Good morning, Madam Chairman. I am pleased to be here and want
to thank you for holding this hearing on-this very important
public health issue. Today we are here to discuss how the Food
and Drug Administration (FDA) can do the best job possible in
protecting and promoting the public health.
INTRODUCTION
As we explore that question, it is important to acknowledge that
we share the same goals. I know, Senator Kassebaum, that you and
members of the Senate Labor Committee understand that American
patients are best served when they are assured that the medicines
they take are safe and really work, that American patients are
most helped when they are assured that medical devices are safe
and really work. The rigorous demand for safety and efficacy
that makes FDA approval the international gold standard is, in
fact, in the best interests of American patients. Likewise, FDA
shares with you the belief that timely access to new drugs and
devices that are shown to be safe and effective is an important
measure of how well the Agency protects and promotes public
health in the United States.
If we are to achieve our shared goals of improving the Agency's
ability to protect and promote the public health, we must base
our work on FDA's current performance. Unfortunately, too many
of our critics justify the call for "reform" based on how the FDA
did its job in the 1980s or earlier. They have missed the
substantial progress that the dedicated doctors, nurses,
engineers, chemists, microbiologists, biostatisticians,
nutritionists and others at the FDA have achieved over the past
several years. They would have us ignore the important lessons
we have learned about the kind of change that will result in
getting safe and effective drugs and devices to the market more
quickly. Those who fail to recognize the Agency's performance
and achievements threaten -- intentionally or not -- to undermine
the real progress the Agency has made. Undermining progress in
critical public health and consumer protection is not "reform."
THE FOOD AND DRUG ADMINISTRATION IN 1996 --
MEETING AND EXCEEDING THE PRESCRIPTION DRUG USER FEE
PERFORMANCE -- GOALS
According to the General Accounting Office (GAO), the average
approval time for new drug applications (NDA) submitted to the
Agency in 1987 was 33 months. For NDAs submitted in 1992 the time
had been reduced to 19 months. These improved approval times
have been made possible by shortening the time for completion of
most first reviews to only 12 months. How did we do it?
Congress, the Agency, and the pharmaceutical industry recognized
that additional resources were one key to improving FDA's review
of drugs and biologicals, and Congress enacted the Prescription
Drugs User Fee Act of 1992 (PDUFA). The Agency, in turn,
committed to very aggressive performance standards, with higher
hurdles in each succeeding year until full implementation in
fiscal year 1997. These performance standards were negotiated
with and agreed to by the pharmaceutical and biotech industries.
We already have achieved one of the major 1997 performance goals.
We achieved it in fiscal year 1994 -- a full three years ahead of
schedule. For the drugs submitted to FDA in fiscal year 1994, we
reviewed and acted upon 96 percent of them on time. In most
cases, that meant first action within 12 months. 1 1 If a major
amendment is submitted by the manufacturer late in the process,
an additional three months is granted.
This improved performance has been validated by GAO. At the
request of this Committee, GAO looked at how FDA was performing
even before PDUFA was enacted. GAO found that review and approval
times for new drugs have been reduced dramatically. In addition
GAO found that by 1994, FDA review and approval times were faster
than those in the United Kingdom -- a country many critics like
to cite as a way of doing things better and faster.
We should never forget that the ultimate goal is ensuring
American patients have access to world-class medicines. By that
measure as well, the FDA is delivering. The story of AIDS
therapies is especially telling. Of the six antivirals used to
treat AIDS, FDA was first to approve them in five instances, DDI,
DDC, D4T, 3TC and Saquinivar. In the case of AZT, FDA acted
contemporaneously with France and the United Kingdom. Two of the
newest and most promising AIDS therapies will be considered at an
FDA advisory committee next week, and we will be the first
country to do so. But the story goes beyond AIDS. Taxol for
ovarian cancer, Fludarabine for lymphocytic leukemia, Pulmozyme
for cystic fibrosis, Betaseron for multiple sclerosis, Riluzole
for Lou Gehrig's disease, and Cognex for Alzheimer's were all
first approved in the United States.
FDA IS A WORLD LEADER IN DRUG APPROVAL
One measure of FDA's drug review performance is found in how we
compare to the performance of other major regulatory agencies
around the world. We looked at the United Kingdom, Germany, and
Japan and found we compare very well. First, there are numerous
drugs with important therapeutic values available here but not in
these other countries. Second, virtually all of the drugs
available in these other countries but not approved here have
therapeutic equivalents in the United States. Third, the United
States is first to approve a significant proportion of "global"
drugs -- those ultimately approved by more than one country.
Finally, we have a strong safety record.
These conclusions are based on our analysis of the "new molecular
entities" (NMEs) introduced anywhere in the world between 1990
and 1994. We looked at when those drugs were approved here and
in Germany, Japan and the United Kingdom -- four countries that
account for 60 percent of global pharmaceutical sales. Let me
just give you a brief glimpse at the numbers in the FDA study,
"Timely Access-to New Drugs in the 1990s: An International
Comparison." There were 58 drugs that had been approved in both
the United States and the United Kingdom. We approved 30 of them
first, the United Kingdom 28. When we approved a drug first, we
did so by an average of 17 months before the United Kingdom; if
they approved first, they were ahead by an average of 15.8
months. There were 44 new drugs approved in both the United
States and Germany. We approved 31 of them first, Germany 13.
