Chairman Bilirakis, and members of the Committee, I am pleased to be here
today as you consider a very important public health issue -- ensuring that the
Food and Drug Administration (FDA) protects the nation's safety and health. Let
me say at the outset that we are committed, as I know you are, to ensuring
timely access to new drugs and devices that are shown to be safe and effective.
We look forward to working closely with you and your colleagues in the House and
Senate on bipartisan legislation that accomplishes this goal.
The FDA's primary Mission for 90 years has been to protect and promote the
public health. I know you share our view that all Americans deserve assurance
that the medicines they take or medical devices they need are safe and really
work, and that the foods they eat are safe. We are committed to maintaining
high standards so that consumers can continue to have that confidence and
assurance. But high standards alone are not enough. Timely access to safe and
effective products is important to the public health as well.
To meet the goal of timely approval of safe and effective products, FDA must
be open to change. This is a time of unprecedented medical challenges and
medical breakthroughs. An important measure of our value as an Agency will be
our ability to keep pace with these changes. Thomas Jefferson said it best:
"Our laws and institutions must (move forward hand in hand with the progress of
the human mind."
As Commissioner, the first way I have sought to effect change is to attract
a new generation of leaders to the Agency. Much of the progress FDA has made
over the past few years began with our five new Center Directors. The many
changes they have made have moved us closer to our goal. Second, we have
vigorously pursued and implemented more than thirty FDA reinventing initiatives
as part of President Clinton's and Vice President Gore's National Performance
Review. Among the changes we have made, are speeding new cancer drugs to
patients and targeting our limited resources to higher risk medical devices
while no longer requiring FDA premarket review of hundreds of categories of
simple devices such as tongue depressors and urinary catheters. Finally, in
addition to the many changes we have already made, the administration is
committed to supporting bipartisan legislation that does not lower current
standards for product safety and efficacy.
If we are to achieve our shared goals of improving the Agency's ability to
protect and promote the public health by assuring the public speedy access to
safe and effective products, 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 1980's 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 to undermine the
real progress the Agency has made. While we share the goal of streamlining our
operations and speeding safe, life saving drugs to the American public,
undermining progress in critical public health and consumer protection is not
Let me explain what we have done.
THE FOOD AND DRUG ADMINISTRATION IN 1996
A. MEETING AND EXCEEDING THE PRESCRIPTION DRUG USER FEE
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. In 1995,
approval times were even better: 16.5 months was the median approval time for
the 82 NDAs approved in that year. For the 15 priority drugs, the median
approval time was 6 months. These latest improvements in approval times have
been made possible by shortening the time for completion of most first reviews
of applications to only 12 months. How did we do it? In 1992, Congress, the
Agency, and the pharmaceutical industry recognized that additional resources
were one key to improving FDA's review of drugs and biologicals. Congress, led
by a partisan initiative of this Committee, unanimously enacted the Prescription
Drug User Fee Act of 1992 (PDUFA). The Agency, in turn, committed to very
aggressive application review 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 Under the provisions of the program, if a major amendment is
submitted by the manufacturer-late in the process, an additional three months is
We should never forget that the ultimate goal is ensuring that American
patients have access to products that work and really make a difference. By
that measure as well, the FDA is delivering. The story of AIDS therapies is
Of the eight antivirals used to treat AIDS, FDA was first to approve them in
seven instances, DDI, DDC, D4T, 3TC, saquinivar, retinovir, and indinavir. In
the case of AZT, FDA acted contemporaneously with France and the United Kingdom.
On March 1, the Agency approved ritonavir, the second in a new class of AIDS
drugs called protease inhibitors, and we were the first country to do so. On
March 13, we approved the newest protease inhibitor, indinavar, and this was
done in 42 days. 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.
B. 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. Three
separate studies demonstrate that FDA compares extremely well. First, at the
request of this Committee, GAO looked at how FDA was performing, even before
PDUFA was enacted. It found that by 1994, FDA review and approval times were
faster than those in the United Kingdom -- a country whose regulatory system
many critics like to cite as a way of doing things better and faster.
Second, FDA conducted an analysis of the "new molecular entities" (NMEs)
introduced throughout 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 of these
NMEs that had been approved in both the United States and the United Kingdom.
We approved 30 of them first, the United Kingdom 28. There were 44 of these
NMEs approved in both the United States and Germany. We approved 31 of them
first, Germany 13. There were 14 of these NMEs approved in both the United
States and Japan. We approved 10 of them first, Japan 4.
Moreover, it is not just the numbers that compared well. We also found that
there are numerous drugs with important therapeutic values available here, but
not in these other countries. On the other hand, virtually all of the drugs
available in these other countries but not approved here have closely related
drugs (i.e., therapeutic equivalents) in the United States. Moreover, the
United States is first to approve a significant proportion of "global" drugs --
those ultimately approved by more than one country.
The third, and most recent analysis was conducted by the Centre for
Medicines Research, an industry funded, not-for-profit research group in the
United Kingdom. This analysis once again demonstrated that FDA is a world
leader in both the quality of its drug reviews and the timeliness of its
approval. CMR found that FDA's median approval time for NMEs in calendar year
1994 and 1995 was as short as that in the United Kingdom and shorter than those
in France, Spain, Germany, Australia, Japan, Italy, and Canada. Moreover, the
FDA has had more first launches of worldwide NMEs than any single European
country since 1990. In fact, CMR's analysis of worldwide NMEs launched in the
United States and Europe showed that the United States has had a higher
percentage of first launches than the top three European countries combined.
What these three studies demonstrate is that if you are an American patient,
you have access to therapeutically important new drugs that have been proven
safe and effective sooner than any other country's citizens.
C. MAKING NEW DRUGS 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 potentially valuable therapies outside of the clinical trials
needed for drug development 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 for whom there is no satisfactory alternative
treatment may get access to a promising drug after clinical testing shows that
it may be effective, but before it is approved for marketing. Under FDA's
"treatment IND" provision, treatment is given under simplified protocols that
collect important safety and, where appropriate, efficacy data.
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 thought to
predict actual clinical outcome, such as longer life or a decrease in
infections. Recently, we announced a new initiative for cancer drugs that
incorporates accelerated approval using tumor shrinkage as the surrogate marker.
"Accelerated approval" is a kind of "conditional approval," because the
applicant must agree to conduct further studies after marketing to measure the
actual clinical outcome, not just the surrogate marker. If the studies do not
verify a clinical benefit, FDA can revoke the approval. We have already
approved ten drugs under this accelerated approval process since it was. put in
place in December 1992. They include six drugs to treat AIDs and AIDs related
illnesses, three drugs to treat cancer, and one drug to treat multiple
Finally, we allow other experimental drugs to be made available under an
emergency or single patient IND for patients who are in need of a drug but do
not meet protocol criteria. As a result of these programs, since 1987 more than
75,000 patients have received access to promising new drugs while they were
D. IMPROVING MEDICAL DEVICE REVIEW TIMES
We also are making significant strides in strengthening our medical device
program. Improvements 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 138 days, down 24 percent from the
182-day average in fiscal year 1994. Moreover, backlogs have been virtually
eliminated. Only nine 510(k)s were overdue at the end of FY 95, compared to 500
a year ago and nearly 2000 in December, 1993. The average review time for those
devices needing premarket applications (PMAs), which in fiscal year 1995 was 20
months, is still too long, but we are making progress there as well.
It is important to remember, however, where the Agency was in the 1980's.
