH from fields such as 
biomedical engineering and health care. Reviewers in the program will 
complete online training modules and instructor-led courses, and obtain 
practical experience in the medical device review process.\15\
---------------------------------------------------------------------------
    \15\ CDRH also announced that it is developing a pilot Experiential 
Learning Program for premarket reviewers. which will include visits to 
academic institutions, manufacturers, research organizations, and 
health care facilities and is intended to give reviewers a better 
understanding of how medical devices are designed, manufactured and 
used. The Experiential Learning Program is in the design stage and 
scheduled to begin as a pilot program in 2012.
---------------------------------------------------------------------------
     On August 15, CDRH issued draft guidance (with a request 
for public comment) to help researchers and manufacturers design better 
quality clinical studies in support of PMA applications for medical 
devices. Manufacturers submit PMA applications for high-risk (Class 
III) medical devices. These applications undergo the most stringent 
type of FDA device review. PMA submissions include data from pivotal 
clinical studies, which FDA uses, along with other information, in 
determining approval.
     Also on August 15, CDRH published draft guidance (with a 
request for public comment) clarifying how benefit-risk determinations 
are made during premarket review of certain medical devices. The 
guidance focuses on PMAs--the regulatory pathway for high-risk medical 
devices. The recommendations made in the guidance are intended to 
improve the predictability, consistency and transparency of the 
premarket review process for applicable devices, and should help 
manufacturers navigate the approval process more easily.

    Question 5. I have another question relating to the consistent 
application of regulatory standards and maintaining a level playing 
field for all manufacturers. Again, I have heard from manufacturers in 
Tennessee who feel that the current criteria demanded by CDRH to 
evaluate new medical devices in a specific product class can seem 
arbitrary. They feel the criteria often are inconsistent with FDA 
precedent for similar devices, and changes in the criteria are not 
scientifically justified by CDRH. They say it has become a noticeable 
trend during the last 2 years, and is exacerbated by staffing changes 
at the agency and lack of reviewer training. More specifically, CDRH 
appears to be applying clinical trial success requirements that are 
significantly different with respect to primary and secondary endpoints 
from those that have been used to evaluate and approve other products, 
even those approved within the past 18 months. The application of new 
standards for approvability of similar products that exceed the 
standards applied to contemporary approvals negatively impact both 
patients and jobs while also increasing healthcare costs by limiting 
competition. Please comment on the regulatory process and statutory 
standards at CDRH that allow review teams to arbitrarily (no scientific 
or regulatory standard basis) apply different criteria to the new 
products of a given class that are far above those criteria used to 
approve similar device types that have been recently (within the past 
18 months) reviewed by an FDA Advisory Panel and approved by the FDA.
    Answer 5. Consistent with the requirements for 510(k) submissions, 
FDA may require clinical data when a firm seeks a new indication for 
use or where there are differences in the technological characteristics 
between the firm's device and its predicate that could affect safety or 
effectiveness. FDA asks for clinical studies in only 8 to 10 percent of 
510(k) submissions, and often the requested studies are simple and 
small. For example, FDA recommends that for pulse oximeters--medical 
devices that indirectly monitor the oxygen saturation of a patient's 
blood--clinical data be collected from as few as 10 patients. In 
addition, for establishing clinical data in support of a 510(k) 
application, the Agency recognizes a standard set by the Association 
for the Advancement of Medical Instrumentation, which requires a 
validation study consisting of as few as 35 subjects for which clinical 
data are required. Consistent with statutory requirements, all PMAs 
contain clinical data.
    The Agency has no data to suggest that, as a general matter, FDA 
has demanded larger, more extensive clinical trials in the past 5 years 
for 510(k)s or PMAs. Clinical studies are tailored to the type of 
device and the specific questions that need to be addressed. That is 
not to say that FDA demands full knowledge and understanding of long-
term risks and performance before it will approve a device for 
marketing. For PMA devices, the Agency increasingly uses its authority 
to require post-approval studies to answer important, specific 
questions regarding device performance after the device has been 
approved for marketing. For example, if there are questions about long-
term durability of an implanted device, the Agency may allow the device 
to be marketed while further data collection continues to address that 
issue.
    Whenever possible, FDA seeks to minimize clinical trial or 
preclinical requirements when scientific knowledge suggests that this 
is appropriate. For example, establishing the safety and effectiveness 
of a first-generation drug eluting stent (DES) required extensive 
preclinical testing programs and clinical studies. However, the 
fundamental work performed to gain initial approval of first-generation 
DES devices has been successfully leveraged by several DES 
manufacturers to decrease clinical trial requirements for next-
generation stents, which typically incorporate modest changes to the 
first-generation design.
    More specifically, FDA reviewers concluded that a single-arm 
clinical trial (rather than a randomized controlled study) would be an 
acceptable design for the pivotal IDE trials of the Boston Scientific 
TAXUS LiberteTM, Abbott XIENCE PrimeTM, and 
Medtronic Resolute next-generation DES. The reason CDRH permitted this 
approach is that these devices represent iterations of prior DES, in 
which a component of the combination product has been modified (e.g., a 
polymer coating or stent platform). This was acceptable based on our 
analysis of the comprehensive preclinical and clinical data generated 
from the prior generation DES, and demonstrates the Agency's 
flexibility and willingness to tailor data requirements when 
appropriate.
    Another example is the total artificial hip. CeramTec purchased the 
rights to the Wright Medical TRANSCEND ceramic-on-ceramic total 
artificial hip clinical data set and approved PMA. Because the 
articulating surfaces of the components are all manufactured by 
CeramTec, FDA allowed manufacturers to use preclinical testing to 
leverage the Wright Medical TRANSCEND data set. Five manufacturers had 
their PMAs approved referencing the TRANSCEND clinical data set with a 
condition of approval to conduct a post-approval study in a new cohort 
of patients.
    This sometimes works in the other direction, too, in that 
information gleaned from competitor application reviews and post-market 
studies may bring to light information that changes the risk-benefit 
analysis and causes the Agency to look more critically at the next 
submission in a product category. This is appropriate. The reasons for 
it cannot always be shared with applicants due to statutory 
confidentiality requirements, possibly causing the Agency to appear 
arbitrary.
    Under the 510(k) Action Plan, we have established an internal 
Center Science Council (Council) to actively monitor the quality and 
performance of the Center's scientific programs and ensure consistency 
and predictability in CDRH scientific decisionmaking. The Council, 
which is comprised of experienced managers and employees, operates 
under the direction of the Deputy Center Director for Science and is 
responsible for overseeing science-based decisionmaking across CDRH, 
including premarket review; periodically auditing decisions and 
assessing program performance; and acting as a resource for staff on 
scientific questions, to support greater consistency in decisionmaking 
and the treatment of cross-cutting issues. We are also creating a 
network of experts to help CDRH resolve complex scientific issues. This 
network will be especially helpful as FDA confronts new technologies. 
And we are instituting a mandatory Reviewer Certification Program for 
new reviewers, as detailed in our answer to question #4.

    Question 6. Last week, the FDA released a report called the 
``Analysis of Premarket Review Times under the 510(k) Program.'' In 
reviewing this report, I am curious about the FDA's conclusion that in 
the Premarket Review Time analysis that poor quality submissions are 
the major cause of the increased review times for 510(k) submissions. 
Is the FDA implying that the medical device industry has universally 
forgotten how to submit a good, quality application? Could another 
explanation be that application process has become less predictable, 
more risk averse, and therefore, is requiring more data and information 
in 510(k) submissions than it has in the past?
    Answer 6. FDA's standards for the review of medical devices are 
specified in statute and our application of those standards has not 
changed.
    Application quality has always varied and the Agency has 
consistently strived to help device manufacturers, many of which are 
small companies, through a sometimes unfamiliar process, rather than 
refuse deficient applications. Since the advent of MDUFA, the time cost 
associated with that extra assistance has taken on added significance.
    The study cited in your question--which is available on FDA's Web 
site at: http:// www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHReports/
ucm263385
.htm--showed that poor submission quality and sponsors' failure to 
address deficiencies identified in first-round AI Letters are major 
contributors to the increase in total review times. We are pleased 
that, in response to FDA calls for improving the quality of premarket 
submissions, the medical device trade association, AdvaMed, has 
improved and made available more training courses for its companies to 
help them develop 510(k) and PMA submissions that meet FDA standards.
    We also recognize our role in this and are taking steps to address 
it. The two reports we released publicly in August 2010, with our 
analyses and recommendations, showed that we had not done as good a job 
managing our premarket review programs as we should and that we need to 
take several critical actions to improve the predictability, 
consistency, and transparency of these programs.
    In January 2011, FDA announced a Plan of Action that included 25 
specific actions that we would take this year to improve the 
predictability, consistency, and transparency of our premarket 
programs. The following month, we announced our Innovation Initiative, 
which included several proposals to help maintain the position of the 
United States as the world's leader in medical device innovation, 
including the creation of a new approach for important, new 
technologies called the Innovation Pathway. For details on specific 
activities, please see our response to question #4.

    Question 7. The Analysis of Premarket Review Times under the 510(k) 
Program, released last week, states that,

          ``FDA develops guidance documents and recognizes standards 
        established by national and international standards development 
        organizations to provide greater predictability, consistency 
        and transparency in our premarket review programs.''

    Yet, I along with my colleagues keep hearing from companies in our 
States that just the opposite is occurring specifically, we hear that 
the goal posts keep being moved. Additional Information (AI) letters 
are issued requiring submitters to provide data that are above and 
beyond what is stated in the guidance documents, as well as other 
deviations from published guidance and standards. What is FDA doing to 
ensure that all guidance available to the public is up-to-date, and if 
not, that all data requirements not addressed in, or changed from, 
current guidance are consistently conveyed to industry prior to 
submission of a 510(k)?
    Answer 7. Developing and updating guidance documents is a resource-
intensive task, currently performed by the same professionals who 
review device applications. Additional resources devoted to guidance 
development are necessary to optimize this function. Nevertheless, we 
are taking steps to improve the guidance development process through 
the 510(k) Action Plan \16\ and have stepped up development of specific 
guidance documents that will make the review process more predictable, 
consistent, and transparent. Examples include streamlining de novo 
classification, clarifying when changes to a device require a 
510(k),\17\ and improving the quality of clinical trials.\18\
---------------------------------------------------------------------------
    \16\ CDRH, ``Plan of Action for Implementation of 510(k) and 
Science Recommendations'' (January 2011), available at http://
www.fda.gov/downloads/AboutFDA/CentersOffices/CDRH/CDRHReports/
UCM239450.pdf.
    \17\ CDRH, ``Draft Guidance for Industry and FDA Staff--510(k) 
Device Modifications: Deciding When to Submit a 510(k) for a Change to 
an Existing Device'' (July 2011), available at http://www.fda.gov / 
MedicalDevices / DeviceRegulationand Guidance/GuidanceDocuments/
ucm265274
.htm.
    \18\ CDRH, Draft Guidance for Industry, Clinical Investigators, and 
Food and Drug Administration Staff--Design Considerations for Pivotal 
Clinical Investigations for Medical Devices'' (August 2011), available 
at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/ucm265553.htm.
---------------------------------------------------------------------------
    The study that you reference \19\ showed that reviewers do not 
often ask for data inappropriately. Results of first round AI Letters 
in Cohort 1 showed that reviewers asked for data that had not 
previously been requested for particular device types only 12 percent 
of the time. Of those requests, 8 percent were inappropriate. Results 
of second round AI Letters in Cohort 2 showed that reviewers asked for 
data that had not been previously requested 4 percent of the time. Of 
those requests, 2 percent were inappropriate.
---------------------------------------------------------------------------
    \19\ CDRH, ``Analysis of Premarket Review Times Under the 510(k) 
Program'' (July 2011), available at http://www.fda.gov/AboutFDA/
CentersOffices/CDRH/CDRHReports/ucm263385.htm.
---------------------------------------------------------------------------
    This analysis shows that poor submission quality and sponsors' 
failure to address deficiencies identified in first-round AI Letters 
are major contributors to the increase in total review times. For 
example, 65 percent of the time FDA sent a second-round Al Letter 
because the sponsor failed to submit information requested in the first 
Al Letter. However, FDA has also contributed to the increase by making 
inappropriate requests for additional information in limited instances.
    FDA will continue to work with industry to identify additional 
actions to reduce the average number of review cycles and the percent 
of 510(k) submissions for which an AI Letter is sent. FDA has already 
taken steps to address some of the issues identified in this analysis. 
We are working to provide greater predictability for industry by 
communicating justified changes in data requirements more quickly and 
transparently. We recently issued a draft Standard Operating Procedure 
for ``Notice to Industry'' Letters,\20\ which provides a format for 
communicating changes expeditiously within the existing Good Guidance 
Practices framework. FDA is also enhancing training for FDA staff and 
industry, which is aimed at reducing inappropriate requests for 
additional information and helping sponsors understand when they are 
required to submit data.
---------------------------------------------------------------------------
    \20\ CDRH, ``Standard Operating Procedure for `Notice to Industry' 
Letters'' (August 2011), available at http://www.fda.gov/downloads/
MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/
UCM259172.pdf.
---------------------------------------------------------------------------
    Through these and other steps we are taking to address weaknesses 
in the 510(k) program, FDA aims to reduce the amount of time to 
clearance for 510(k) devices, while ensuring that we maintain the same 
standards of safety and effectiveness. It is our hope that taking 
actions to increase submission quality and avoid inappropriate requests 
for additional information will prevent avoidable delays and reduce 
review times, which will, in turn, get safe and effective devices to 
market faster.