When we approved a drug first, we did so by an average of 17.9
months before Germany; if they approved first, they were ahead by
an average of 10.8 months. There were 14 new drugs approved in
both the United States and Japan. We approved 10 of them first,
Japan 4. When we approved a drug first, we did so by an average
of 22.4 months before Japan; if they approved first, they were
ahead by an average of 18.5 months. If you are an American
patient, you have access to therapeutically important new drugs
sooner than any other country's citizens.
MAKING NEW PRODUCTS AVAILABLE SOONER
In addition to shortening review times, the Agency,has developed
a number of innovative and well accepted mechanisms that give
seriously ill and dying patients access, to potential therapies
before they are approved for marketing. We recognize that this
approach has its risks. But we also recognize that when it comes
to getting needed therapies to terminally ill patients, the
riskiest thing we can do is to be unwilling to take risks.
We have instituted innovative pre-approval policies, such as the
"treatment IND," under which patients may get access to a
promising drug after clinical testing shows that it may be
effective, but before it is approved for marketing. We also have
developed a process to accelerate approval of drugs for serious
and life-threatening diseases, by approving such drugs for
marketing before the data from traditional clinical trials are
complete, if the drug shows an effect on a "surrogate marker." A
surrogate marker is a laboratory measurement, such as an increase
in the number of CD4 cells in a person with HIV, that is used to
predict actual clinical outcome, such as longer life.
IMPROVING DEVICE REVIEW TIMES
Improvements also have been made in the times for the review and
approval of medical devices. With respect to the so-called
510(k) process, through which 98 percent of all medical devices
evaluated by FDA reach the market, the average review time in
fiscal year 1995 was 137 days, down 24 percent from the 184-day
average in fiscal year 1994. The average review time for those
devices needing premarket applications (PMAs) is still too long,
but we are making progress there as well. The average PMA review
time in fiscal year 1995 was 20 months.
It is important to remember, however, where the Agency was in the
1980s. Congress found -- as did the Agency itself -- that the
scientific and medical standards for the review of medical
devices were lacking. FDA looked at devices the way an engineer
would; we did not focus sufficient attention on whether the
device would actually make the patient better. Congress told us
to do better, and we have. The clinical standards for medical
device reviews have been bolstered significantly, and now we are
hard at work on reducing the review times.
IMPROVING ANIMAL DRUG AND FOOD ADDITIVE REVIEW TIMES
Although most of the discussion of FDA reform focuses on the
human drug and device review processes, the Agency also has
significant responsibility for the review and approval of animal
drugs and food and color additives. The American food supply is
one of the safest in the world. The premarket determinations
that animal drugs are safe and effective, especially when they
are intended for use in food producing animals, and that food
additives and color additives are safe constitute critical links
in the food safety chain.
As is the case with human drugs and devices, the Agency has
recognized the need to improve the timeliness of the product
review processes in both these areas. In the new animal drug
area, approval times that had steadily increased between 1988 and
1994 have begun to decline. This is particularly significant
given the changing nature of the types of applications being
submitted to the Agency. Five years ago, a large part of the
applications were for combination feed drugs. These consist of
two or more drugs already approved for specific indications and
species. Today, we are receiving many more applications for new
chemical entities, new species or new applications. As a result,
the complexity of the applications has increased considerably.
The Center for Veterinary Medicine (CVM) has developed procedures
to facilitate the development of better applications and to
expedite the review process. Through pre-Investigational New
Animal Drug exemption conferences and phased submission-of the
technical sections of the New Animal Drug Application, CVM has
reengineered the review process to decrease approval times and
increase the availability of safe and effective animal drugs.
Similarly, the Center for Food Safety and Nutrition has developed
a plan to increase the timeliness and predictability of Agency
action on food and color additive petitions. First, in order to
address the backlog of pending petitions, the agency has
allocated additional resources to the program: 23 additional
Agency scientists have been reassigned temporarily to the food
additive program; the Agency is awarding contracts for expert
review of certain portions of food additive data packages; and
one and one-half million dollars have been spent on enhanced
computing facilities for the program. With these efforts we will
begin to see a decrease in the petition inventory.
In addition to these added resources, we instituted a threshold
of regulation policy under which indirect food additives that do
not present any substantial safety concerns are exempted from the
petition process. The Agency processed 47 submissions under this
new policy in 1995.
Here again, we recognize that one way to decrease review times is
to improve the quality of the food additive petitions that are
filed with the Agency. We have been working with the industry to
do that. FDA personnel have begun conducting workshops for
petitioners to discuss what data are needed to file a complete
food additive petition.
Food additives are distinctly different than drugs and devices.
Whereas drugs and devices provide therapeutic benefits to certain
individuals, food additives will potentially be consumed by
everyone in the population. Whereas drug and device approvals
are product specific, a food additive approval results in a
regulation permitting anyone to manufacture or use the additive,
consistent with any patent protection and in conformance with the
limitations of the regulation. These facts contribute to the
unique safety concerns relating to food additives and the unique
features of the review process of food additives. We welcome the
opportunity to discuss this process further at another time.
REDUCING PRODUCT REVIEW TIMES, STRENGTHENING MANAGEMENT AND
ELIMINATING UNNECESSARY REGULATORY BURDENS
We have improved review times without sacrificing the high
standards that give Americans confidence that their drugs are
safe and work. Under PDUFA, the Agency was assured of adequate
resources to do the job and the job was clearly defined through
performance goals. At the same time, how to achieve those goals
was left to Agency management, and accountability to Congress was
assured through the five year authorization. That was real
reform. Reauthorization of this program should be a cornerstone
on which we build other improvements.