Congress found -- as did the Agency -- that the standards for the review of
clinical data on how to use 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 review times
E. IMPROVING ANIMAL DRUG AND FOOD ADDITIVE REVIEW TIMES
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 number of the applications were for combination
feed drugs, which consist of two or more drugs each already approved for
specific indications and species. Today, more applications are for new chemical
entities, new species, or new indications. As a result, the complexity of the
review 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. By meeting with sponsors prior to the submission
of their investigational new animal drug exemption applications and encouraging
the 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 Applied Nutrition (CFSAN) 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 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
was spent for enhanced computing facilities. With these efforts, we have
already begun to see a decrease in the petition inventory.
Second, we instituted a threshold of regulation policy under which
noncarcinogenic 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.
Finally, we again recognize that one way to decrease review times is to
improve the quality of the food additive petitions 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 and studies are needed
for a complete food additive petition.
REGULATORY INITIATIVES AND MANAGEMENT REFORMS
Mr. Chairman, 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
The progress we have made 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. The Agency's contribution to the
Administration's Reinventing Government Initiative well demonstrates the depth
of our commitment to improving our regulatory processes.
FDA's initiatives, which will speed the availability of new products,
streamline FDA procedures, and reduce regulatory burden without sacrificing
safety, touch all of the regulated product areas. In biologics, for example, we
have eliminated the establishment license application (ELA) and individual lot
release requirements for well characterized therapeutic biotech drugs.
According to the biotechnology industry, these changes will save their companies
millions of dollars, reduce required paperwork by thousands of pages, and cut
drug development time by months. In drugs and biologics, we have reduced and
are working to continue to reduce the number of manufacturing changes that
require pre-approval and have proposed regulations to reduce the number of
environmental assessments required to be submitted by industry.
In the device area, not only have we exempted 572 categories of low-risk
medical devices from premarket review, we also recently began implementing a
pilot program for the third party review of certain low risk medical devices in
classes I and II.
In the area of food safety, FDA is working with the industry to build safety
controls into their food production system. The Hazard Analysis Critical
Control Points System (HACCP), towards which the Agency is moving, is designed
to replace the old system of detecting and correcting problems after they occur
with a system of preventing them in the first place. It permits companies to
devise and implement food safety plans uniquely suited to their needs.
Finally, in the area of animal drugs, we are seeking to replace the current
system of requiring submission of medicated feed applications for individual
feeds with a system to license facilities that comply with GMPs.
I do not have time today to adequately list or describe all of our
initiatives, so I am attaching an appendix to my testimony that sets forth
summaries of our efforts and accomplishments. Collectively, these efforts
reflect the Administration's commitment to reinventing government while
preserving the important health and safety protections that the American people
rightly expect for these products.
THE HOUSE REFORM BILLS
Mr. Chairman, I would like to address the three reform bills that are the
subject of today's hearing. We understand, from conversations with the
majority, that there likely will be some changes to the three bills and we look
forward to working with members of the Committee to improve these bills.
However, my testimony today is based on the bills as they were introduced and as
they stand before the Committee today.
Rather than address each bill and provision separately, I will address the
concepts or provisions about which the Agency has the most serious concerns.
First, I will address a concept common to all three bills, and one that the
Agency finds to be extremely troublesome the privatization of FDA's review
Second, I will discuss a number of other provisions that we believe would
result in unsafe products being sold to the American public.
Third, I will address the provisions that are problematic because they
actually lower current efficacy standards.
Fourth, I will discuss the provisions in the food bill that undermine the
Nutrition Labeling and Education Act of 1990, one of Congress's most popular
public health measures in the last decade.
Finally, I will touch briefly on the bureaucratic requirements these bills
impose, which will make it harder, not easier, for FDA to meet its goal of
quickly getting quality products on to the market.
A. ALL THREE BILLS WOULD GIVE PRIVATE PARTIES THE RESPONSIBILITY FOR
FUNCTIONS THAT DIRECTLY AFFECT THE PUBLIC HEALTH
All three bills include privatization of FDA's review functions.
Specifically they would permit third parties to make approval decisions for new
drugs, devices, food and color additives, and health claims for foods. The
bills would allow the review of these products and claims by reviewers who are
paid by the industry to perform the reviews. In some instances, FDA would have
a short, not very meaningful, opportunity to review the decision of the third
party before that decision becomes final.
However, when a third party decided to initially classify a device into
class II, which is the class into which 80-90% of all non- exempt devices fall,
FDA would have no opportunity to review the decision; it would automatically
become final, even if the third party incorrectly classified a high risk device
as class II.
The concept of privatization of product application reviews is problematic
for a number of reasons. First, FDA's scientific and clinical experts are
charged with exercising independent and unbiased judgment. They comply with
stringent financial disclosure and conflict-of-interest requirements designed to
protect the decision- making process against bias. It is not clear how or
whether this independence can be maintained with the private sector,
particularly since the sponsor gets to choose and pay the private party and
repeat business may depend on the sponsor's satisfaction with the private
Second, FDA's reviewers have extensive knowledge about all of the similar
products that are made by different companies around the country. When a
reviewer looks at all of the drugs for arthritis and other inflammatory
diseases, or all of the heart valves, what that reviewer learns from each review
increases his/her understanding of that group of drugs or devices and their
effect on the body. As a result, FDA reviewers see problems that reviewers with
less information might not see.
This expertise was brought to bear five years ago when the Defense
Department (DOD) was getting ready to do battle against Sadam Hussein. To
protect our troops from possible chemical warfare, the DOD worked with a
manufacturer to come up with a cream that could protect our soldiers, skin from
chemical attack. DOD asked FDA to look at the data developed by the company.
our reviewer, who had looked at many other similar products, thought that some
of the methodology to test the product was oddly out of line as compared to
other topical skin protectants, and so he asked our investigators to verify the
firm's claims. As it turned out, the consultant hired to develop test methods
for the firm submitted fraudulent information and the data did not support the
use of the cream against chemical attack. The DOD did not use the cream, and
the consultant was prosecuted. You are not likely to find in the private sector
the kind of expertise and breadth of knowledge that allowed FDA to uncover the
problems with the multishield cream.
The third problem with privatization is the lack of continuity. For
example, FDA's reviewers are able to work with the same drug over time -- first
reviewing the IND, then reviewing the NDA. By staying involved in a drug's
development, reviewers can build on what they already know. Third party
reviewers may have little knowledge of the specific development process for the
product and/or of the development agreements made during the process.
Mr. Chairman, we believe that contracting out product review to third
parties should be done only if there is evidence that it can be done safely. A
pilot is essential to determine if that can be done. This is why FDA is
conducting its pilot program for low risk medical devices. We are trying to
determine whether third parties can accomplish the goal of getting safe and
effective products to the American public.
The privatization provisions in the bills raise additional concerns. For
example, some seem to be applying different arguably lower -- standards for the
products being reviewed. For example, the drug provision indicates that third
party reviews shall be conducted under the standards and requirements of the
Act, but also states that the approval standard for third party reviews is a
"reasonable assurance,, of safety and effectiveness, apparently an intention to
lower the standard from the one currently in the FDC Act. For food additives
being reviewed by a third party, the standard has been changed (arguably
lowered) from "safe" meaning a "reasonable certainty of no harm," to a
"reasonable assurance" that the food additive may be safely used.
