59

on this latter point. We in the drug industry are fully aware of the
important role played by FDA in protecting consumers in_ matters
of public health and would in no way wish to see the FDA dis-
banded or rendered impotent in carrying out this portion of its mis-
sion.

It is of interest that although the FDA traces its roots back to
the 1830's, it has never had a congressionally approved mission
statement. Thus, my first recommendation for FDA reform consists
of a legislative mandate that clearly describes the mission of FDA
in terms of what it should do and the balance it should have be-
tween enforcement and insuring the availability of important new

rugs.

I would propose that the following key elements be part of that
mission statement: To facilitate a timely availability of safe and ef-
fective drug products; to encourage efficient drug development, to
take prompt action to avoid inappropriate health risks; to assure
global harmonization of safety and efficacy standards; and to facili-
tate the flow of medical information.

However, the mere statement of a mission is not sufficient. Sen-
ior managers of FDA come and go, and with them the enthusiasm
for one or another of individual mission statements may wax or
wane. Thus, as a second initiative and equally important to the
first, I would recommend the creation of a policy and performance
review commission to oversee the operation of FDA.

This commission would consist of persons not employed by the
Government, but expert in drug development and drug use in the
United States. This proposed commission would have the power to
recommend policy and personnel changes within the agency as the
result of an observed failure to perform consistently in concert with
the letter and spirit of the mission statement.

While such a commission would report directly to the Secretary
of HHS, an annual report to Congress of its findings and rec-
ommendations would assure appropriate congressional oversight
that the commission is effectively providing the necessary focus of
the FDA on the availability of safe and effective new therapies to
American consumers.

There are, of course, several other initiatives that might provide
incremental improvement to the function of the FDA, and I would
support those mentioned by previous speakers.

Due to time constraints today, I would suggest that if only three
initiatives were implemented—the mission statement, the policy
and performance review committee and the elimination of detailed
data verification as suggested by Dr. Blois—the entire process
would be vastly improved to the great benefit of and with no addi-
tional risk to the American public.

Thank you for your kind attention.

[The prepared statement of Mr. Powell follows:]


123

fact, they had a policy that they would not take faxes from compa-
nies.

When I went there they had kind of an nascent e-mail system.
There were two desktop computers in the entire division. That has
been changed because of the user fee program because we have had
the dollars not only to invest in human resources, but to invest in
infrastructure that will bring this agenc into the 20th century as
we begin to go to the 21st century. That has been a remarkable im-
provement in resources.

Mr. CLINGER. One of the suggestions is all the user fees are not
actually going directly to speed drug approvals. Is there a siphon-
ing off of some of the user fee resources for purposes other than
direct approval of the drug approval?

Dr. LUMPKIN. I can speak only to the Center for Drugs. I will tell
you that at the Center for Drugs, we are fully aware of the statu-
tory language that says these dollars must be spent for what is de-
fined in the user fee statute as a review of human drug products.
That is what we have spent the dollars for.

As with any other kind of that kind of program, there are obvi-
ously the internal and the congressional Government audits. We
are ready for that. I do not think there will be any problem if some-
body audits the spending of the dollars that the Center for Drugs
has done.

One of the things I think is interesting that was part of the pro-
gram that people may not realize is that the dollars were clearly
additive dollars onto the base appropriation level that existed in

Because it is a 5-year Program that is scaling up the employment
on the human resources side over a 5-year period, we knew that
in the first half of the program the majority of the money that we
had coming in was going to be available to spend on infrastructure
because the human resources were going to be a much smaller por-
tion of the expenses at that point of the program.

As we now are building up to the FTE, full-time equivalent, ceil-
ings that are allowed under the program, clearly a much, much
higher percentage of the dollars are going for the Suman resources
salaries part of it.

I think you will see as we do the congressional financial reports
in the coming years that the percentages are going to be switching
from infrastructure to human resources simply because of the in-
crease in numbers. That is the way the program was outlined.

Mr. CLINGER. Finally, the suggestion was made by a number of
the industry panelists and others that the agency should make
greater use of outside resources for the clearance process. Do you
want to comment on that?

Dr. LUMPKIN. Yes, sir, I am happy to. I think there are several
issues that we need to think about when you think about using
outside resources. First of all, we actually do use some outside re-
sources at this point in time.

One of the elements of the user fee program or the user fee legis-
lation is that we are prohibited from using user fees to pay for
those, but that is again an issue that can be dealt with.

We have had both success in failures in using outside reviewers.
I can tell you about some of those because I think it gives you some


25

Hope is based, at least partly, on knowledge of your disease
and the support you receive from the healthcare system. | believe
that the more options people with ALS have for treatment, the more
opuons they will also have for education. Why is this so important
you may ask? I would like to explain-by discussing my personal ©
bout with AIS. sos

In 1981, I was first diagnosed with a brain tumor. Several
months later, I was diagnosed with ALS and was told matter-of-
facUy that I had a 10 percent chance to live six months to two years.
Yes...that's right...a 10 percent chance to live another six months.
Faced with this diagnosis, I searched for public information and.
found nothing that provided a different perspective ~ nothing gave
any hope at all.

With physicians telling me there was nothing to offer and no
reason to plan for the futurc, we did the unexpected — Ronn and I
got married and started a family because we knew then that we had
a chance to move toward death or toward life with all the hope we
could muster. ‘ so

: In some respects, we have created our own hope in the absence
of any positive news. I began seeing a nutritionist and started an.
aggressive anti-oxidants program. Diet and exercise became tangible
ways to "do something”. And, of course, with two young boys, our
family activites are filled with athletic activities and other family-
oriented moments that only increase my appreciation of time.


ay

9

20

2

2

154

diagnostic devices. During those years from the 1960's until the late 1980’s, the Beld of
clinical laboratory science made tremendous advances in areas where automation was
possible, The academic and health care industry brought to market equipment, test kits, and
techniques that have brought down the cost of chemistry and hematology testing dramatically.
‘If we think health care is expensive now, try doing the same number of tests nationwide, but
with a manual system. You would see costs increase several fold. Moreover, there were great.
impravements in the accuracy and the types of tests that were generally available to the public.
‘These goldcn years of development occurred without the degree af FDA regulation that is in
place today. If increased regulation had been in place then, ] feel that progress would not
have happened as quickly. We can be grateful that major advances in reducing the cost-per-
test through automation have alresdy occurred in two of the three major laboratory areas.
Now, there is technology that makes it possible to begin to automate the last major
area of tsb testing - the clinical microbiology lab which helps with diagnosis of infectious
diseases. In my opinion, the development of this new technology is being slowed by the
increased FDA regulation in this area. Never before has it been mare important to keep up
the rapid pace of new lab test development and sutomation. It is common to read about new
infectious diseases, new strains of old diseases, and antibiotic resistant microbes that are
evolving. These demand rapid responses in our abiity to test and evaluat these infections.
Moreover, efforts to lower costs in clinical microbiology laboratories, one of the most
expensive sections of the lab because ofthe manual nature of the work, is being hampered by
the slow development of automation and slow acceptance by the FDA of the new molecular
‘based technologies. Why is it that the country that made the major advances in molecular


149

related, In other words, the goal is to be asked back. This ercates pressure to conforming to the party line
of the FDA, and the party line of the FDA is not necessarily in the best interest of people with AIDS.
‘There have been published descriptions in books about AIDS, including the recent “Good Intentions,” and
“Asceptable Risk” of what has gone on at thc mectings of review panels. These ditcussions. which I urge
‘you to read or have your staff read, include comments from individuals on the review panels for A7.T and
cother drugs in which they describe a party line literally developing over hunch and a decision inexplicably
changing.

Or ovurse il is easy to criticize. I would not want to limit my statement to criticism without addressing at
least briefly how it could be a better system. The system for approving drugs for life threatening illnesses
should be as follows: sell safety trials, followed by a limited release of the drug with a requirement that
the company continue to collect data, If a company fails to continue research, the drug could be
withdrawn from the market. Currently the FDA puts huge artificial roadblocks in the way of drugs being
released, and then turns around and does NOT require companies to continue to collect data. The most
well known example of this in the AIDS arena is DDI, where it is generally belicved by clinicians that we
will never know the best way to use this drug because it was released based on limited data (a position I
‘would support) but then the company ws never held to its commitment to continue to collect data, John
James, the editor of AIDS Treatment News, a very well respected treatment newsletter, has made a
number of proposals along the Lines that we would support for bow to move drugs through the system
more quickly, I hope the committe will take the time to femilisrize yourselves With some of these
proposals.

Finally, regardless of the spotific remedy, we belicve the power of the FDA needs to be reduced, and they
need to understand that there are a government organization that is paid by the people of the United States
to work for them, They seem to belicve thet their scientific expertise somehow gives them the right to
rmake moral end ethical decisions fot thereat of ws. The decision where to draw the line on safety va
efficacy is not really a technical issue. It is a matter of public policy which citizens and their electod


COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
WILLIAM F. CLINGER, JR., Pennsylvania, Chairman

BENJAMIN A. GILMAN, New York CARDISS COLLINS, Minois

DAN BURTON, Indiana HENRY A. WAXMAN, California

J. DENNIS HASTERT, Ilinois TOM LANTOS, California

CONSTANCE A. MORELLA, M ROBERT E. WISE, JR., West Virginia

CHRISTOPHER SHAYS, Connecticut MAJOR R. OWENS, New York

STEVEN SCHIFF, New Mexico EDOLPHUS TOWNS, New York

ILEANA ROS-LEHTINEN, Florida JOHN M. SPRATT, Jx., South Carolina

WILLIAM H. ZELIFF, JR, New Hampshire LOUISE McINTOSH SLAUGHTER, New

JOHN M. McHUGH, New York York

STEPHEN HORN, California PAUL E. KANJORSKI, Pennsylvania

JOHN L. MICA, Florida GARY A. CONDIT, California

PETER BLUTE, Massachusetts COLLIN C. PETERSON, Minnesota

THOMAS M. DAVIS, Virginia KAREN L. THURMAN, Florida

DAVID M. MCINTOSH, Indiana CAROLYN B. MALONEY, New York

JON D. FOX, Pennsylvania THOMAS M. BARRETT, Wisconsin

RANDY TATE, Washington GENE TAYLOR, Mississip;

BARBARA-ROSE COLLINS, Michigan

GIL GUTKNECHT, Minnesota ELEANOR HOLMES NORTON, District of

MARK E. SOUDER, Indiana Columbia

WILLIAM J. MARTINI, New Jersey JAMES P. MORAN, Virgi

JOE SCARBOROUGH, Florida GENE GREEN, Texas

JOHN B. SHADEGG, Arizona CARRIE P. MEEK, Florida

MICHAEL PATRICK FLANAGAN, Illinois FRANK MASCARA, Pennsylvania

CHARLES F. BASS, New Hampshire CHAKA FATTAH, Pennsylvania

STEVEN C. LATOURETTE, Ohio ——

MARSHALL “MARK” SANFORD, South BERNARD SANDERS, Vermont
Carolina (Independent)

ROBERT L. EHRLICH, JR., Maryland
JAMS L. CLARKE, Staff Director
KevIN SABO, General Counsel
JUDITH McCoy, Chief Clerk
Bub MYERS, Minority Staff Director

SUBCOMMITTEE ON NATIONAL ECONOMIC GROWTH, NATURAL RESOURCES, AND
REGULATORY AFFAIRS

DAVID M. McINTOSH, Indiana, Chairman

JON D. FOX, Pennsylvania COLLIN C. PETERSON, Minnesota
JOHN M. McHUGH, New York HENRY A. WAXMAN, California
RANDY TATE, Washington JOHN M. SPRATT, JR, South Carolina
GIL GUTKNECHT, Minnesota LOUISE MCINTOSH SLAUGHTER, New
JOE SCARBOROUGH, Flori York
JOHN B. SHADEGG, Arizona PAUL E. KANJORSKI, Pennsylvani
ROBERT L. EHRLICH, JR., Maryland GARY A. CONDIT, California

Ex OFFicio

WILLIAM F. CLINGER, JR., Pennsylvania CARDISS COLLINS, Mlinois
MILDRED WEBBER, Staff Director
KAREN BARNES, Professional Staff Member
Davip WHITE, Clerk
DAVE SCHOOLER, Minority Professional Staff

an


119

many of these drugs were considered priority drugs for the Amer-
ican population.

Now, I cannot say whether or not these would be priority drugs
in the British population because I do not know in the British
pharmacopeia as to what they have or might not have already
available,

Tf you look at some of these drugs, we are talking about drugs
like Felbamate for unresponsive epilepsy; Gallium Nitrate for can-
cer related increased calcium levels; Plistrelin for post puberty;
Imiglucerase for Gaucher’s disease; Stavudine for the HIV infec-
tion; Tacrine for Alzheimer’s disease; and Succimer for lead intoxi-
cation in children.

I think you will all agree that these are very, very important
drugs that are available in the United States during this period of
time that are not yet available in the United Kingdom.

Again, you have to look at the data from both sides as far as
what we have available here that they do not have and what we
do not have available that they do have at the present time.

Mr. MCINTOSH. Thank you. I just wanted to ask you, what does
NME—

Dr. LUMPKIN. I am sorry. New molecular entity, meaning it is a
brand new chemical never previously marketed here. I am sorry for
that.

Mr. McINTosSH. Mr. Clinger, do you have any questions?

Mr. CLINGER. No questions, Mr. Chairman.

Mr. McINTOSH. Mr. Fox, do you have any questions?

Mr. Fox. You have heard the testimony of the witnesses dealing
with the companies that are trying to produce the drugs. You have
heard the poignant testimony, 1 might add, from those who are
waiting for the drugs, some of who receive, some who have not.

I think the bottom line is while the U.S. citizens appreciate the
fact that the FDA is trying to make sure we have pure drugs and
we know we are doing a good job of that as an agency and individ-
uals, I think you also have heard very clearly and in a bipartisan
fashion the fact that the country is reaching out saying we need
to have help with these drugs.

As the chairman said a moment ago, people have illnesses where
they may not have long to live and their life expectancy is at best
questionable how long it will be. We need the agency to before we
start regulating in areas that you think might not be advisable, is
there a blueprint for speeding up the process so we do not export
jobs, we do not export drugs and become the last country to have
the benefit of the scientific and expertise from a medical point of
view that we have educated here and could have been produced
here, but has gone overseas because we over regulated ourselves
out of existence?

Is there a blueprint from the agency that we should be aware of
before we delve into new regulation that you will not like?

Dr. LuMPKIN. I am not sure we will not like the new regulation.
I think we would be the first to say that I think there are a lot
of things that presently exist that we would agree need to be dealt
with. Perhaps some of the—

Mr. Fox. What would they be in simple terms?


68

Testimony of Bruce Carroll
Manager of Government Relations
Centocor, Inc.
Before the United States
House Commitice on Government Reform and Oversight
‘Subcommittee on National Economic Growth, Natural Resources,
and Regulatory Affairs
June 9, 1995

Thank you Mr. Chairman for the opportunity to testify today. Good moming members of the
subcommittee. My name is Bruce Carroll, Manager of Government Relations at Centocor, the
largest biotechnology company in Pennsylvania, located in nearby Chester County. Our President
and Chief Executive Officer, David Holveck, was unable fo be here today, so I am presenting

testimony on his behalf.

I am pleased to discuss some of the issues facing the health care technology industry and to
suggest a few reasonable and achievable ways to improve the role that the Food and Drug

Administration plays in making new and innovative technologies available in the U.S. and abroad.

Centocor employs over 300 people in our Chester County facility and nearly 600 tow
worldwide, We focus on development, manufacturing and marketing diagnostic and therapeutic
products for human health cate which are used in managing patients with infectious, cardiovascular

and autoimmune diseases, and cancer.

Its fair to say that Centocor has had an overall positive experience with the FDA. For

example, approval for our first therapeutic, a cardiovascular drug called ReoPro, was accomplished in


152

changed sides has published a book on how to deal with the FDA
that is a little over $500. If I could just review for you a little bit
of the advertisement, I would close.

The book tells how we have gotten to dotting the i’s and crossing
the t’s. It is not whether it really works and is good. It is not sci-
entific. It is just looking for irregularities. Even a tiny irregularity
can result in delays, fines, black listing.

The fear of the FDA that results in this kind of book makes it
so the small companies do not bring out the diagnostic devices as
quickly as I saw in earlier years, and it takes the large companies
years before they finally bring products out. Even when they do,
they use them everywhere else. We are the last place that they are
willing to tackle.

If you could change that and make it so that we just had to prove
equivalence, which is the way we used to do it, it would be better.
Instead we must try to prove that it is better. If it proves equiva-
lence we could then allow the scientific community to gradually
through evolution make it better just the way the airplane got bet-
ter as the years went on.

Thank you very much.

[The prepared statement of Dr. Jungkind follows:]


19

country are relying on today to produce the wholesome, plentiful and affordable
food supply that we enjoy in this country. The impact of these tolerance
revocations would be to drive up producer and consumer costs, derease yield and
quality of our growers’ fruit and vegetable crops and increase consumer
dependence on food imports. It is particularly frustrating to me to face these
potential impacts over an issue that has no relation to public health. Both EPA and
industry are in agreement that this issue is not related to health and safety but rather
is an idiosyncracy of the law. However, EPA is under court order and will have to

move to revoke these tolerances whether it agrees with the court decision or not.