    Question 8. I'm concerned about what appears to be a lack of 
urgency on the part of FDA with respect to newer, better therapies to 
treat diabetes and obesity. These are diseases that increasingly 
threaten our Nation's health care system--diabetes alone accounts for 
one-third of Medicare costs and almost 80 million Americans have pre-
diabetes (on top of the 25.8 million Americans already living with the 
disease).
    My home State of Tennessee has one of the highest obesity rates at 
being over 30 percent, and obesity is nearing epidemic proportions 
across the country. We are at a time in our history where reports by 
distinguished journals of medicine and health experts say today's 
children are likely to be the first generation to live shorter, less 
healthy lives than their parents. This is a health care crisis. One of 
the biggest reasons for this is the growing childhood obesity problem, 
and the increasing rates of diseases normally associated with adults 
such as Type 2 diabetes, heart disease, and other chronic illnesses.
    What are you doing to encourage the development of new therapies to 
treat these diseases? Are you considering using the authority given to 
the FDA under REMS to follow the drugs closely after approval?
    It's essential that we take strong steps to prevent the spread of 
diabetes through better nutrition and physical fitness, but we must 
also encourage innovation of better therapies to treat diabetes and 
obesity. What are you doing to support that needed innovation?
    Answer 8. FDA recognizes the rising incidence of diabetes in the 
United States and the need for innovative therapies to treat this 
chronic condition. We currently have 11 different drug classes to treat 
Type 2 diabetes, and many of these newer therapies became available 
within the past 5 to 7 years, despite the withdrawal of troglitazone in 
1999 for liver toxicity and the cardiovascular safety concerns of 
rosiglitazone presented at two public meetings in 2007 and 2010.
    These safety concerns serve as a reminder that while the goal is to 
ensure effective treatments for diabetes to the American public, these 
therapies must be carefully studied to ensure that side effects do not 
outweigh the benefits of blood sugar control, especially when 
physicians and patients have many classes of drugs from which to 
choose. For this reason, FDA held a 2-day public advisory committee 
meeting in July 2008 to seek scientific advice on the design of 
diabetes drug development programs to evaluate the cardiovascular 
safety of these drugs. In December 2008, a Guidance for Industry was 
published, outlining FDA's requirements for new anti-diabetic 
therapies: ``Diabetes Mellitus--Evaluating Cardiovascular Risk in New 
Anti-diabetic Therapies to Treat Type 2 Diabetes.''
    The Guidance calls for more extensive evaluation of new anti-
diabetic therapies to help to ensure that these therapies are safe and 
effective. However, to avoid delay in approving innovative therapies, 
FDA has employed new authorities under the FDA Amendments Act of 2007 
FDAAA and required companies to collect such data through post-
marketing studies. Since December 2008, FDA has approved four new drugs 
for the treatment of Type 2 diabetes.
    Similarly, we recognize that obesity poses a serious public health 
problem to this country. In 2007, FDA issued a draft guidance document 
for industry entitled ``Developing Products for Weight Management.'' 
FDA is committed to working with pharmaceutical companies to bring new 
obesity drugs with favorable benefit-risk profiles to the market, but 
obesity has been a difficult area in which to develop drugs with 
favorable benefit-to-risk profiles. Two obesity drugs and one dietary 
supplement have been withdrawn from the market because they increased 
blood pressure and, in the case of the two obesity drugs, were 
documented to increase the incidence of stroke and/or heart attacks. 
FDA took another class of obesity drugs off the market because they 
increased the risk for heart valve disease, in some cases, requiring 
patients to have open heart surgery to replace their damaged valve. An 
additional drug to treat obesity that was recently approved by the 
European Medicines Agency (EMA), but not by FDA, was later withdrawn 
from the European market due to an increased risk of suicide. We must 
make sure that any new products to treat obesity are safe, while taking 
into account the public health impact of obesity.
    FDA is planning a scientific meeting to discuss obesity drugs and 
cardiovascular safety, and we are also planning to attend stakeholder 
meetings involving pharmaceutical companies, patient advocacy groups, 
and obesity experts to discuss development of obesity drugs. We expect 
these meetings to be very helpful to industry in developing drug 
products to treat obesity.
    As FDA evaluates new drugs for the treatment of obesity, we will 
carefully consider the role of Risk Evaluation and Mitigation 
Strategies (REMS) and required post-marketing studies to ensure that 
the benefits of the drug outweigh its risks.

    Question 9. In the last PDUFA bill (FDAAA), the critical path 
partnerships were authorized and FDA has awarded collaborative 
agreements to several entities. It is my understanding that one of 
these collaborations has made it possible for the industry to share 
their data from clinical trials for Alzheimer's disease. From FDA's 
perspective, what has been learned and will other disease databases 
result from this work?
    Answer 9. One of the greatest challenges facing biomedical sciences 
in the 21st century is the development of better treatments for 
neurodegenerative diseases. The two most prevalent of these, 
Alzheimer's disease and Parkinson's disease, exert a heavy and growing 
burden on our society. Our lack of knowledge about the specific cause 
or causes of either disease is a major obstacle to the development of 
new treatments that have the potential to cure or prevent these 
devastating and tragic diseases.
    The Coalition Against Major Diseases (CAMD) was formed by the non-
profit Critical Path Institute, in cooperation with FDA, patient 
organizations, the medical products industry, and the Engelberg Center 
for Health Care Reform at the Brookings Institution. CAMD's focus is to 
develop new tools and methods that can be applied during the 
development of new treatments for neurodegenerative diseases, focusing 
on Alzheimer's and Parkinson's first. In CAMD, data integration and 
sharing are planned to create a quantitative disease-progression model 
that includes biomarkers that potentially identify discrete patient 
subsets of the disease. CAMD, working with the Clinical Data 
Interchange Standards Consortium, has developed and published data 
standards for Alzheimer's clinical trials. CAMD has been able to pool 
data from 11 clinical trials conducted by seven pharmaceutical 
companies into an Alzheimer's disease database that describes the 
natural history of the disease in over 4,000 patients. This database, 
along with the mathematical models of the disease available to 
researchers in the field, will allow clinical investigators to more 
accurately predict the outcome for a given clinical trial, the length 
of time needed for the trial, how many patients should be enrolled in 
the trial, and how genetic subsets of the population might respond. 
Hopefully, CAMD efforts will help reduce the failures in development of 
new drugs for Alzheimer's and will be a model for the establishment of 
other disease databases.

    Question 10. The EU has made a significant long-term commitment to 
advancing the science that supports drug development with the goal of 
increasing investment and productivity for the biotech industry in 
Europe. I understand that they committed 1 billion euros and the 
industry is matching it with in kind contributions. They proclaim that 
this is the largest public private partnership in the world. What can 
the United States do to protect its investment in biotechnology? In 
this country, is the industry actively participating in the critical 
path public-private partnerships? Can we do more to encourage their 
participation?
    Answer 10. Yes. Industry is participating in Critical Path and 
other public-private partnerships, but there is much more we can do. 
Government investment in regulatory science, combined with FDA-driven 
policy approaches to promote medical product innovation, are critical 
to maintain U.S. competitiveness in an increasingly globalized market.
    The closest counterpart to the European IMI is the Critical Path 
Initiative, which is currently funded at a level of $18 million 
annually. FDA's new Regulatory Science Initiative seeks to build on the 
Critical Path program by expanding awareness and laying out a strategy 
for making investments in key applied scientific areas that will 
facilitate increasing innovation and safer and more efficacious medical 
products. In addition, the Regulatory Science Initiative addresses the 
entire product lifespan, from preclinical through post-market, 
including assessment of real-world performance of drugs, patient 
utilization and communication, and outcomes.
    On October 5, 2011, FDA released a blueprint to lay out key policy 
suggestions that, in conjunction with regulatory science investments, 
will drive medical product innovation. The goal is to enhance both the 
health of the American people and the health of the medical product 
industry, a key component of our technology sector, and an area where 
the United States still leads in innovation and creativity.
    Public-private partnerships between FDA, other government agencies, 
industry, and academia are a central component of both our innovation 
and regulatory science strategies. But government investments in the 
form of dollars and sound cross-agency collaborations and policies must 
be made to maintain U.S. leadership in the biotechnology sector. In our 
extensive discussions with business leaders from both large and small 
medical product development companies, it is clear that companies want 
to collaborate and will invest in these important areas, both in 
dollars and through partnering--if they see a significant and sustained 
commitment from the U.S. government to support the infrastructure, 
science, and policies that create an environment poised for innovation 
and global competitiveness.
    In 2007, Congress created the Reagan-Udall Foundation as a vehicle 
for public-private partnerships in regulatory science. The Foundation 
has been able to initiate a few regulatory science partnerships, but 
absent the funding support initially contemplated has not been able to 
build a robust scientific program.

    Question 11. One area of focus in the PDUFA V proposal is on 
advancing Regulatory science, specifically, as stated by the Agency, 
Enhancing Regulatory Science and Expediting Drug Development. What 
process will you use to set priorities for how to enhance regulatory 
science? Will the industry and patients have voices in setting these 
priorities?
    Answer 11. FDA is recommending a set of specific review program 
enhancements that will strengthen the science and expedite drug 
development as part of the PDUFA V recommendations. Under PDUFA V FDA 
would commit to accomplish all of these enhancements and not prioritize 
among them. These PDUFA V recommendations are the product of FDA's 
extensive negotiations with industry and parallel consultations with 
patients and other stakeholders from April 2010 through May 2011 and 
reflect the priorities identified by these groups. The initiatives 
included in these recommendations are directly related to areas where 
specific near-term advances can be made to reduce the scientific 
uncertainty, business risk, and in some cases reduce the time and other 
resources required for new drug development.
    These enhancements include:

    1. Promoting Innovation Through Enhanced Communication Between FDA 
and Sponsors During Drug Development;
    2. Methods for meta-analysis;
    3. Biomarkers and pharmacogenomics;
    4. Use of patient-reported outcomes (PROs); and
    5. Development of drugs for rare diseases.

    As stated below, each of these addresses specific challenges with 
the current drug development and review processes.

    1. Promoting innovation through enhanced communication between FDA 
and sponsors during drug development:

     Problem: New drug innovators operate at the cutting edge 
of science but may have less experience with FDA regulatory 
requirements to ensure substantial evidence of safety and efficacy. 
Timely communication between FDA and sponsors during development helps 
to ensure efficient and effective drug development, and also helps 
achieve FDA's mission by making safe and effective new drugs available 
in a timely manner.
     Proposed Recommendation: FDA will develop a dedicated drug 
development communication and training staff in CDER and CBER, focused 
on enhancing communication between FDA and sponsors during development. 
The liaison staff will conduct a range of tasks including 
identification and dissemination of best practices for enhanced 
communication and development of training programs for review staff. 
FDA will publish a guidance describing its philosophy on timely 
interactive communications and the scope of appropriate interactions 
with sponsors during drug development.