Moreover, under the privatization provisions, FDA is faced with a nearly
impossible burden if it disagrees with a third party that a product should be
approved. For example, the drug and device provisions state that when a third
party recommends approval, the application is deemed approved unless FDA finds
that there is a reasonable probability that the drug or device is not safe or
effective. Under the food and color additive provisions, FDA can only deny
approval of a food or color additive recommended by a third party if the Agency
can demonstrate that there is a "reasonable probability" that the additive is
Historically, it has been the responsibility of the drug, device, and
additive manufacturers -- those who would profit from the products' uses -- to
demonstrate to the Agency that the products they propose to market are in fact
safe and, where appropriate, effective. In the case of drugs and devices, FDA's
responsibility has been to review the evidence and either approve the drug or
device if the Agency concurs that the product has been shown to be safe and
effective, or refuse to approve the product if, in the Agency's opinion, safety
or effectiveness has not been demonstrated. In the case of food and color
additives, FDA's responsibility has been to review the evidence and either
approve the additive if the Agency concurs that the product has been shown to be
safe or refuse to approve the additive if, in the Agency's opinion, safety has
not been demonstrated.
To require the Agency to demonstrate that a product is not safe or, where
appropriate, not effective, is to require FDA to demonstrate something for which
there may be no data because sufficient studies have not been conducted.
Because more often than not there is a lack of evidence of safety or
effectiveness, (rather than definitive evidence showing that a product is unsafe
or ineffective), this will be an extremely difficult burden for the Agency to
meet. The effect of this shift in the burden of proof is to virtually remove
FDA from the evaluation of any product that a manufacturer chooses to have
reviewed by a private party. Since many of these products literally involve
life and death and since there are at best very serious doubts about whether
these private organizations can do an adequate job, this provision will
seriously jeopardize the public health.
Finally, because there is a risk that only third parties that err on the
side of approving applications and petitions will succeed in this market, there
is a risk that the incentive will be for third parties to approve applications
and petitions -- not to critically review them. If what this bill is trying to
accomplish is getting safe and effective products on to the market, broad
privatization will not accomplish that end.
B. ALL THREE BILLS WOULD INCREASE THE POSSIBILITY OF
PRODUCTS REACHING THE MARKET
Many of the provisions in the House bills weaken the standards under which
FDA has operated. Obviously, we have serious concerns about the provisions that
would change the basic efficacy standards, and I plan to spend some time
discussing those provisions. But first, I would like to discuss the other
measures in these bills that would undermine the Agency's ability to protect the
American public from unsafe products. These provisions undercut safety either
because they exempt certain activities or products from FDA review or oversight
or because they limit the type of information that FDA can ask for or review.
Although there is some overlap, I will address the bills separately.
1. H.R. 3199 -- Drugs and Biologics
Removal of Protections for Subjects of Drug Testing. As you know, FDA plays
an important role in overseeing the safety of drug experimentation in humans.
H.R. 3199, however, eliminates much of our ability to protect human subjects.
For example, the bill shortens the amount of time FDA has to review an
investigational new drug application (IND) before clinical trials can begin. It
also cuts back on the amount of information FDA can receive when it is
evaluating whether to allow an investigational new drug to be administered to
human subjects for the first time. The shortened timeframe and the limited
information together make it difficult for FDA to stop a potentially dangerous
trial. In addition, Phase I and Phase II studies (which are the earliest stages
of drug testing in humans) could be conducted without any FDA review of the
Finally, the bill limits FDA's ability to stop a clinical trial. In fact,
the bill would permit trials to continue even though the investigators are not
qualified or the sponsor has submitted inaccurate information to the
investigator. The effect of the bill is to eliminate important protections that
now exist for these investigational studies.
Summary Data. After a sponsor of a new drug has completed its studies, it
compiles a new drug application (NDA), which includes a report summarizing the
results of the study. In addition to that report, the sponsor will have primary
data, which consist of data tabulations (listing of the data points) and case
reports (i.e., the forms on which the investigators have listed their
Under current law, when FDA reviews an NDA, it receives the summary report
and the data tabulations for all study subjects. FDA initially receives the
actual case reports only for subjects who have died or dropped out of the study,
unless the Agency asks for additional case report forms.
Section 4 of H.R. 3199 would permit sponsors to submit summary data -- i.e.,
the study report -- and only those data tabulations and case reports relating to
deaths or drop outs due to adverse reactions. If FDA wants to see the
additional data tabulations or case report forms, the office director must make
a request in writing and must specify the reasons for the request for a
This provision will seriously compromise FDA's review process. The
submission of primary data is important for a number of reasons. First, it is
essential to discovering and discouraging the submission of fraudulent data.
Second, summary reports sometimes contain errors that can be discovered only
by, reviewing primary data. Third, summary data have been screened, processed,
and interpreted by the sponsors, who often just do not see the shortcomings of
their drugs. Someone who does not have an economic interest in the outcome of
the study should be taking a hard look at the underlying data to verify the
interpretation of summary data.
Finally, problems associated with a drug may be visible through an
examination of the primary data that are not visible from a summary. For
example, the sponsor may attribute deaths and discontinuations of study subjects
to causes other than the drug, but review of the raw data may show that those
adverse reactions are associated with the drug itself. Under the bill, if the
sponsor does not think that the drug caused a death or drop out, the sponsor
simply would not submit the data tabulations or case report forms.
Even hints of information found in patient report forms can reveal or lead
to critical information. For example, when a reviewer in the Center for Drug
Evaluation and Research reviewed the patient data for dilevalol, a drug used to
treat high blood pressure, she (not the company) noticed that three of the
subjects suffered from liver injury while on the experimental drug. Based on
her knowledge of this class of drugs, and the fact that other drugs of this type
rarely caused this type of side effect, she decided to look further. The
company then examined recent data available from Japan and Portugal, where the
drug had already been approved. The company found severe liver injury as well
as deaths. Based on this careful observation by an FDA reviewer, the drug was
not approved in the United States, and it was removed from the market worldwide.
Mr. Chairman, I frankly cannot think of what the objections to submission of
primary data might be. The sponsors already have the data. Given the fact that
this data may now be submitted on computer disks rather than in hard copy, the
"truckloads of paper" argument does not hold. If FDA's drug review times did
not meet or exceed the Prescription Drug Use Fee Act goals, which the Agency and
the drug industry jointly established, the argument against primary raw data
might be that it delays FDA's review. However, FDA is meeting the PDUFA goals.
The only possible reason that sponsors can have for not wanting to submit
primary data is that they do not want FDA to scrutinize their data. The testing
of drugs that we make available to the American public should undergo this type
Limiting Consideration of Certain Effectiveness Data. H.R. 3199 also limits
what FDA can look at in making a determination of effectiveness. For example,
Section 5 provides that the determination of effectiveness cannot include the
evaluation of relative effectiveness unless the effectiveness of the drug is
explicitly compared in the labeling to that of another drug.
Although FDA generally does not base its approval decisions on whether one
product works as well as another, there are circumstances where such
considerations are important. For illnesses with significant public health
implications, such as those that are serious or life-threatening or that involve
public health transmittal risks (e.g., sexually transmitted diseases) it
generally would be unconscionable to allow marketing of drugs that are less
effective than existing therapies.
For example, FDA require a 95 percent efficacy rate for gonococcal
eradication for products intended to treat-gonorrhea. This is an efficacy rate
products can meet today. Similarly, FDA refused to approve an HIV test kit that
demonstrated a lower accuracy rate than one already on the market. It generally
would not be in the public interest to have products available that are less
effective in treating a public health epidemic or serious or life threatening
Section 5 also provides that the determination of effectiveness cannot
include the evaluation of any use not explicitly included in the labeling. This
appears to prohibit FDA from requiring, in the labeling, warnings about
indications for which a product is dangerous or known not to be effective.