The progress we have made, however, is the result of much more
than the additional resources available under PDUFA and extends
beyond the drug review process. Of equal significance has been
the commitment of Agency management to streamline and improve the
way we regulate. I think we all can agree that strong consistent
management, the removal of unnecessary regulatory burdens, and
the elimination of wasteful or inefficient practices all serve
the critical public health goals to which we are committed. A
review of the Agency's contribution to the Administration's
Reinventing Government Initiative well demonstrates the depth of
our commitment to improving our regulatory processes. For
example, we have changed the way we regulate biotechnology
products, instituted management reforms ranging from team review
to greater use of outside expertise, eliminated or modified
product and process reviews where the public health risks did not
justify the allocation of resources devoted to those tasks,
simplified and expedited the export process, engaged industry in
a constructive dialogue about how to do more. We are committed
to doing more, and we welcome the opportunity to work with you,
Senator Kassebaum, and the Committee, and to continue working
with the industry, on further improvements.
REINVENTING PRODUCT REVIEW: S. 1477 AND OTHER REFORM
PROPOSALS
We appreciate having the opportunity to discuss the "Food and
Drug Administration Performance and Accountability Act of 1995,"
S. 1477, and the impact this bill would have on the Agency's
ability to protect and promote the public health. I would like
to acknowledge and commend the chairman for her leadership on
these issues. We look forward to working with you and the other
members of the Committee on these important issues.
There are many sections of S. 1477 which we believe could be the
basis for constructive improvements, and-on which we hope to be
able to continue to work with the Committee in developing strong
legislative improvements. These provisions include a statement
of Agency mission, specification of performance standards,
changes to the export requirements, contracting-out authority,
establishment of adequate reporting systems to enhance Agency
accountability and the need for greater input into the guidance
documents that we issue.
The general thrust of this legislation is, I believe, how the
Agency can do its job better, more efficiently. We share the
Chairman's concern with these issues. We heeded and acted upon
the concerns you and others -- Senator Kennedy, Senator Mikulski,
Senator Frist -- expressed at the hearing last April. We
recognized and have addressed many areas that needed improvement.
We recognize there is more to do.
As the Committee has requested, we are going to address in some
detail the product review process, and whether it would be
feasible to meet the review times set forth in S. 1477 without
compromising our existing standards of safety and effectiveness
and without additional resources. our testimony will focus on the
drug review process, although the comments generally are
applicable to the other product reviews for which we are
responsible. We will then address the other provisions in the
bill, except for those dealing with promotion of off-label uses
(Section 407), which will be discussed separately in Mr.
Schultz's testimony tomorrow.
We must remember that today's drugs, and science, are not what
they were a few decades ago. It may look as though what a
company is doing now -- showing that a drug is safe and effective
-- is the same thing it was doing decades ago. But that is not
the case. What the public, the scientific community and
regulators around the world expect is very different now. Until
just a few decades ago, clinical drug testing was largely an ad
hoc anecdotal observational art -- patients received a drug and
clinicians assessed whether individual patients were helped or
harmed. In recent decades, indeed in recent years, a great deal
of data and understanding have accumulated regarding many aspects
of clinical development, including placebo effect, multiplicity
of endpoints, post hoc analyses, surrogate endpoints, sources of
investigator bias, subset analyses, effects of demographic
factors (gender, age, race), drug interactions and impact of
concomitant therapies. With these understandings has come a
realization that both the observational approach and clinical
trials which are not carefully designed, while-they may correctly
identify treatments whose benefits are dramatic and adverse
effects are highly limited, often give incorrect impressions
regarding a treatments' safety and efficacy. Thus, the old
approaches often led to countless incorrect practice decisions
(e.g., unnecessary appendectomy and hysterectomy, use of
antibiotics for the common cold, for example.)
Moreover, there are new technologies with which we must now learn
how to deal with -- xenotransplantation, transgenic animals,
devices that hold biological systems inside of them, robotics,
neural networks, computer guided surgery, gene therapy, and
neucleic acid vaccines to name a few. We need to develop
scientifically-sound ways to both protect and promote the public
health in areas of explosive growth and uncertain science.
ELEMENTS OF DRUG REVIEW BY FDA
Every application submitted to the Agency purports to demonstrate
that a drug is safe and effective for treatment of a specified
ailment or condition. Upon independent review, however, many
applications do not support an objective finding that the drug,
in fact, is safe and works. The Agency's job is to conduct that
independent review. The basis for the Agency's decision is the
data collected by the sponsor during pre-clinical and clinical
testing. We have to determine that the studies are well designed
and capable of demonstrating safety and effectiveness. We also
have to determine that the data on which we make our decision
have integrity: that the trials actually were conducted and done
so consistent with the protocols, the primary data accurately
reflect the actual clinical results, and the company's analyses
of the data are fair and objective. The various components of a
typical drug application -- chemistry, toxicology,
biopharmaceuticals, etc., -- and the types of questions that need
to be answered in determining whether a drug is safe and
effective are outlined in Attachment 1.
For each medical product, there must, on balance, be demonstrable
net benefits that are greater than the risks. Few, if any, new
products are totally safe; so judging their safety becomes a
risk- benefit decision. We must determine if each new drug or
device is safe enough in view of its anticipated benefits and the
comparative benefit of other available treatments. The benefits
of a lifesaving drug or device, where there are limited treatment
options, might justify its marketing despite known risks, even
when the risks involve serious injury or death. This is often
the case with drug therapies for cancer. On the other hand, for
lesser benefits, the risk patients are willing to accept from a
drug or device goes down commensurately.