    Methods for meta-analysis:

     Problem: Currently, there is no consensus on best 
practices in conducting a meta-analysis. FDA is often forced to 
evaluate meta-analyses of published or unpublished clinical trials, 
usually addressing a high visibility safety problem for an approved 
product. Review and evaluation of a meta-analysis, sometimes conducting 
the Agency's own meta-analysis, can exceed FDA's current scientific and 
computational capacity.
     Proposed Recommendations: FDA will develop a dedicated 
review team to evaluate scientific methods, limitations in the methods, 
and potential best practices for the conduct of meta-analyses. FDA will 
also hold a public meeting on the current and emerging approaches to 
meta-analyses, and develop guidance on FDA's intended approach to meta-
analysis in the regulatory review process and in regulatory 
decisionmaking.

    3. Biomarkers and pharmacogenomics:

     Problem: Pharmacogenomics and the application of qualified 
biomarkers have the potential to decrease drug development time. 
Qualified biomarkers can enrich clinical trials by demonstrating 
benefits, establishing unmet medical needs, and identifying patients 
with a predisposition to adverse events, and regulatory submissions of 
this type have increased recently, outstripping FDA capacity for 
review.
     Proposed Recommendations: FDA will increase clinical, 
clinical pharmacology, and statistical capacity to adequately address 
submissions that propose to utilize biomarkers or pharmacogenomic 
markers in development programs. FDA will hold a public meeting to 
discuss potential strategies to facilitate scientific exchanges in 
regulatory and non-regulatory contexts.

    4. Use of patient-reported outcomes (PROs):

     Problem: Study endpoint assessments are increasingly an 
important part of successful drug development, requiring rigorous 
evaluation and statistical design and analysis. However, there is a 
high study-failure rate for PRO endpoints not qualified in advance of 
phase 3 trials. Early consultation could ensure that endpoints are 
well-defined and reliable.
     Proposed Recommendations: FDA will enhance clinical and 
statistical capacity to address submissions involving PROs and other 
endpoint assessment tools, including providing IND consultation, and 
will convene a public meeting to discuss PRO qualification standards, 
new endpoint measurement theory, and implications for multinational 
trials.

    Development of drugs for rare diseases:

     Problem: Regulatory oversight of rare disease drug 
development is complex and resource intensive. Recent trends in orphan 
designations may indicate an expected future increase in 
investigational activity and marketing applications for orphan 
products.
     Proposed Recommendations: FDA will develop guidance 
related to advancing and facilitating development of drugs for rare 
diseases, increase outreach to patient representatives and industry 
regarding development of these drugs, convene a public meeting to 
discuss complex issues in clinical trials for studying drugs for rare 
diseases, and develop and implement training for all review staff on 
development and review of drugs for rare diseases as part of the core 
reviewer curriculum.

    In August 2011, FDA released its Strategic Plan for Regulatory 
Science. The strategic plan describes the Agency's intent to 
collaboratively enhance the process for developing and evaluating 
promising new products and defines the Agency's highest cross-cutting 
priorities linking to several themes contained in a report from CDER as 
well as other reports across the Agency.
    CDER released its draft report entitled ``Identifying CDER's 
Science and Research Needs'' in July 2011. This report is an essential 
first step to formulating regulatory science priorities, which will 
guide development of a CDER regulatory science and research agenda. 
Release of the Science and Research Needs Report is the culmination of 
an exhaustive process that started with interviews of over 200 
reviewers and scientists from across CDER--those who are closest to the 
regulatory processes and the regulatory science needed to support those 
processes. The comprehensive report on regulatory science and research 
needs was compiled from these discussions.
    We have opened a docket to solicit critical input from our external 
stakeholders in industry, academia, and patient organizations, and our 
governmental partners, on CDER's draft report ``identifying CDER's 
Science and Research Needs,'' and to solicit input on additional 
critical science needs, ongoing efforts to address them, and creative 
mechanisms for collaboration. Further, we will be continuing to ask our 
reviewers for input and are making the identification of critical 
regulatory science challenges an ongoing process. We have provided our 
reviewers and scientists a direct route to comment on our science needs 
document and to add new challenges. This mechanism for horizon scanning 
will provide an ongoing system to identify emerging regulatory science 
issues. While we compile external and internal comments, we will be 
examining our current regulatory science and research portfolio to 
identify areas where progress is being made and to identify critical 
gaps that are not being adequately addressed.

    Question 12. Patient response and satisfaction with treatment is an 
area that often is left out of our discussions yet new medicines should 
keep patient benefit front and center. I understand that the Critical 
Path Institute is the Agency's partner working with the industry to 
develop standardized, validated questionnaires and electronic diaries 
to be used in testing new drugs and devices. How many Agency scientists 
are working with them and would more resources and FTE speed up this 
important work?
    Answer 12. Study endpoint assessments, known as patient-reported 
outcomes (PROs), are an important part of successful drug development. 
PROs are critical in understanding the drug benefits and harm from the 
patients' perspectives. However, PROs, like other outcome assessments, 
require rigorous development to ensure validity and reliability to 
support claims of clinical benefit.
    Early consultation between FDA and outcome assessment developers 
can ensure that endpoints are well-defined and reliable. In addition to 
the Critical Path Institute, FDA is working with several other public 
and private partners, including the Foundation for the National 
Institutes of Health and individual NIH institutes to develop 
standardized questionnaires, clinician assessments, and electronic 
diaries under the qualification pathway. Qualification is the 
regulatory conclusion that within the stated context of use, the 
results of assessment with a particular tool can be relied upon to have 
a specific interpretation and application in drug development and 
regulatory decisionmaking and labeling. Outcome assessments that 
undergo qualification will be publicly available, eliminating the need 
for multiple drug sponsors to repeat this critical work. Therefore, 
these activities promise to make medical product development and 
clinical trials more informative and efficient.
    A dedicated FDA staff provides review for PRO measures, not only 
under the qualification pathway (e.g., with the Critical Path 
Initiative), but also in the context of specific investigational drugs. 
Therefore, the number of full-time employees (FTEs) currently dedicated 
to this work is difficult to calculate. It is clear, however, that the 
Agency does not have the capacity to meet the current demand for both 
of these review processes. In CDER, the primary review team for PRO 
measures and other clinical assessment tools includes a total of seven 
individuals, including the director and a temporary fellow. The team 
reviews the tools in conjunction with the clinical reviewers in the 
Office of New Drugs (OND) and also provides consultation and advice to 
the submitters.
    FDA recently announced its proposed recommendations for PDUFA V. We 
propose several measures to enhance regulatory science and expedite 
drug development, including a proposal to increase clinical and 
statistical staff capacity to more efficiently and effectively respond 
to submissions that involve PROs and other outcome assessment tools. We 
also propose a public meeting to discuss FDA's qualification standards 
for development tools, new measurement theory, and implications for 
multi-national trials.
                              senator burr
    Question 1. For each of the FDAAA review performance goals, what 
was the average length of response time for the Agency? What was the 
average length of response times that did not fall within the 
performance goals?
    Answer 1. Under performance timelines associated with PDUFA IV, 
which was enacted as part of the FDA Amendments Act of 2007 (FDAAA), 
FDA has committed to review and act on 90 percent of original New Drug 
Applications (NDAs) and Biologics License Applications (BLAs) \21\ 
within 10 months of receipt for standard applications and 6 months for 
priority-designated applications.\22\ The performance level of 90 
percent was chosen in acknowledgement of the fact that in some cases it 
is appropriate that FDA continue its review of an application past the 
goal date to address important outstanding issues. In fact, in some 
cases FDA continues its review past the PDUFA goal date to address 
remaining issues so that the application can be approved on that review 
cycle and thus avoid the need for a second review cycle that would be 
triggered by issuance of a complete response letter by the PDUFA goal 
date. This can allow a drug to be available to patients in a more 
timely manner while allowing the Agency to still meet its 90 percent 
goal for actions.
---------------------------------------------------------------------------
    \21\ Note that FDA relied on data captured by PDUFA and MDUFA 
reporting requirements to provide these responses. Therefore, they do 
not include data on applications reviewed by the Agency that are not 
subject to user fees.
    \22\ It should be noted that a review action does not imply 
application approval. NDAs and BLAs submitted for FDA review may 
receive a complete response that does not allow marketing approval, but 
identifies the application deficiencies that would need to be addressed 
in order to obtain marketing approval.
---------------------------------------------------------------------------
    As of March 31, 2011, FDA's average review time for priority NDAs 
and BLAs filed in fiscal year 2010 and reaching a regulatory action is 
approximately 6.6 months,\23\ compared with 5.8 months for priority 
applications filed in fiscal year 2006. As of March 31, 2010, the 
average review time to regulatory action for standard original NDAs and 
BLAs filed in fiscal year 2010 is 10.3 months,\24\ compared with 10.6 
months for standard applications filed in fiscal year 2006.
---------------------------------------------------------------------------
    \23\ FDA was able to meet its PDUFA goals 100 percent of the time, 
even though the review time on average is 6.6 months, because the 
Agency may extend goal dates by 3 months when the sponsor submits a 
major application amendment within 3 months of the goal due date. 
Therefore, some priority goats may be extended to 9 months, resulting 
in the higher average,
    \24\ This number reflects the average review time for standard 
applications as of March 31, 2011, and final performance can be 
expected to change slightly, given that 25 percent of fiscal year 2010 
standard implications were still pending within goal as of this date.
---------------------------------------------------------------------------
    We are pleased to report that as of March 31, 2011, for 
applications received in fiscal year 2010, FDA has met its PDUFA review 
goals 100 percent of the time for priority applications and 97 percent 
of the time for standard applications, with 5 percent of priority 
applications and 25 percent of standard applications still pending FDA 
review, all within their PDUFA goal.\25\
---------------------------------------------------------------------------
    \25\ For more information on PDUFA performance, see the 2010 report 
to Congress: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/
Reports/UserFeeReports/Perform
anceReports/PDUFA/UCM243358.pdf. Please note that the data as of March 
31, 2011, may differ from the figures in the Performance Report, which 
reflect more current data as of September 30, 2010.
---------------------------------------------------------------------------
    It is important to note that the PDUFA goal for an application may 
be extended by up to 3 months if the sponsor submits a major amendment 
(e.g., a new clinical study report) during the last 3 months of review. 
If FDA completes its review and issues its action on or before the 
extended goal date, this is counted as having met the PDUFA goal even 
though the overall time required for the review may be 9 months 
(priority) or 13 months (standard). This provision is included in the 
PDUFA performance goals to avoid an unnecessary second cycle of review 
in cases where the clock extension can allow FDA to complete its review 
of the major amendment and approve the application in that review 
cycle. This explains why the average review time for a cohort of 
applications can be greater than 6 (priority) or 10 (standard) months, 
even if all the applications in the cohort are acted on or before their 
PDUFA goal date.

    Question 2. Since 1993, among all regulatory actions that count as 
meeting PDUFA performance goals, what percentage were:

    a. Approvals?
    b. Not approved?
    c. ``Complete Response'' letters?

    Answer 2. For all original applications \26\ filed and action taken 
within PDUFA performance goals by FDA from fiscal year 1993 through 
fiscal year 2011, as of July 2011, 74 percent of the products have 
received Approval actions,\27\ which include Approval and Tentative 
Approval, and 26 percent of the products have only received Non 
Approval actions, which include Not Approvable, Approvable, Withdrawn 
after filing, and Complete Response.
---------------------------------------------------------------------------
    \26\ This response assumes that the term ``original applications'' 
is defined as original Filed NDAs and BLAs as well as resubmissions. 
This does not include supplements.
    \27\ We define the Approval-Non Approval determination on the 
current status, as applications currently with a Non Approval action 
can still be approved in the future.
---------------------------------------------------------------------------
    It should be noted that as of August 2008, FDA replaced the 
``Approvable'' regulatory action and the ``Not Approvable'' regulatory 
action with the ``Complete Response'' regulatory action. We cannot 
distinguish between ``Not Approved'' and ``Complete Response'' as 
questioned and so we compared products that have received Approval 
actions compared to products that have not received Approval actions. 
Since every review cycle requires a regulatory action, any application 
that has not received an Approval action has received a Non Approval 
action.