Manufacturing Changes. As you know, FDA's ability to keep our nation's drug
supply safe does not end with approval of a new drug. FDA is vigilant to make
sure that the subsequent manufacturing of those approved drugs will not
adversely affect their safety or effectiveness. Manufacturing changes that are
made with the best intentions sometimes result in making a drug more dangerous
or less effective. Because of the devastating impact manufacturing changes can
have, we have made certain that companies tell us about the changes they are
making and we ask that some changes come in for FDA review and approval before
they are made. H.R. 3199 would permit drug and device manufacturers to make
many risky manufacturing changes without first coming to FDA.
Specifically, section 13 of the drug bill would permit manufacturers of
drugs, most biologics, blood, and blood components to make many changes in
manufacturing without prior approval as long as there is not a resulting change
in formulation or release specifications, the changes are validated, and FDA is
notified in an annual report. Other manufacturing changes would require
validation, end-product testing (to determine equivalence), and notification to
FDA at the time of the change (although not necessarily before a product
manufactured under the changed conditions is in distribution).
The concern we have with the approach for drugs, most biologics, blood, and
blood components is that even changes that do not affect formulations or release
specifications can still change the safety and effectiveness of a product.
Similarly, equivalence testing may not always detect problems that can affect
safety and efficacy. Moreover, such products may be in distribution before FDA
has had time to react to the change.
Perhaps, our concerns are best illustrated by the infamous "Cutter" incident
with Salk polio vaccine. Salk polio vaccine is a "killed" vaccine -- i.e., it
is free from any live virus. In the 1950's Cutter made a seemingly minor change
in the manufacturing process -- it simply changed the type of filtration process
used in the manufacture of the vaccine. That change let live virus into the
vaccine. None of Cutter's end-product testing was able to detect the deadly
change. Eleven people (including children) contracted polio and died, and about
two hundred more got polio before the vaccine could be pulled from the market.
Another example relates to a change in the method of growing the cells from
which a biotechnology heart drug was made. The new method caused a change in
the fine structure of the drug molecule. This change was not detected by final
product testing, but it resulted in a less effective dose. Similarly, without
submitting the change to FDA for review, a firm changed the particle size of
bulk carbamazepine, a seizure medication. Although the product met existing
specifications, the change in particle size caused the drug to absorb moisture,
and thus, to dissolve more slowly than did the product made from the approved
source. The slower dissolution may have resulted in patients absorbing the drug
more slowly and thus, getting smaller doses. FDA received reports of seizures
in persons taking the drug made from the changed bulk drug.
Similarly, under these new bills, a manufacturer could change the method of
viral inactivation in a blood product used to treat hemophilia without first
coming to FDA. A change to a new method that was incapable of such inactivation
could result in a product that transmits hepatitis or HIV. Because FDA would
not learn about the manufacturing changes until the public actually is receiving
the product, it could act only after the public has been exposed to a product
capable of transmitting hepatitis or HIV.
In sum, we know that even seemingly minor-manufacturing changes can make a
significant difference and that the problems wrought by those changes will not
always be picked up by end product testing. The bills, provisions that change
how manufacturing changes are regulated is going to permit manufacturers to make
changes that will harm the public.
GMP Inspections. After a drug has been approved, FDA conducts good
manufacturing practice (GMP) inspections to ensure that the company can make the
drug the same every time, so that batch after batch of the drug has the same
therapeutic profile. Otherwise, the public may receive drugs that do not have
the effect they are supposed to have or actually could cause harm. H.R. 3199
permits those inspections to be conducted by third parties. Although FDA has
been exploring the use of third party inspections, it objects to section 10 of
H.R. 3199 because it essentially eliminates FDA's involvement when a third party
performs the inspection.
Pursuant to section 10, a third party performing a GMP inspection generally
would not submit a copy of its observations to FDA, even when GMP problems
exist. Instead, the third party would oversee corrections and then when the
company achieved compliance would just certify to FDA that the company is in
compliance. The Agency would never even know that problems had existed.
Moreover, FDA would not be able to conduct a GMP inspection for two years after
the third party certification, "unless justified by good cause." This is
problematic because conditions can change: a change in ownership or internal
management may change manufacturing conditions, or personnel may simply drift
into bad habits. The latter is more likely to occur if companies know that FDA
could not reinspect for two years. Awareness that FDA can inspect at any time
Pharmacy Compounding. One of the most glaring examples of a provision that
undermines FDA's authority to protect the public from unsafe and ineffective
products is found in Section 18 of the drug bill. Section 18 exempts drugs that
are compounded by pharmacists on the order of a licensed physician from the drug
and device provisions of the Act, and it exempts bulk drug products or other
drugs intended for use by pharmacists for compounding from all of the Act's
provisions, except those that relate directly to identity, purity, or quality.
The exemption has no constraints on the volume of compounding. It is likely
to encourage large-scale manufacturing under the guise of pharmacy compounding.
It would allow bulk drug suppliers or drug manufacturers to circumvent the
approval requirements of the Act by shipping bulk drug substances to
pharmacies for reconstituting or other processing. A shadow industry of
unapproved generic drugs is likely to develop.
Moreover, the exemption would allow potentially dangerous compounding. For
example, sterile drugs could be compounded (even on a large scale) without
regard to current good manufacturing practices (CGMPs) for sterile products.
Improperly compounded sterile products could result in serious adverse effects,
2. H.R. 3199 -- Blood, Blood Components, and Human Tissue
Blood and Blood Components. H.R. 3199 deletes blood and blood components
from the definitions of "biologic" and "drug." It eliminates the Public Health
Service Act provisions relating to blood and blood components and creates a new
regulatory scheme for them. We are concerned, however, that the new regulatory
structure could endanger the nation's blood supply.
Although the language of the bill is unclear, there appears to be more
limited authority to seize and recall certain dangerous blood and blood
components. Moreover, the new standard for license suspension would be more
difficult to meet. The bill further provides that even revocation or suspension
of a license would not prevent the use of products that have left the control of
the licensee unless the public health actually had been harmed. Even an
extremely high risk of death might not permit FDA to prevent the use of such
products through revocation or suspension. Finally, the provision permitting
third party GMP inspections would encourage the blood industry to be inspected
by the organizations, accredited by FDA, to which they themselves belong. Will
the American public have confidence in the safety of the blood supply when the
manufacturers can self inspect?
Human Tissue. H.R. 3199 also sets forth a separate regulatory scheme for
human tissue. It appears to define human tissue as including some or all
cellular and gene therapies and it provides that human tissues may not be
regulated as drugs, devices, or biologics. However, cellular and gene therapies
should be subject to premarket controls because they require safety and efficacy
determinations and more stringent manufacturing controls.
Pursuant to H.R. 3199, FDA may regulate human tissue only if it
demonstrates, in writing published in the Federal Register and after a hearing
before the Commissioner, that voluntary regulation under generally accepted
standards is inadequate to protect the public health with respect to any
particular type of human tissue or human tissue generally.
FDA has already made the determination that regulation of human tissue is
necessary. The voluntary standards in place prior to 1993 when FDA issued
regulations requiring HIV and hepatitis testing for tissues did not adequately
protect the public health. Imported tissue from hepatitis infected donors was
being brokered to U.S. companies for use in patients. Moreover, HIV has been
transmitted to patients through HIV-infected domestic tissue. Requiring FDA to
revisit the question of the adequacy of voluntary standards is simply an
unjustified waste of the Agency's scarce resources.