There is a solution to avoid this oncoming cri

but action must be taken quickly
before EPA initiates the revocation process as dictated by the consent decree. The

solution is to adopt the recommendations of the National Academy of Sciences and
to establish a single uiniform safety standard that applies to all food - whether raw
or processed. The NAS recommendations will both avoid the crisis and be more
protective than the current Delaney Paradox. This approach has been adopted in
HR 1627 - the bill recently reported out of the DORFA subcommittee. This bill
eliminates the forced distinction between tolerances for raw commodities and
processed foods under FFDCA and puts the authority for the establishment of
tolerances for pesticide residues in all "food" under Section 408 thus removing
processed foods from the authority of the Delaney Clause in Section 409. Under
Section 408, EPA can apply a single de minimus or negligible risk standard to all
food and find its way out of the Delaney Paradox.

In addition to creating a single negligible risk standard for all food, there are a
number of other provisions in HR-1627 that will improve the food safety provisions
of both FFDCA and FIFRA. Among these are provisions that


15

TESTIMONY OF MRS; FAITH SAMOWITZ.
June 9, 1995

Mr. Chairman and Members of the Committe:

My name 4s Faith Samowitz, and here with me today is my son,
David. David and I want to thank you for this opportunity to

talk directly to lawmakers about the effects of government
regulation on our lives.

David has epilepsy. When he was about 9 years old, he would
sometimes say, "I have the spots," or “I have the flicks." I
thought he was just a very imaginative child until, one day, he
told me he couldn't see. He walked around like a blind person,
and I noticed that his pupils were dilated. I immediately took
him to a neurologist, who diagnosed a seizure disorder and,
finally, epilepsy.

We don't know what caused David's epilepsy. There ere
several possible causes of this disorder -- including brain
injuries, metabolic disorders, and infections. Epilepsy is a
neurological disorder affecting some four million Americans. with
about 100,000 new cases reported each year. The disorder is
marked by recurring seizures.

There are different types of seizures. David has
experienced Grand Mal and Complex Partial seizures. In 1987,
after we had exhausted all medications and combinations of
medications available in the U.S., David's neurologist, Dr.
Stanley Resor suggested we try some medications that were having
some success in England but were not available here. Now that

David is taking these four medications, his seizures are not so


128

Before the Kefauver amendment, the Food and Drug Administra-
tion was concerned with safety. I am sure that in Senators’ and
Congressmen’s minds it was helping the country be rid of snake oil
salesmen who could claim almost anything would “grow hair on a
billiard ball and make childbearing easy.”

Obviously it is a sensible thing, which | support, to forbid the
sellers of drugs, whether they are drugstores or manufacturers, to
make claims which cannot be supported. I am not advocating im-
mediate repeal of the Kefauver amendment. I am advocating that
we take another look at it.

Previous speakers today have addressed the matter that of
course we want drugs of proven effectiveness. That makes a good
line. That is a good point, as I would think of it, because the Food
and Drug Administration, and let me quote you, “. . . recognizes
that the FD&C Act does not limit the manner in which a physician
May use an approved drug.”

Once a product has been approved for marketing, a physician
may choose to prescribe it for uses or treatment regimens for pa-
tient populations that are not included in the approved labeling.

I think if you examine the process by which the manufacturer
achieves approval for an indication of efficacy, you can see that he
is unwilling to spend millions of dollars and take years of time to
receive approval for things of limited market value. Therefore, the
efficacy requirements of the FDA are inherently limited.

The efficacy as stated by the FDA will never be a comprehensive
list of what the drug is for. That could lead us to a situation in
which physicians are afraid to prescribe a drug, even though they
have a perfect right to prescribe it, because it is not one of the list-
ed approvals.

They are fearful that they will find themselves in court facing a
plaintiff's attorney who says well, you used this drug and the pa-
tient then died. You used the drug and it was not approved. Well,
it was not illegal, yet it was not approved.

By twisting that around, you can see the chilling effect on the
medical professional of having a book, Physicians Desk Reference,
which I understand there are a million copies printed a year, half
of them sold in book stores, which lists these approvals and indica-
tions with the implication that the medical profession is limited to
them when they are not.

There are several of the Medicare carriers, one in Louisiana in
particular, who have started to refuse to pay for certain drug regi-
mens in their jurisdiction—it has not happened to me—because the
drugs were being used for a purpose that was not an approved pur-
pose.

Nobody ever claimed that these approved purposes were com-
prehensive, but when they start to limit your ability to have Medi-
care pay for them, you can see that the whole process here of the
Kefauver amendment, which had a benign purpose when it started,
is now a subject which I feel ought to be re-examined and relooked

at.

Mr. McIntosu. Dr. Fisher, if I could ask you to go ahead and
summarize, that would be great.

Mr. FISHER. That is all I have to say. I would be glad to answer
questions.


134

perhaps through implementation of a faster fast track, as Rep-
resentative Fox suggested earlier.

Deafness to progress has been justified by citing the absence of
FDA approval as cited in the PDR. The use of a given agent in the
appen led resolution to the testimony I provided, and I cite the
third Whereas, which Dr. Fisher cited earlier.

It is this firmly forced upon the pharmaceutical houses
exhorbitant sums to overcome. What I do not understand is the jus-
tification that new agents were not necessarily emulated in Amer-
ica. It may very well be because of the overall cost of submitting
an IND. In the interim, under the guise of FDA determinism, indi-
cates therapy is denied.

Certainly the FDA should disclaim responsibility for determining
if a new drug is any better than a related drug. This is a hot topic
with me because I was very interested in Vinticin, which is a
sulphate. I studied it as a Fellow. Eli Lilly tried to get it approved,
but it was not considered to be any better than the others. There-
fore, it was not approved. A lot of us still feel it is the best one for
lung and esophageal cancer, and we feel that these diet pills should
have been allowed to compete in the open market.

Off-label prescriptions, which we have discussed here earlier, are
routine. They are drawn from recent knowledge gained from read-
ing foreign literature and reviewing Presentations. I want to give
you an example, which is close to my heart right now.

Ihave a patient who is my age with malignant melanoma metas-
tasized to his brain, to his skin, to his liver. I read the ASCO ab-
stracts, which is the American Society of Clinical Oncology, which
suggest a certain drug may do him a favor. I gave it to him. This
is o

I am waiting to see what happens and whether or not he will be
covered on an outpatient level by the insurer. Although I thought
it was a Jong shot, it was the best we could offer him right now.
This is something that happens commonly, as discussed previously.

Regarding the issue of cost, everyone can explain why the other
fRy should pay for a given service. This is really the part I would
hke to explain to you that has not yet been discussed.

When clinical research requires financial support, patients look
to insurers, insurers look to academicians, academicians look to in-
dustry, industry looks to Government and Government looks to pa-
tients. Cannot this loop be broken?

How might the FDA promulgate policies which could facilitate
and compensate 85 percent of the patients that arise in community
hospital settings, not just for cancer?

This is why the NCI established the CCOP program a decade
ago. That is the Community Clinical Oncology Program. Here the
local hospital physician sort of flip flops. Instead of the usual situa-
tion when the academic center contracts to a local entity to conduct.
clinical research, in a CCOP the local entity was funded and then
it choose which academic institutions with which to relate and
where to acquire their clinical protocols.

It was anticipated the composition of the study group would re-
flect the entire population having a given malignancy in the com-
munity because of the fact they would be using a community based
effort.


74

Up to that point, EPA had allowed tolerances for pesticide resi-
dues in processed foods as long as those residues posed a dietary
risk of less than one in 1,000,000 to consumers. A risk of less than
one in 1,000,000 is considered as de minimus by EPA and is gen-
erally accepted as such by the scientific community.

The EPA had formally adopted this policy in response to the
1987 study by the National Academy of Sciences that concluded
that this de minimus approach applied to both raw and processed
foods would be more protective of the public health than strict ap-
plication of the Delaney clause with its different standard for set-
ting tolerances for processed and raw foods.

The court ruled that the Delaney clause did not allow for this de
minimus exception, but rather required a zero standard for pes-
ticide residues in processed foods and ordered EPA to revoke the
tolerances in that particular action that could not meet this zero
standard.

The second event occurred earlier this year when EPA and a
number of environmental groups signed a consent decree to settle
a legal action over the strict application of the Delaney clause.

As a result of this decree, EPA has agreed to review the applica-
tion of the Delaney clause to almost 40 pesticides and over 100 tol-
erances over the next several years. This review could result in the
revocation of a majority of these tolerances and end the use of
these chemicals on the affected crops.

Without going into details, the uses that would be affected are
not minor perturbations, but rather represent the loss of critical
tools that the farmers of our country are relying on today to
produce the wholesome, plentiful and affordable food supply that
we enjoy in this country.

The impact of these tolerance revocations would be to drive up
producer and consumer costs, decrease yield and quality of our
growers’ fruit and vegetable crops and increase consumer depend-
ence on imported foods.

It is particularly frustrating to me to face these potential impacts
over an issue that has no relation to public health. Both EPA and
industry are in agreement that this issue is not related to health
and safety, but rather it is an idiosyncracy of the law. However,
EPA is under court order and will have to move to revoke these
tolerances whether it agrees with the court decision or not.

There is a solution to avoid this oncoming crisis, but action must
be taken quickly. The solution is to adopt the recommendations of
the National Academy of Sciences and to establish a single uniform
food safety standard that applies to all food, whether raw or proc-
essed.

This approach has been adopted in H.R. 1627, the bill recently
reported out of the DORFA subcommittee. This bill eliminates the
forced distinction between raw and processed foods. Under section
408, a$ required in H.R. 1627, EPA can apply a single standard to
all food.

There are other provisions of H.R. 1627 that will also enhance
the safety of our food supply, but time does not permit me to go
into the other provisions. However, while the Delaney clause is the
centerpiece of H.R. 1627, all of these other provisions are an inte-


32

We feel reforms of the FDA are needed, but we must not aban-
don the hard fought for improvements in the AIDS drug ap roval
process that have been made under pressure from the AIDS com-
munity. I owe my life and good health to these programs.

If the FDA turns its back on persons with AIDS the way much
of the rest of the Federal bureaucracy has, we will suffer the con-
sequences of the human as well as monetary expense of such short-
sighted planning. Persons with AIDS will be hospitalized sooner
and kept there longer.

Our goal is an improved FDA that will expedite approval of
drugs that will keep persons like myself, who has never been in the
hospital for HIV related infections, out of the hospital for many
more years of productive life. We can do it with your help.

Thank you for listening.

(The prepared statement of Mr. Kuromiya follows:]


108

necessary resource levels. The bill was drafted so that the

resources would be additive to the FY 1992 existing resource

base.

Drug approval data at the time suggested that there was
considerable room for improvement in review times. Between 1970
and 1989, FDA approval times consistently averaged between 2 and
3 years. In those years, FDA approval typically took about 1 to
2 years longer than the fastest European countries. There were
improvements in the early 1990's as the median approval times

fell below 24 months and as average times dropped toward 2 years.

It was clear that if PDUFA worked as anticipated there would be
enormous benefits to the prescription drug industry. An often
cited study by Dr. Lasagna at Tufts, indicates that a one

year delay in a drug approval costs the sponsor 19 million in
1987 dollars, which translates into 25 million in 1995 dollars.

[Vol.xX, Journal of Health Economics, pg. 107, 128 (1991)]

Under the user fee legislation FDA agreed to very ambitious goals
with respect to drug reviews, review times that would have been
impossible to achieve only a few years ago. By 1997, once the

legislation is fully implemented, the goals provide that the


39

Mr. McINTOSH. Thank you very much, Mr. Kuromiya. We appre-
ciate you coming forward and testifying today.

Now we move into a brief session on questions from the panel-
ists. In order to save time for my colleagues, I will take your ques-
tions that you have for the agency and formulate them at one of
the later parts of the panel.

Does anyone have any questions for this set of witnesses? Mr.

‘ox?

Mr. Fox. Yes. Kiyoshi, I will start with you. Do you feel that the
problems that were brought on by Thalidomide have created a go
slow attitude within the FDA?

Mr. Kuromiya. Yes. I could go on to other areas where the FDA
has looked away while 430,000 people died from cardiac and res-
Piratory conditions related to smoking cigarettes. Over 40,000 die
each year from secondary effects of cigarette smoking, more than
die from AIDS each year. That is another area, though.

Mr. Fox. But there is an over reaction, as far as you are con-
cerned?

Mr. Kuromva. There is an over reaction. I think we have be-
come overly conscious or overly cautious in terms of protecting the
public.

We know the entire Thalidomide story. Persons with AIDS are
rapidly enrolling in clinical trials that use Thalidomide for ulcers
and its antiviral. We are quite aware of the situation with fetuses,
and protections are taken. Otherwise, Thalidomide is a relatively
benign drug, even as compared to the approved drugs for persons
with AIDS and approved drugs for chemotherapy, which are quite
toxic.

Mr. Fox. All the members up here today are working on the leg-
islation that you made reference to, which would be when filed the
Life Extending/Lifesaving Drug Act of 1995. It occurs to me that
your testimony is quite pointed, as were the other witnesses in this
panel, regarding the importance of speeding up the process.

Do you think we should put time lines on it? From your perspec-
tive, what do you think the legislation should be or the corrections
within the agency should be to speedup the process? Give us a spe-
cific guideline.

Mr. Kuromiya. One area, for example, which the FDA really is
not prepared to take on is biologicals. I think that there are some
groundbreaking new developments in this area.

The FDA is using overly cautious procedures requiring extra lev-
els of viral deactivation, for example, in the area of vaccines, thera-
peutic and preventive vaccines. We feel that this slows down the
process and keeps potentially valuable drugs both from being test-
ed and from moving through the drug approval process at a rapid
pace.

Mr. Fox. I have no further questions, Mr. Chairman.

Mr. McInrosu. Thank you, Mr. Fox.

Mr. Clinger?

Mr. CLINGER. I just_would like to thank all of the witnesses for
your very moving and compelling testimony. I think it has been
enormously helpful I know to us because you have corroborated
what I think we have all known, and that is that there is an un-
conscionable delay in making medicines available to you that could


164

To summarize, I would like to suggest that the FDA, has been most appropriate in
charting a course through very treacherous waters. To further aid their efforts, I would
suggest increased standardization in both the review process and the monitoring process.
Also, I would like to see a network of local medical experts involved as the study
proceeds reviewing it concurrently not in a retrospective fashion. Again, J think that we
are truly in many senses an international medical community and attempts to collate and
organize data on an international level would be to everyone's benefit.

Thank you very much.

LD 5. OO

LA oO. | DO.

President, Concorde Clinical Research, Inc.

Associate Professor, Family Practice, Philadelphia College of Osteopathic Medicine
Director of Research, Philadelphia College of Osteopathic Medicine

TOTAL P.@?


64

scientific and medical personnel due to the highly competitive nature of the demand
for these same resources by the drug industry, as well as colleges and universities.
Scientists, who for a number of reasons are drawn into academia, private practice
or other private (non-drug industry) endeavors, should be made available on a
contractual basis to review data and information on the safety and efficacy of new
therapies. They could provide advice to the agency on making the appropriate
decisions on the availability of these medications to practicing physicians in the
United States.

A final suggestion is that the agency reengineer its process for drug safety and
efficacy review. Currently, FDA requires submission of not only detailed analyses
and summaries of the data and information collected during the development of drug
products, but also all of the supporting data and documentation related to those
summaries and analyses. This requirement results in an application which literally
consists of a “truckload” of paper, or its equivalent in electronic media, which, in
turn, must be reviewed by the FDA staff. (For example, it is not unusual for an
application to consist of over 900 volumes of material, whereas the same application
submitted to the British authorities would typically consisted of fewer than 50

volumes.

We would propose a system of certification of the analyses and summaries (based
‘on the raw data retained by the sponsor and subject to inspection by the agency in
the event of the need for verification) and the elimination of full data submission
and verification by the FDA review staff. We believe that this is a redundant and
unnecessary task which consumes considerable time and resources, and provides no
further assurance of the credibility of the database on which the analyses are based.

Page 5


148

have to smuggle drugs into this country ~ assuming they have the meses to pey eash for thera — in an
attempt to save their lives.

‘The cow to the pharmaccutical companies to jump through thexe hoops ix enormous. As a result. only the
biggest companies can afford to stay the coursc. Smaller companies either must seek a larger partner, or,
in many cases, give up. Another story we are familiar with in Philadelphia illustrates this point. The
drug involved was called Imreg, and it was, like the Salk Vaccine, an immune modulator. It looked
promising in carly tests. The company thought it was working well with the FDA. Then, unexpectedly at
‘an FDA hearing, new questions which they company had not been aware of, were raised by the FDA.
Eventually it led to accusations that the researchers in the study had known who was receiving drug and
who was receiving plsceho. Fiventually, the company, unable to raise continued capital was farced to
give up. Two years latcr, a scientific review of the data involved in lmreg was published. The reviewers
found no hasis for the sccusations made against the researchers in the study. This review was published in
the peer reviewed scientific literature, But by then it wst too late, Let me emphasize this point: the
physicians who conducted this study in Philodelphia. which included two leading researchers at a major
AIDS hospital, were convinced that the data showed promise — and that their patients were doing better
and staying healthier. Was it the cure? Probably not. But it could have been a drug that helped people,
and it was destroyed by the Food and Drug Administration and their arrogant bureaucrats

‘AS we have looked into this as activists, we huve come to believe that one of the reasons this problem
cccurs is the system of peer review that the FDA employs. Supposedly neutral outside scientists are
brought in periodically, and asked to comment on proposed drug trials. There are several problems with
this cystem First, as far as we understand it, while the outside reviewers are supposed lo stale direct
conflicts of interest (although this seems to be only a recent development) they are not required to disclose
conflicts involving reseurch on products that might compete with the drug under study. In other words. if
their research finding will directly benefit from the failure of a competing drug, they are not required to
disclose this. Second and more important, the main goal of a reviewer attending thesc mcctings is career


35

Many of us who have HIV infection or AIDS owe our present good health to the drugs
‘which through such innovative programs as expanded eccess, treatment INDs, accelerated
approval, compassionate use, and peraliel track, We need even more such orograms:
‘which get experimental drugs of potential treatmont benefit to the people who have urgent
need for them... and get them to these persons fast. once safety has been established. As
persons with AIDS, we are tired of waiting endlessly for drugs of proven sataty to make
their way through the approval process. This Is an area we feel David Kessler has made
some progress and yet wa have the feeling that all our gains will soon be fost and the FDA
will loose sight of Ite mission as Kessier tries to go beck on the reforms that have expedited
the process of getting drugs to the people who need them, once toxicities are known and
safety Issues are resolved.