    Question 3. If the Agency did not count ``complete response'' 
letters, or ``approvable'' or ``not approvable'' responses towards the 
performance goals, how would the reported performance goals since 1993 
be adjusted? In short, what percentage of the time does FDA complete 
its review of an application--approve or not approve--during the first 
review cycle?
    Answer 3. Each review cycle requires a regulatory action. Approval 
actions include Approval and Tentative Approval, and Non Approval 
actions include Not Approvable, Approvable, Withdrawn after filing, and 
Complete Response.\28\ Thus, the answer to this question is the same as 
above.
---------------------------------------------------------------------------
    \28\ As stated above, in August 2008. FDA replaced the 
``Approvable'' regulatory action and the ``Not Approvable'' regulatory 
action with the ``Complete Response'' regulatory action.

    Question 4. With respect to pre-market applications, of the device 
PMAs acted upon by the FDA and counted towards the reported user fee 
performance goals, what percentage of the reported performance goals 
---------------------------------------------------------------------------
were:

    a. Approvals?
    b. Approvables?
    c. Not Approvables?
    d. Denials?
    e. Withdrawn applications?

    Answer 4. [Note: Numbers were rounded; therefore percentages don't 
always equal 100.]


------------------------------------------------------------------------
                                Fiscal     Fiscal     Fiscal     Fiscal
                              year 2008  year 2009  year 2010  year 2011
                                  [in        [in        [in        [in
                               percent]   percent]   percent]   percent]
------------------------------------------------------------------------
PMA Orig. & Panel (non-
 expedited):
  Approvals.................         36         16         36         56
  Approvables...............         18         27         28         22
  Not Approvables...........         27         30         33         22
  Denials...................          0          0          0          0
  Withdrawn.................         18         27          3          0
PMA Orig. & Panel
 (expedited):
  Approvals.................         25         25         75        100
  Approvables...............          0         25          0          0
  Not Approvables...........         75         25         25          0
  Denials...................          0          0          0          0
  Withdrawn.................          0         25          0          0
180-day Supplements:
  Approvals.................         71         71         54         75
  Approvables...............         13         12         12          3
  Not Approvables...........         16         15         30         12
  Denials...................          0          0          0          0
  Withdrawn.................          1          2          4         10
Real-Time Supplements:
  Approvals.................         89         88         75         84
  Approvables...............          1          1         13          5
  Not Approvables...........         10         11         12         11
  Denials...................          0          0          0          0
  Withdrawn.................          0          0          0          0
------------------------------------------------------------------------


    Question 5a, b, and c. With respect to 510(k) submissions, of the 
submissions acted upon by the FDA and counted towards the reported user 
fee performance goals, what percentage of the reported performance 
goals were:

    a. Substantially Equivalent determinations (clearance)?
    b. Not Substantially Equivalent determinations (denial of 
clearance)?
    c. Not Approvables?
    Answer 5a, b, and c. The following table shows the percentage of 
510(k) MDUFA decisions in each fiscal year that were substantially 
equivalent (SE) or not substantially equivalent (NSE). Only SE and NSE 
decisions are counted in the user fee performance goals.


------------------------------------------------------------------------
                                     Total # MDUFA
          Decision cohort               510(k)       SE  [in    NSE  [in
                                       decisions     percent]   percent]
------------------------------------------------------------------------
Fiscal year 2008..................           3,669         83          4
Fiscal year 2009..................           3,829         80          4
Fiscal year 2010..................           3,786         73          8
Fiscal year 2011..................           3,929         78          5
------------------------------------------------------------------------
[Note: Decision cohort was used in order to provide data as close to
  real-time as possible.]


    Question 6. For questions 4, and 5 above, how many approvals or 
clearances occurred on a first-cycle review?


----------------------------------------------------------------------------------------------------------------
                                                                    Fiscal      Fiscal      Fiscal      Fiscal
                1st Cycle PMA approval decisions                   year 2008   year 2009   year 2010   year 2011
----------------------------------------------------------------------------------------------------------------
PMA Orig & Panel (non-expedited)................................    12 (36%)     6 (16%)    13 (33%)     5 (56%)
PMA Orig & Panel (expedited)....................................     1 (25%)     1 (25%)     3 (75%)     1 (25%)
180-Day Supplements.............................................   114 (71%)   115 (71%)    71 (54%)    45 (75%)
Real-Time Supplements...........................................   215 (89%)   246 (88%)   192 (75%)   134 (84%)
----------------------------------------------------------------------------------------------------------------



---------------------------------------------------------------------------------------------------------------
                                                              Fiscal year  Fiscal year  Fiscal year  Fiscal year
                 1st Cycle PMA SE decisions                       2008         2009         2010         2011
----------------------------------------------------------------------------------------------------------------
510(k)......................................................  1,276 (41%)  1,076 (34%)    769 (27%)    674 (42%)
----------------------------------------------------------------------------------------------------------------
[Note: All receipt cohorts are still open--data will change; all data are as of 8/31/2011.]


    Question 7. Beginning in 1992 and for every year thereafter to 
present, please report on the average time for the review of a human 
drug application (NDAs, BLAs, and supplements). For the same time 
period, please report on the percentage of human drug applications 
approved on a first cycle review.
    Answer 7. Please see the chart attached as Appendix 1. PDUFA was 
first enacted in 1992, and 1993 represents the first year we reported 
data. Thus, we have provided data from 1993 to present.

    Question 8. Has the increase in user fees in MDUFA II translated 
into more timely or faster review periods? Has the increase in user 
fees in MDUFA II resulted in an increase in the number of FDA-approved 
or cleared products for patients? Has the increase in fees resulted in 
fewer review cycles per submission compared to previous user fee 
agreements?
    Before addressing the performance issues raised in this question, 
it is important to note the context for the increase in user fees that 
took place as a result of the enactment of MDUFA II in 2007. Those user 
fee increases were intended to cover the anticipated increase in the 
cost of maintaining FDA device review staffing levels that were 
achieved at the end of MDUFA I, which FDA believed would be sufficient 
to meet the performance goals regarding timely decisionmaking. The 
increases were not intended to achieve any particular outcomes of those 
decisions, such as product approvals or clearances.
    The average review time for original PMAs and Panel Track 
Supplements (supplements for a new indication, which contain new 
clinical data) has improved from 11 months in fiscal year 2005 to 8 
months in fiscal year 2009 (Tier 1 goal: 60 percent of original PMAs 
and Panel Track Supplements in 180 days). This is a 42 percent decrease 
in days from 2005 to 2009.
    With respect to the Tier 2 goal for PMAs and Panel Track 
Supplements (90 percent in 295 days), there has been a 48 percent 
decrease in days from 2005 to 2009. These improvements are the result 
of more efficient submission management due to additional resources 
provided through MDUFA and process improvements implemented by FDA.
    Although FDA is meeting its 510(k) performance goals under MDUFA, 
overall time to decision (i.e., FDA review time plus industry response 
time) for 510(k) submissions has increased over the past 10 years, due 
primarily to an increase in the number of review cycles and in the 
amount of time companies take to respond to requests for additional 
information.
    We recognize our role in this and are taking steps to address it. 
The two reports we released publicly in August 2010, with our analyses 
and recommendations, showed that we have not done as good a job 
managing our pre-market review programs as we should and that we need 
to take several critical actions to improve the predictability, 
consistency, and transparency of these programs.
    For example, we have new reviewers who need better training. We 
need to improve management oversight and standard operating procedures. 
We need to provide greater clarity for our staff and for industry 
through guidance about key parts of our premarket review and clinical 
trial programs and how we make benefit-risk determinations. We need to 
provide greater clarity for industry through guidance and greater 
interactions about what we need from them to facilitate more efficient, 
predictable reviews. We need to make greater use of outside experts who 
understand cutting-edge technologies. And we need to find the means to 
handle the ever-increasing workload and reduce staff and manager 
turnover, which is almost double that of FDA's drugs and biologics 
centers.
    In January 2011, FDA announced a Plan of Action that included 25 
specific actions that we would take this year to improve the 
predictability, consistency, and transparency of our premarket 
programs. The following month, we announced our Innovation Initiative, 
which included several proposals to help maintain the position of the 
United States as the world's leader in medical device innovation, 
including the creation of a new approach for important, new 
technologies called the Innovation Pathway.
    Since then, we have announced additional efforts to improve our 
premarket programs, including actions to improve our program for 
clinical trials and the Investigational Device Exemption (IDE) program. 
The actions we are taking can be grouped into three main areas of 
emphasis:

     Create a culture change toward greater transparency, 
interaction, collaboration, and the appropriate balancing of benefits 
and risks;
     Ensure predictable and consistent recommendations, 
decisionmaking, and application of the least-burdensome principle; and
     Implement efficient processes and use of resources.

    Specific steps that we are taking, many of which are supported by 
industry, include:

     Issuing guidance clarifying the criteria used to make 
benefit-risk determinations a part of device premarket decisions to 
provide greater predictability and consistency and apply a more 
patient-centric approach by considering patients' tolerance for risk in 
appropriate cases (draft guidance issued August 15, 2011);
     Creating standard operating procedures for when a reviewer 
can request additional information regarding a premarket submission and 
at what management level the decision must be made to provide greater 
predictability, consistency, and the appropriate application of the 
least-burdensome principle by reducing the number of inappropriate 
information requests (Standard Operating Procedures issued November 
2011).
     Developing a range of updated and new guidances to clarify 
CDRH requirements for predictable, timely, and consistent product 
review, including device-specific guidance in several areas such as 
mobile applications (draft guidance released July 19, 2011) and 
artificial pancreas systems (to be completed by the end of 2011);
     Revamping the guidance development process through a new 
tracking system and, to the extent resources permit, core staff to 
oversee the timely drafting and clearance of documents (to be completed 
by the end of 2011);
     Improving communication between FDA and industry through 
enhancements to interactive review (some of these enhancements will be 
in place by the end of 2011);
     Streamlining the clinical trial and IDE processes by 
providing industry with guidance to clarify the criteria for approving 
clinical trials, and criteria for when a first-in-human study can be 
conducted earlier during device development to create incentives to 
bring new technologies to the United States first (guidance to be 
issued November 2011) (IDEs are required before device testing in 
humans that involve significant risks may begin, and they ensure that 
the rights of human subjects are protected while gathering data on the 
safety and efficacy of medical devices);
     Implementing internal business process improvements to 
ensure that decisions are made by the appropriate level of management, 
that decisions are made consistently and efficiently, and that we 
appropriately apply the least-burdensome principle. For example,
    CDRH created the internal Center Science Council to actively 
monitor the quality and performance of the Center's scientific programs 
and ensure consistency and predictability in CDRH scientific 
decisionmaking (Center Science Council established March 31, 2011);
     Creating a network of experts to help CDRH resolve complex 
scientific issues, which will ultimately result in more timely reviews. 
This network will be especially helpful as FDA confronts new 
technologies (Standard Operating Procedures issued September 30, 2011);
     Instituting a mandatory Reviewer Certification Program for 
new reviewers (program launched September 2011);
     Instituting a pilot Experiential Learning Program to 
provide review staff with real-world training experiences as they 
participate in visits to manufacturers, research, and health care 
facilities, and academia (to begin in early 2012);
     Providing industry with specific guidance on how to ensure 
the quality and performance of clinical trials while applying the 
least-burdensome principle, and thereby conduct studies that are more 
likely to support the approval of their products (guidance released 
August 15, 2011); and
     Streamlining the de novo review process, the pathway by 
which novel, lower-risk devices without a predicate can come to market 
(draft guidance released September 30, 2011).