3. H.R. 3201 -- Devices
H.R. 3201 is similar to the drug bill in that it severely undermines FDA's
authority to ensure that safe and effective devices are being marketed. Like
the drug bill, it does this by limiting FDA's authority to review certain
devices, limiting FDA's access to information about devices, and limiting FDA's
authority to ensure that devices, once approved, remain safe and effective.
Exemptions from Filing a 510(k). H.R. 3201 first undermines device safety
by allowing many significantly modified devices to go on the market without any
kind of review. It does this by eliminating the requirement for a manufacturer
to file a premarket notification (510(k)) under certain conditions.
Section 9, for example, exempts all Class I devices from the requirement of
submitting a premarket (section 510(k)) notification, which is the clearance
process for most devices. FDA has already exempted 572 categories of class I
devices from premarket notification. FDA had public health reasons for not
exempting all class I devices. For example, FDA needs to review tests on the
technical performance of hearing aids to ensure that they function as intended.
Similarly, FDA should have an opportunity to review rebreathing devices, which
are used as components within certain anesthesia machines, volume ventilators,
and resuscitation devices and which have been directly related to death, serious
injury, and serious illness resulting from complications caused by their design,
and/or performance. Finally, it is extremely important to the public health
that blood warmers not go on the market without any review. After all, the
administration of blood that is at the wrong temperature can be fatal. Yet,
H.R. 3201 would eliminate these and other important reviews.
Section 9 also eliminates FDA's role in assuring that modifications made to
a device do not adversely affect its safety and effectiveness. It does so by
eliminating the requirement that a manufacturer file a 510(k) for any
modification other than a major change in intended use if the modification can
be shown not to adversely affect the safety and effectiveness of the device.
Thus, changes to materials, power sources, control mechanisms, and manufacturing
processes would be permitted and FDA would not see data. This provision creates
an enormous loophole to the general requirement that devices be cleared by FDA
prior to marketing.
Change and innovation are important -- over time, many of the devices we now
use have improved greatly -- but companies cannot always tell when their design
changes are going to have deadly- consequences. The Shiley heart valves
illustrate this point. The company had made an artificial valve for diseased
aortic and mitral valves of the heart. Picture a metal circle -- like the ring
on a key chain -- with a disc inside the ring that would open up to 60 degrees,
thereby letting blood flow through the valve. Unfortunately, there were blood
clotting and blood flow problems with the 60 degree heart valve.
The company thought that they could fix the blood flow and blood clotting
problems by having the valve open up to 70 degrees. At the time it was reported
that the 60 degree valve suffered from metal fatigue and could break, causing of
catastrophic events, which often resulted in sudden death. Nonetheless, Shiley
manufactured the new 70 degree valves and sold them in Europe (though not in the
US, because Shiley did not have the engineering and clinical data we asked for).
Unfortunately, the company's theory that the 70 degree valve would be better
proved wrong. The 70 degree valve had a failure rate that was 6 times higher
than that of the 60 degree valve. Had the 70 degree valve been sold in the US
market, many more people would have died. This experience shows clearly the
importance of independent review for "improvements" to devices.
It is as important for class II devices that are life sustaining or
otherwise critical, as it was for the Shiley heart valve.
GMP/510(k) Linkage. H.R. 3201 not only removes numerous devices from FDA
review, it also fails to ensure the safety of the products for which 510(k)s
actually do get filed. For example, section 9 prohibits FDA from withholding a
510(k) decision because of a failure to comply with GMPs. This removes the
basic assurance that new devices will be well made and work as intended. Under
section 9, even a company with known manufacturing problems directly relevant to
its new device, might have to be given clearance to market its device. (A
similar provision appears in the drug bill, which prevents FDA from ascertaining
GMP compliance prior to approving a new drug. This prevents FDA from knowing
that a drug manufacturer can reliably and consistently produce high quality
Exemptions from PMA Requirements. H.R. 3201 also would weaken the safety
standards for the most complicated category of devices-- devices that currently
must obtain approval of a premarket application (PMA) prior to being marketed.
For example, section 9 virtually eliminates PMA review and approval of devices
for specific uses. It 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 indications.
Suppose, for example, that a manufacturer of an ultrasound device, approved
for the general diagnostic use of evaluating soft tissue, wants to market its
device for the higher risk, specific use of diagnosing cancerous breast lumps.
H.R. 3201 could prevent FDA from requiring the manufacturer to produce data
showing that the ultrasound device effectively differentiates between a
cancerous and benign lesion. Without data clearly demonstrating the
effectiveness of ultrasound for this use, many women could have cancerous lumps
misdiagnosed as benign, and thus forgo early lifesaving treatment.
Limiting Consideration of Certain Effectiveness Data. For the more
complicated devices that actually would remain subject to FDA review under H.R.
3201, the bill includes the same effectiveness determination limitation as the
drug bill. The concerns expressed regarding the drug bill's limitations on
evaluating comparative efficacy and uses not included in the labeling apply
equally to devices. In addition, Section 8 of H.R. 3201 prohibits FDA from
evaluating clinical outcomes for devices, unless the device is labeled as having
a therapeutic effect. It appears that the Agency would be prohibited from
looking at whether devices really help patients -- for example, whether patients
with artificial hearts did well or died prematurely -- unless the outcome is
part of an explicit labeling claim. This emasculates the present system that
requires certain devices be shown to clinically perform as intended and produce
useful outcomes for patients and ultimately will impair clinical decision-
making by health care providers.
Manufacturing Changes. As with drugs, FDA's responsibility for safe
products does not end when a device is approved by FDA. Manufacturing changes
can greatly impact the safety of medical devices. Section 9 would permit
manufacturers to make significant manufacturing changes to devices subject to
the 510(k) provisions without first coming to FDA. Section 11 of-the device
bill would eliminate the need for PMA supplements for changes that "do not
actually affect device safety or effectiveness." In effect, this relieves
manufacturers from seeking FDA approval for certain changes in manufacturing
processes, sites of manufacture, sterilization procedures, etc. The risk is
that a manufacturer will determine that a change does not affect safety or
effectiveness, when in fact, it does.
Decreased Ability to Monitor Marketed Devices. The Safe Medical Devices Act
of 1990 added a number of provisions to the FDC Act designed to enable FDA to
monitor devices after they were sold. Specifically, it added a requirement for
device tracking to enable FDA or the manufacturer to quickly and efficiently
alert patients if a device subsequently proves faulty and presents serious
health risks. It also added a post marketing surveillance provision to
supplement the approval process because Congress felt that premarket approval
could not detect all possible problems that might occur after a device is put
into general use. Finally, it added a requirement for user reporting because
there were device injuries occurring in hospitals that were never reported to
FDA. H.R. 3201, however, eliminates user reporting and significantly curtails
FDA's ability to monitor marketed devices under the other two provisions.
For example, section 14 severely restricts FDA's ability to require device
tracking. Specifically it changes the criteria for a tracking requirement, and
it eliminates FDA's discretion to apply the provision to "any other device." FDA
used this "discretionary" authority to require tracking of implantable infusion
pumps, silicone breast implants, and other silicone related devices. The
legislation will eliminate our ability to track devices the failure of which
could have significant public health implications.
Section 15 limits the type of device that can be the subject of postmarket
surveillance. The most problematic aspect of this provision is that it only
permits FDA to require postmarket surveillance for devices "first introduced or
delivered into interstate commerce after January 1, 1991." This would preclude
FDA from requiring postmarketing surveillance of devices such as the Shiley
heart valves, Landmark catheters, and foam-coated breast implants -- all
products shown to subject their users to health risks.