The availability for review by the Agency of the primary data on
which the sponsor bases its claims of safety and efficacy is
critical to the drug review process. I would like to commend the
Chairman for recognizing this in her bill. Why is it not
sufficient for the Agency to rely on summary data? Experience
repeatedly has demonstrated that review of primary data is
critical to verify, inter alia, the following: that responses of
tumor and infections were correctly categorized and were truly
due to the study drug; that judgmental endpoints are supported by
objective data and not subjected to bias; and, that adverse
events are correctly categorized as to severity and causality by
the drug. Additionally, access to primary data improves both the
quality and speed of the analysis by permitting the reviewer to
confirm that each analysis included only and all appropriate
subjects, perform critical analyses to determine to relationship
of drug effects to age, gender, race, disease stage, concomitant
therapies, and other key factors, and assess the impact of the
drug on parameters that may not have been summarized by the
sponsor. Thus, provision of primary data not only allows
verification, it facilitates better and faster analyses of the
safety and effectiveness of the drug.
Many different types of problems have been identified in the
review process. For example, has the sponsor asked the right
questions during drug development? A case in point involved the
development of certain drugs to treat heart failure
(phosphodiesterase inhibitors), when concern arose about
potential adverse effects on survival. Studies were therefore
conducted to examine both the symptoms of heart failure, and the
impact on survival. Unfortunately, it was discovered that
although the drugs improved the symptoms of heart failure, they
significantly decreased survival. As a result, the sponsors did
not pursue approval of these drugs.
Another example of the types of problems that have been
identified through the Agency's review of drug applications is
found with a product known as Multishield Topical Lotion.
According to the manufacturer, this lotion was supposed to be
effective in preventing skin absorption of mustard gas. It was
proposed for use by American troops in Desert Storm.
When FDA raised questions about the Multishield IND, our
laboratories attempted to test Multishield, using the methodology
the drug's manufacturer provided to us that purportedly showed
the product met its IND specifications. The test results shown in
the firm's batch records could not be duplicated by FDA--our
chemists found the methodology simply could not work. We found
that the analytical work he did and the test results he provided
were fraudulent.
The purveyor of this fraud is now serving time in jail. More
importantly, as a result of FDA's review, the safety of our
Desert Storm troops was not endangered by distribution of an
unreliable product on which they would have been relying on for
protection against this chemical warfare agent.
Finally, in 1989 FDA reviewed an NDA for dilevodol, a beta
blocker, that was marketed in Europe and about to be launched in
the United Kingdom. our review revealed several cases of severe
liver injury that led to non-approval. Subsequently, the
sponsor's review of marketing experience in Portugal and Japan
also revealed several instances of fatal liver injury, and the
drug was withdrawn worldwide.
Finally, we also have to determine that the company can make the
drug the same every time, so that batch after batch of the drug
has the same therapeutic profile. Through good manufacturing
practice inspections we compare what the company puts in its
chemistry and manufacturing controls section of its application
with what it is actually prepared to do at the manufacturing
plant.
FEASIBILITY OF S. 1477 REVIEW TIMES
FDA has been engaged in a continuous improvement effort that
involves identifying ways to reduce regulatory burden and improve
our ability to protect and promote public health and safety. We
believe that this criteria should be the test by which any reform
proposal is measured.
The question presented by the Committee is whether it is
feasible, without lowering our safety and efficacy standards, and
without additional resources, to meet the review times set forth
in S. 1477. S. 1477 requires that by July 1998 the Agency would
be reviewing all drugs within 180 days, and priority drugs within
120 days (Sections 103 and 204). Comparable review times would
be established for other products.
We have examined this question very carefully and I do not
believe that the Agency could meet the product review times set
forth in S. 1477, with existing resources, without compromising
existing public health protection. Moreover, I believe that by
focusing on further reducing drug review times beyond that agreed
to in PDUFA we run the risk of undermining the progress we are
making toward shortening the overall time it takes to get drugs
to patients.
What does it take to review an application within four to six
months? First, it takes an excellent application. With only four
to six months there would be little opportunity to obtain
clarifications or additional information from the sponsor.
Although every application could be reviewed exactly as it is
submitted, very few applications are so complete and accurately
presented as to be approvable without further discussion with the
sponsor. Second, it requires having the necessary review staff,
including all the various disciplines, ready to work on the
application the day it comes in the door. That means other work
needs to be put on hold. Third, it means companies will need to
be fully ready to manufacture the drug -- so that FDA can start
the pre-approval inspection at the same time we start the
substantive review. Fourth, the shortened review times will
compromise the effectiveness of advisory committees.
Particularly for applications that present complex problems or
involve substantial public health issues, these committees rely
on the Agency to validate, and analyze and present clinical
research findings. The timeframes for review and advisory
committee consideration jeopardize the Agency's ability to
perform this function for the committees.
The Cost of Shortening Review Times
Shortening review times to those specified in S. 1477 would
adversely effect, in a number of ways, the goal of getting safe
and effective drugs to consumers as quickly as possible.