    A recent FDA analysis \29\ shows that poor submission quality is a 
major contributor to the increase in total review times. The most 
common deficiencies included:
---------------------------------------------------------------------------
    \29\ CDRH, ``Analysis of Premarket Review Times Under the 510(k) 
Program'' (July 2011), available at http://www.fda.gov/AboutFDA/
CentersOffices/CDRH/CDRHReports/ucm263385.htm
#5.

     Inadequate device descriptions;
     Discrepancies throughout the submission;
     Failure to address necessary information as outlined in 
guidance documents;
     Problems with the proposed indications for use;
     Completely missing performance testing; and
     Completely missing clinical data.

    In addition, sponsors' failure to address deficiencies identified 
in first-round AI Letters is a major contributor to the increase in 
total review times. For example, 65 percent of the time, FDA sent a 
second-round AI Letter because the sponsor failed to submit information 
requested in the first AI Letter.
    FDA has already taken steps to address some of the issues 
identified in this analysis. We are working to provide greater 
predictability for industry by communicating justified changes in data 
requirements more quickly and transparently. We recently issued draft 
Standard Operating Procedures for Notice to Industry Letters,\30\ which 
provides a format for communicating changes more quickly within the 
existing Good Guidance Practices framework. FDA is also enhancing 
training for staff and industry, which is aimed at reducing 
inappropriate requests for additional information and helping sponsors 
understand when they are required to submit data. We will continue to 
work with industry to identify additional actions to reduce the average 
number of review cycles and the percent of 510(k) submissions for which 
an AI Letter is sent.
---------------------------------------------------------------------------
    \30\ CDRH, ``Standard Operating Procedure for `Notice to Industry' 
Letters'' (August 2011), available at http://www.fda.gov/downloads/
MedicalDevicesRegulationandGuidance/Guidance
Documents/UCM259172.pdf.
---------------------------------------------------------------------------
    Through these and other steps we are taking to address weaknesses 
in the 510(k) program, FDA aims to reduce the total time to clearance 
for 510(k) devices, while assuring that we maintain the same levels of 
safety and effectiveness. It is our hope that taking actions to 
increase submission quality and avoid inappropriate requests for 
additional information will prevent avoidable delays and reduce total 
time to decision, which will, in turn, get safe and effective devices 
to market faster.
    With regard to PMA applications, FDA's internal analysis found 
that, for those PMAs that were not reviewed within the performance 
goals, the main reasons for the longer review times were:

     Poor quality clinical studies, such as clinical trial 
execution issues and problematic data analyses;
     Reviewer turnover, especially changing medical officers 
and branch chiefs; and
     Taking a PMA to an FDA advisory committee. (In general, 
all PMAs for the first-of-a-kind device are taken before the 
appropriate advisory panel for review and recommendations. The 
preparation for an FDA advisory committee involves significant calendar 
time and review team resources.)

    Question 9. Beginning in 2007, and for every year thereafter, what 
percentage of products seeking to rely solely on foreign clinical trial 
data for approval have been approved without requiring any further 
clinical requirements, such as domestic clinical trials? Since 
enactment of FDAMA in 1997, how many products have been approved based 
just on foreign clinical trial data?
    Answer 9. We are unable to provide statistics in response to this 
question, as FDA does not track applications on the basis of the source 
of the clinical data.
    FDA does not require studies to support drug or device approvals to 
be conducted in the United States. Data collected from other countries 
can be used to support a product's safety and effectiveness. Foreign 
studies performed under an IND or IDE must meet the same requirements 
of 21 CFR part 312 or 21 CFR part 812, respectively, that apply to U.S. 
studies conducted under an IND or IDE. The acceptance of foreign 
clinical studies not conducted under an IND or IDE, as support for a 
marketing application, is generally governed by 21 CFR 312.120 and 21 
CFR 814.15.
    A marketing application based solely on foreign clinical data 
meeting U.S. criteria for marketing approval may be approved if:

     the foreign data are applicable to the U.S. population and 
U.S. medical practice;
     the studies have been performed by clinical investigators 
of recognized competence: and
     the data may be considered valid without the need for an 
on-site inspection by FDA or, if FDA considers such an inspection to be 
necessary, the Agency can validate the data through an on-site 
inspection or other appropriate means.

    The following are examples of drugs approved on the basis of 
foreign data:

     Eloxatin (oxaliplatin) for injection--was approved under 
FDA's accelerated approval regulations, based exclusively on foreign 
clinical data from trials conducted in Israel, Singapore, Australia, 
and 17 European countries.
     Aggrenox (aspirin/extended-release dipyridamole)--Capsules 
were approved based exclusively on foreign clinical data from trials 
conducted in 13 European countries.

    The following are examples of devices approved on the basis of 
foreign data:

     The FC2 Female Condom was approved using clinical data 
from investigations conducted in South Africa.
     The Boston Scientific Corp. Express LD Iliac Premounted 
Stent System was approved using clinical data generated from trials in 
the Netherlands, Belgium, 
the Czech Republic, Poland, and Canada. In an effort to ensure that FDA 
was open to the OUS (outside the United States) clinical data being 
used to support PMA 
approval, the sponsor had several pre-IDE, interactions with FDA. In 
these pre-
submission interactions, agreement was reached on the retrospective 
performance goal that would be applied to the study data. In addition, 
the review team worked interactively with the sponsor through a number 
of minor pre-clinical and clinical issues prior to submission of the 
PMA.

    Question 10. The Commissioner's testimony states that, ``FDA aims 
to review priority new molecular entities more quickly--6 months vs. 10 
months for standard drugs'' and that ``Priority NMEs represent truly 
innovative medicines generally targeted at severe illnesses with few or 
no available therapeutic options.'' Is the Agency meeting the 6-month 
and 10-month review targets for priority and standard NMEs? The 
testimony also states that the Agency is ``on track for approving a 
historically high percentage of priority NMEs for 2011.'' What is the 
percentage the Agency is on track to approve with respect to both 
priority and standard NMEs for 2011?
    Answer 10. As of March 31, 2011, for applications received in 
fiscal year 2010, FDA has met its PDUFA goals 100 percent of the time 
for priority applications and 97 percent of the time for standard 
applications, with 5 percent of priority applications and 25 percent of 
standard applications of these applications still pending FDA review, 
all within their PDUFA goal.\31\ This performance exceeds our goal to 
review and act on 90 percent of original NDAs and BLAs \32\ within 10 
months of receipt for standard applications and 6 months for priority-
designated applications.\33\
---------------------------------------------------------------------------
    \31\ For more information on PDUFA performance, see the 2010 report 
to Congress: http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/
Reports/UserFeeReports/PerformanceReports/PDUFA/UCM243358.pdf. Please 
note that the data as of March 31, 2011 may differ from the figures in 
the Performance Report, which reflect more current data as of September 
30, 2010.
    \32\ Note that FDA relied on data captured by PDUFA and MDUFA 
reporting requirements to provide these responses. Therefore, they do 
not include data on applications reviewed by the Agency that are not 
subject to user fees.
    \33\ It should be noted that a review action does not imply 
application approval. NDAs and BLAs submitted for FDA review may 
receive a Complete Response that does not allow marketing approval, but 
identifies the application deficiencies that would need to be addressed 
in order to obtain marketing approval.
---------------------------------------------------------------------------
    As of July 2011, of the six priority applications received and 
acted upon in fiscal year 2011, four of which were NMEs, all were 
approved. This number could increase as current pending priority NME 
applications mature to their review performance goal dates. It is 
premature to report on performance for fiscal year 2011 standard NME 
applications.

    Question 11. The Commissioner's testimony states that ``so far this 
year, FDA has approved 21 new, groundbreaking medicines . . . '' What 
percentage do these 21 medicines represent of the total applications 
submitted for review? What percentage do these 21 medicines represent 
of the total approvals for 2011?
    Answer 11. Approval figures in the response to this question are 
for calendar year (CY) 2011. As of July, there were 63 total Approvals, 
of which 21 were for NMEs/new BLAs. These NMEs/new BLAs represent 33 
percent of the total Approvals. These figures will change as additional 
applications are approved during the remaining months of CY 2011.
    FDA generally reports PDUFA performance in terms of cohorts of 
applications received in a given fiscal year. Because FDA is still 
receiving applications in CY 2011 and since there are still pending 
applications in the fiscal year 2011 cohort that are within their PDUFA 
goal date, it would be premature to otherwise assess program 
performance based on CY or fiscal year 2011 information. The most 
recent measure of program performance is contained in FDA's response to 
Question 12 below.

    Question 12. Please report on the total number of human drug 
applications (NDAs, BLAs, and supplements) received by FDA each year 
beginning in 2000 to present. Please report on the total number of 
applications approved on first cycle review and what percentage of 
total applications and total approvals they represent for each year.
    Answer 12. Please refer to the data in the tables below. Because 
the fiscal year 2011 cohort of applications has not yet matured (i.e., 
applications in this cohort are still pending and within their PDUFA 
goal date), FDA is reporting on the receipt cohorts from fiscal year 
2000 through fiscal year 2010. We have also provided the data by 
priority and standard applications as this is typically how FDA reports 
data on the performance of the drug review program.
    You had also requested the percentage of total approved 
applications in each year that were approved on the first cycle. We 
could not provide a valid statistic in response to this request. Total 
approvals in a given year include approvals of resubmitted 
applications. As requested, this statistic could never be 100 percent 
since the denominator of total approvals contains approvals of 
resubmitted applications that could never be counted in the numerator 
of first cycle approvals.

                             Number of NDAs, CDER BLAs, Supplements, and Resubmissions Filed, Approved First Cycle and Total Approved for Fiscal Years 2000 to 2011
                                                                                NDA and BLA Original Submissions
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                         Fiscal year                             2000        2001        2002        2003        2004        2005        2006        2007        2008        2009        2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Filed Submissions (Priority/Standard).............       30/90       11/82       12/84       19/83       28/94       29/73       31/87       22/81      31/103      20/116       18/83
Approved First Cycle (Applications Received, Filed, and            15/31        2/16        7/31        9/29       16/45       19/28       21/40       15/32       18/44       11/50        9/42
 Approved in First Cycle) (Priority/Standard)...............
Percentage of Filed Submissions that were Approved First         50%/34%     18%/20%     58%/37%     47%/35%     57%/48%     66%/38%     68%/46%     68%/40%     58%/43%     55%/43%     44%/52%
 Cycle (Priority/Standard)..................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


                                                                                NDA and BLA Efficacy Supplements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                         Fiscal year                             2000        2001        2002        2003        2004        2005        2006        2007        2008        2009        2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Filed Submissions (P/S)...........................      19/155       8/150      34/124       35/99      50/149      42/106      45/139      45/138      36/104      42/102      19/100
Approved First Cycle (Applications Received. Filed, and            15/65        4/79       15/66       24/52       36/83       27/80       35/92       26/99       23/72       27/65       11/68
 Approved in First Cycle) (Priority/Standard)...............
Percentage of Filed Submissions that were Approved First         36%/71%     14%/76%     35%/70%     36%/55%     46%/66%     48%/73%     63%/81%     50%/79%     48%/74%     60%/78%     37%/78%
 Cycle (Priority/Standard)..................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


                                                                              NDA and BLA Manufacturing Supplements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                         Fiscal year                             2000        2001        2002        2003        2004        2005        2006        2007        2008        2009        2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Filed Submissions (Prior Approval (PA)/Changes         672/745     542/896    598/1142    608/1072    596/1239    699/1206    638/1305    674/1365    628/1180    712/1199    721/1078
 Being Effected (CBE))......................................
Approved First Cycle (Applications Received, Filed, and          519/681     411/838    446/1029     440/999    468/1172    573/1144    515/1247    529/1301    460/1083    517/1093     510/944
 Approved in First Cycle) (PA/CBE)..........................
Percentage of Filed Submissions that were Approved First         77%/91%     76%/94%     75%/90%     72%/93%     79%/95%     82%/95%     81%/96%     78%/95%     73%/92%     73%/91%     71%/88%
 Cycle (PA/CBE).............................................
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