‘We have fears regarding the FDA reforms in the bill that Democrat Ron Wyden of Oregon
has promised to introduce before Memorial Day. And the Republican bill, we are assured
will follow in a few days. Both bills are expected to dereguiste Phase ! clinical trials, but the
Democratic version will almost certainly not codify accelerated approval. Beceuse of these
Moves, we afe going to wake up and find the AIDS drug pipline is empty.

During the 1950s drug approval was a relatively quick and simple process in the US, like it
is today in Europe. Then camo thalidomide. Several hundred babies wore born with
horrible defects after European regulators approved the drug for morning sickness without
raslizing it could affect the fetus. Capitalizing on the tragedy, liberals in Congress expanded
the FDA's powers and altered its priorities. These policies have hindered drug approval ever
sinca. .A survey of 137 new drugs approved by the FOA between 1986 and 1991 found
that on the average the same products were approved by European regulatory agencies 4.1
years faster then by the FDA. Investigational new drug (IND) application filing to new drug
application (NDA} submission items averaged 2.5 years for the 19605, 4.4 yeors for the
1970s, 5.5 years for the 1980s, and 6.1 years for the 1990s. To give an exemple of how
this may Indirectly harm many persons in this country. an application for epproval of a
vaccine tor Hepatitis A was flled with the FDA 32 months ago. Though FDA hes yet to
reach 8 decision, it is already on the market in 40 other countries, Through 1992, 92
Monoclonal antibodies had been approved in Europe, compared to only 8 In the United
States. 42 new vaccines had been spproved in Europe against 8 in the United Stats. 64
recombinant DNA products were approved in Europe against 21 in the United States.



67

FDA the discretion to put specific products in class III if they feel
it is needed.

One final note of interest regarding regulation of IVD’s. We have
studied the citizens petition recently filed by the Indiana Medical
Device Manufacturers Council regarding the FDA’s development of
guidance and other similar documents. We would like to add our
support to the observation that guidance can play a most useful
and valuable role when the FDA takes the time to involve the pub-
lic in the initiation, development and implementation of those docu-
ments.

Well developed guidance helps reduce industry’s cost and time
requirements when preparing premarket submissions. For guid-
ance documents to play that role, however, the public needs to con-
tribute to the process by which they are created so that the FDA
decisions are well informed.

Obviously, IVD over regulation is a specific problem that the di-
agnostic component of the medical technology industry faces. We
also support efforts from HIMA, the Health Industry Manufactur-
ers Association, and BIO, the Biotechnology Industry Organization,
and their efforts for FDA reform proposals.

Three other items that we are interested in which HIMA and
BIO are Supportin are restructuring. the overlapping procedures
between CBER and CDER within the FDA; reforming the FDA reg-
ulations on exporting, and that includes support of H.R. 1300 intro-
duced by Congressman Upton; and reform of the FDA marketing
procedures.

One quick example is our new heart drug. The launch of the
drug was held up because the size of the generic brand was not ex-
actly 50 percent of the final size of the brand name itself. That is
why we are interested in the marketing procedures aspect of the

In closing, on behalf of Mr. Holveck and the employees at
Centocor, I want to thank the members for focusing on this crucial
public policy issue. Mr. Holveck has stated numerous times that he
believes a sensible, market friendly, incremental approach to FDA
reform is the best way to move forward.

We in the medical technology industry will continue to drive
ahead to innovate and create products that meet unmet medical
needs such as cancer, arthritis and heart disease. We need a well
run and market driven regulatory process to help make that hap-

pen.
Thank you.
[The prepared statement of Mr. Carroll follows:]


104

Agency will make decisions on 90 percent of drug applications
within 12 months. Medically important drugs will be reviewed
twice as quickly, with reviews on 90 percent of those products to

be completed within 6 months.

As a result, by 1997 the U.S. drug review process will be as fast
as that of any country in the world with a developed drug
approval process. This will be accomplished without diminishing

the public health protections FDA traditionally has maintained.

Significant progress already has been made. During the first 2
years of the user fee program, all drug approval times have
fallen significantly. As expected, shortened review times have
led to shortened approval times. In 1994, the average time for
approving prescription drugs that are new chemicals was 19.7
months, down 24 percent from 1992, and the median time was 17.5
months, down 33 percent from 1992. Priority drugs, drugs that
represent a significant advance over the drugs that already are
available, were approved even more quickly, the median time being

15 months, down 42 percent since 1992.

The data are even more impressive for drugs approved in 1994 that

were reviewed under the user fee program. The median review time


167

Could you give your name for the record and your company
again?

Mr. BOEHRINGER. John Boehringer, B-O-E-H-R-I-N-G-E-R,
Boehringer Laboratories, Inc., 500 East Washington Street, Norris-
town, PA.

Mr. Fox. Right here in town. Thank you very much, Mr.
Boehringer.

Chairman Clinger, did you have any questions for the witness?

Mr. CLINGER. No.

Mr. Fox. If we have other witnesses who wish to testify, please
come forward and identify yourself. We will be happy to have your
testimony.

Ms. DeLuca. Hello. Thank you for allowing me to speak. I am
Barbara DeLuca. I am the executive director for the Linda Creed
Breast Cancer Foundation.

I am speaking on behalf of 2,600,000 million who have been diag-
nosed with breast cancer. I must tell you that two of those youn;
women I attended funerals for this week. Too many women of al
ages are losing their lives to breast cancer.

In the last 30 years, nothing has changed in the way breast. can-
cer is treated, with the minor exception of some hopeful new drugs
that have appeared on the market, Tamoxifen being one of them,
Taxol being one of them, and Taxotere hopefully could be one of
them.

When a women is in the last throes of her disease, Taxol has
been the one hope. I know one woman who had given birth to a
child and then was able to have her life extended for 1 full year
because of Taxol.

We are hopeful to see new drugs coming onto the market. In the
last few years, because of a grassroots movement, women across
the country have been fighting for new funding for research. That
money has increased slowly. That money has not increased enough
and we are hoping that it will not be cut in the next few wee!
because it is so desperately needed.

When drugs are discovered with those new research funds, we
hope that they will come to fruition and come to the market with
all safety measures having been taken, so that women will have
the choice of having their lives saved by new drugs that are being
brought to us.

I thank you very much.

Mr. Fox. Your last name again?

Ms. DeLuca. DeLuca.

Mr. Fox. And you are local? What is your——

Ms. DeLuca. I am with the Linda Creed Breast Cancer Founda-
tion that is located in Philadelphia.

Mr. Fox. I would like to say first of all, thank you for your poign-
ant testimony. We are very familiar with the Linda Creed Founda-
tion.

We have spoken out in recent weeks in the Appropriations Com-
mittee to try to fully fund the women’s healthcare initiative. As
well, we had a witness today who was supposed to speak just to
what you talked about with the drugs not yet approved, Taxotere,
except that she had chemotherapy yesterday and was so debilitated
that she could not be here to speak to us.

Ss


126

companies to do, and we know that when you look at our experi-
ence over the years that we have not had a problem that has been
picked up by our review of the environmental! impact in the produc-
tion of drugs that come through our shop.

That is one of the things that we propose to do away with, but
that is taken care of by other people. We do not need to do that,
and the companies do not need to do that for us. There are, yes,
sir, things that I think we could do away with in there.

Mr. TaTE. If I can ask one quick last question? Have there been
any studies by your particular agency on how much time it takes
for these companies to fill out these forms?

Dr. LUMPKIN. Let me say this.

Mr. TarTE. It seems to me to fill out 100,000 pages; I mean, just
filling out our tax returns takes forever-——

Dr. LUMPKIN. Right.

Mr. TaTE [continuing]. Let alone filling out 100,000 pages.

Dr. LUMPKIN. They are not filling out forms that we end them,
for example.

Mr. fate. Right. I understand. They are doing the studies and
so forth.

Dr. LuMPKIN. Right. Right. These are pages of reports that they
send in.

I can only speak from my own personal experience. I know that
when we were putting together applications for submission to the
agency when I was in industry they would often take—obviously it
is being done in a project managed way that as you finish one
thing you are beginning to get that part of the application ready
and it is all kind of going in a concurrent process there, but it
clearly takes in many respects between 6 months to a year to fi-
nally get everything put together to send it in.

ir. TATE. Is that taken into account in the requirements you
have as to how long it takes? Is that any part in the factoring in
of what you are requesting, how long it takes to fill these things
out? Is that part of the equation?

Dr. LUMPKIN. I think it is. It clearly is part of —

Mr. TaTE. The more you have to fill out, the longer it takes to
et these drugs approved, which drives up the cost. It is costing
lives.

Dr. LuMPKIN. I think the question that you are going to is not
an issue of just what to fill out, but whether it is necessary-——

Mr. TaTE. Exactly, on both ends.

Dr. LUMPKIN [continuing]. To fill out the forms.

Mr. TATE. How long it takes, and also if you are filling out forms
that take this long and you are discussing whether you should even

get rid of them ail together in regards to environmental concerns,
it seems like a waste of time.

Dr. LUMPKIN. Right, and I think that that is exactly what people
were going to, as I was saying, particularly——

Mr. TaTE. Especially when people need these particular drugs
and so forth. It seem to me that there is a lot that can be done
to speed that process up to really save people’s lives or make their
lives better.

Dr. LUMPKIN. I think we agree with you.

Mr. TaTE. I look forward to working with you.


45

Page 2.

process. This targeted, rational approach involves experiments with enzymes and
Cellular receptors to seek potential pharmaceutical compounds, through screening and
rational design, that modify the activity of these molecules.

Agood example of this evolution is the comparison between ALDOMET, a drug to treat
high blood pressure discovered in the 1950's and VASOTEC, @ drug discovered in the
1980's to treat the same condition. ALDOMET was discovered by testing compounds
directly in animals and patients for lowering blood pressure without knowing the drug's
molecular action. VASOTEC was designed using a precise test tube assay that clearly
defined its mechanism of action. A patient requires between 1,000 and 2,000
milligrams of ALDOMET for effective treatment whereas a 5 to 10 milligram dose of
VASOTEC is highly effective. There is inherently much greater safety for the patient
associated with such a low dose of a patent medicine targeted to a precise biochemical
mechanism.

However, the regulatory process has not yet been sufficiently modernized to take Into
account these advances in the discovery process. The review and approval system
remains cumbersome and restrictive, almost as if new drug candidates will be less safe
and effective than previously was the case. Yet it is clear that the science of the
discovery of new prescription medicines has been moving in exactly the opposite
direction.

NEW DISEASE TARGETS WILL CHALLENGE OUR INDUSTRY

This is an exciting time for our industry, without question, but a time in which as Merck's
own experience illustrates, R&D on complex chronic illnesses is increasingly
challenging and costly. The approaches to treatment of the degenerative diseases of
‘an aging population during the next decade will test our skill at molecular engineering
and require commitmants to R&D of enormous magnitude. In testing drugs in older
patients with chronic ilinesses, larger trials for longer times are required to insure safety
and efficacy. It must always be remembered that innovative pharmaceutical R&O0
remains synonymous with high risk and high costs.

Looking at just two major disease targets where industry scientists are at work—cancer
and AIDS—we can offer an impressive pipeline of hope, but within a constant shadow of
potential failure. At Merck, we have research projects to combat these diseases in
various stages of development, from early laboratory investigation to full scale clinical
investigations,

CANCER: Let me begin with cancer. The field of research for the treatment of cancer
is undergoing a dramatic change. Molecular understanding of the metabolic pathways
that go awry and cause cancerous growth of cells has progressed dramatically in the


87

Mr. PETERSON. I am just curious. How do we change that? I do
not think you are going to change Congress’ attitude. They do not
get riled up unless somebody riles them up a lot of times.

Mr. MoLt. I agree that changing FDA might be easier to change
than Congress.

Mr. PETERSON. Dr. Powell?

Mr. PowELL. I would like to comment. I have thought about that
a bit. In my testimony I proposed that there be an oversight com-
mittee to make sure that the FDA is following the mission state-
ment that Congress would pass.

That oversight commission would have the authority and the
power to recommend policy and personnel changes within the agen-
cy. I would think that they could also be given the power to award
bonuses for good performance against the mission. The moneys for
those bonuses could come from the user fees.

It seems to me there are all kinds of opportunities to change the
incentive system so that it is more like a commercially incentive
system. People work for a reward, and they avoid punishment. It
seems to me that that would work.

Mr. PETERSON. My question is has anybody put that in writing?
Is there any kind of proposal that is out there that we could loo!
at? Can you put that in writing for us?

Mr. MoT. We could, sure. I think we have been thinking along
those lines.

It is difficult. I did not want to be glib before, but it really is a
difficult thing to try to put true incentives on that kind of system
because by nature it should be a cautious system. As David Blois
said, we do not want to approve drugs that are not safe, so it is
difficult.

Mr. PETERSON. Dr. Larkin, on the Delaney item, I serve on the
Ag Committee, but I do not serve on I think it is the DORFA sub-
committee dealing with this. Does that bill fairly well have every-
one’s support now? Is EPA behind it?

et LaRKIN. EPA has problems with certain aspects of it. I
think——

Mr. PETERSON. On the Delaney part of it?

Mr. LarKIN. No, not on the Delaney part. I think there is una-
nimity over changing Delaney.

Mr. PETERSON. How about within the environmental community?
Are some of the radical environmentalists on board finally or not?

Mr. LARKIN. I would say that the middle of the road environ-
mentalists are probably on board. I would say that there are fringe
elements that are not.

It becomes somewhat of a trading act in that you can fix
Delaney, but what will you give us in return? That is really where
we are at right now.

Mr. PETERSON. We keep running into these different groups that
want to do things that I do not think we can accomplish. There are
these people that claim that they want zero risk and that they are
never to blame and that they are always the victim.

Is there some way we could have some Government programs so
that we could give them this and then charge three or four times
more than what we charge everybody else if that is what they want
and then use that money to get at some of these problems?


8

One of the things that the staff informed me that she was hoping
we would be able to do is make more drugs available to help con-
trol the nausea that comes from chemotherapy so that that type of
incident would not happen to her. Her statement will be here, and
our best goes out to here. I hope she feels better as she struggles
with that treatment.

[The prepared statement of Ms. Zakarian follows:]


THE NEED FOR FDA REGULATORY REFORM
TO PROTECT THE HEALTH AND SAFETY OF
AMERICANS

FRIDAY, JUNE 9, 1995

House or REPRESENTATIVES,

SUBCOMMITTEE ON NATIONAL ECONOMIC GROWTH,

NATURAL RESOURCES, AND REGULATORY AFFAIRS,
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT,
Norristown, PA.

The subcommittee met, pursuant to notice, at 10:07 a.m. in
Courtroom B, third floor, Montgomery County Courthouse, Main
and Swede Streets, Norristown, PA, Hon. David M. McIntosh
(chairman of the subcommittee), presiding.

Present: Representatives McIntosh, Fox, Tate, and Peterson.

Ex Officio Present: Representative Clinger.

Also present: Representative Walker.

Staff present: Mildred Webber, staff director; Jon Praed, chief
counsel; Karen Barnes, professional staff member; David White,
clerk; Judy Blanchard, deputy staff director for the Committee on
Government Reform and Oversight; and Bruce Gwinn, minority
senior policy analyst.

Mr. McINTosH. The Subcommittee on National Economic
Growth, Natural Resources, and Regulatory Affairs is convened to
order.

It is a pleasure to be here today in this part of Pennsylvania. I
appreciate my vice chairman, Mr. Fox, making all the arrange-
ments for us. He has done a tremendous job.

Let me say to you here who are lucky enough to have him in
Congress, he has been working very hard on our subcommittee and
doing an excellent job of representing the interests and the needs
of the people here in Pennsylvania.

I am also very pleased that with us today is the chairman of the
full committee, Mr. Clinger, who has been guiding us on the sub-
committee. He was kind enough to allow a freshman to chair one
of his subcommittees and has been very helpful to me in setting up
our committee and making sure that it works well and runs effi-
ciently.

Also with us is Mr. Peterson, the ranking minority member, who
is here from Minnesota. I also appreciate it, Collin, when you are
able to join us. It shows that this is a bipartisan effort to look at
regulatory problems and try to find solutions that will make it bet-
ter for all Americans.

(ey)


150

representatives should debate Scientists should provide the necessary background inforrastion, but polivy
makers and the public should make the policy. Then technicians oan decide how to apply the policy.
Currently the bureaucrats at the FDA seem to fee! they heve the right to tell people faced with life
threatening illness how much rik they ahould be allowed to take, More than tha, they seem to feel they
Ihave the right to tell people with life threstoning illness that they cen't usc a medicine until they, the FDA,
are sure it works. But, if someone plausibly thinks it MIGHT work, then if I were a pervon living with
this devestating disease I would say: let me and my doctor be the judge of that, not some faceless

‘bureaucrat.