First, reviewers will be unable to spend time with sponsors
obtaining clarifications or answers to questions that arise in
the course of the review. The only way to get the information
will be through additional review cycles. That means it will take
longer for drugs to get to market. The alternative, though less
likely, outcome would be that reviewers will feel compelled to
approve drugs based on less information, with fewer analyses and
much greater uncertainty for patients and physicians about how
the drug works and how safe it is. And that means we will have
lowered our standards.
Second, Agency resources devoted to product review would need to
be greatly expanded, and existing expertise duplicated many times
over. We would need to have enough reviewers in every scientific
discipline so that there would be reviewers with the appropriate
expertise ready to begin a review the day an application was
filed. This would mean that the Agency would need to severely
reduce work other than product approval reviews, work that in
many instances contributes significantly to public health.
One of the non-product review areas that would suffer, and where
the Agency is making important contributions that should reduce
the time it takes to get drugs to market, is in helping companies
understand in the clinical design phase what they need to do to
establish safety and effectiveness. Right now, an unacceptably
high number of NDAs are never approved. This means that
companies are investing time and money into drugs that should be
abandoned or into drug trials that do not demonstrate safety and
efficacy. Through a variety of mechanisms, we are trying to help
companies better understand what is required to establish safety
and effectiveness. For example, we will meet with companies and
review their protocols in depth, not limiting our review to the
severe flaws that could stop the trial.
We also help guide entire areas of inquiry when we take the
clinical efficacy issues for a disease state to advisory
committees to gain a common understanding of what all companies
need to do in a given area. Similarly, we are helping all
companies with their drug development when we work with Japan and
the European Union on the international harmonization efforts,
through the International Conference on Harmonization, so that
clinical trials will be useful in marketing applications all
around the world. These early efforts to address overall drug
development times are likely to provide far greater value than
an, incremental reduction in drug review times.
Under the S. 1477 timeframes, the Agency also would be required
to limit its involvement in the production and post-approval
areas. Both of these are critically important to companies and
patients. Drug production problems result in a number of
different types of adverse consequences for patients. For
example, one recent class I recall involved an albuterol spray
that was contaminated with bacteria. The result was that these
bacteria were being sprayed into the lungs of the people using
the product. In fiscal year 1995, there were 251 product
recalls. We need to be able to inspect, monitor production, and
protect the public from poorly made drugs that are dangerous or
of limited usefulness.
Right now we learn much about a drug after it is on the market.
Clinical trials typically involve only hundreds or a few
thousands of patients in carefully controlled research settings.
Once on the market, they often are prescribed to hundreds of
thousands of people. The first several years a drug is on the
market teaches us about events that occur in a very low rate,
such as the aplastic anemia associated with felbamate, and
therefore do not occur in clinical trials. We also learn about
reactions related to ordinary medical use, such as the severe
anaphylactic reactions caused by zomax that were related to how
patients took the drug under ordinary circumstances. This
knowledge enables us to adjust labeling and drug availability
depending on what we learn after the drug is widely used in
practice.
Shortening the review times also will adversely impact Agency
programs that are not related to drugs or other product approval
process, such as the safety of the blood supply, food safety and
tampering, and mammography quality. Our efforts to protect the
public from unsafe imported products -- whether it is
botulism-contaminated mushrooms or hepatitis-contaminated human
tissue, will have to be curtailed. It also will severely curtail
our ability to respond appropriately to emerging public health
threats, crises, or even to new areas where a little work would
have a large payoff.
OTHER PROVISIONS OF S. 1477 THAT COULD COMPROMISE EXISTING
STANDARDS
A number of provisions in S. 1477, in addition to the proposed
review times discussed above, that we are concerned cannot pass
that test. Rather than going section by section through the
bill, I will briefly discuss the most significant of these
provisions.
New Approval Standards: Bound Medical Practice And Scientific
Studies
There are several sections of the bill that would establish new
and lower product approval standards. For example, Section 407
would establish a new process for approving new uses of existing
drugs that would completely bypass the drug approval process. It
would establish a procedure for recognizing new uses based on
medical practice. Unlike the current requirement, the bill
provides that if an off-label use has existed for five years, is
"common" among experienced clinicians and is reasonable based
upon experience and other confirmatory evidence, that use could
be included in the product's labeling. This provision moves us
away from the accepted scientific standard of evidence back
toward evidence based solely on ancedotal experience. Medical
history is replete with examples of products and procedures that
were based on medical ancedote, not evidence, and were thought
for years by most clinicians to be effective but later turned out
to be useless and sometimes even dangerous. Indeed, when the FDA
worked with the National Academy of Sciences National Research
Council to review the effectiveness of drugs first sold in the
U.S. before the effectiveness standard was set in 1962, 1,124 of
3,443 drugs on the market, being marketed for various claims,
were pulled from the market because they were not effective.
We are not saying that individual clinical judgments about
individual patients should not be made. They are necessary and
appropriate on a patient-by-patient basis. But to base drug and
device labeling on such a "pattern of practice" standard would be
offering the public far less protection than it has today. It
also could have the unintended consequence of becoming a
disincentive for companies to collect the data necessary to
demonstrate whether off- label uses are effective.