4. H.R. 3200 -- Foods and Animal Drugs
Delaney Clauses. For more than 35 years, consumers have known that
manufacturers are not permitted to add to food for human consumption or food and
color additives that have been shown to induce cancer. Manufacturers have had
the burden of proving that additives or animal drugs used in livestock are safe.
The Delaney clauses were premised on a simple public-health principle: Because
the public is exposed to many sources of cancer risk (many unavoidable and
involuntary), this risk should not be increased by intentionally adding
carcinogens to food.
H.R. 3200 would change the long-standing safety standard to which food and
color additives that have been held for almost 40 years. H.R. 3200's safety
standard of negligible, de minimis, or insignificant risk would result in the
intentional addition to the diets of American consumers carcinogenic food and
color additives that heretofore have not been permitted. Furthermore, this
change, whatever negative public health impact it might have on its own, must be
considered in the context of another significant safety-related change
proposed in H.R. 3200. Under the bill, when a food or color additive is
reviewed by a third party, the burden of proof shifts from the manufacturer, in
whom the responsibility for safety demonstration has resided since 1958, to the
FDA. In such circumstances, to prevent the marketing of a carcinogen
intentionally added to food, the Agency would be required to show that the
additive causes a significant cancer risk or that there otherwise is a
reasonable probability that the additive is unsafe. It is clear that these
provisions ask the American public to take on additional risk from foods without
any concomitant benefit.
Although FDA is willing to consider changes to the Delaney clause, our
overall focus must remain on assuring that the public is adequately protected.
As you know, the Administration has recommended, and I have supported,
legislation that would remove pesticide residues from consideration under the
Delaney clause. That change was recommended only because it was coupled with
other changes to the overall regulatory scheme for pesticides, including the
creation of a higher, risk-only, health-based standard for residues along with
provisions that would assure a more careful consideration of the effects of
pesticide residues on infants and children. In proposing to eliminate the
Delaney clause, H.R. 3200 not only fails to provide these extra measures of
safety and public assurance, but, as noted, actually weakens the safety standard
for food and color additives and makes it more difficult for FDA to deny
approval to an additive that, according to the Agency's assessment, has not been
shown to be safe. Thus, under the bill, the protection afforded to consumers
from unsafe additives falls short of that proposed by the Administration for
pesticide residues and that provided by current law.
Preemption. H.R. 3200 prohibits states from establishing requirements
(including prohibitions) for a food, drug, or cosmetic that relate to FDA's
adulteration, misbranding, or new drug authority if it is not identical to a
requirement authorized or required by the FDC Act. It also prohibits states
from imposing any notification requirement for a food, drug, or cosmetic that
provides for disclosure of the constituents, source, or method of production or
processing such product or for a warning concerning the safety of the product or
any component or package thereof unless such requirement is identical to a
requirement prescribed under the FDC Act.
The effect of this sweeping preemption provision is to take away states,
authority to impose requirements to ensure the safety of the food, drug, and
cosmetic supply. It basically would place this responsibility totally in the
hands of the federal government. Thus, if the state of California wanted to
require the maker of Rio hair dye, which caused users' hair to fall out, to warn
consumers, or the state of Texas wanted to require a warning on ephedra, they
could not unless the Federal government had identical warning requirements.
Moreover, at the same time this legislation is transferring all responsibility
to FDA, it is weakening FDA's ability to fulfill that responsibility. For
example, together the Delaney clause provision and the third party review
provision undermine FDA's efforts to ensure the safety of the American food
supply. This provision also could have the effect of preempting state personal
injury lawsuits involving foods, drugs, and cosmetics. (Compare Medtronic, Inc.
v. Lohr v. Medtronic, Inc., 56 F.3d 1335 (11th Cir. 1995), cert. granted, 64
U.S.L.W. 3497, 3500 (U.S. January 19, 1996) (Nos. 95754, 95-886) and cases cited
Finally, a problem with the preemption provision, in the food area in
particular, is that there are certain areas (such as grocery stores and
restaurants) that, partially due to FDA resource constraints, have traditionally
been regulated by states and localities. State and local regulations are
critical to protecting the public health. Frequent inspections by state and
local authorities ensure that restaurant and nursing home kitchens are sanitary
and that food is handled safely. The states are responsible for ensuring that
the fast food hamburgers we so often enjoy have been cooked at the appropriate
temperature. Yet, under H.R. 3200, they may no longer have that authority.
Because of the prohibition in the bill, some areas that significantly impact the
public health could be virtually unregulated.
Increased Risks From minor Animal Species Receiving Ineffective Drugs. This
legislation would adversely affect the public health, not only because of the
bills, impact on the regulation of drugs, devices, and foods, but also because
of H.R. 3200's impact on animal drugs. For example, H.R. 3200 would eliminate
the requirement to show effectiveness of animal drugs intended for uses in minor
species or for minor uses. Elimination of a requirement to show effectiveness
takes us back to before 1962. There is no point to having drugs that cannot be
shown to be effective. Moreover, the availability of ineffective animal drugs
has implications for both animal and human health. The use of ineffective
animal drugs in minor species or for minor uses can lead to the unnecessary
suffering and death of animals and an increase in the potential for the
transmission of diseases from animals to humans. It may also increase the
potential for development of bacterial resistance to antibiotics.
Combination Animal Drugs. H.R. 3200 also changes the standards for
approving combination animal drugs. It would permit a sponsor to market a
combination animal drug containing two or more drugs that are targeted to the
same indication without having to show that each drug provides some additional
benefit. Moreover, it would not require the sponsor of a combination animal
drug to establish the safety of the combination to the animal targeted to
receive the combination.
Prior to enactment of the current animal drug laws, manufacturers marketed
drugs that contained significant amounts of multiple powerful antibiotics to
treat infections in milk cows without showing that each antibiotic added to the
effectiveness of the drug. The marketing of similar products today, as the bill
would permit, increases the risk of antibiotic resistance, which could result in
less effective human antibiotics, and could lure farmers into paying for drugs
that are unnecessary and dangerous.
Dangerous Animal Drug Residues. One final provision that would affect the
public health by eliminating certain animal drug protections is in the drug and
device bills. Both add a new section 909 to the FDC Act that prohibits FDA from
limiting or interfering with a health care practitioner's authority to prescribe
or administer legally marketed drugs or devices. This provision appears to
interfere with FDA's current authority to restrict a veterinarian's use of
certain animal drugs in food producing animals on the grounds that such use
could adulterate the food supply.
For example, chloramphenicol is an antibiotic currently approved for use in
non-food producing animals to treat respiratory and urinary tract infections.
It has not been approved for use in food producing animals because it is
associated with severe side effects (e.g., aplastic anemia and death). Under
new section 909, however, a veterinarian could prescribe chloramphenicol in food
producing animals. Persons who consume the meat from those animals would be
exposed to the chloramphenicol and its adverse side effects.
C. ALL THREE BILLS WOULD UNDERCUT CURRENT EFFICACY STANDARDS
THE POSSIBILITY OF INEFFECTIVE AND UNSAFE PRODUCTS REACHING THE
The privatization provisions that appear in all three bills would lower the
approval standards for products subject to third party review. A number of
additional provisions in the bills lower the efficacy standards for products
regardless of whether they are subject to third party review.
Common Medical Practice. Section 5 of the drug bill would permit the
approval of a new use of a previously approved drug on the basis of a
demonstration that the new use is common among clinicians experienced in the
field and represents reasonable clinical practice based upon reliable clinical
experience and confirmatory information. Basically, the bill assumes that if
many doctors prescribe a drug for a particular unapproved use, then that
unapproved use must work.