Thus on behalf of people living with HIV in the Philadelphia area, let me say that I hope Congress will
ect to curb sorne of the power of this agency. We need regulation. We do not need arrogance and
insensitivity to the needs of people with life thrcatcning illnesses.

Thank you very much for this opportunity to sppesr hefore you.


42

Our first witness is Dr. David Blois, who is vice president of
worldwide regulatory affairs with Merck & Co.
r. Blois.

STATEMENTS OF DR. DAVID BLOIS, VICE PRESIDENT, WORLD-
WIDE REGULATORY AFFAIRS, MERCK & CO.; ACCOMPANIED
BY JAMES T. MOLT, VICE PRESIDENT, WORLDWIDE REGU-
LATORY AFFAIRS, RHONE-POULENC RORER; ROBERT POW-
ELL, VICE PRESIDENT AND DIRECTOR, REGULATORY AF.
FAIRS, SMITHKLINE BEECHAM PHARMACEUTICALS; BRUCE
CARROLL, MANAGER, GOVERNMENT RELATIONS DIVISION,
CENTOCOR, INC.; AND ROBERT H. LARKIN, DIRECTOR, REG-
ISTRATION AND REGULATORY AFFAIRS, AGRICULTURAL
CHEMICALS BUSINESS, ROHM AND HAAS CO.

Mr. BLors. Good morning Mr. Chairman and Congressman Fox
and members of the committee.

As you mentioned, I am vice president of worldwide regulatory
affairs for Merck. In this capacity, I am responsible for interaction
with health authorities around the world which oversee the devel-
opment, the review and approval of Merck’s new drug and vaccine
products.

Merck has over 4,000 employees living in Montgomery County
who are very interested in seeing Merck and the U.S. pharma-
ceutical industry as a whole continue to be a world leader in the
development, discovery and marketing of new medicines and vac-
cines,

It is important to state from the outset that Merck supports a
strong regulatory system, one that assures the safety, efficacy and

uality of medicines and vaccines. At the same time, we feel that
there are changes in the U.S. regulatory system that are important
to allow continued innovation by the U.S. pharmaceutical industry.

We can and should eliminate unnecessary delays and bureau-
cratic procedures while maintaining high standards for safety, effi-
cacy and quality for new medicines.

We have seven specific recommendations which we would make
in the effort to reform regulation. First, FDA should focus on drug
approvals. At present, FDA’s primary focus is on protecting the
U.S. public from unsafe medicines and vaccines. We feel that the
agency’s resources should also be focused on FDA’s positive role in
assuring timely availability of new drugs and therapies. Thus, we
propose that FDA’s mission statement be amended to provide bal-
ance between safeguarding the public and promptly approving im-
portant new drugs.

Second, we need to eliminate excessive and unnecessary paper-
work. The amount of data which is required to be submitted for re-
view by FDA should be limited to what is reasonably required by
a competent scientist to make a decision on safety and efficacy.
This type of submission has proven to be more than adequate for
highly sophisticated European drug regulatory authorities which
focus their review on the substantive issues of safety and efficacy
rather than auditing or reanalyzing data.

Third, we need to improve FDA management practices. The re-
view process is still too often beset by long review times and delays
in approval. We would like to see a managed review process which


161

Another suggestion that I would like to voice at this point is that we increase the degree of
standardization in all aspects of the review process. There is too much reliance on the
individual bias of the reviewers, so that, frequently a pharmaceutical company is pointed in
one direction and then there is a change in a reviewer which requires redirection. This
adds expense and time to the approval process. I would like, therefore, to suggest that
there be standard clinical pathways for a variety of therapeutic areas so that a company
going into the approval process will have an excellent idea of exactly what type of studies
are required in the developmental process. I would like to see specific pivotal studies
required for areas such as hyperzeasion, adult on-set diabetes, congestive heart failure, etc.
There is no questions that each drug has different potentials and different dangers, and of
course, these individual variances will have to be addressed, but the better that everyone
understands what is required going into the process, the quicker the approval can be
accomplished.

I also would like to suggest that the same standardization process be applied to the
monitoring at the investigational sites. It has been my personal experience that the
monitoring is very much dependent upon the individual biases of the Reviewer at the
clinical sites. Frequently, as an investigator, one feels that they are uncertain as to. what
exactly the FDA is looking for in its field trips. Also, as a related issue, most of the
monitors coming out to the sites have limited medical knowledge. They come to visit my
site on one day, and the next day, they visit water ice manufacturer to determine the

purity of their process, I believe that it is vital and imperative that we have medically


13

Mr. McINtosH. Thank you very much, Mr. Carroll. I appreciate
your testimony.

Our final witness on this panel is Dr. Robert Larkin, who is an
agriculture chemicals expert with Rohm and Haas Co.

Dr. Larkin, welcome.

Mr. LaRKIN. Good morning, Mr. Chairman, and members of the
special field hearing.

My name is Robert Larkin, and I am director of registration and
regulatory affairs for the agricultural business of Rohm and Haas
Co. I have responsibility for the registration of our agricultural
chemicals worldwide.

Rohm and Haas, as you might know, is a multinational chemical
company with headquarters in Philadelphia. Our worldwide sales
in 1994 totaled over $3.5 billion, of which agricultural chemicals
makes up approximately 15 percent.

I want to thank you for the opportunity to address your commit-
tee this morning. Rohm and Haas Co. is not directly involved in the
pharmaceuticals business, although a number of our products are
used in the packaging or processing of food and pharmaceuticals
and, therefore, are regulated by the Food and Drug Administration
as indirect. additives.

This morning, however, I want to focus my remarks to a very
specific section of the Federal Food, Drug and Cosmetic Act that
has great impact on our agricultural chemicals business. That sec-
tion is section 409, which contains the so-called Delaney clause.

As you are undoubtedly aware, the Delaney clause was added to
the Federal Food, Drug and Cosmetic Act almost 40 years ago in
order to protect the Nation’s consumers from the presence of cancer
causing agents in processed foods.

The Delaney clause establishes a different standard for setting
tolerances for pesticide residues of carcinogens in raw versus proc-
essed foods. This different standard leads to the nonsensical situa-
tion in which the same pesticide residue that is legal on grapes, a
raw food, is illegal on raisins, considered a processed food.

The National Academy of Sciences coined the phrase the Delaney
paradox to describe this disconnect in the statute.

The clause was enacted at a time when relatively little was
known about the causes of cancer and when methods of analysis
were able to detect chemicals in food at only the parts per thou-
sand level. Although the enactment of the Delaney clause by Con-
gress in 1958 might have been appropriate in light of science at
that time, the passage of 40 years has made the Delaney clause an
anachronism.

Instead of protecting the public health, the National Academy of
Sciences concluded in their 1987 report that strict application of
the Delaney clause might indeed increase the risks to the public
from pesticide residues in their food supply.

You might ask why after 40 years the reform of the Delaney
clause has suddenly become such an important issue. The reasons
lie in recent legal actions. The first action occurred in 1992 when
the Ninth Circuit Court in California ruled that EPA could no
longer interpret the Delaney clause as having a de minimus excep-
tion.


82

phases as you go toward approval of the drugs? Phase I, II and II?
Is that it? Can you tell us where the slow down seems to occur,
Doctor?

Mr. BLoIs. Yes. The phases are really segments of the clinical de-
yelopment Program, but let me state that before we start clinical
development—that is, testing a drug in humans—we do a battery
of animals studies to make sure that from animal studies the drug
is safe at least in those tests and that there is some hope for effi-
cacy—that is, that the drug will work.

Following completion of those studies, we submit to FDA an IND,
which Dr. Molt referred to, which allows us to initiate human clini-
cal studies. It is at that point that we start what we call phase I,
which is really studying healthy volunteers as a rule, depending on
the disease. It is usually in healthy volunteers to assess the safety
and tolerability of the drug.

As we get information from that, if the drug is relatively safe or
has an acceptable safety profile, we will expand the study of the
drug into patient populations, relatively small and controlled at
first, expanding as we get information about the drug. Those would
be phase II studies.

e then expand into large scale phase III studies, which confirm
the safety and efficacy in a relatively large population. By large
Population, I am talking about maybe up to 1,000 or 2,000 patients.

‘ollowing completion of those studies, we assemble all the infor-
mation which we have gathered in preclinical, phase I, phase II
and phase III, submit those data to FDA in the form of a new drug
application, and FDA reviews and rules on those data.

Now, in terms of areas where there may be areas for improve-
ment in the process, first off, 1 agree with what some of the other
Banelists have said. We do not want to see unsafe or ineffective

made available to the public. That, in my estimation, does
not benefit anybody.

Mr. Fox. I do not think anybody wants that. You are right.

Mr. BLoIs. One of the areas that I think can be improved signifi-
cantly is in the area of summary data, which I mentioned. In the
original IND submission, there is a requirement for submission of
more detailed data than perhaps is needed, recognizing that 9 out
of 10 drugs that enter the IND phase never make it to the market-
place.

It would be reasonable to focus our effort on the amount of infor-
mation necessary at that point in time, not to look at a product as
if it were going to go fully through the approval process.

ain, at the time of submission of a new drug application, I
think it is reasonable to submit summary data rather than all of
the raw data that were gathered during a clinical investigation.

One other area that I think needs to be looked at, and it goes
back to the present status of our scientific approach, is there is cur-
rently a requirement that we have two “pivotal” studies, two large
confirmatory studies.

We would propose that the requirements be switched to one large
study demonstrating safety and efficacy, followed by confirmatory
data from other sources so that we do not have to do by rote two
studies, but rather can look at innovative ways to confirm clinical
results and again assure safety, efficacy and quality of a product.


THE NEED FOR FDA REGULATORY REFORM TO
PROTECT THE HEALTH AND SAFETY OF AMERI-
CANS

HEARING

BEFORE THE

SUBCOMMITTEE ON NATIONAL ECONOMIC GROWTH,
NATURAL RESOURCES, AND REGULATORY AFFAIRS

OF THE

COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES

ONE HUNDRED FOURTH CONGRESS
FIRST SESSION

JUNE 9, 1995

Printed for the use of the Committee on Government Reform and Oversight

ae

U.S. GOVERNMENT PRINTING OFFICE
95-445 CC WASHINGTON : 1996

For sale by the U.S. Government Printing Office
‘Superintendent of Documents, Congressional Sales Office, Washington, DC 20402
ISBN 0-16-053795-9



108

requirements for those products. This change will eliminate
about 700 pages of unnecessary regulations from the Code of

Federal Regulations.

Finally, I would like to mention the issue of exports of
unapproved drugs. I want to emphasize that this is not an issue
on which the Agency has any particular expertise. In fact there
is a strong argument to be made that this is not really an issue
of public health since products not approved in the United states
inevitably get to other countries, whether we allow their export
or not. Instead, the issue turns on the extent to which we, as a
country, are comfortable with permitting the export of products

which cannot be sold here, but which are sold in other countries.

Current law allows drugs to be exported to 21 industrial
countries identified in the Federal Food, Drug, and Cosmetic Act,
if the drug is under investigation (IND) in the United states,
the foreign country approves of the shipment, and certain other
conditions are met. Export of unapproved drugs to other

countries is not permitted by law.

12


es

181

g

abounds with articles describing sucoces with unapproved or off-label uses, and 1
am quite free to use the drugs if I believe what I read.

This sweward siroon leads 10 iuplaustle consequences, Many dnugs enjoy

wi uso by the medical for and indications which the

candeeurers are uot pected io cl wppae 0 come aout whan dg

‘bas passed the efficacy test for some minor purpose develope a or
nm required FD, ppl sdvertioe the ‘exe

the rather huge suma to achieve FDA. to

indications. At the aame time, many physiclane are inhibited from the

drug in useful way ocanse they an sees the Paycian Desk Reference there is
(DA stamp of approval for that use. They can easily envision themsclves
courtroom accused of doing unapproved things, and are often convined plaintiff
attorneys will characterize the situation as unorthodox if not improper. In

words, even if such use is not Hegal, it is unapproved. ‘You would nce wane your
doctor to do ‘unapproved things, now, would you?

We have reached sination in which x drug requires twelve Years and a hundred
million dollars to prove even one point of efficacy. No indications
receive FDA sanction unless the manufacturer is willing to spend more years and
millions to get the sanction. Indeed, manufacturers are often

produce a different sized tablet because of the cost to them .of achieving FDA
approval for a smaller pill. This is true even though 1 as a physician have a
perfect right o prescribe a diferent dosage and have the local druggist make ft
up ina capsule, iy the Proposed use has only « anual! sales potential, or if the
P&tent protection has only a short duration, the manufacturer will not pay for the
Clinical trials . The FDA is too overburdened with other applications to do it on
its own initiative. And so, some physicians run an unwarranted malprectice risk
dy: using the drug, while other physicians are too timid 10 stray beyond the
published approvals; and so their patients are deprived of benefits. It would be
far better if the FDA were completely silent about efficacy.

‘The efficacy requirement imposes an even worse problem at the beginning of the
process. Unril the manufacturer has eatablithed some sort of efficacy for some
‘Kind of problem, the drug is unobtainable. For years I have been hearing doctors
with foreign accents praise the diabetic drug Metformin, and read many articles in
the medical literature which convinced me of its great superiority. Finally, this .
January the FDA agreed with the rest of the world. Marketing of the drug was
surprisingly delayed until May. For years I had been treating diaberics in ways I
kmew were inferior to Metformin, only to hear from the manufacturer's
‘Tepresentative that patent bad expired and the manufacturer was therefore dubious
for a while about marketing the drug in the US at a profit. This Gilbert and
Sullivan comedy only occurred last month, but already 2 dozen of my patients have
Teported gratifying results from a drug J knew was excellent 16 ycars ago.

. . .



159

June 5, 1995

PAPER ON THE SUGGESTIONS FOR MODIFICATION OF THE
PROCESS FOR DRUG APPROVAL IN THE UNITED ST. ‘ATES

_ Comments on Monitoring Aud Review Of New Drug Applications And The Clinical

Process Through Which Drugs Become Approved

These comments are based on my experience dealing with the FDA for thirteen years and
my involvement in approximately 300 pharmaceutical studies during that period of time.
In almost every instance the FDA has moved appropriately and has made reasonable
decisions as to the efficacy and safety of the drugs in question. It is important to note that
the FDA must walk 2 very fine line in the drug approval process because if it moves too
rapidly to eppfove a new medication it exposes a population to a risk involving unknown
side effects. Also if someone is using a new medication that is not efficacious, it keeps
that patient from being given an opportunity to use other therapeutic modalities which
may have some effectiveness. On the other hand, if the FDA moves too slowly, it may
prevent efficacious modalities from being applied to a population. This, of course, bas
come to the forefront most noticeably in the treatment of AIDS. Again, it is important to
understand that frequently public expectations are heightened by the press and they do not
understand all of the ramifications and potential dangers of new medications. It is said
that it takes a million doses of a medication to develop a side effect profile completely so




109

The Administration proposes to reduce administrative burdens on
the export of drugs to the 21 countries, and in particular to

eliminate the requirement that there be an IND in the United

States before the product may be exported to a foreign country.
In addition, the Administration proposes to work with Congress on
changes in the current law based on an examination of whether to
amend the present list of 21 countries, and whether to adopt

other changes.

CONCLUSION

Clearly, we are in an era of change: the role of the patient in
today's health care environment has changed; the pharmaceutical

industry has experienced profound restructurin:

j} new technologies
and previously unknown illnesses must be understood; ever
escalating health care costs challenge our ability te respond to
ever increasing need. FDA has been working to meet the

challenges these changes present.

Years ago, a case could have been made that the Food and Drug

Administration was taking too long to approve drugs and that in

23


30

We need even more such programs which get experimental drugs
of potential treatment benefit to the people who have urgent need
for them and get them to these persons fast once safety has been
established. As persons with AIDS, we are tired of waiting end-
lessly for drugs of proven safety to make their way through the ap-
proval process.

We have fears regarding the FDA reforms in the bill that Demo-
crat Ron Wyden of Oregon has promised to introduce before Memo-
rial Day. The Republican bill, we are assured, will follow in a few
days. Both bills are expected to deregulate phase I clinical trials,
but the Democratic version will almost certainly not codify acceler-
ated approval. Because of these moves, we are going to wake up
and find the AIDS drug pipeline is empty.

During the 1950’s, drug approval was a relatively quick and sim-
ple process in the United States, like it is today in Europe. Then
came Thalidomide. Several hundred babies were born with horrible
defects after European regulators approved the drug for morning
sickness without realizing it could affect the fetus.

Capitalizing in the tragedy, Congress expanded FDA’s powers
and altered its priorities. These overly cautious policies have hin-
dered drug approval ever since.

In November 1994, the experimental AIDS drug, 3TC, then in
phase III testing, was shown to significantly increase and extend
the efficacy of AZT, the standard therapy, when combined with it.
The 3TC/AZT combination cannot be approved until the spring of
1996. The FDA wants another level of clinical end point studies.

Meanwhile, more than 100,000 AIDS patients will remain on the
far less effective AZT monotherapy, a drug which is shown to lose
effectiveness after a year or so of use. Persons who are not among
the lucky 17,000 who have gotten on a compassionate use program
or the additional thousands on the waiting list are out of luck.