Similarly, Section 702 would virtually eliminate approval of
devices for specific uses. It would for the first time recognize
any use "included within a general use for a predicate device" as
an approved use for 510(k) devices. If enacted as is, this
provision would allow a device originally marketed for one
clinical-indication to later be marketed for other indications,
even high risk ones, with only the submission of an abbreviated
application (510(k)) that would not document the product's
effectiveness for the new indication. Suppose, for example, that
a cardiac catheter were originally approved for mapping the
electrical activity of the heart. After it is on the market, it
is offered for a new use: to save lives by preventing a fatal
disturbance of the heart rhythm. Under the bill, it is unlikely
that we would be able to ask for data showing whether the
catheter worked to save lives or was just a costly and failed
false hope. Even worse, if the catheter were to work some of the
time, in some kinds of patients, there would be no assurance of
clinical data, independent review, or accurate labeling to help
doctors sort out who are those patients where it is most likely
to work, or most risky.
Furthermore, Section 703 would require the Agency to accept
scientifically soundstudies in lieu of well-controlled clinical
trials for medical devices. Although the phrase "scientifically
sound studies" is not defined, it is assumed that what is
intended is something less than well controlled clinical trials.
In our view this could turn modern day science on its head by
instituting a preference in law for lower quality scientific
evidence, such as anecdotal reports and case studies in lieu of
controlled trials. In essence, this would reverse the most
significant component of the 1962 Act, the requirement that
sponsors establish that products work before they can be
marketed.
We understand that controlled studies are not the only way to
show that a drug or device works and they are certainly not the
only way used today. But, there is essentially unanimous
agreement in the scientific world that they are stronger evidence
than the alternatives in this bill. In every case, the Agency
would have to assume the burden of not only specifically asking
for good science in the form of well-controlled data, but would
have to explain why it was being required in lieu of the lower
standard.
We agree that a problem exists with the extent to which drugs and
devices are being used for indications that have never been
approved. Some of those uses likely are beneficial. We know
there have been some that were deadly, even though they were
thought to be sound medical practice. The solution to this
problem, however, should be one that results in the collection
and review of the necessary data to establish efficacy, not one
which will undermine the efficacy requirement. We would like to
work with the Committee on developing those solutions.
We also are concerned that the bill would eliminate FDA's role in
assuring that modifications made to a product do not adversely
affect its safety and effectiveness. Under the bill, unless the
manufacturer's own data show that safety and effectiveness were
to diminish, FDA could not require data on the modified product
(Section 702 and 707). Yet we know such modifications can carry
initially unrecognized risk. Take the case of the soft tissue
fixation device used in orthopedic surgery, the device was on the
market to be used to anchor soft tissue during shoulder surgery.
The manufacturer wanted to change the materials being used and
modify the design. After reviewing the data for the proposed
modifications, the Agency asked the manufacturer to perform
clinical trials. The study showed that the head of the modified
device often broke off after the surgery and lodged in the
shoulder joint, causing severe pain and often the need for
corrective surgery. Further, the modified device could form the
basis for new use claims and, as I described previously, there
would be no way to assess the scientific basis for the new
claims.
We are equally concerned that the bill would remove even the
basic assurance that most new devices will be well made. Under
Section 702 a company, even one with known manufacturing problems
directly relevant to its new device, would have to be given
marketing approval even though the Agency has evidence the firm
is unable to produce a quality product.
Eliminating Consideration of Comparative Effectiveness
Another area where the bill would decrease the protection of the
FDC Act involves consideration of comparative effectiveness.
Although the Agency generally does not base its approval
decisions on whether one drug works as well as another already
approved therapy, there are circumstances where such
considerations are very important. For illnesses with
significant public health implications, such as measles or
sexually transmitted diseases, it would be unconscionable to
allow marketing of drugs which are less effective than existing
therapies. For example, for products intended to treat gonorhea,
the Agency requires a 95 percent efficacy rate. Similarly,
vaccines for measles or other highly contagious diseases must be
as effective as possible. The same consideration exists for
therapies for the treatment of serious or life-threatening
illnesses.
For both devices and drugs, the bill apparently would prohibit
the Agency from considering uses for which a product could be
marketed, unless those uses are explicitly included as label
claims (Section 408). It appears this section would even
prohibit the Agency from looking at clinical outcomes resulting
from use of a device -- for example, whether patients with
artificial hearts did well or died -- unless the outcome is part
of an explicit label claim.
Section 408 also might prohibit the Agency from requiring
sponsors to include in their labeling information about
indications for which the drug should not be used. One of the
advantages of clinical trials is that they often provide
information about when a drug should not be used, as well as
information about when it works. Requiring a sponsor to include
such information in the labeling can prevent very serious injury.
Similarly, restricting the Agency's ability to use information it
obtains from adverse reaction reporting and other types of
post-marketing surveillance does not make sense.
Fentanyl is a powerful painkiller that was approved for use
through a transdermal patch for pain control in patients, such as
those with terminal cancer, who had developed a tolerance to
opiods. Physicians and dentists began using the patch for
conditions like post operative pain, in persons who were not
opiod tolerant. This caused severe respiratory distress in some
patients, and resulted in several deaths. Based on this
experience, the Agency required the sponsor to make significant
labeling changes and to include in its labeling a specific
warning about this dangerous, unapproved use. Obviously, the
sponsor never intended that its product would be used on patients
who could not tolerate such powerful medication. Section 408
could limit the Agency's ability to include this type of
important information in product labeling.
Substitution of Judgment: Third Party Approvals And Other
Mechanisms To Bypass FDA's Decisions
There are a number of provisions throughout the bill which would
allow companies to market pro-ducts without FDA approval, if the
Agency fails to meet review deadlines. Under Section 404, for
example, a company that has obtained a European Union approval
could market its product without FDA approval if the Agency fails
to meet the review time.