A drug may come into widespread use for a condition because common
experience suggests that the drug seems to work. Unfortunately, experience
shows that testing in clinical trials often demonstrates that the drug is not
effective and in fact, may be harmful. Medical history is replete with examples
of products and procedures that were based on medical anecdote, not evidence,
and were thought for years by most clinicians to be effective, but later turned
out to be useless and sometimes dangerous. It may be hard to believe, but
clinical experience often provides the wrong answer.
For example, in the late 1980's, physicians began to prescribe the drugs
encainide and flecainide, for heart attack victims who were experiencing
ventricular premature complexes (VPCs), a type of asymptomatic or minimally
symptomatic abnormal rhythm of the heart. This off-label use for these drugs,
which were approved for other types of abnormal heart rhythms, was intended to
prevent the increased mortality of heart attack victims. The use became so
widespread that the National Institutes of Health decided to study it. At the
time, everyone was so sure that the drugs worked for the new use that it was
thought to be unethical to conduct a controlled clinical trial because that
would mean that certain patients would not receive encainide or flecainide. To
nearly everyone's surprise, that study demonstrated not only that the drugs were
ineffective in reducing the risk of death, but also that the drugs were actually
harmful in the patients for whom they were being prescribed off-label. This
bill would permit unproven uses such as this to get onto the drug label.
This legislation would move us away from the accepted scientific standard of
evidence and back towards evidence based solely on anecdotal experience.
Anecdotal reports and poorly controlled observations have proven not to suffice
because they can be wrong. We know this because, in 1962, Congress told us to
take a hard look at the drugs that entered the market prior to the addition of
the efficacy standard to figure out which ones actually worked and which ones
did not work, but were still being prescribed by doctors. With the assistance
of the National Academy of Sciences, FDA looked at the objective scientific
information available on 3,443 drugs. The result of this review found that only
one-third of the drugs really worked. The other two-thirds either were not
effective, despite the beliefs of physicians, or could not be shown to be
H.R. 3199 would perpetuate the kind of inappropriate and unproven medical
practices that existed prior to 1962. It also could have the unintended
consequences of creating a disincentive for companies to collect the scientific
data necessary to demonstrate whether a product is effective for a particular
We must ask ourselves, is it a good idea to go back to the pre- 1962 era and
permit drugs to be labeled for uses if some doctors think they work for those
uses, or are we better off with the current system where there are incentives-to
do the studies to find out scientifically whether the drugs work for new uses?
FDA is on the side of getting the scientific information. The public has a
right to drugs that actually work as intended.
Approval of Drugs for Serious and Life Threatening Diseases. Section 5 of
the drug bill also provides that an application for a new drug for a serious or
life-threatening condition shall be considered to have substantial evidence if
it could fairly and responsibly be concluded by experts that there is a
reasonable likelihood that the drug will be effective in a significant number of
patients and that the risk from the drug is no greater than the risk from the
This provision undermines the efficacy standard and shifts the risk analysis
away from risk/benefit. FDA strongly supports getting drugs for serious and
life threatening diseases to patients as quickly as possible. The Agency has
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." Thus far, this has been proving to be a successful process.
FDA does not and cannot, however, support a provision that would allow approval
of a new product that has not been adequately tested.
Product Approval Standards. All three bills contain provisions that
explicitly lower the efficacy standard. Section 5 of the so drug bill provides
that "one or more" clinical investigations may be needed to show effectiveness.
The Agency's current presumption is that, for pharmaceuticals, ordinarily,
replicated evidence is expected, but FDA, in particular circumstances (i.e.,
where a single study offers internal evidence of consistency of the product's
effectiveness), may rely on a single adequate and well-controlled trial. The
provision, on its face, does not appear to change that presumption. However, we
understand that its purpose is to create a presumption that one adequate and
well controlled trial will be sufficient for purposes of approving a new drug.
The Agency strongly opposes a change that would eliminate the replication
requirement for drug approval. It is a basic tenet of science that data can be
considered reliable only if, when an experiment is run for the second time, it
produces the same findings and observations that it produced the first time.
The American public deserves to receive drugs that have been tested according to
well accepted scientific principles.
Section 8 of the device bill changes the current effectiveness standard to
include a maximum of one clinical investigation and establishes that no clinical
investigation will be required unless the Secretary first consults with a
classification panel. Because devices, unlike drugs, have the mechanism of
action designed into them, the need for demonstrated replication has not been a
part of the way we have reviewed clinical data on devices over the last 20
years. Nevertheless, in those cases where the devices mechanism of action is
poorly understood, replication of clinical data is correspondingly important.
Finally, section 201(a) of the animal drug bill redefines the "substantial
evidence" criteria that currently must be met to establish efficacy. The
provision changes the substantial evidence requirement from adequate and
well-controlled studies to scientifically sound studies. The requirement that
the studies fairly and reasonably show effectiveness has been changed to a
requirement of a reasonable assurance of efficacy. The provision also
eliminates the requirement for field investigations unless FDA justifies in
writing the need for such investigations to show the effectiveness of animal
drugs. This lower standard for effectiveness for new animal drugs is not
Off Label Use. The drug and device bills make it legal for a sponsor to
disseminate medical texts, journal articles, and government information, and to
make presentations at medical and scientific meetings and have displays at trade
shows about off label uses.
These provisions assume that the various activities it permits are not
promotion and do not encourage off-label uses or uses of investigational
products. Their effect, however, is to make it possible for sponsors to promote
off-label uses and investigational products.
FDA knows that there are important off-label uses of approved products. In
this context, it is important that physicians have access to accurate
information about drugs and devices. But we also know that allowing the
promotion of these kinds of uses by companies with a financial interest in the
products, use can have very serious public health consequences.
The fundamental problem with permitting the promotion of off- label uses is
that not all off-label uses help patients; some do not work and some are
harmful. The only way to know which ones are safe and effective is to collect
and analyze the data supporting a finding of safety and efficacy. Permitting
the promotion of off-label uses based on studies reported in journal articles or
other texts or unpublished materials, which clearly are an inadequate basis for
approval, would undermine the efficacy standard.
One of the most serious consequences of allowing companies to promote
off-label uses is that companies would have no incentive to conduct or fund the
necessary scientific research and to present data to FDA to verify the safety
and efficacy of those off-label uses. In fact, because the Agency might
determine that the new use is not supported by the evidence, there would be an
incentive to avoid FDA review. For devices, the incentive problem is
exacerbated because the investigational device provisions (Section 4) would
permit more widespread use of investigational products, which the sponsors can
now promote and for which they can be compensated.
If off-label uses could be promoted, manufacturers would have an incentive
to do the minimal number of studies necessary to obtain approval for the first,
narrowest/easiest indication and then heavily promote the product for other
broader -- and possibly more speculative -- uses. For example, interferon-alpha
2b was approved for use in hairy cell leukemia, of which there are
approximately 300-400 cases per year. It subsequently was approved to treat
chronic hepatitis B and C, of which there are tens of thousands of cases per
year. If the manufacturer of interferon alpha 2b could have promoted the
product for chronic hepatitis B and C -- the much broader use -- based on
preliminary data, we might never have learned whether interferon alpha 2b
actually works to treat hepatitis B and C.
Because the incentive to conduct research on uses of drugs and devices will
decrease, the end result will be that the dissemination of off-label information
will actually reduce the amount of good scientific information that health care
providers receive about drugs and devices.