Only persons with a CD4 count of below 100, in other words,
with very advanced AIDS, qualify; not to get the drug, but to be
put on the waiting list. I have a CD4 count that was 10 in Decem-
ber. It is much higher now by virtue of my access to 3TC. I must
admit that I was unable to get the drug through the usual FDA
channels and was forced to look to community resources. Otherwise
I potentially face earlier disease progress and death. We need to
speed up the process, not slow it down.

Another example. A number of AIDS treatment activists and
former clinical trial participants from Philadelphia have been fight-
ing for 5 years now to get approval for expanded trials of Jonas
Salk’s HIV-1 immugen, a therapeutic vaccine for persons already
infected with HIV, a product which has been in human trial since
1988 with a perfect safety record.

It was not until January that tentative approval for phase III
trials was granted for a multicenter study of several thousand indi-
viduals. Many of them signed our petitions and have been waiting
over 3 years.

Because of the costly and slow process, many small biotech com-
anies, including Immune Response Corp., the manufacturer of the
alk immugen, are nearly bankrupt by the time they get to the

point of approval, slowing down the process even more from the


89

commonly looking at are different and require long periods of
study.

Mr. CLINGER. Somebody recommended using outside experts to
do some of this. Would that help?

Mr. PowELL. I think it would. One of the problems the FDA has
is it spends a lot of time verifying and documenting data that is
submitted for new drug applications, which are the No. 1 priority
obviously even of the agency.

As a result, they do not have the time to devote to working with
the manufacturers during the development of the drugs. Often
times development will be delayed just for the simple reason we
cannot get meetings with the FDA in a timely fashion to discuss
and agree on programs.

I think that the use of outside sources would help alleviate that
problem, reducing the amount of data verification that the FDA re-
viewers have to do and would allow them to have more time to
work with the manufacturer and speedup the drug development
process in general.

Mr. CLINGER. Have you sensed in recent years or months or
whatever, that the FDA has become more responsive to these kinds
of concerns?

Mr. PowELL. Yes, I think it has, but it is severely constrained
with resources. They have the same problem everybody else has.
The resources have to be assigned to the jobs that are primary. If
the process is so complex that they spend a lot of time reviewing,
they do not have time for the other things.

Mr. BLois. I would just like to add that the user fee legislation
which came into place in 1992 I think has produced a noticeable
change. It has now made available the resources for FDA to have
in place to review applications when they are received, and we
have seen significant improvement in the overall process and a
focus on the timeliness of the review.

That has been something that has been a very positive effect,
and I think Dr. Lumpkin may reflect on that later on.

Mr. McInTosnu. If the gentleman would yield?

Mr. CLINGER. Yes.

Mr. MciIntosu. Is that also the case with some of the new
biotech companies? Do you find that additional resources have
speeded the review?

Mr. CaRROLL, Our president is a firm believer in the user fee if
it is allocated where it is supposed to be. He has cited the fact that
the speedier approval of our drug was a direct result of the user
fee.

Mr. CLINGER. I just have one final question, and that has to do
with where the disease is terminal, where there are no cures for
these diseases such as we heard testimony here today.

What are the down sides to just approving it? Why should we
hold up any potential help in that area? Why would we interpose
any time between the availability of that drug, unproven as it may

e

Given the fact that the disease we are dealing with is terminal
anyway, is there not some advantage to allowing that to go for-
ward? What is the down side of not allowing it to go forward?


84

I agree with Dr. Blois that probably from one large study you can
form a conclusion based on whether the benefit outweighs the risk.
I think what FDA is excessively dwelling on is the risk aspect of
the equation. I think other developed countries look at both sides
of the equation.

Mr. WALKER. Do we have a better record overall than other coun-
tries in terms of preventing drug risk?

Mr. MOLtT. There is no data that shows that, for instance, Euro-
peans have any more adverse reactions than the United States
population does.

Mr. WALKER. So in other words, our complicated system, in your
view, is not leading to a system that is getting less risk in the sys-
tem?

Mr. Mott. That is what our problem is.

Mr. BLots. In response to your first question, I would say that
the United States review system is different from the European
systems in different ways. They are all complicated in many of the
ways.

ne of the primary differences is in the requirement for data
submission and the process of reviewing raw data, reanalyzing
manufacturer’s data, auditing manufacturer’s data. That is not
present in most or in any European system. It is a much deeper
Teview and assessment of the data than what is done in any Euro-
pean city.

Mr. WALKER. Is there any other nation at all comparable to the
Delaney clause, Dr. Larkin?

Mr. KIN. No. The United States is unique in that aspect. It
stands alone.

_ Mr. WALKER. It does make it kind of complicated in full competi-
tion.

How many of your companies are manufacturing a product out-
side this country which is unavailable in this country? Two. Two
of the companies are manufacturing.

Were any of the products that you are manufacturing outside the
country developed in this country?

Mr. POWELL. Our products are developed globally. We have ap-
Provals in other countries before the United States generally as a
rule.

Mr. WALKER. What I am getting at is I know of a situation that
is developing for Centocor, for example, in Chester County where
from what I understand about our system, we in fact can research
and develop the drug here, it can in fact be made available in other
countries—in other words, be approved in another country—but
then we cannot manufacture it here to sell in that other country
unless it is available in this country. Is that correct? Is that where
our law is right now?

Mr. CARROLL. There are exporting regulations, especially on the
device side, so that it is easier to manufacture a device overseas
and sell it overseas than it is to manufacture it here and export
it.

In our case, we do manufacture here and export it, but we
have—

Mr. Waker. I am talking specifically now about drugs. Am I
correct that under our laws if the drug is unavailable in this coun-


12

CAN ACT 4

importance of off-label use in providing advances in treatment for people with cancer.

But thase who would improve their profits at the expense of people's lives argue that
they should not pay for off-label use, because if the FDA doesn’t approve a use, it couldn't
be effective, a kind of circular reasoning.

The self-serving hypocrisy of this position need not be underscored: it’s apparent
‘enough. But the problem remains. At its core is the nature of the approval designation. There
are many other reasons, but under the constraint of time I can only strongly suggest that the
FDA must approved drugs “for the management of cancer.” Period.

There is another element of FDA thinking that irresponsibly and inhumanely violates
patient needs and rights:

FDA operates on a “breakthrough” sssumption: that when a drug is available to treat
‘one type of cancer, any subsequent drugs for the same condition are not as utgently needed.
This may be true for other diseases, in which one drug (and I am thinking of countless
instances, such drug for Tourette's syndrome, and such), where a
one-drug-fits-all” standard applies. That is not true in cancer, for two teasons:

1/ There are few certainties about cancer; how any patient responds to treatment is
highly individual. No doctor can predict how anyone will respond to any drug ot regimen. A
range of drugs is needed to accommodate the variety of human responses.

2/ With time, people can become resistant to a drug. New drugs are needed if the
patient is to continue to fight the disease.

The need for more drugs to be approved more quickly does not change when one drug
is already out there. The FDA risks my life-- and yours— in its assumptions.

Fifth, the FDA cannot operete in secrecy, because that's where its power comes from.
If an Advisory Committee rejects a drug, subsequent hearings must be public ~and
must go to @ higher court.

The history of the FDA is replete with wasted time, groundless questions, go-slow
procedures, and political maneuvering, I would cite the approval of Gancyclovir as the
quintessential example of time wasted, lives wasted. The FDA hax no sense of the urgency of
people who need drugs to treat serious diseases.


approvals of our New Drug Applications (NDAs) for Rilutek and Taxotere®
from the U.S. Food and Drug Administration (FDA) later this year. I will use
these two products to illustrate areas where we see strengths in the FDA
process and conversely where we see opportunities for significant change
with the goal being a better and more responsive FDA.

Let me start with the example of Rilutek where we have seen some
positive results stemming from recent FDA initiatives for  self-reform.
Rilutek is indicated for the treatment of amyotrophic lateral sclerosis or ALS,
which is also known as Lou Gehrig's Disease. Generally patients survive
three to five years after diagnosis. There are approximately 30,000 ALS
patients in the US. Results of the largest ever Phase III trial conducted in
ALS, demonstrated that Rilutek is the first compound to prolong survival in
this disease. Since there is no approved treatment for ALS, RPR has
submitted documentation to FDA to allow patient access to Rilutek under a
Treatment IND, before full marketing approval is potentially granted. The
Treatment IND is a mechanism put in place by FDA to bring promising new
drugs to the public before the NDA is approved. We concur with the
statements made by William Shultz, Deputy FDA Commissioner for Policy,
in his recent testimony before Congress that initiatives such as Treatment
INDs help FDA accomplish its "twin goals of protecting the public and
promoting the rapid availability of effective drugs". Our one concern is that
patient access through a Treatment IND does not become a disincentive for
FDA to approve the NDA. It is this concept of incentives for FDA that brings
me to my main point.

sti t_F


96

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Hesith Service

Food end Orug Administration
Rocevile MD 20857

STATEMENT BY
MURRAY M. LUMPKIN, X.D.
DEPUTY DIRECTOR FOR REVIEW MANAGEMENT

CENTER FOR DRUG EVALUATION AND RESEARCH

FOOD AND DRUG ADMINISTRATION
PUBLIC HEALTH SERVICE

DEPARTMENT OF HEALTH AND HUMAN SERVICES

SUBCOMMITTEE ON ECONOMIC GROWTH,
NATURAL RESOURCES, AND REGULATORY AFPAIRS
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
U.8. HOUSE OF REPRESENTATIVES

NORRISTOWN, PENNSYLVANIA

JUNE 9, 1995

YOR RELEASE ONLY UPOW DELIVERY


%
gral part of improving the laws governing pesticides in this coun-
try.

In conclusion, I would like to ask you for your support in imple-
menting the conclusions of the National Aca lemy of Sciences to es-
tablish a food standard for setting a tolerance for all food that
would be more protective of the public health than the standards

of the current Delaney paradox. You can do this through support
of H.R. 1627.

Thank you.
[The prepared statement of Mr. Larkin follows:]


36

In November 1894, the experimental AIDS drug STC, then in Phase Ill testing, wes chown
10 significantly increase and extend the efficacy of AZT, the stenderd therapy, when
combined with it. The 3TC/AZT combinstion cannot be approved until the spring of 1996.
The FDA wants another level of clinical endpoint studies. Meanwhile, more then 100,000
AIDS patients will remain on the far less effective AZT monotherapy, © drug which has been
shown to lose effectiveness after a year or so of use. Persons who ere not among the lucky
17,000 who have gotten on a compessionate use program or additional thousands on tha
waiting list, are out of tuck. Only persons will a CD4 count of below 100, In other words
with very advanced AIDS, qualify, not to get the drug but to be put on # waiting list. I have
a CD4 count that was 10 in December and is much higher now by virtus of my access to
3TC. But! must-admit, that] was unable to get the drug through the usual FDA channels
‘and was forced to look to community resources. Otherwise | faced potentially earlier
disease progress and death. We need to speed up the process, not slow It down.

Today, nearly ali major US drug companies run most of, if not all, their Phase { clinical triste
in Europe. Since the FDA failed to implement Competitiveness Council reform of Phase t,
early clinical research fled the country to avold the US regulatory burden. FDA's fallure to
reform Phase | disadvantages small American biotech companies who lack European
research centers. For example, a number of AIDS treatment activists and formar clinical tral
Participants from Philadelphia hava been fighting for 6 years now to get spproval for
expanded trials of Jonas Salk’s HIV-1 Immunogen (a therapeutic vaccine for persons siready
intecteo with HIV}, 8 product which has been in human trials since 1988 with's perfect
safety record. It was not until January that tentative spproval for Phase Il! trisis was
granted for a multicenter study of several thousand individuals, many of them signed our
potitions and have been waiting for over three years. And because of the costly and slow
process, many small biotech companies Including immune Response Corporation (the
manufacturer of the Salk immunogen} are nearly bankrupt by the time they get to the point
‘of approval, slowing down the process evan more from the point of view of PWAs who feel
life-saving drugs are belng kept from them because of Lureaucratic red tape.

As compared to Europe, the FOA demands excessive and expensive (in time and resources)
caution in early clinical research. In Phase t, the FDA commonly demands decreased
doeages, lengthy observation periods, and discussions at each stage. The FDA, often
requites raw data where European agencies eccept summaries of dats in New Orug
Applications (NDAs), so US applications from biotech companies can sometimes amount to


48

Pages

2. Eliminate unnecessary paperwork

The amount of data required for submission and subsequent review by the FDA should
be limited to what is reasonably required to determine safety and efficacy. The Agency
‘should accapt comprehensive summary data (which could be subsequently audited),
rather than require 100 percent of the raw data resutting from clinical trials. This
Process has proven sufficient in other highly effective European drug regulatory
‘systems and has greatly speeded reviews and has focused those reviewed on the
‘substantive issues of safety and efficacy rather than on auditing or re-analyzing an
applicant's data.

3. Improve Management Practices

The review process is still too often beset by long review times and delays in approval.
There is a diffusion of responsibilities, long down times when little action is occurring
and a lack of delegation of authority. We would like to see a managed review process
which sets specific goals and milestones and a system which holds reviewers and
supervisors accountable for meeting the timetables. Such a process would prevent
long periods of Inactivity and the attendant delays in approvals.

4 Contract out selected review functions:

It is clear that FDA resources are limited for the amount of work its scientists must do.
Currently, FDA empioyees review ail parts of a new drug application, or a supplemental
new drug application, write up their findings and make recommendations to their
supervisors. While agency reviewers are knowledgeable and efficient, a much larger
‘and broader group of reviewers is available in the academic, scientific and medical
communities.

Experiments with outside reviewers have begun and should be continued to determine
if the review process can be expedited, made more effective, and less costly without
less of quality or continuity. The scientific information contained in a new drug
application or a supplemental NDA could be processed by an FDA supervisor and then
‘sent to academic scientists in the best medical centers around the country for
‘evaluation. | believe that academic scientists would relish such a role in new drug
discovery. Not only would their participation greatly speed the review process by
broadening the pool of experts, but it would assure that the best expertise nationally
was applied to each application. The process, if managed property, could enhance
judgments of the safety and efficacy of new medicines and vaccines.

This process is an extension of what is actually done today in that FDA utilizes outside
Advisory Committees for evaluating safety and efficacy. Advisory Committees
comprised of outside experts, and other outside contractors, such as the MITRE.
Corporation, have proven that outside reviews are possible and can work wall.
Extending the concept further makes good sense and initiative should be made to try


117

Dr. LUMPKIN. Yes, sir.

Mr. PETERSON [continuing]. You did not explain. Could you ex-
plain to me what that is?

Dr. LUMPKIN. I would be happy to.

{Chart.}

Dr. LUMPKIN. This was a chart that I was going to use if indeed
the question came up, and it did, about comparing the United
States’ approvals to approvals in other parts of the world.

Again, this is a point | was trying to make relative to what hap-
pens if you look back at the decade between the mid 1970’s and the
mid 1980's and you look at the half decade between 1990 and 1994.

What this particular chart says is that if you look back at cal-
endar year 1994, there were in this country 22 what we call new
molecular entities. There were over 60 new drugs that were ap-
proved. Sixty-two it was. Of those 62, 22 were actually brand new
molecular entities, meaning that that chemical had not been ap-
proved previously in this country in any kind or form.

When you look at those 22, in decades in the past often times
you would say well, a great majority of those had been approved
in other countries before they were approved here. We found very,
very few back in the 1970’s—it usually was around 15 or 20 per-
cent—that were approved first in the United States.

Of those 22, nine were approved in the United States first. We
were the first country for that number. When you look at the oth-
ers, and you can just see the various countries there, the other
drugs were approved first in those particular countries. That is all
I was trying to show with that. We are seeing a change in this
country of first approval.

It is interesting also, since the example of Great Britain was
brought up, if you look back in the mid 1970’s at the numbers of
first approvals in the United States and first approvals in the Unit-
ed Kingdom, you will find that of that total number, about 75 per-
cent were approved first in the United Kingdom.

If you look over the last 5 years, you will see that that splits
about 50/50. That involves about 115 or 120 drug products. Half of
those were approved first in the United States, and half were ap-
proved first in the United Kingdom.

Mr. PETERSON. One further thing. Could you explain to me then
when I was over in Israel why we had American companies telling
me that they had set up their operation over there because they
could not get done what they needed to get done in the United
States so they had moved the whole operation to Israel? There
were quite a few of them.

Dr. Lumpkin. I am not sure, sir, about many of the specific cases
that you talk about.

It is interesting, though, that you bring up the question of Israel
because there is a joint technology consortium that has recently
been put together between the United States and Israel. We at the
FDA have been invited to be a part of that and actually have been.

We have made several presentations to Israeli delegates and Is-
raeli industry representatives about the drug approval process here
in the United States and about the use of feracli data and Israeli
manufacturing processes for drugs to be marketed here in the Unit-


53

TESTIMONY OF JAMES T. MOLT, Ph. D
U.S. HOUSE GOVEKNMENT REFORM & OVERSIGHT COMMITTEE
June 9, 1995

Good Morning. My name is James Molt. I am the head of Worldwide
Regulatory Affairs for Rhéne-Poulenc Rorer. Rhéne-Poulenc Rorer is a U.S.
corporation, headquartered in Collegeville, Pennsylvania, dedicated to the
discovery, development, manufacturing, and marketing of human
pharmaceuticals. [ hope you will not mind, but to save everyone's time, I will
refer to my company by using the initials "RPR" instead of Rhéne-Poulenc
Rorer, for the balance of my brief remarks. In 1994 RPR invested $600
million, or 15% of sales on research and development. RPR's research
programs are focused on six therapeutic areas: Cardiovascular Diseases,
Central Nervous System Disorders, Infectious Diseases, Cancer, Respiratory
Diseases, and Bone Metabolism/Rheumatology. Because of RPR's dedication
to the discovery of medicines that will improve human health and the quality
of life of people throughout the world, and because of my often rewarding but
sometimes frustrating experiences in dealing with drug regulatory agencies,
I really. appreciate this opportunity to talk about what can be done to re-
engineer and streamline the drug approval process in the United States. For
that reason, [ want to thank Congressman Fox for providing this forum, and
members of the Committee and staff for having me here today.