                                             Resubmissions of NDA and BLA Original Submissions, Efficacy Supplements, and Manufacturing Supplements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                         Fiscal year                             2000        2001        2002        2003        2004        2005        2006        2007        2008        2009        2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Original NDA and BLA Resubmissions................          78          62          62          62          81          51          60          66          52          62          51
Number of Original NDA and BLA Resubmissions Approved.......          45          42          42          44          55          37          41          37          36          39          34
Number of Efficacy Supplement Resubmissions.................          35          36          36          56          58          46          30          41          42          33          28
Number of Efficacy Supplement Resubmissions Approved........          27          25          28          43          43          29          21          26          25          18          19
Number of Manufacturing Supplement Resubmissions............         145         178         177         250         219         175         186         152         170         209         262
Number of Manufacturing Supplement Resubmissions Approved...         124         122         137         199         183         153         164         133         129         184         211
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


    Question 13. Many concerns have arisen regarding the regulatory 
certainty of the FDA's review process for drugs and devices. How could 
FDA better articulate requirements and develop more predictable 
approaches so that sponsor applications have a higher likelihood of 
first cycle approvals? How can FDA provide more timely and transparent 
guidance to sponsors regarding expectations with regard to compliance 
with the Agency's regulations?
    Answer 13. FDA has been taking action for some time to help drive 
innovation in new drug development. In 2004, FDA launched its Critical 
Path Initiative, FDA's national strategy to help advance pharmaceutical 
innovation. Our long-term efforts are showing positive signs, and FDA 
will continue to support the scientific community to advance new drug 
development.
    The key challenges facing scientific progress and innovation in 
drug development are cost and uncertainty. Stakeholders in all areas of 
industry repeatedly tell FDA that their biggest obstacle to successful 
drug development is uncertainty. FDA has taken an approach to 
supporting new drug innovations by generating initiatives to drive down 
development costs and reduce uncertainty in all phases of drug 
development.
    FDA is spearheading several initiatives to directly reduce the cost 
of drug development. For example, we are making great progress in the 
area of Adaptive Trial Design. Clinical trials do not always go as 
planned and Adaptive Trial Design allows the drug sponsor to change a 
clinical trial after patients are enrolled without compromising 
researchers' ability to assess the effectiveness of the drug being 
studied. This helps researchers make important changes to studies that 
otherwise may be delayed or discontinued and helps bring down the costs 
of clinical trials, which are often extremely expensive. We have also 
co-founded the Clinical Trials Transformation Initiative with Duke 
University to modernize the entire clinical trial system.
    FDA is also working to reduce the scientific uncertainty in drug 
development. For example, we have collaborated with the European 
Medicines Agency (EMA) to found the Predictive Safety Testing 
Consortium (PSTC). The PSTC has brought together scientists from 17 
drug companies, who collaborate to share and validate each other's 
safety methods. Such collaboration advances scientific knowledge and 
helps the industry to develop safer drugs faster and less expensively.
    FDA's recommendations for PDUFA V include proposals aimed at 
promoting innovation through enhanced communication between FDA and 
sponsors during drug development. Enhanced communication should help 
sponsors better understand how to best test their products for safety 
and effectiveness and ultimately bring new treatments to the U.S. 
market.
    One proposal will establish a new review model for the more 
innovative products (New Molecular Entity New Drug Applications and 
original Biologics License Applications) aimed specifically at 
decreasing the number of review cycles needed for approval. This model 
should provide greater transparency and improve communication by 
increasing the level of interaction between FDA and sponsors during the 
FDA review process. Similarly, FDA's PDUFA V recommendations also 
include a proposal to improve communication with sponsors during drug 
development. This proposal will establish a dedicated drug development 
communication and training staff that will conduct a range of tasks 
associated with enhancing communication between the review team and 
sponsors.
    Furthermore, FDA is committed to continuing to improve the 
surveillance of products after they have reached the market. Our PDUFA 
V recommendations include funds to continue implementing FDA's Sentinel 
Initiative. This is FDA's evolving electronic ``active surveillance'' 
system, which will augment FDA's current safety monitoring program. The 
new system will transform FDA's ability to track the safety of drugs, 
biologics, and medical devices after they reach the market and will 
help to answer key safety questions about medical products in near 
real-time.
    Our efforts to improve the predictability of the device review 
process are described in our response to question #8 submitted by 
Senator Burr.

    Question 14. The possibility of first cycle approval or clearance 
appears to vary by review division. What steps is FDA taking to ensure 
a consistent risk-benefit approach across divisions? Please describe 
the application of the FDA's new risk-benefit matrix that was recently 
made operational.
    Answer 14. In both CDRH and CDER, the review divisions evaluate 
applications from different therapeutic areas, and each therapeutic 
area has different benefit-risk considerations. For example, FDA will 
accept more risk with a drug to treat a potentially fatal and 
previously untreatable form of cancer than we would for a chronic but 
non-serious condition such as mild eczema. However, FDA has identified 
the need to establish a formal, systematic benefit-risk assessment 
within disease areas.
    CDER is currently developing an enhanced structured approach to 
considering benefits and risks in the Agency's drug regulatory 
decisionmaking. We have gathered input from senior CDER leadership and 
reviewers to ensure the development of a tool that can serve as a 
template for the full range of benefit-risk decisions. In addition, 
CDER has piloted the use of the benefit-risk framework for 
pharmaceuticals in 10 case studies across review divisions in OND. In 
the PDUFA V recommendations, the Agency has committed to expanding 
implementation of CDER's benefit-risk assessment framework in the drug 
review process, including workshops on patient-focused drug 
development. FDA will also conduct a series of public meetings with the 
relevant patient advocacy communities to review the medical products 
available for use in specific therapeutic areas. The therapeutic areas 
to be discussed will be chosen through a public process. We will begin 
execution of the plan to implement that framework by the end of the 
fourth quarter of fiscal year 2013.
    With respect to medical devices, CDRH recently issued, with request 
for public comment, a new draft guidance \34\ describing factors to 
consider in making benefit-risk determinations in device premarket 
review. This draft guidance explains in detail the many factors for FDA 
to consider when weighing the probable benefit of a device versus its 
probable risk, and also gives examples of how the factors interrelate 
and how they may affect FDA's decisions. These factors include, among 
others, whether the device is a first-of-a-kind treatment or 
diagnostic, whether the device provides significant improvement in 
diagnosis and patient management of a serious disease, how known risks 
of the device can be mitigated, reliability of the study, whether there 
are multiple studies and the strength of those studies, what amount of 
risk the target population will tolerate in light of the condition 
being treated or diagnosed and the probable benefit of the device, and 
whether there are alternate treatments or diagnostic techniques 
available.
---------------------------------------------------------------------------
    \34\ CDRH, ``Draft Guidance for Industry and Food and Drug 
Administration Staff--Factors to Consider When Making Benefit-Risk 
Determinations in Medical Device Premarket Review'' (Aug. 15, 2011). 
available at http://www.fda.gov/MedicalDeviceRegulationandGuidance/
GuidanceDocuments/ucm267829.htm.
---------------------------------------------------------------------------
    By clarifying FDA's decisionmaking process for medical devices in 
this way, we hope to improve the predictability, consistency, and 
transparency of the review process for applicable devices. The draft 
guidance includes (also for public comment) a draft worksheet that 
reviewers may use in making benefit-risk determinations; we believe 
that this level of documentation will be very helpful in maintaining 
the consistency of review across the different review divisions and it 
will provide further assurance that an appropriate decision is reached. 
The draft guidance is not in final form or in effect at this time, but 
CDRH has requested that interested persons provide their comments on 
the guidance by November 14, so that those comments can be considered 
before we begin work on the final version.

    Question 15a. In 1997, Congress passed the FDA Modernization Act, 
which gave amongst other things, new authority to review and 
subsequently approve drugs based on limited clinical data and that 
demonstrated efficacy based on a validated surrogate endpoint.
    How many oncology drug applications (NDAs, BLAs, and supplements) 
approved by FDA were granted accelerated approval since 2001?
    Answer 15a. Between January 1, 2001, and August 30, 2011, there 
have been 39 oncology drug applications (NDAs, BLAs and supplements) 
approved by FDA under Accelerated Approval.
    Between January 1, 2001, to December 31, 2010 (time period 
referenced in questions below), there have been 36 oncology drug 
applications (NDAs, BLAs and supplements) approved by FDA under 
Accelerated Approval.

    Question 15b. For each year, from 2001 through 2010, how many of 
these accelerated applications did FDA: (i) Successfully complete in 
the first cycle?
    Answer 15b(i). Between the years 2001 and 2010 (denominator of 36 
oncology drug applications), 32 of these accelerated approvals were 
completed within the first cycle.
    Question 15b(ii) Approve on the basis of two on-going confirmatory 
studies?
    Answer 15b(ii). Between the years 2001 and 2010, 30 of these 
applications had at least one ongoing confirmatory trial at the time of 
accelerated approval. A minority of applications have more than one 
post-approval clinical trial required to demonstrate clinical benefit 
for the specific indication approved under Subpart H.
    Question 15b(iii). Approve on the basis of a single-arm study or on 
the basis of a more lenient statistical orthodoxy?
    Answer 15b(iii). Between the years 2001 and 2010, 23 oncology drug 
applications (NDAs, BLAs and supplements) have been granted Accelerated 
Approval based on single-arm trials.

    Question 16. What is the FDA doing to identify and limit 
redundancies within the Agency, including high numbers of FTEs who do 
not review applications, to improve its productivity and efficiency?
    Answer 16. It is important to recognize that both CDER and CDRH are 
responsible for a variety of complex functions that are not directly 
associated with the review of new drug and medical device applications. 
Examples of these functions include ensuring industry's sustained 
compliance with manufacturing requirements, performing post-market drug 
and device safety surveillance and risk communication, developing 
guidance for the pharmaceutical, biologics, and medical device 
industries, conducting post-approval inspections of domestic and 
foreign facilities, and analyzing and responding to Citizen Petitions. 
CDRH also is responsible for implementation of the Radiation Control 
for Health and Safety Act and the Mammography Quality Standards Act. In 
addition, there are essential cross-cutting activities that must be 
performed by CDER and CDRH personnel to support premarket regulatory 
review, including management, planning, policy, information management, 
and science-related activities. These non-review functions are critical 
to successful regulation of pharmaceuticals and medical devices and to 
the overall health and safety of the American public.
    To promote productivity and efficiency, CDER is designing a quality 
systems framework to enhance regulatory review and its supporting 
cross-cutting business processes, to ensure consistent, scientifically 
sound, high-quality work product. CDER has also been focusing on the 
``Lean'' methodology for managing work, focusing on the key principles 
of maximizing value while also eliminating redundancies or other waste 
in business processes. In addition, CDER recently published its Data 
Standards Plan, which includes several cost-cutting initiatives, such 
as transitioning from paper submissions to an electronic data 
submission system.
    Likewise, CDRH is actively working to enhance its efficiency and 
productivity. For example, starting next month, the Office of Device 
Evaluation (ODE) will pilot an internal corrective and preventive 
action (CAPA) system--a database in which 
office-level issues, such as inconsistency in application of policies 
or failure to follow policies or SOPs, will be entered and assigned to 
a staff member for followup and resolution. The CAPA system will 
formalize existing continuous improvement efforts and help to ensure 
that identified issues are tracked to resolution and appropriate 
corrective and preventive actions are taken. Office-level management 
will periodically review the information contained in the CAPA system 
to ensure adequate resourcing and timely resolution of issues. CDRH is 
also working to modernize the tracking system that the Center uses to 
manage and track premarket submissions that are under review and to 
provide review performance reports. Advanced features are being added 
to the system to allow for better management reports used by review 
branch chiefs for everyday work and to provide reports for past 
performance to identify areas in need of improvement. This project will 
modernize the premarket database systems to enable the Center to 
identify, collect, search, and report on medical devices in a 
consistent, reliable, and efficient manner. These efforts are vital to 
support and enhance the Center's premarket, post-market, and 
compliance-related activities.