The underlying rationale for such provisions appears to be that
they would serve as a mechanism for holding the Agency
accountable for its performance. The problem with them, however,
is that they allow the concept of accountability to completely
override the statute's primary objective that drugs and devices
be proven to be safe and effective before they can be marketed.
Although we fully agree that the Agency must be held accountable
for its performance, this can and must be accomplished without
sacrificing existing protection.
The concept of marketing approval by default is not new. Prior
to the 1962 drug amendments that required sponsors to demonstrate
that their products work, drugs could be marketed if the Agency
failed to act within specified time frames. Proponents of the
amendment to require an affirmative determination by the Agency
of safety and efficacy as a prerequisite for marketing approval
recognized the critical importance of the Agency's review, and
the need to give the Agency greater flexibility in light of the
volume of new drug applications, the increasingly more complex
nature of such applications and the availability of expert
personnel to review those applications.
These same factors motivated Congress in 1990 to change a similar
marketing approval by default provision in the device statute.
As a result of those changes, the Agency must make an affirmative
finding of substantial equivalence for devices to be marketed
under the 510(k) clearance process. This change, like that in
1962 for drugs, enhanced the protection afforded the public.
The reliance on approvals by other countries does little to
ameliorate the problem. Assuming that a drug or device legally
marketed in the European Union should be marketed here simply
because of the passage of time places an extraordinary faith in
an untested, unevaluated system still in its infancy. under these
provisions, we are concerned that the only way FDA could prevent
a European Union- approved product from being marketed in the
U.S. would be for FDA to prove that it is unsafe or ineffective.
Essentially, this would take us back to the type of drug
regulation that existed in this country prior to 1938, with the
commensurate significant loss in consumer protection.
It should be noted that although this provision would tie the
FDA's hands regarding drug and device approvals, it would not
require the same allegiance to foreign government actions for a
decision to withdraw marketing approval or not to approve the
product in the first place. Under S. 1477, if the European Union
or United Kingdom withdraws a drug from the market, it would not
automatically be withdrawn in the U.S. Moreover, this provision
could provide foreign owned companies, particularly those that
are government subsidized, a dangerous competitive tool in the
world market.
The bill's requirement for third party reviews is equally
troubling. The third party review sanction set forth in Section
743 raises particular concerns, in addition to those generally
applicable to the feasibility of third party review. Once the
provision is triggered, it would interrupt consideration in the
middle of the overall process for many applications. Companies
would be faced with having reviews performed by a third party
reviewer who has very little knowledge of the specific
development process for the drug and/or of the agreements made
during that process. The contracting requirement assumes that
well trained staff, free of conflicts of interest yet familiar
with the regulatory review process will be readily available to
perform this work. We doubt whether that would be, in fact, the
case.
The feasibility of third party review raises important questions
that should be, and are being, carefully examined. FDA's
scientists and experts are charged with exercising independent
and unbiased judgement. They comply with stringent financial
disclosure and conflict of interest requirements designed to
protect the decision- making process against bias. It is not
clear whether, and how, this independence can be maintained with
private sector review organizations. The Agency has initiated two
different pilot projects to assess the feasibility of such a
program.
The substitution of judgment also extends to the manufacturing
area. When a contractor has given a manufacturer good marks for
its production processes, FDA is prohibited from inspecting the
plant for two years unless the Agency learns through other means
that there is something seriously wrong at the plant.
The bill also undermines consumer protection through other
default mechanisms. Now, if FDA suspends or revokes the license
of a blood bank because it has created a public health danger, it
is shipping HIV-contaminated blood, it cannot resume shipments
until it has fixed its manufacturing problems. Under S. 1477, a
blood bank that has had its license suspended or revoked can
resume shipping blood even before it has fixed its manufacturing
problems, if the FDA misses the 30 day reinspection deadline by
even one day. (Section 606)
Similarly, the changes the bill proposes for review of indirect
food additives could result in unsafe food additives being sold
if FDA does not fully review an indirect food additive
notification and publish its decision on that food additive in
the Federal Register within 90 days. (Section 902) The 90 days is
an unrealistically short deadline; it would take many FTEs not
provided for in this bill, to lower review times to 90 days.
Therefore, FDA either will be forced into premature disapprovals,
or it will have to watch as the public is exposed to industrial
chemicals which pose a potentially serious risk to the public
health.
Expanding Access To Unapproved Therapies
The provisions for treatment access to investigational products
are clearly intended to meet real patient needs. But as drafted
they go too far. We, too, want patients who have no good
treatment options to have access to the newest therapies, even
before they have been fully studied and evaluated. We have made
experimental drugs available early-on in the process by our use
of treatment INDs, parallel track, single patient protocols, and
emergency use INDs. But we do it in a way that still permits the
basic research on the drug to be done, so that eventually
physicians and patients know whether the promising therapy really
works, and how best to use it.
Unfortunately, S. 1477 (Section 202) would permit drug and device
companies to side-step completely FDA's approval process and go
into the manufacture, promotion, and sales of a product for any
serious disease or condition without FDA approval. Under S.
1477's provisions, expanded access protocols could be given for
any product that diagnoses, monitors, or treats a serious disease
or condition, so long as other therapy is not "comparable or
satisfactory."
In addition, S. 1477 would permit the manufacturer to widely
promote the availability of the expanded-access protocol.