Widespread promotion of unapproved uses also raises significant safety
concerns. Even under current law, which prohibits the promotion of off-label
uses, we know of a number of instances where physicians have used drugs for
off-label uses that have resulted in disastrous consequences. The off-label use
of encainide and flecainide, discussed earlier, was supported by published peer-
reviewed journal articles. If the unapproved uses had been heavily promoted by
drug companies, it is estimated that thousands more unnecessary deaths would
The current law governing promotion requires balance. Changing the law to
allow the distribution of journal articles and other similar materials that
promote off-label uses will allow drug sales representatives to provide
materials that describe favorable study results of their product for a
particular use, without providing copies of materials that demonstrate the other
view. What makes this situation even more troubling is that when FDA has
evidence that a particular use is unsafe or ineffective, federal confidentiality
laws frequently inhibit our ability to disseminate that information. Thus,
there are off-label uses about which positive studies appear in the literature
and negative data are contained in our files. Depending on its source, FDA may
be unable to use the negative information to ensure that the medical community
and the public have all of the available facts on which to base treatment
decisions. At the very least, it is irresponsible to open up promotion of off
label uses without giving the Agency explicit authority to rebut that promotion.
FDA recognizes that there are important off-label uses. We believe,
however, that the best way to address concerns that information about those uses
is not reaching medical practitioners is to get those uses for which the drug
actually works in the labeling. As you know, a subsequent indication for a new
drugs is added via a supplemental new drug application, which often needs to
present only efficacy information to support that new use.
FDA has been developing ideas for encouraging and expediting efficacy
supplements for unapproved uses. These include: taking steps to help expedite
the review of efficacy supplements; clearly explaining what data is needed for
efficacy supplements for new indications; and seeking out the most appropriate
off-label uses and getting them onto the label.
D. H.R. 3200 ROLLS BACK THE PROGRESS MADE BY THE NUTRITION LABELING
EDUCATION ACT OF 1990
In 1990, Congress passed the Nutrition Labeling and Education Act (NLEA).
The driving force behind the NLEA was the desire to end consumer deception and
to help consumers in choosing a healthful diet. Among other things, the NLEA
sought to ensure that claims about the nutrient content of foods (e.g., "high in
vitamin C") would make sense to consumers and that consumers would receive
accurate information about the health benefits of foods. The NLEA accomplished
these goals by defining nutrient content claims and by requiring that FDA review
proposed diet/disease claims to ensure that there is an adequate scientific
basis for the claim. H.R. 3200 not only significantly rolls back the progress
that NLEA made on both of these fronts, it also undermines our ability to
provide information to consumers by limiting the type of information we can
require on the food label. For example, section 104 limits our ability to
require disclosure of a method of production or an ingredient.
Synonyms. The NLEA sought to make sense out of the panoply of nutrient
content claims on food labels, by standardizing the terms that could be used.
only those descriptors defined by FDA (through notice and comment rulemaking)
(e.g., "low", "good source of" or "high") could be used. H.R. 3200 amends that
provision to permit synonyms of those defined terms, provided only that they are
not false or misleading.
The bill allows food manufacturers to determine appropriate synonyms. There
is no standard for companies to meet before using a new descriptor and the
burden would be on the Agency to prove that a term is not a synonym for a
defined term or that the term is false or misleading. This provision could
result in a large increase of nutrient content descriptors. The uniformity and
clarity that the NLEA created would be lost. The resulting plethora of
uncontrolled terms would confuse consumers by diminishing the educational value
of the defined terms. For example, is "lots of fiber" a synonym for "excellent
source of fiber" or "good source of fiber"? The use of such vague terms would
permit marketers to expand the market by blurring the distinctions between the
nutritive value of different products.
FDA's current regulations permit a company to petition for the use of
synonyms. In addition, FDA recently proposed to amend its nutrient content
claim regulations to permit manufacturers to use synonyms of defined nutrient
descriptors as long as such synonyms are not false and misleading and the
synonym is "anchored" to the defined term -- i.e., the defined term appears
prominently on the label. The Agency's proposal properly balances the concern
of unbridled uses of synonyms that can lead to consumer confusion with
industry's need for greater flexibility to market the healthful aspects of their
Health Claims. H.R. 3200 would allow any materials prepared or distributed
by any federal health agency or by the National Academy of Sciences to serve as
the basis for a health claim -i.e., to fulfill the significant scientific
The provision is vague and overly broad. The bill would appear to allow ANY
information prepared for whatever reason (i.e., not specifically for the purpose
of evaluating a diet/disease claim relationship) to form the basis of a health
claim. For example, materials relating to a particular diet/disease
relationship prepared and distributed as background for a hearing by the NAS or
a briefing by NCI could be used as the basis for a health claim. Moreover,
information contained in pamphlets written by a private organization and
distributed by a Federal health agency or the NAS could form the basis for a
health claim under this provision. Information could be taken out of context.
Finally, there appears to be no remedy for FDA if it disagrees with a claim
evaluation made by another agency. FDA would be unable to require a private or
public debate about the meaning of the data or information that is relied upon
to make the diet/disease claim.
This provision fundamentally alters the criteria for health claims that were
so carefully worked out in the Nutrition Labeling and Education Act of 1990.
Under the bill, there would be no single body to make decisions on health
claims. Because there may be inconsistent decisions by different organizations
using different standards, we would see the type of consumer confusion and
misinformation that was rampant before passage of the NLEA. Even worse, we may
see cases where claims that come from information prepared or distributed by a
federal health agency or the NAS are just wrong. For example, although reports
and recommendations of certain federal health agencies and the National Academy
of Sciences indicated that beta- carotene prevents lung cancer, subsequent
studies found not only that beta-carotene was not effective in reducing the risk
of cancer, but that for some persons (e.g., smokers) it actually increased their
risk of cancer and death.
E. THE REFORM BILLS WOULD INCREASE BUREAUCRATIC REQUIREMENTS
WITHOUT PROVIDING ADDITIONAL RESOURCES
All three bills impose significant, new administrative burdens. For
example, they require the Agency to hold numerous meetings throughout the review
process and to provide detailed written responses to sponsors on virtually any
issue that may arise throughout the review process. They also require the
Agency to establish a dispute resolution process, which duplicates existing
mechanisms, and they subject virtually any FDA decision about drugs to judicial
review (thus, threatening to paralyze the Agency with useless litigation).
The excessive burden imposed by the bills is perhaps best illustrated by a
provision in the device bill. Section 11 first creates thirteen new deadlines,
many of which are unreasonably short. And then, having created these deadlines,
which we probably cannot meet, it requires a report be submitted to the
Commissioner and the Secretary every time a deadline (including one of the eight
interim deadlines) in the bill is missed. The Commissioner then has 10 days to
provide an explanation to the applicant of the reasons for failure to meet the
deadline. The Secretary must submit an annual report to Congress that
summarizes each of these missed deadlines. This provision takes deadlines and
reporting to the extreme.
Mr. Chairman, I have spent the past five and a half years pushing very hard
to get safe and effective products to patients as quickly as possible. We have
a strong foundation on which to build: 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 drugs for life- threatening illnesses.
The problem we see with the three bills now being considered is that too
often they try to solve yesterday's problems with untested solutions. our
concern is that these measures, if enacted into law, would not only do little to
actually help FDA get products to patients faster they would undermine our
ability to protect American citizen's from unsafe and ineffective products.
Be assured, that the FDA and the Administration will continue to push for
change, but the right kind of change. We look forward to continuing to explore
new ideas on how to best assess new product effectiveness, how to get products
labeled to reflect the best data on their use, how to facilitate clinical
development and how to get the Agency's independent review of new products done
expeditiously so that important scientific advances move to the bedside more