    Question 17a. There appears to be a lack of transparency and 
timeline consistency in the development and submission of FDA's 
scheduling recommendations through HHS and DEA. Unnecessary delays in 
process result in delayed patient access to new medicines.
    Is there a documented, formal procedure for completing the 
scheduling recommendation made by CDER Controlled Substance staff and 
the submission of FDA's recommendation to DEA?
    Answer 17a. FDA's role in scheduling drug substances under the 
Controlled Substance Act (CSA) is to perform a scientific and medical 
evaluation of drugs and to provide, through the Secretary of Health and 
Human Services, a recommendation to the Attorney General as to whether 
a drug should be controlled. Under the CSA, the Attorney General is 
required to request from the Secretary of Health and Human Services 
(Secretary) an evaluation of certain medical and scientific factors for 
a drug or other substance, a recommendation as to whether the substance 
should be controlled or not controlled under the CSA, and, if 
controlled, the appropriate level of control or ``schedule'' under the 
CSA. The CSA establishes the factors and findings determinative for 
control.
    The CSA requires the Secretary of the Department of Health and 
Human Services (HHS) to notify the Attorney General, through the Drug 
Enforcement Administration (DEA), at the time an NDA is submitted for 
any drug having a stimulant, depressant, or hallucinogenic effect on 
the central nervous system and it appears that the drug has an abuse 
potential. HHS has delegated this function to FDA. FDA's CDER, and the 
Controlled Substance Staff (CSS), perform this role for the Agency. In 
addition, proceedings to add, delete or change the schedule of a drug 
or other substance may be initiated by petition to DEA from any 
interested party such as a drug manufacturer, medical society, pharmacy 
association, public interest group, State and local government, or an 
individual citizen.
    Throughout the drug development process, CSS evaluates preclinical, 
clinical, and epidemiological data to determine whether a drug under 
review requires abuse liability studies or scheduling under the CSA and 
recommends additional measures, such as those related to risk 
management, if needed, directed to reducing abuse, misuse and overdose. 
In addition, international drug control treaties to which the United 
States is a signatory may affect the regulation of new drugs with abuse 
liability. CSS also contributes to this area and works with the 
appropriate government agencies, including DEA, the National Institute 
on Drug Abuse (NIDA), HHS, and the U.S. Department of State.
    The procedure for completion of the scheduling request and 
submission to DEA involves CSS analyzing the factors and findings 
determinative for control and preparing the scheduling recommendation 
(if appropriate); consulting with NIDA, FDA Office of Chief Counsel, 
the CDER Center Director, and the FDA Commissioner; reviewing the 
scheduling recommendation; and forwarding to the Assistant Secretary 
for Health, who makes the HHS recommendation for scheduling that is 
transmitted to DEA. This procedure is described in the FDA/CDER draft 
guidance entitled, Guidance for Industry: Assessment of the Abuse 
Potential of Drugs.

    Question 17b. During FDA's human drug review process, when does 
work related to a potential scheduling recommendation start? Are there 
timeline requirements for each step? How is the Agency performance 
relative to this process measured?
    Answer 17b. The Agency's evaluation of the abuse potential of a 
drug, whether under IND or NDA review, is subject to review timelines 
established under CDER's OND for all of the review divisions relative 
to CDER's Good Review Practices and PDUFA. Drug scheduling under the 
Controlled Substances Act (CSA) is a separate process that is largely 
carried out in parallel with the PDUFA timeline. The Agency's goal for 
completing the assessment of abuse potential of a drug is the timeline 
for approval of the drug within the PDUFA timeline.
    Typically, FDA does not begin its medical and scientific evaluation 
to support a scheduling recommendation until it receives a formal 
request from DEA. FDA may also initiate such an evaluation during the 
drug development process. Such an evaluation typically begins during 
the investigational stages of drug development or when an application 
to market a new drug is received by FDA and the Agency determines that 
the substance may be a candidate for scheduling under the CSA.

    Question 17c. What steps, if any, is FDA taking to improve 
transparency and consistency of the Agency's work on scheduling 
recommendations that are ultimately submitted to DEA?
    Answer 17c. It is important to understand that NDA review and drug 
scheduling are two independent review processes regulated by two 
different laws. NDA review and approval is under the FD&C Act and 
timelines for review are established by PDUFA, while the process for 
drug scheduling is under the CSA. Even though these two processes are 
independent from a regulatory perspective, FDA strives to coordinate 
the CSA scheduling of a drug as closely as possible with that drug's 
approval for marketing.
    There are many factors influencing the time it takes for HHS to 
develop a final scheduling recommendation. The steps necessary to 
develop a scheduling recommendation need to be performed in a certain 
order. A delay in any step of the process can adversely affect the 
timeliness of scheduling relative to the NDA action date.
    Some of the factors that can potentially affect the timeliness of 
the drug scheduling process are:

    1. Timeliness, quality and completeness of data submitted by the 
drug company (Commercial Sponsor) to support drug scheduling 
determination by FDA.
    2. Completion of all primary reviews for the new drug product 
(medical/pharmacology, clinical pharmacology, chemistry, and scientific 
issues).
    3. Review and clearances by multiple Federal agencies (legal/
regulatory issues).
    4. New or precedent-setting medical and legal issues requiring 
regulatory policy development.

    In order to expedite the scheduling process and to guide Sponsors 
on the type of studies needed to characterize the abuse potential of a 
drug, FDA/CDER published in January 2010, draft guidance entitled, 
Guidance for Industry: Assessment of the Abuse Potential of Drugs link: 
http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/UCM198650.pdf. In addition, 
FDA communicates to Sponsors the importance of an early interaction and 
high-quality submissions to support scheduling.
    If sufficient information exists to make and support a drug 
scheduling recommendation, the FDA procedure, though complex, is not 
excessively long or delayed and closely parallels the PDUFA timeline.
    Once the HHS recommendation is with DEA, FDA is removed from the 
process and not involved in scheduling other than to respond to DEA 
questions on issues that may need to be clarified.
                             senator hatch
    Question 1. As we briefly discussed at the hearing, I hear from 
companies on a weekly basis about their plans to move their development 
efforts and manufacturing overseas to places like Europe because the 
regulatory pathway that is more predictable and reasonable when it 
comes to assessing safety and effectiveness. This move overseas results 
in the United States quickly losing its innovation edge over the rest 
of the world, not to mention the thousands of jobs being lost. What 
specific actions have you taken, to encourage manufacturers to remain 
in the United States? How does an increase in user fees compliment 
these efforts?
    Answer 1. FDA's mission includes promoting the public health and 
that includes facilitating medical product innovation with respect to 
drugs, biologics, and devices. Global production of FDA-regulated goods 
has exploded over the past 10 years, but increased globalization has 
been seen across nearly all business sectors in the United States. Both 
the pharmaceutical and medical device industries are moving business 
overseas, mostly because of decreased costs in manufacturing and in 
conducting clinical trials. However, they are still submitting their 
products to FDA so that they can have access to the U.S. market.
    The key challenges facing scientific progress and innovation in 
drug and device development are cost and uncertainty. Stakeholders in 
all areas of these industries repeatedly tell FDA that their biggest 
obstacle to successful product development is uncertainty. FDA has 
taken an approach to supporting new medical product innovations by 
generating initiatives to drive down development costs and reduce 
uncertainty in all phases of product development. FDA is spearheading 
several initiatives to directly reduce the cost of drug and device 
development.
    FDA is also making great progress in the area of Adaptive Trial 
Design. Clinical trials do not always go as planned and Adaptive Trial 
Design allows the drug sponsor to change a clinical trial after 
patients are enrolled without compromising researchers' ability to 
assess the effectiveness of the drug being studied. This helps 
researchers make important changes to studies that otherwise may be 
delayed or discontinued and helps bring down the costs of clinical 
trials, which are often extremely expensive. We have also co-founded 
the Clinical Trials Transformation Initiative with Duke University to 
modernize the clinical trial system.
    In addition, FDA is working to reduce the scientific uncertainty in 
drug development. For example, FDA has collaborated with the European 
Medicines Agency (EMA) to found the Predictive Safety Testing 
Consortium (PSTC). The PSTC has brought together scientists from 17 
drug companies who collaborate to share and test new methods that are 
more reliable predictors of human safety. Such collaboration advances 
scientific knowledge and helps the industry to develop safer drugs 
faster and less expensively.
    We are committed to continuing to improve the surveillance of 
products after they have reached the market. Our PDUFA V 
recommendations include funds to continue implementing FDA's Sentinel 
Initiative. This is FDA's evolving electronic ``active surveillance'' 
system--which will augment FDA's current safety monitoring program. The 
new system will transform FDA's ability to track the safety of drugs, 
biologics, and medical devices after they reach the market and will 
help to answer key safety questions about medical products in near 
real-time.
    In 2004, FDA launched its Critical Path Initiative, FDA's national 
strategy to help advance pharmaceutical innovation. Our long-term 
efforts are showing positive signs and FDA will continue to support the 
scientific community to advance new drug development. Many of the 
concepts and initiatives set in motion by FDA's Critical Path 
Initiative may be beginning to show signs of benefit. For instance, as 
of July 23, 2011, FDA has approved 21 novel new drugs, equaling the 
total approved during all of 2010. The list of novel new drugs includes 
the first drug to treat lupus in over 56 years, a completely new 
treatment for chronic obstructive pulmonary disease (COPD), the first 
skin cancer therapy for metastatic melanoma (skin cancer) that 
demonstrates an improvement in overall patient survival, the only drug 
shown to be effective against medullary thyroid cancer, a new agent 
that can help diagnose Parkinson's disease, and two new and highly 
effective treatments for hepatitis C. Additionally, the 2011 NME list 
includes drugs intended for post-surgical use: one to decrease the 
likelihood of rejection after a kidney transplant and another to 
prevent deep vein thrombosis and pulmonary embolism after knee and/or 
hip replacement surgery.
    In the device area, most of the proposed actions under CDRH's 
Innovation Initiative would foster innovation for all types of devices. 
For example, the new Innovation Pathway, if adequately resourced, could 
be applied to all or most devices for which a clinical study has to be 
conducted. In addition, the 25 actions the Agency announced it would 
take in 2011 to improve the 510(k) review process are intended to 
facilitate innovation for all types of devices by improving the 
predictability, consistency, and transparency of our pre-market review 
program.
    Periodic reauthorization of MDUFA ensures that the device review 
program continues to operate on a sound financial footing, to the 
benefit of patients, health professionals, and industry. In part this 
is related to both existing workload and inflation that FDA experiences 
in operating the program.

    Question 2. With a medical device tax about to hit the industry 
across the board in 2013, shouldn't the Federal Government be looking 
for ways to unburden industry instead of making their burden greater by 
adding more user fees on top of an already onerous medical device 
excise tax?
    Answer 2. FDA has no jurisdiction or policy role with respect to 
the medical device excise tax.
    Medical device user fees consist of congressionally authorized 
private money, which is paid by medical device companies to FDA in 
return for FDA's commitment to meet specific performance goals. 
Congress first authorized FDA to collect user fees from device 
manufacturers in 2002, with the passage of the Medical Device User Fee 
and Modernization Act (MDUFMA); \35\ in 2007, MDUFMA's user fee 
authorities were reauthorized by Congress for another 5-year 
period.\36\
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    \35\ P.L. 107-250 (2002).
    \36\ Medical Device User Fee Amendments of 2007 (MDUFA 2007), 
enacted as Title II of the Food and Drug Administration Amendments Act 
of 2007 (FDAAA: H.R. 3580; P.L. 110-85).
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    The authority to collect user fees is subject to two statutory 
triggers: if either trigger is not satisfied for a given fiscal year, 
FDA loses authority to collect user fees. The first trigger prohibits 
FDA from collecting fees if direct congressional appropriations to FDA 
for salaries and expenses related to devices and radiological health 
fall below a certain threshold. The second trigger requires that fees 
only be collected and available to defray increases in the cost of the 
resources allocated for the process for the review of device 
applications.
    FDA has the authority to collect three types of medical device user 
fees: application fees (paid each time an application is submitted), 
establishment fees (paid annually by all non-exempt establishments), 
and product fees (paid annually for each qualifying Class III device). 
The amount of each type of user fee is determined by Congress. 
Application and product fees are set as a percentage of the PMA fee 
(also called the ``base fee''). The law prescribes both the base fee 
amount for each fiscal year, and also the percentage of the base fee 
that constitutes most other fees; the law raises the base fee annually 
by a certain percentage. The amount of the establishment fee (unlike 
the other user fees) is set in its own section of the medical device 
user fee law.
    Because medical device user fees consist solely of congressionally 
authorized private money, FDA may only collect fees as authorized by 
Congress (and in the amounts set forth by Congress) in the user fee 
law.
    The current medical device user fee law is set to expire on 
September 30, 2012. As required by the 2007 user fee law, FDA is 
currently engaged in the process of working with various stakeholders--
including the regulated industry, as well as consumer and patient 
groups--to prepare for user fee reauthorization in 2012. As part of 
that process, FDA will publish its recommendations for the 
reauthorization in the Federal Register, provide a public comment 
period, hold a public meeting, and then revise its recommendations upon 
consideration of the public comments. FDA is required to transmit its 
recommendations for reauthorization of the user fee program to Congress 
no later than January 15, 2012.