(Section.202) Unlike FDA's current system for cost recovery under
a treatment IND, there is no requirement in the bill that
adequate enrollment be obtained for clinical trials that are
designed to determine the safety and effectiveness of the
product, and that the manufacturer pursue marketing approval with
due diligence. In short, the patient would have to pay full
price for an experimental product, and the company would be under
no obligation to ever find out its true value. Coupled with the
provisions for cost recovery, promotion of the availability of
experimental treatments would create a climate where the
unscrupulous could sell untested hope with scant risk of being
found out and only weak sanctions if they were. The 1995 Health
and Human Services Inspector General's review of
commercialization of unapproved medical devices shows this is not
just a theoretical risk but a predatory business practice hard to
control even with today's stronger law.
Advisory Committee And Scientific Review Groups
We agree that advisory committees are an important part of FDA's
review processes. We value the guidance and direction we receive
from these outside experts. But S. 1477 would create "scientific
review groups" that would be expensive, difficult to handle
administratively, and would meet so often that we doubt that
respected experts would be willing to serve on them. (Section
106)
Perhaps more importantly, the scope of the scientific review
groups set up by S. 1477 is so expansive they would have the
ability to second-guess any significant scientific decision made
by FDA, to an extent that the scientific review groups would
become a shadow FDA. Now, advisory committees usually meet three
to four times a year; this bill would require that they meet at a
minimum six times a year (Section 106), at an increased cost to
the Agency of approximately $6,000,000. The costs in fact would
be higher, because advisory committees would have to meet much
more often in order to hear appeals on every significant decision
made by FDA on whether a clinical trial should start, how a
protocol should be designed, or whether an application should be
accepted for review by the Agency (Section 107). The bill also
places other unreasonable demands on both FDA and the review
committee members, in that it would triple the time before which
meetings must be announced and agendas set, and permits committee
members to be inundated with paper and lobbied by companies and
other individuals. In short, scientific review committees would
impede drug review, not enhance it.
We also think that there must be appropriate methods for
appealing decisions made by first-line reviewers, when a company
disagrees with such a decision. Those mechanisms exist, and last
June I asked the Center directors to review the existing appeal
mechanisms, make improvements where possible, and insure that
companies are aware of the availability of such mechanisms.
There already have been significant changes in how appeals from
clinical holds are handled, and the Centers are working hard to
train their staffs so fewer decisions need to be appealed. But
taking every disagreement to a scientific panel during the entire
drug development phase will inhibit, rather than enhance,
communication between industry and FDA, creating an adversarial
process in place of a cooperative one, and ultimately increasing
overall drug review times.
Limiting Agency Flexibility in Review Process
There are a number of provisions in S. 1477 that would
dramatically limit the Agency's ability to manage its resources
efficiently. These provisions would adversely affect both the
product review process and the other public health activities of
the Agency. For example the bill orders the Agency to consider
certain products (such as radiopharmaceutical drugs) in
particular divisions (Section 402); it forces us to keep biologic
product licenses, even when we are willing to eliminate them for
some types of biologics (Section 606); conversely, it eliminates
establishment licenses, even for products that could be most
simply and effectively regulated using ELAs. (Section 606) ELA
reviews have found examples of cross-contamination and seriously
violative air handling systems. In addition, certain
technologies may actually be more flexibly regulated by the use
of the ELA, for example, cellular and gene therapies, and
xenotransplantation products (tissues and organs transplanted
from animals to humans). GMPs alone would not be adequate to
assure that proper controls are maintained to prevent the spread
of infectious diseases.
It should be beyond dispute today that you cannot legislate good
management. We need to have clear performance goals and we need
to be held accountable for meeting those goals. But we need the
flexibility to change in response to changing conditions,
reallocate resources to address the most significant public
health problems, to respond to emerging issues. Good management
comes first and foremost from good managers. I believe we have
such managers, and that they should be allowed to do their jobs.
There also are sections of S. 1477 that express laudable goals,
but again are so expensive as to be totally unrealistic in this
budgetary climate. Information systems (Section 104), the formal
publication and compilation of all policy statements (Section
105(B)), the extensive meetings on clinical trial design, and the
additional advisory committee meetings would cost more than FDA
could conceivably afford to spend in these areas.
Similarly, the time frames specified for a variety of actions,
such as reinspections and issuance of regulations are
unrealistically short.
Conclusion
I hope the concerns I am expressing about this bill will not be
construed as commitment to the status quo. The Agency looks
forward to continuing to work with the Committee and others on
new ideas on how we assess new product effectiveness, how we got
productions labeled to reflect the best data on their use, how we
get clinical development, and how we get the Agency's independent
review of new products to go faster so scientific advances move
to the bedside more quickly. I agree that we need to consider
alternative ways to determine whether new uses for existing
products are sufficiently scientifically credible to be included
in a product's labeling. We also recognize that some claims for
diagnostic products or surgical tools are supported by different
kinds of data from those we generally expect for other kinds of
products. We need to describe clearly when this is the case.
There are provisions of this bill that reflect good ideas. As I
stated at the beginning, we believe that there is still a great
deal that we can do to improve our ability to get safe and
effective products to patients as soon as possible. We have a
strong foundation in the Prescription Drug User Fee Program, the
efforts that have been made under the Administration's
reinventing government initiative, and our successes in
expediting development and approval of AIDS drugs, on which to
build. The Agency and industry have demonstrated that by working
together we can develop reasonable solutions to regulatory
problems solutions that serve and promote the public health. We
look forward to working with the Committee and the industry on
finding even more ways to improve the existing system.