Pharmaceutical research is an extremely risky, costly, and lengthy
process, not only for my company, but also for the patients that are waiting
for the development and approval of important new medicines. Rilutek and
Taxotere® are the brand names of two potentially important new therapies
in our near-term research pipeline. We are very hopeful that we will receive


138

FDA Testimony 6/0/98

Rep. Jon Fox page 3

Oncologists are aware of the limited utility of our ai ntarium, and we are

often eager to try e series of agents until we might find one which “works” for
a given patient. The FDA's restrictions often serve to preclude this approach.
Our patients would be grateful were you to remove obvious impediments to the

availability of new drugs; euch legislation would cost the governsent nothing.

Regarding the issue of “cost,” everyone can explain why “the other guy” should
pay for a given service. When clinical research requires financial support,
patients look to insurers, insurers look to academicians, academicians look
to industry, industry looks to government, and government looks to patients.

Cannot this loop be broken?

How to harness the force of patient responsibility will not be addressed here;
using Medical Savings Accounts is cited as @ key proposal dealing. with it.
What, then is the parameter which determines whether patients become involved
in clinical research? And--whatever this consideration may be--how might

1fsh policies which would facilitate the conduction of quality

governnent esti

clinical trial? And--whatever the protocol

ight be--how may community-based

patients acquire such agents, without having to travel to university settings?

For cancer, the Clinical Cooperative Oncology Program (CCOP) was established:

the local physician/hospital contracta with an academic center through which
Ata clinical observations ere added to those draw from a large patient sample.

In this way, it's anticipated that the entire population having a given dis

e
will be reflected in the composition of the study group. Large-scale studies

exist, also, for cardiology patients, but there now existe no methodical

approach to implementing such a systea for patients with other disea:



49

Pages

uch extensions as an evolution of the process. Deadlines could be given to outsider
reviewers to insure timeliness and their remuneration for reviews linked to the
timeliness of the review. If outside reviews work without loss of quality or continuity,
this proposal would potentially greatly reduce FDA costs by shifting a greater
responsibility to the private sector.

5. Eliminate non-essential regulation

Agency procedures should be revamped to significantly revise the regulations requiring
the submission and approval of even minor changes in manufacturing procedures for
drugs and biologicals. These revisions can be made without any impact on the safety
and efficacy of the product. Here also, the FDA should allow for extemal review of

applications containing clinical data. Since the product is already on the
market and has been proven safe, this cost-effective approach would free FDA
resources for critical functions that cannot be delegated.

6. Realign Agency resources along functional lines

The approval process for drugs and therapeutic biologicals, i.e., those with the same
therapeutic use as manufactured drugs, should be combined. Old statutory distinctions
between the regulation of drugs and biological products should be eliminated, except
where there is a clear scientific basis for treating such products differently. At the same
time, the parallel and often redundant Establishment License Application (ELA) and
Product Licensure Applications (PLA) for biologics should be consolidated into a single
review process.

7. Enhances Global Competitiveness

In light of the significant resources required for the development of a new drug, this
dovalgonent is noe efhcaonty cone cn a gloeal esis 2c nat the promeam wit ast the
regulatory requirements of any sophisticated regulatory authority. The FDA is actively
involved in the tripartite International Conference on Harmonization (ICH) process to
standardize the regulatory requirements among Japan, Europe and the United States.
This effort needs to continue.

Regulatory impediments and inefficiencies to globalization of research and
manufacturing need to be removed. We should make decisions on worldwide sourcing
of investigational drugs used in clinical trials and for locating our manufacturing
facilities based on good business decisions, not on the geographic location of a facility.
The Congress should revise the Drug Export Amendments Act of 1986 to allow U.S.
Pompei, xport any Product (including veterinary medicines) to a country in which
the product has received the appropriate regulatory approval. In addition, memoranda
of understanding should be established with overseas reguiatory authorities that would


8

You might ask why, after forty years, the reform of the Delaney Clause has suddenly
become such an important issue. The reasons lie in recent legal actions. The first
action occurred in 1992 when the Ninth Circuit Court in California ruled that EPA
could no longer interpret the Delaney Clause as having a de minimus exception.
Up to that point EPA had allowed tolerances for pesticide residues in processed
foods as long as those residues posed a dietary risk of less than one in a million to
consumers. A risk of less than one in a million is considered as de minimus by EPA
and is generally accepted as such by the scientific community. EPA, had formally
adopted this policy in response to the 1987 study by the National A.cademy of
Sciences that concluded that this de minimus approach, applied to both raw and
processed foods, would be more protective of the public health than strict
application of the Delaney Clause with its different standard for setting tolerances
for processed and raw foods. The Court ruled that the Delaney Classe did not
allow for a de minimus exception but rather required a zero standard for pesticide
residues in processed foods and ordered EPA to revoke the tolerances in that

particular action that could not meet this zero standard.

The second event occurred earlier this year when EPA and a number of
environmental groups signed a consent decree to settle a legal acticin over the strict
application of the zero standard of the Delaney Clause. As a result of this decree,
EPA has agreed to review the application of the Delaney Clause to almost 40
pesticides and over one hundred tolerances over the next several years. This review
could result in the revocation of the majority of these tolerances and end the use of
these chemicals on the affected crops.

Without going into details, the uses that would be affected are not ninor
pertubations but rather represent the loss of critical tools that the farmers of our


88

It is very frustrating trying to deal with it. Generally everybody
is on board except for just a few fringe groups.

As I understand, they are going to put this in the farm bill. Is
that what we are planning on doing?

Mr. LARKIN. Excuse me?

Mr. PETERSON. I think we are going to try to put this in the farm
bill, as far as I know.

Mr. LARKIN. I think we hope it stays out of the farm bill because
that complicates things further. We would rather handle it stand
alone and not get it mixed up with trading subsidies for Delaney
clause changes, etc.

Mr. PETERSON. I see. I have heard some rumors that they might
put it in there. I think it maybe would make it easier to do it, But
we will just have to see what happens.

Thank you, Mr. Chairman.

Mr. McINTosH. Thank you, Mr. Peterson.

Chairman Clinger.

Mr. CLINGER. Just a couple of questions. I am reading a book
called Thickening of Government, which suggests that in any bu-
reaucracy there is an inevitability about over time new levels of
control. New bureaucracies are built in. In other words, the Gov-
ernment almost inevitably grows in scope and jurisdiction.

Given your experience in dealing with FDA over the years and
seeing the fact that we have now gone from 6 years to 10 to 12
years in terms of time, how much of that is due to what this author
suggests is just the inevitable thickening of Government and the
adding of additional layers of review and approval? And, how much
is it attributable to improvement of science, the requirement that
things become more complex, more difficult to determine? Can you
quantify the differences?

Mr. Biois. I can start to quantify. I think that there are times
in the process that are attributable both to the manufacturer and
to the agency requirements.

We have looked at the time for just starting trials, and we think
we can improve 2 to 3 months in that framework. I think if you
look at the other end of the spectrum in terms of the review proc-
ess, and that is a regulatory requirement, we can improve that by
some several months.

If we look at the approval process, I think that the timeframes
are coming down significantly. We talked about 19 months earlier.
The user fee legislation would have action in 12 months for stand-
ard new drugs and 6 months for priority drugs. We can take that
19 months down perhaps to 12 months at max.

In terms of the manufacturer’s time, if we go back to one of the
comments I made about the two pivotal trials and cut that to one
pivotal trial plus other data, 1 think we can save some time there.

On the other hand, though, I think we need to understand the
science and the types of studies that we are doing. The disease
processes we are looking at are chronic diseases now. We are look-
ing at long term, and that by its nature requires longer periods of
st

udy.

I think there are timeframes that could be saved in the regu-
latory process, but I think we also would need to recognize that
what we are as an industry doing and the types of diseases we are


43

sets specific goals and timeframes and a system which holds re-
viewers and supervisors accountable for meeting timeframes. Such
a process would eliminate periods of inactivity, which add nothing
to the approval process.

Fourth, as mentioned earlier in your opening comments, Mr.
McIntosh, we would like to see an increased use of non-FDA sci-
entists. Currently, FDA employees review an application, write up
their findings and make recommendations to supervisors. However,
FDA has limited resources for carrying out these activities.

The FDA has already begun experiments with outside reviewing
scientists, and these experiments should continue to determine if
this review process can lead to more efficient and less costly review
without sacrificing quality or continuity. Not only would the par-
ticipation of academic scientists greatly speed the review process by
broadening the pool of experts, but it would also assure that the
best scientists reviewed the application.

Fifth, we should eliminate nonessential regulation. Agency proce-
dures should be revamped to eliminate approval requirements for
changes in manufacturing processes which add nothing and have
no effect on safety or efficacy of products.

We need to realign agency resources along functional lines. Old
statutory distinctions between the regulation of drugs and biologi-
cal products should be eliminated except where there is a clear sci-
entific basis for treating such products differently. At the same
time, the parallel and often redundant licensing requirements for
biological products should be consolidated into a single application
and review process.

Finally, we need to enhance global competitiveness. To optimize
the use of our resources, the process of new drug development is
most efficiently done on a global basis. In this way, the results of
the development program will meet the regulatory requirements of
any sophisticated health authority.

gulatory impediments and inefficiencies to globalizations and
manufacturing need to be removed. As an example, companies
should be able to base decisions on worldwide sourcing of investiga-
tional or marketed drugs based on good business practices, not on
the location of a facility.

The American public should expect high standards for safety and
efficacy of new medicines and vaccines. Merck has accepted this re-
sponsibility and demands from our employees the best science and
the best scientific practices.

We do not want to lower the standards for the approval of impor-
tant medicines and vaccines. Rather, reform should improve man-
agement practices and streamline the review process so that we
can provi le innovative medicines and vaccines to the patients who
need them as quickly as possible.

In closing, I would like to thank Congressman Fox for hosting
this hearing, and we are pleased that you are taking the lead in
examining the issue of FDA regulatory reform, which is so impor-
tant to maintaining a strong employment base of the research
based pharmaceutical industry here in eastern Pennsylvania.

I thank you for being here, and I will answer any questions at
the appropriate time.

[The prepared statement of Dr. Blois follows:]


129
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122

ond when it is their use of the drug that is a miracle drug that
might help them. I think we need to find a way to get through that.
jr. LUMPKIN. Sure.

Mr. Fox. I am finished, Mr. Chairman. Thank you.

Mr. McINTosH. Thank you very much, Mr. Fox.

Chairman Clinger.

Mr. CLINGER. Thank you very much, Dr. Lumpkin, for your testi-
mony.

There is a lot of talk in Washington obviously about downsizing,
streamlining, eliminating, combining and what have you. FDA is
not immune from that exercise, both, I gather, internally and with-
in the administration and within the Congress.

One of the suggestions would combine the Center for Biologics
Research and Evaluation with the Center for Drug Evaluation and
Research on the theory that they really have sort of parallel re-
sponsibilities and maybe we could do the same job as well in one
shop. How does that strike you?

Dr. LuMPKIN. I have never worked in the Center for Biologics, so
I cannot give you kind of a personal perspective on their procedures
and what they do.

1 think when you look at biologics there are, however, some very
different kind of products that are there. They are the traditional
biologics like vaccines and blood products, and then there are the
new biotech products that are called therapeutic biologics.

1 know the people have talked about that group of biological
products having more similarities to the traditional chemical drugs,
so that might be something that people would want to think about,
as opposed to bringing both Centers together—to think about look-
ing at just those products that might be more akin to the chemical

rugs.

ir. CLINGER. How badly stressed out is the agency now in terms
of resources? We have heard discussion here that you are reall
having trouble keeping all the balls in the air and getting the wor!
lone.

Dr. LUMPKIN. There is plenty of work to be done. There is no
doubt about it. I think one of the biggest things that our employees
will come and say is a staff will come in and say what is our prior-
ity. It is kind of like in many other places I have been, whether
it is Government or industry or academia.

They are all your priorities, whether it is doing new drugs,
whether it is looking at new IND’s, whether it is meeting with com-
panies, whether it is answering congressional inquiries, whether it
is dealing with the press. There is a whole gamut because people
in this country are interested in drugs. It affects every American
in their medicine cabinet. That is part of the reality of working
there.

I will say that as far as the new drug review process is con-
cerned, the user fee program has been a godsend. There is no doubt
about it, not only from a human resource perspective, but an infra-
structure resource.

When I came to the FDA in 1989, when I went to my division
this was a division responsible for all of the antibiotics in the Unit-
ed States. It had 66 staff members and not one fax machine. In


127

Mr. McIntTosH. Thank you, Dr. Lumpkin.

Let me say that I would like to keep the record open. There are
several questions that I had that if we could, I will submit to you
in writing. One of them will have to do with a subject that I guess
I want to say a few statements more than a question.

You mentioned the use of medical journals as a way doctors can
get information about the use of drugs. The whole issue of regula-
tion of off label uses and distribution of information about that and
regulation of information on cost effectiveness I think is an area
where the agency, quite frankly, has made a stupid decision in
terms of trying to regulate and manage that.

What they ought to do is focus their efforts on making sure that
it is true information and not try to restrict the type of dissemina-
tion of information as long as it is true and accurate because one,
you are not going to be able to do it. It is going to be like nailing
Jelly to the wall. It is going to go all over the place, and people are
still going to get the information out. Two, I think it also does a
disservice to the patients and the medical community when that ef-
fort is made.

Some of my questions have to do with that. I hope we can pursue
a discussion of that area and that you will take that back to the
agency because I know some of the other offices are also engaged
in that type of effort.

Dr. LUMPKIN. We will be happy to answer that.

Mr. McINTosH. All right.

Dr. LUMPKIN. We would be happy to discuss it with you.

Mr. McINTOSH. Thank you. Thank you for coming. I do appre-
ciate it.

Dr. LuMpKIN. It is my pleasure. Thank you, sir.

Mr. McINTosH. Our next segment of the hearing is what we refer
to as the open mic segment.

Let me introduce Karen Barnes, who is one of the staff members
for the subcommittee. Karen will be making the mic available to
people who would like to testify. I know several people have indi-
cated to Mr. Fox and to Karen that they would like to testify dur-
ing that time.

if I could ask you to state your name for the record and any writ-
ten testimony you have provide to Karen so that we can put that
into the record? Also, please keep your statements as brief as pos-
sible so that we can get as many people as we can in during this
time; ideally 3 minutes. If you need a little bit longer, we can do
that.

Karen, why do you not start out.

Mr. FISHER. Mr. Chairman, I am Dr. George Ross Fisher. I prac-
tice in Philadelphia, and I am a member of the House of Delegates
of the American Medical Association, although I am not speaking

for them.

I am submitting for the record a copy of my resolution to the
AMA, which will considered next week after their amendment
deliberation. :

My remarks may seem radical to you. I am addressing my re-
marks to the subject of whether the Kefauver amendment is en-
tirely wise; that is to say whether the focus of the FDA on efficacy
is wise.


151

Mr. McINTosH. Thank you very much, Dr. Cionci. I think that
is a very eloquent statement of the problem in some ways.

Our next witness is Dr. Jungkind. Welcome.

Mr. JUNGKIND. Thank you. I will be brief because I realize how
late it is. I will just tell one very brief story with four very brief
components.

One of the areas that I did not hear touched on at all, and it may
have been touched on earlier, is that the FDA regulates diagnostic
devices, lab tests. This is an area that I think is a relatively new
area of their regulation. It is an area that they are just getting
their stride in. Unfortunately, their stride is going down the same
wrong road that they have taken with over regulating some of the

S.

e very brief thing that I need to say next is that I have been
working on development of laboratory tests for over 20 years. We
have done over 3,500,000 tests. I have had hundreds of employees
over the years and have helped bring many, lab tests to market
and have been the primary test site for several FDA approved au-

its.
I have seen the FDA gradually change over the years to the point
where something that was a very good scientific study published in
the best journals and the amount of paperwork involved with that,
evolved to my last clinical trial where I walked into the office and
my whole office was filled with boxes of paper. I thought maybe
they had accidently shipped me the entire paperwork for the entire
Nation! It was just for a few hundred patients, and this was a re-
sult of the new FDA rules coming into diagnostic devices.

The next component of the story I want to say is how would you
like to be the person that just won the Nobel prize for creating one
of the greatest scientific discoveries in microbiology technology?
This is an American, Dr. Cary Mullis, who discovered the polym-
erase chain reaction. Right after that, a number of other people dis-
covered some very similar kinds of techniques.

The technique has the ability to alter a major segment of our
clinical laboratory testing detecting for infectious diseases. It is
possible to detect a unique fingerprint of every infectious organism
and do it very rapidly and effectively and give a rapid, accurate di-
agnosis. What good are the drugs if you really do not know what
is the infecting agent? If you can speed diagnosis up, it will help
the patient recover.

How would woo like to have the FDA with their new set of rules
making it so that we are the last country on earth to get to benefit
from this technology, the last industrialized nation?

Europe is well ahead of us. I just completed the major clinical
work on a major piece of automated equipment. Where is it going
to be introduced first? It is going to be introduced in Europe. Japan
has it. Europe has tests for HIV, tuberculosis, hepatitis C plus the
one that finally was approved in the United States, chlamydia,
which is the most common sexually transmitted disease in industri-
alized nations.