    Question 3. Is the current draft guidance that the FDA issued in 
2007 still consistent with FDA's current policies and views of what 
sponsors need to demonstrate in order for an obesity drug to obtain 
approval?
    Answer 3. Yes. The current draft guidance is consistent with FDA's 
current policies and views for what sponsors need to demonstrate for 
effectiveness of an obesity drug. The 2007 draft guidance states:

          In general, a product can be considered effective for weight 
        management if after 1 year of treatment either of the following 
        occurs:

           The difference in mean weight loss between active-
        product and placebo-treated groups is at least 5 percent and 
        the difference is statistically significant.
           The proportion of subjects who lose greater than or 
        equal to 5 percent of baseline body weight in the active-
        product group is at least 35 percent, is approximately double 
        the proportion in the placebo-treated group, and the difference 
        between groups is statistically significant.

    To fully evaluate an obesity drug for approval, it is important to 
consider the weight-loss efficacy or benefit of a drug in the context 
of the drug's potential risks or harms, thereby determining whether the 
drug's benefits outweigh its risks and is therefore appropriate for 
approval.
    FDA is planning a scientific meeting to discuss obesity and 
cardiovascular safety, and we are also planning to hold a series of 
stakeholder meetings where we bring in pharmaceutical and patient 
groups, FDA, and other experts to talk about how obesity drugs should 
be developed. We expect these meetings to be very helpful to industry.

    Question 4. I was pleased to see the President's Executive order 
directing agencies to examine both their existing and new regulations 
to make sure they are not unnecessarily burdensome for industry and 
that they support innovation. What actions and initiatives have you 
done or are you currently doing or plan to do in response to the Order. 
In addition, while the Order, as I understand it, only formally extends 
to actual regulations, much of the work the FDA does is by guidance or 
other sub-regulatory activities which have a huge impact on industry. 
What other activities beyond re-evaluating the regulations are you 
doing in the spirit of the Executive order. Will you be evaluating the 
actions you are taking to implement the 510(k) reform plans in the 
spirit of the President's order--in particular by looking at whether 
any additional burdens on industry are truly necessary and how your 
actions will support innovation?
    Answer 4. The President has directed Agencies to review regulations 
and other procedures to see if they can withdraw or modify regulations, 
or otherwise improve procedures, to reduce regulatory burden and 
improve competitiveness, innovation, economic growth, and jobs, while 
assuring safety. As a first step in the regulatory review, the 
Secretary of HHS asked each component Agency to do an inventory of its 
existing significant regulations to provide information that will 
assist HHS in constructing an ongoing retrospective review process. FDA 
sought comment on how the Agency could revise its existing review 
framework to meet the objectives of Executive Order 13563, regarding 
the development of a plan with a defined method and schedule for 
identifying certain significant rules that may be obsolete, 
unnecessary, unjustified, excessively burdensome, or counterproductive. 
FDA focuses its retrospective review effort on regulations that have a 
significant public health impact and regulations that impose a 
significant burden on the Agency and/or industry. FDA has under review, 
or has identified, over 40 rules as candidates for regulatory review.
    FDA already estimates the effects of its regulations on industry 
when we initially promulgate the regulation and has been doing so for 
over 30 years. The laws and Executive orders that the Agency follows 
require FDA to measure the effect of regulations on employment, 
innovation, and economic growth. For example, the Unfunded Mandates 
Reform Act of 1995 requires that major rules include estimated effects 
on employment, competitiveness, and growth. Another example is 
Executive Order 12866, which requires all Federal agencies to consider 
effects on innovation, when writing regulations.
    On April 27, 2011, FDA published a notice in the Federal Register, 
requesting comment and supporting data on which, if any of our existing 
rules are outmoded, ineffective, insufficient, or excessively 
burdensome and thus may be candidates for review. This docket closed on 
June 27, 2011. FDA is now reviewing the comments received and will be 
using the comments to inform its future regulatory review activities.
    Relating to medical devices, FDA has already identified 
improvements to regulatory science as well as other initiatives--such 
as its medical device innovation initiative, the 510(k) Plan of Action, 
and the FDA/CMS voluntary pilot for parallel review of medical 
devices--that will help it and the industries it regulates innovate and 
remain competitive.
    With respect to initiatives under the 510(k) action plan, those 
implemented by guidance or regulation will be subject to public comment 
periods. Those requiring legislation are for Congress to determine. The 
rest were well-vetted through the numerous opportunities afforded 
industry and the public to comment on the proposals.
    We are also converting the device registration and listing process 
to a paperless system, allowing for the utilization of the latest 
technology in the collection of information, while maintaining an 
avenue for companies for which paper applications are more convenient. 
This will speed reporting and analysis of adverse events and 
identification of emerging public health problems, as well as lower 
costs for manufacturers.
    We are also revising device pre-market approval regulations 
(Special PMA Supplement Changes Being Effected) to remove duplicative 
requirements and streamline and clarify regulatory requirements. And we 
will be proposing to allow the use of validated symbol in device 
labeling, without the need for accompanying English text, thereby 
reducing the burden of labeling requirements by permitting 
harmonization with labeling for international markets.
    Relating to drugs, FDA has reviewed its regulations and guidance 
documents to identify areas in which the Agency can reduce burden on 
industry and support innovation. FDA has identified several areas where 
activities are already in progress to achieve these objectives. For 
example, through regulations and guidance, FDA is clarifying and 
streamlining safety reporting requirements for drug manufacturers to 
improve the overall quality of safety reporting, to harmonize certain 
reporting requirements with international standards, and to ensure 
timely reporting of safety signals with critical public health 
implications. In addition, FDA is revising existing regulations and 
guidance documents, as well as developing new regulations and guidance, 
to facilitate the electronic filing of various types of information 
that drug manufacturers are required to submit to the Agency. Our 
initiatives on this front include drug registration and listing 
information, manufacturing site information, drug safety reports, and 
clinical study data for new applications and supplements. These changes 
are expected to reduce the administrative burden on applicants and 
allow for more efficient and comprehensive data review by the Agency. 
FDA is committed to continuous review of its regulatory framework to 
improve procedures, streamline the process for compliance with 
regulatory requirements, and balance innovation strategies with our 
obligation to ensure the safety and efficacy of human pharmaceuticals.

    Question 5. Last month the FDA issued, ``Draft Guidance for 
Industry: Dietary Supplements: New Dietary Ingredient Notifications and 
Related Issues.'' As you know, this document is voluminous and takes 
some time to properly evaluate and analyze. Considering the potential 
impact the guidance may have on industry will you extend the comment 
period to provide stakeholders with enough time to review and to submit 
well thought out comments on the draft guidance?
    Answer 5. Yes. FDA announced in the September 9, 2011, Federal 
Register (76 FR 55927) that we are extending the comment period on the 
New Dietary Ingredient guidance by 60 days. until December 2, 2011.

                                                                                           Appendix I
                                                                                NDA and BLA Original Submissions
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                   Fiscal year                     1993    1994    1995    1996    1997    1998    1999    2000    2001    2002    2003    2004    2005    2006    2007    2008    2009    2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Percentage of Filed Submissions that were           57%/    28%/    47%/    68%/    44%/    53%/    63%/    50%/    18%/    58%/    47%/    57%/    66%/    68%/    68%/    58%/    55%/    44%/
 Approved First Cycle (Priority/Standard).......     21%     22%     29%     41%     45%     31%     42%     34%     20%     37%     35%     48%     38%     46%     40%     43%     43%     52%
Median FDA Time to First Action (in Months).....   10.9/   12.0/    9.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.1/    6.1/    6.0/
                                                    12.8    12.0    12.0    12.0    12.0    11.9    10.0    10.0    10.0    10.0    10.0    10.0    10.0    10.0    10.0    10.0    10.0    10.0
Mean FDA Time to First Action (in Months).......   10.6/   10.4/    8.7/    6.8/    9.1/    6.2/    6.2/    6.4/    6.5/    6.1/    6.2/    5.9/    6.4/    6.0/    6.7/    8.3/    7.2/    6.7/
                                                    15.4    12.8    11.9    12.0    11.6    11.5    11.2    10.2    10.5    10.2    10.2    10.2    10.6    10.6    11.3    10.8    10.5    10.3
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                                                                                NDA and BLA Efficacy Supplements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                   Fiscal year                     1993    1994    1995    1996    1997    1998    1999    2000    2001    2002    2003    2004    2005    2006    2007    2008    2009    2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Percentage of Filed Submissions that were         0%/96%    26%/    15%/    12%/    17%/    24%/    32%/    36%/    14%/    35%/    36%/    46%/    48%/    63%/    50%/    48%/    60%/  37%/71
 Approved First Cycle (P/S).....................             48%     47%     51%     76%     78%     80%     71%     76%     70%     55%     66%     73%    81%)     79%     74%     78%
Median FDA Time to First Action (in Months).....    9.3/    5.7/    6.0/    6.0/    4.4/    6.0/    6.0/    6.0/    6.0/    5.9/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/    6.0/
                                                    17.4    12.0    11.8    11.7    11.2    11.4    10.0     9.9     9.9     9.9    10.0    10.0     9.9    10.0    10.0    10.0    10.0    10.0
Mean FDA Time to First Action (in Months).......    9.0/    7.1/    8.2/    6.6/    4.5/    6.8/    6.0/    5.7/    6.7/    5.9/    6.0/    6.0/    5.9/    6.1/    6.3/    6.4/    6.8/    6.3/
                                                    18.6    13.3    10.6    10.1     9.6    10.3     9.6     9.4     9.5     9.3     9.3     9.6     9.3     9.9    10.2    10.4    10.2    10.0
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                                                                              NDA and BLA Manufacturing Supplements
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
                   Fiscal year                     1993    1994    1995    1996    1997    1998    1999    2000    2001    2002    2003    2004    2005    2006    2007    2008    2009    2010
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Percentage of Filed Submissions that were            71%     74%     67%     85%     83%     86%    78%/    77%/    76%/    75%/    72%/    79%/    82%/    81%/    78%/    73%/    73%/    71%/
 Approved First Cycle (PA/CBE)..................                                                     90%     91%     94%     90%     93%     95%     95%     96%     95%     92%     91%     88%
Median FDA Time to First Action (in Months).....     5.9     5.3     4.7     4.8     5.1     5.2    3.9/    3.9/    3.9/    3.9/    3.9/    3.9/    3.9/    3.9/    3.9/    4.0/    3.9/    3.9/
                                                                                                     4.4     4.9     5.5     5.8     5.8     5.8     5.7     5.8     5,9     6.0     5.9     5.9
Mean FDA Time to First Action (in Months).......     7.1     6.4     4.5     4.3     4.5     4.5    4.0/    3.8/    3.7/    3.6/    3.6/    3.7/    3.7/    3.9/    3.9/    4.5/    4.3/    4.2/
                                                                                                     4.3     4.1     4.5     4.9     5.0     5.1     5.1     5.5     5.6     5.8     5.6     5.7
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    [Whereupon, at 12:00 p.m., the hearing was adjourned.]

                                   


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