It to me just seems laughable that here is the technology that is
American as red, white and blue. Everyone else in the world is get-
ting to use it and not us because the companies are afraid of the
FDA; in fact, so afraid that one of the FDA people that has


10

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155

biology is the nation reaping the least medical tast benafit from this technology among
industrialized nations? For example Dr. Cary Mullis, an American discovered the first of the
DNA amplification technologies - the polymerase chain reaction (PCR). He won the Nobel
prize for his discovery. His discovery makes it possible to diagnose many diseases, especially
infectious diseases faster and better than ever before. It can be 2 new gold standard for
detection of microbes. Moreover, PCR and related amplified DNA based technologies such
asLCR, SDA, BCA, and NASBA can be automated, cventuslly resulting in reduced labor
costs that can lower testing costs in microbiology as it bas for chemistry and hematology.
We can also give better care which eventually lowers costs as well. An example is more
accurate and faster diagnosis of tuberculosis which can save thousands of dollars per case.
However, development of these new technologies is being slowed because of the over
zealous rules and requirements that the FDA has imposed 00 test development. The FDA
Tequires proof of equivalence to existing technologies for most new lab tests. However, the
FDA requires a much higher standard for these new DNA amplification based tests.
Specifically the FDA has imposed more complex clinical wials for these tests. I am actively
involved in these and other clinical trials, The new FDA regulations have raised my research
costs dramatically. Tt costs me roughly double to do clinical trials now. Moreover, I don’t
‘think that the tridls are any better when measured by production of « better product. There is
more detiled record keeping, more extensive case history eoording; and mare’ tention to
“the FDA game” rather than focusing on the science. To illustrate the general awareness of
the increased mumber of problems that the new FDA regulations can cause, there is a ncwly
released book costing over $ 500 to help us understand and play the new “FDA game”.


CONTENTS

Statement of:

Blois, Dr. David, vice president, Worldwide Regulatory Affairs, Merck
& Co.; accompanied by James T. Molt, vice president, Worldwide Regu-
latory Affairs, Rhone-Poulenc Rorer; Robert, Powell, vice president and
director, latory Affairs, SmithKline Beecham Pharmaceuticals;
Bruce Carroll, manager, Government Relations Division, Centocor, Inc.;
and Robert H. Larkin, director, Registration and Regulatory Aifai
Agricultural Chemicals Business, Rohm and Haas Co .

Kuromiya, Kiyoshi, director and editor, Critical Path AI 3

mowitz, citizen witness; David’ Samowitz, citizen witness
Mariah Giadis, citizen witness .. ”

Lumpkin, Dr. Murray M., Deputy Director for Review Management, Cen-
ter for Drug Evaluation and Research, Food and Drug Administration;
accompanied by Dr. George Ross Fisher, trustee (Philadelphia), Penn-
sylvania Medical Society: Dr. Robert B. Sklaroff, Medical College Hos:

NtalElkins Park; Dr. Michael R. Sperling, chief of Medical/Surgical

gram, Comprehensive Epilepsy Center, Graduate Hospital; Dr. Jack
Cionci, chair, Montgomery County AIDS Task Force; Donald Jungkind,
Thomas Jefferson University; Dr. David O. Ginsberg, president, Con-
corde Clinical Research, Inc.; John Boehringer, president, Bochringer
Laboratories; and Barbara DeLuca, executive director, Linda Creed
Breast Cancer Foundation .. a

Letters, statements, etc., submitted for the record be

Blois, Dr. David, vice president, Worldwide Regulatory Affairs, Merck
& Co., prepared statement of ..

Carroll, Bruce, manager, Government Relations Division, Centocor, Inc.,
prepared statement of .... sess sas seen at

Cionci, Dr. Jack, chair, Montgomery County AIDS ‘Task Force, prepared
statement of... esses se

Fisher, Dr. George Ross, trustee (Philadelphia), Pennsylvania Medical
Society, prepared statement of ...

i r. David O. president, Concorde Clinical Research, Inc., pre-

Gladis, Mariah, citizen witness, prepared statement of ...

Jungkind, Donald, Thomas Jefferson University, prepared statement of

Kuromiya, Kiyoshi, director and editor, Critical Path AIDS Project, pre-
pared statement of svn sven evnteneeennpnavenia

Larkin, Robert H., director, Registration and Regulatory Alfairs, Agricul.
tural Chemicals Business, Rohm and Haas Co., prepared statement

Lumpkin, Dr. Murray M., Deputy Director for Review Mana;
ter for Drug Evaluation and Kesearch, Food and Drug At
prepared statement Of ...cscsssssressseeseses netinssnente se

Molt, James T., vice president, Worldwide Regulatory Affairs, Rhone-
Poulenc Rorer, prepared statement of ... sence

Powell, Robert, vice president’ and director, Regulatory Affairs,
SmithKline Beecham Pharmaceuticals, red statement of ..

Samowitz, David, citizen witness, prepared statement of

Samowitz, Faith, citizen witness, prepared statement of aoe

Sklaroff, Dr. Robert B., Medical College Hospital-Elkins Park, prepared

Sperliny chief gical Program, Comprehen-
sive Epilepsy Center, Graduate Hospital, prepared statement of ...c--
Zakarian, Beverly, president, Cancer Patients Action Alliance, prepared
statement of .... . . nea,

and

Page

42

13


145

Many members of the HIV community join buyer clubs. These
are mostly underground where you go into Canada or into Mexico
or overseas. The problem is people have tried this, and some of
them have died.

T can give you an example of Compound Q, of which at least six
people independently taking this drug died. tt may have been due
to inaccuracy in the strength they were taking because there was
no one looking over their shoulder to guarantee the dosage that
they were taking. This is where the FDA comes in and does a re-
markably pood job.

Up until now, AIDS has been nearly 100-percent terminal. I am
saying nearly because we have long-term, nonprogressives, people
who have had this disease for years, beyond the 10 years that they
are usually told they have when they are first diagnosed.

You have heard the eloquent testimony of my friend and col-
league, Kiyoshi Kuromiya, who publishes the Critical Path, which
I consider the premier medical monthly AIDS newsletter. I say
medical because I use this as a reference every month when it
comes to my doorstep. I pray that Kuromiya continues to be a long-
term, nonprogressive.

In closing, I would say just as we physicians who treat people
with HIV ask the nations to join in the management of their care,
so should the FDA grant these same people decisionmaking on
which drugs they may like to test.

These patients, my friends, have everything to gain and nothing
to lose. It is their body and their life.

Thank you.

[The prepared statement of Dr. Cionci follows:]


106

biologics. Additional changes will be announced in the near

future.

First, drug companies are frustrated that it often takes months
to get FDA approval for a manufacturing supplement to their
original product applications--even for minor changes in

the content or manufacturing process of a drug or biologic.

These could be changes in the product itself, such as the use of
a new color additive, or changes in the manufacturing process,
such as the use of a new machine. We believe there are many such
changes that do not need to be reviewed by the Agency or which
should require only brief notice to the Agency. FDA is preparing
guidance to the industry for when a manufacturing supplement will
or will not have to be submitted to FDA. Our guiding principle
is to require FDA review of manufacturing changes only when the
change raises issues pertaining to safety or effectiveness. We
will not need to review the change if it does not raise
significant safety or efficacy issues. We intend to issue
guidance for most products sold in tablet form by the end of this
year. A similar publication covering other dosage forms,
including controlled release drugs, liquids, and semi-solids will
be completed by the end of 1996, which will eliminate our current

review of more than 800 supplemental applications.

10


66

Mr. McINTosH. Thank you very much, Dr. Powell. I appreciate
your testimony today.

Our next witness on this panel is Mr. Bruce Carroll, who is the
manager of government relations for Centocor.

Mr. Carroll, thank you for joining us.

Mr. CaRROLL. Thank you, Chairman McIntosh and members of
the committee.

My name is Bruce Carroll, manager of government relations at
Centocor, the largest biotechnology company in Pennsylvania lo-
cated in nearby Chester County. Our president and chief executive
officer, David Holveck, was unable to be here today, so I am pre-
senting testimony on his behalf.

Centocor employs over 300 people in our Chester County facility
and nearly 600 total worldwide. We focus on the development,
manufacturing and marketing of diagnostic and therapeutic prod-
ucts, and they include products for cancer, cardiovascular disease
and infectious disease.

It is fair to say that Centocor has had an overall positive experi-
ence with the FDA. For example, approval of our first therapeutic,
a cardiovascular drug called ReoPro, was accomplished in an ex-
traordinarily speedy matter with final approval coming just 1 year
after initial application.

Today, however, I would like to talk about the device side of our
company and the FDA. Centocor also produces in vitro diagnostic
tests, which are the routine laboratory tests that everyone goes
through that is part of a physical exam. Centocor’s tests are used
in the management of ovarian, pancreatic, breast, lung and other
types of cancers.

After investing 10 years and $20 million seeking FDA approval
for these products, only one Centocor product, and that is an ovar-
ian cancer test, has ever been approved for use in the United
States. That is because these blood tests are regulated by the FDA
in a category of medical device known as class III, which is de-
signed for high risk devices such as heart valves, pacemakers, cer-
tain devices implanted into the body and devices which are used
for life sustaining or lifesaving purposes.

These products are also subject to the highest levels of regulatory
control. Unlike other class III products which are critical to main-
taining human health, our blood tests do not have the potential to
be intrinsically unsafe because they are never used in the body and
are not used as the sole basis for medical decisionmaking.

FDA approval of a class III IVD test requires submission of data
from extensive evaluations, which for products like ours take many
years to complete and which ultimately cost many times the an-
nual expected revenues for the product.

As a partial remedy, Centocor recently filed a petition with the
agency seeking reclassification of a limited number of IVD tests.

ie agency has been supportive of that initially. We would wel-
come any assistance from this committee to further that initiative
with the agency.

A more complete solution to the issue of unnecessarily strict reg-
ulation of these blood tests can be accomplished through legisla-
tion. Again, we ask Congress to consider reclassifying these types
of IVD’s from class III to class Il, while at the same time giving


52

women with advanced breast cancer. It has been shown to work
even after other chemotherapy has failed. I think the absence today
of Beverly Zakarian shows that breast cancer is a particularly dev-
astating disease where new therapies are sorely needed.

We submitted an NDA for Taxotere to FDA last July. FDA re-
viewed the application in a very commendably fast 4 months. FDA
arrived at the conclusion that the benefit of Taxotere did outweigh
its risk.

The drug approval system in the United States is cautious. FDA
usually does not act alone. For major decisions, they seek a second
opinion from an independent board of experts known as an advi-
sory committee.

‘or Taxotere, the advisory committee pointed out to FDA the
risk side of the equation without doing too much to reinforce the
benefit. In the end, the advisory committee offered equivocal advice
on whether or not to make the drug available.

Without a strong vote of support from their advisory committee,
FDA did not act on their previous conviction, and Taxotere remains
unapproved today while FDA continues to ask for more information
about the risks of the compound.

It is clear that the system, and that includes FDA and its advi-
sory committees, and it is a system which is cautious, will produce
fewer new drugs than one that has its goal to make more drugs
available to the patient. This caution stems partly from fear of pub-
lic retribution for approving a drug that turns out to have a side
effect profile that was different or greater than what FDA thought
it was.

To change FDA, we must change their incentive system. FDA
has to have less fear of public retribution for underestimating the
true risk of a drug and be more sensitive to the needs of the pa-
tients who need therapies.

Mr. McIntosu. If I could ask you to go ahead and summarize?

Mr. MOLT. I am.

Mr. MCINTOSH. Thank you.

Mr. MOLT. This is the hard part. How are we going to make this
happen? Certainly one answer is to rewrite the laws under which
FDA operates. Another, and it is not necessarily exclusive, is to in-
crease congressional oversight and perhaps consolidate jurisdiction
over FDA into one committee. Congress should focus on creating an
environment where inaction by FDA is as much a cause for inves-
tigation as a bad action.

‘e know the change in FDA will not be easy, but we are encour-
aged by the efforts such as those made by Congressman Fox and
you. We at RPR are ready to help in any way possible.

We realize that there is a real opportunity to make lasting, con-
structive changes to FDA that will be of benefit to the patients. It
is very clear from what we need today that the patients are wait-

ing.
fithe prepared statement of Mr. Molt follows:]


101

In recent years, d4T and many other breakthrough drugs have been
approved in the United states before they were approved in other

countries such as the United Kingdom, Germany, and Japan.

EXPANDING ACCESS

Second, over the past ten years FDA has formalized and
implemented a variety of programs to make promising drugs that
are being tested but have not been approved available to
patients. Under FDA's "Treatment IND" provision, patients for
whom there is no satisfactory alternative treatment receive pre-
approval access to a promising drug after clinical trials have
shown that it may be effective and does not have unreasonable
risks to the patient. Treatment is given under simplified
protocols that collect important safety information. Similarly,
our parallel track program allows HIV-infected patients who are
unable to join a controlled trial access to the experimental
drugs. We also 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.


26

It has been said before that "To love life is to love ime”. This
brings me back to the action I hope this Committee will take.
Perhaps it is easiest if I state the key issues that can help save or at
least maximize ume for ALS patients. .

1) START COMBINATION DRUG TRIALS NOW ~ The question
is under what circumstances will the FDA accept the submission of a
protocol for a clinical trial utilizing two experimental drugs, both
having completed the safety trial phase? And, if the FDA won't
consider this scenario, they need to explain their rationale and what
it will take to change their position.

2) IMPROVE THE EXPANDED ACCESS PROCESS -- People with
life-threatening illness want expanded access and the choice to take
experimental drugs when they have reached or completed Phase IIL
How can FDA expedite and facilitate this access? What is the FDA
going to do to streamline this process to help potentially save lives?

3) BREAK DOWN BARRIERS TO EXPERIMENTAL DRUGS —
Patients are willing to pay for experimental drugs, either personally
or via health insurance. In the case of ALS, we don't have any
approved drugs on the market yet. To encourage compassionate
access for new drugs, drug companies should be able to ,
commercialize or gain a profit from the sale of these drugs,


22

ticular disease, researchers commonly design future trials that
compare the reference drug versus a new drug or a combination of
the reference and new drug.” Once we have a drug that works in
ALS, why should patients have to take placebo?

Since 1992, there is a new drug that is more effective in treating
ALS. I tried to get that drug, but because of FDA regulations I was
not able to get it because they knew that it would not help in 1992,
I had many friends with ALS who were still alive in 1992. Now it
is 1995, and we need these drugs available.

I urge them to hurry and make it available. I am running out
of time. I thank you, and I know that my husband and sons thank
you. Let us make this opportunity available now.

{The prepared statement of Ms. Gladis follows:]


105

for user fee submissions approved in 1994 was 13.5 months. The
median approval time for priority drugs was 10.4 months. (See

attached charts)

The user fee program is changing the culture of the Agency.
Although the drug review deadlines are ambitious, they are
realistic. We are all benefitting. FDA reviewers are beginning
to get the resources they need to review drug applications faster
and still maintain a high standard to ensure safety and
effectiveness. The drug companies benefit from getting their
products on the market earlier in the United states, which helps
get the products approved abroad. And, most importantly, the
patients who might benefit from use of a drug have quicker access

to then.

REINVENTING REGULATION OF DRUGS

The fourth initiative encompasses the reforms recently announced
by the Clinton Administration as part of President Clinton and
Vice President Gore's National Performance Review. In April we

proposed five significant changes for regulation of drugs and


162

knowledgeable people monitoring the clinical sites. Also, I think it is better to monitor
the clinical trials as the trials are in progress as opposed to several years after they end.
This would expedite the process. To this end, I would suggest that the FDA involve
knowledgeable medical people on a local level. That is, to organize a national network of
medical personnel, preferably physicians, who would be willing to monitor and review
studies as they are in the process of happening as opposed to retrospectively. This would
- allow ongoing dialog with both the pharmaceutical company sponsoring the study and the
FDA as to any potential problems in the carrying out of the study and as to their
‘independent appraisal of the drug in question.

Also it is vital to expand standardization onto an international level. Clearly, we are
becoming a global community, particularly on a medical or pharmacological basis, and
medical problems which crop up in Africa, Europe, or other parts of the world eventually
bear directly on the population here. The drug approval process has to be considered in B
world-wide context. T understand that this is being done currently, but I believe that great
efforts must be made so that data can be captured in a standard fashion throughout as
much of the world as possible so that it can be interchangeable and so that studies being
done in France, Germany or Italy can apply directly to the approval process in the United
States. By the way, it is my experience in reviewing certain drugs which are approved in
Europe and in working with them in the United States that the FDA has been quite
appropriate in its frequently jaundiced view of some of these products. It seems to me
that we have indeed been more appropriate here than in many other countries world-wide


165

Mr. Fox. Did you want to proceed? Please identify yourself and
your affiliation.

Mr. BOEHRINGER. My name is John Boehringer. I am president
and owner of Boehringer Laboratories, I appreciate Congressman
Fox hosting this hearing here.

I grew up in Congressman Walker’s territory and went to school
there. My home and my plant, my manufacturing facility, are in
fact 2 miles down the road here.

Mr. Fox. Thank you for coming.

Mr. BOEHRINGER. I would like to bring out a little heard voice
here today from the small device manufacturing companies. We
heard of the billion dollar activities, but we started in my base-
ment. After a career in engineering, I worked at the University of
Pennsylvania to develop some devices, five of which ultimately
ended up on top of Mount Everest in the University of California’s
scientific research project.

More recently, if you have a hip or a knee replaced, we are the
leader in blood collection equipment to replace your blood as your
knee and hip are being replaced.

I will make a statement unequivocally today that I could not
start my company today in the environment that we have with the
FDA and the regulatory environment that we face. To me, as an
American citizen that is a very sad thing.

We are already started in business, so that aspect of it only slows
me down, but the people that are coming along and keeping our in-
dustry alive—we have not seen any competitors, for example, in
suction equipment. There were eight 10 years ago. There are three

today.

In blood collection and reinfusion, which is extremely important
given the blood supply situation, there are about eight of us now.
I predict in 5 years there will probably be three of us.

To give you an idea on the FDA regulations, just to give you one
horror story, we had to requalify polyethylene. A small company
here in Norristown, PA, had to go to the FDA and requalify the use
of polyethylene, which is probably used in millions of devices, be-
fore we could get approval.

That meant that we had to spend the money for an independent
lab. We had to wait for the approvals. We had to wait while they
advanced our application so we could get that done. It was just a
tragedy is what it was. It delayed us for over a year in bringing
this blood supply equipment to the market.

I have four recommendations coming out of this that I would like
to suggest.

One of the things that is happening to all of us is a subtle thing
but it is very effective, and that is the measurements that the FDA
are reporting to you in Congress about reduced backlogs is non-
sense. What they measure in backlog is not from the time that we
submit. They measure backlog from the time we resubmit. If there
is any sort of delay or anything that they measure, they are meas-
uring from the latest resubmission.

en they sent us back to requalify polyethylene, they started
measuring the backlog from the time we resubmitted that applica-
tion. This goes on and on and on. This is not an isolated incident.


169
that FDA is not fostering delay of approvals, but in fact facilitating

drug access.

‘e hope that the combined wisdom of those who hear this testi-
mony, and I want to thank especially also David Samowitz and his
mother who gave poignant testimony which was excellent. I appre-
ciate his courage in coming forward and speaking for those who
could not be here. You really are the human element behind why
we are here. We wish you the best in your life career. If we can
help as Members of Congress to move that along, we hope you will
call us on a personal basis.

Frankly, we are all appreciative of those members who were
here. The members of the committee that Mr. Clinger chairs who
could not be here will be receiving that testimony formally, and we
very much appreciate all that you have done and will do to move
us forward here in the United States to take care of our patients.

We thank you very much. If there is no further testimony, I will
formally adjourn the meeting. Thank you for coming.

(Whereupon, at 1:55 p.m. the subcommittee was adjourned.]

e)


34

spproval of drugs for persons with AIDS, we were surprised and disturbed that Kensler
neglected to highlight this area in his proposed FDA reforma. Perhaps a clue to Kessler’s
anub of AIDS drugs csn be found in his article for the March 1995 Sc/entitic American in
which he claimed ACT UP members have undergone a change of heart and now prefer the
slow progression of drugs through the FDA to accelerated approval. According to one
pharmaceuticel company lobbylat, not only the FDA director but “Kessiar's people” are all
over Washington telling everyone thet AIDS activists want the FOA to slow down,

Korster failed to mention in his article that the activists to whom he seferred were not really
ACT UP members, they were from Treatment Action Group (TAG), a group that broke from
ACT UP a couple of years ago, primarily because of disagreement over the pace of drug
approval. Kessler also falled to mention the firestorm of opposition in both ACT UP end
within the AIDS patient community, sparked by TAG’s asking him to stow dewn, Over 100
AIDS organizetions, including ACT UP groups from many cities, signed @ consensus letter
‘supporting fester drug approval. During two days of hearings thet took piace Inst
September, he listened to scores of angry persons with AIDS (PWAs} and treatment
activists from round the country [including myself) demanding that he approve AIDS drugs
faster. nat slower.

Kessler was st that meeting, listoning to David Barr and other TAG membors, chenge their
position and join the majority to say that they favored accelerated approval. Yes, ‘he reltered
that meating at a March 28 Congressional hearing, and Jim Driscoll quotes him, in 3 recent
bay Area Reporter article: “| was at @ fascinating meeting. ano it was 3 real eye-opener, .

It was with AIDS activiats ... the same activists who were scaling the walls of Parkiawn a
number of years ago, saying ‘FDA speed up the drug approval process.’ Thay came in and
said to me, ‘Commissioner, you are approving drugs too quickly. We don’t know how to
‘take them, when to take them, in what dose to take them, We need to know whether these
drugs work."”

Kesster's cynical, even dishonost, manipulation of the community's pocition shows B real
contempt for people with AIDS. One drug company lobbyist told Jim Driscoll that this new
perception~that AIDS oetivists no longer want FDA to approve AIDS éruge faster will hurt
efforts to get life-saving drugs to persons ike me as fast as ic esfely pncsible. Ne predictes
that companies will stop Investing In AIDS If they think the FDA wilt slow down on
approving new AIDS drugs, and Congrass may writg an FDA reform bill that epeeds
everything except AIDS drugs.


115

specifics of individuals or cases where this has happened. I would
be very interested in it. I know Dr. Kessler would be very inter-
ested in it. | know our ombudsman, the IGA and all kinds of people
who would be very interested in it. If any of the members here
know of such things, please let me know.

Mr. McINTosu. I think you may need to take some positive, ag-
gressive steps such as indicating if someone has_ complained
against the agency there will be an assurance they will not be put
on the reference list or some other means that they view as being
very punitive.

ir. LUMPKIN. Yes, sir.

Mr. McINTosH. Let me turn to one other substantive question,
and this was the one raised by our witness, Ms. Gladis. Really I
took two questions from her testimony and would like to pose them
to you.

ne was specific, and that was what are the chances that they
are actually ping, to be able to get a treatment IND and a new
drug approval for the drug Rilutek?

e other one is more general. She put it this way. What are we
being protected from when she is likely to die of her disease fairly
imminently? If there is a drug out there that may extend her life,
even at some risk to her, would it not be better to let her make
that choice?

If you could address both that specific and the general question?

Dr. LuMPKIN. Sure. Let me address the general question first,
and then I will be happy to come back to the specific.

I think you bring up and she brought up the exact point I was
talking about with so-called mechanisms we have in place. I think,
just as you would imagine, too, that if any of us had the diseases
that these people were talking about up here, you think about what
would you want if you had the disease or if someone whom you
loved had the disease. You would clearly want them to have access
to anything that had the potential of helping them get through
this. I think that is a very clear point.

People have to realize that when you are talking about makin;
a benefit risk assessment that when you are talking about life
threatening illnesses, there is a completely different risk benefit as-
sessment than you have for illnesses for which there are less toxic
therapies or more efficacious therapies available.

I think that from that perspective, that was the whole idea be-
hind our treatment IND program. That would allow someone when
the clinical data were being developed and you are beginning to get
the early data that something is effective, but you know there is
going to be the independent confirmatory data that is necessary
plus the timing of assembling data and getting it reviewed.

You want people during that period of time to have access to
something that they think might be beneficial. That is the whole
idea behind a treatment IND program. I think there are ways that
that lead can be met. Clearly there might be other ways. We are
very interested in hearing if other Reople have that idea.

Now, as far as the idea of people making their own decision, I
think that is exactly what the treatment IND allows. It allows the
person before something goes on the market to make their own de-
cision of whether, based on the data that they know about at that


136

Robert B. Sklaroff, M.D., Associates
‘Medical Oncology/Hematology

MEDICAL ARTS BUILDING
60 E. Township Line Road, Suite 130
Etkins Park, PA 19117-2253

215/663-8200

1200 Locus! Street, Ist Floor
Philadelphia, PA 19107-5605

June 9, 1998

to: U.S. Rep. Jon David Fox

re: “Improvements in the Regulation of Drugs" - Draft Testimony

Mr, Chairman, thank you for the epportunity to discuss the iapact of the Food
and Drug Administration upon the daily experiences of an oncologist, I will
follow-up Dr. Pisher‘s comments regarding the Kefauver Amendment and add other
points regarding how your efforts could provide focus to the PDA's activities.
The key concept which will be explored is how to integrate research into the

clinical setting, ensuring reimbursement for delivery of basic medical care.

Government should guide the citizenry; it should neither dictate its activities
nor engage in Laissez Faire. Thus, removing the “efficacy” requirement would
unleash the FDA to protect Americans without unduly restricting innovation. and
the insertion of an intersediary “stage” in the approval process would create

a structure which would encourage use of new drugs earlier than now occurs,

Last week, a colleague told me that the H.M.O. created by Traveler's Insurance
Company for Medicare patients had determined that it would not finance the
provision of Taxol to patients with lung cancer. This disease affords limited
therapeutic options, and many researchers consider Taxol to be a ‘first-line

agent; therefore, they're upset that it cannot be offered to their patients.


58

Mr. McINTOsH. Thank you very much, Dr. Molt.

Our next witness on this panel is Dr. Robert Powell, who is the
vice president and director of regulatory affairs for SmithKline
Beecham Pharmaceuticals.

Dr. Powell.

Mr. PowELL. Thank you, Mr. Chairman. Mr. Chairman and Mr.
Fox, I would like to thank you for the opportunity to testify before
this committee.

SmithKline Beecham is one of the world’s largest healthcare
companies. We discover, develop, manufacture and market human
pharmaceuticals, including innovative childhood and adult vac-
cines, over the counter medicines, health related consumer prod-
ucts and clinical laboratory testing services.

We are a very large employer in the Commonwealth of Penn-
sylvania with over 6,500 employees, including over 1,700 employees
in the 13th Congressional District.

When I joined the pharmaceutical industry well over 30 years
ago, things were considerably less complicated than they are today.

is is true not only from the point of view of the complexity of
drug development, but from the complexity of drug regulations as
well.

The combination of these two evolving and increasing complex-
ities has made the development of useful new drugs an extremely
formidable task and has added considerable expense and time in
getting useful new therapies to the American public. In fact, it now
takes on average well over 10 years to conduct the studies nec-
essary to support a new drug application.

During this time, the FDA is directly involved with every aspect
of the development. Nevertheless, in 1994, it took an average of 19
months for the agency to evaluate new drug applications that were
submitted at the end of the development process.

This is not to say that FDA has been unresponsive to the grow-
ing problems of complexity in the development of drugs. As a mat-
ter of fact, as a result of the implementation of user fees and the
specific performance goals associated with them, the current 19-
month average review time represents a reduction of review time
from the approximately 30 to 33 months that was standard for the
12 years prior to 1994.

evertheless, other sophisticated regulatory agencies are able to
review the safety and efficacy of new drugs considerably more rap-
idly. For example, the United Kingdom approves new drugs follow-
ing an average of 6 months of review, 1 year faster on average than
FDA, and these applications are generally based on the same data
base as those in the United States.

It is the consumer, of course, who must ultimately bear both the
economic and social cost of delays in the availability of useful new
therapies resulting from the system that has evolved over the 33
years since the 1962 drug amendments.

There is perhaps an even greater price to be paid for the increas-
ing complexity and cost of drug development. Some drugs may
never be developed at all.

In the next few minutes, I would like to suggest some ideas that
I believe would improve the drug development process in the Unit-
ed States without compromising patient safety. Let me assure you


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16

TESTIMONY OF

Robert H. Larkin, Ph. D.
Director Of Registration and Regulatory Affairs
Agricultural Chemicals
Rohm and Haas Company
Philadelphia, PA

Before the
Special Field Hearing
US House of Representatives
Norristown, PA

June 9, 1995

Good morning Mr. Chairman and members of this Special Field Hearing. My name
is Robert Larkin, and | am Director of Registration and Regulatory Affairs for the
Agricultural Chemicals Business of Rohm and Haas Company. | have responsibility
for the registration of our agricultural chemicals worldwide. Rohm and Haas
Company is a multinational chemical company with headquarters in Philadelphia.
Our worldwide sales in 1994 totalled over 3.5 billion dollars of which agricultural
chemicals made up approximately 15%.


28

Last week, I lost the use of the fourth finger on my left hand.
Access to a drug like this (Rilutek) may have prevented or delayed
many of my losses in my case. Others have lost more than a finger,
others have already lost their lives,

Thank you Congressman Fox and fellow members of the Committec.


94

an efficient review process, we will then begin to see decreases in
approval time.

Mr. Chairman, I also want to take just a couple of minutes to
talk a little bit about some of the other issues that witnesses have
already brought up today because I think these are clearly very,
very important issues that we need to talk about.

That is not just using the user fee program as a way of gettin,
the overall process under control, but also realizing that the overal
process does not always meet the needs of every individual and the
needs of every disease.

I think we at the agency have instituted several programs that
have been highlighted already to try to meet those other contin-
gencies that are clearly just as important as the overall perform-
ance of the FDA Center for Drugs.

One is the expedited availability. You have heard already about
the fast track procedures for life threatening illnesses. You have
heard about the accelerated approval regulations that went into ef-
fect in 1992. Under these new procedures, we have been able, for
example, to approve AZT in three and a half months. We have been
able to approve some of the new drugs that are related to AIDS
such as d4t prior to their approval in the United Kingdom, Ger-
Many or Japan.

These we think are some very good ways to begin to deal. It
might not be the final answer, but clearly it is an improvement
over what the Center has had in the past. We are coming to grips
with the fact that with life threatening illnesses it is a different sit-
uation than for just another drug to treat strep throat.

The other thing that I wanted to spend just a couple of minutes
on to talk about were the kinds of situations that many of the early
witnesses were talking about where you have situations where
drugs are being developed and people are believing that indeed we
are beginning to get some early data that these things are effective.

The issue then in life threatening illnesses is how to afford ac-
cess for patients that need this while at the same time not destroy-
ing your ability as a community to find out the ultimate truth
about the drug, whether indeed for the great majority of people
who have that disease the drug is going to be safe and effective.

I think under our expanded access programs, be it treatment
IND’s, be it parallel track, be it emergency IND’s, in the last 6
years we have afforded access to over 75,000 Americans who need-
ed and wanted access to drugs that were still under development.
They were still undergoing the clinical trials development. These
were people who were not in the clinical trials.

I think we are very sensitive to this. We are trying to be very
sensitive to this, and we are willing to work. We have shown |
think that we are willing to work with the communities to come
up with programs that will afford access in these situations, but at
the same time try to protect us as a community, protect our ability
to find out the ultimate truth of these drugs in our clinical trials
program,

In conclusion, Mr. Chairman, I just want to say, as you pointed
out, there are a lot of other things that are being discussed right
now. That is part of actually the tremendous fun of being at the
Center for Drugs right now.


CAN ACT 1
Mr. Fox, thank you for inviting me to offer my remarks to.you and-your distinguished
colleagues this morning.

‘This is what's needed at the FDA: » can-opener~ to rip the lid off an agency that's
been vacuum-packed for too long, impervious to public accountability of scrutiny, self-
contained. It’s time to open it to light and air and get rid of the rot inside.

1am here not to speak of my own experience ten years ago when I needed # cancer
treatment drug that was not yet FDA-approved --although that’s what first tumed my attention
to the FDA as the silent, but controlling, partner in the life of everyone with cancer-- but as
the Executive Director of CAN ACT, 2 patient-advocacy organization whose mission has been
identifying the FDA as a barrier to people who seek life-saving therapies to fight their
disease,

Tam not here to speak only of my own interest in having every possible new drug
available to treat cancer, but to represent the interest of millions of people living with cancer
in these proceedings.

Why should people who are fighting for their lives have to fight their government for
the drugs they need to fight the disease?

Because the agency charged with the responsibility of protecting the safety of
consumers has never understood that the stekes are different for people with life-threatening
illness. It cannot comprehend that we do not want to be protected to death. It does not accept
‘as a concept that a real risk of death from illness should give rise to different considerations,
and greater flexibility, in drug approvals. It does not accept it because politically it never had
to, but it was playing politics with my life, and the lives of other people with cancer.

I've been involved with the FDA just about es long as the present Commissioner, and
a lot less profitably. I'm convinced that nothing but a can-opener will work. It will take brute
force to reforn the FDA, because neither reason, nor cammon sense,--not even humane
considerations have made sny difference in the past. There Ihave no reason to think they
will in the future.


7

| want to thank you for the opportunity to address your Committee this moming.
Rohm and Haas Company is not directly involved in the pharmaceuticals business,
although a number of our products are used in the packaging or processing of food
and pharmaceuticals and therefore are regulated by the Food and D-ug
Administration as indirect additives. This morning, however, | want to focus my
remarks to a very specific section of the Federal Food, Drug and Cosmetic Act that
has great impact on our agricultural chemicals business. That section is Section 409
which contains the so-called "Delaney Clause”.

As you are undoubtedly aware, the Delaney Clause was added to the Federal Food
Drug and Cosmetic Act almost forty years ago in order to protect the nation's
consumers from the presence of cancer-causing agents in processed foods. The
Delaney Clause establishes a different standard for setting tolerance: for pesticide
residues of carcinogens in raw versus processed foods. This different standard leads
to the nonsensical situation in which the same pesticide residue that is legal on
grapes, a raw food, is illegal on raisins, considered a processed foo. The National
Academy of Sciences coined the phrase the "Delaney Paradox" to describe this
disconnect in the statute. This Clause was enacted at a time when relatively little
was known about the causes of cancer and when methods of analysis were able to
detect chemicals in food at the part per thousand level. Although the enactment of
the Delaney Clause by Congress in 1958 might have been appropriate in light of
science at that time, the passage of forty years has made the Delaney Clause an
anachronism. Instead of protecting the public health, the National Academy of
Sciences concluded in their 1987 report that strict application of the Delaney
Clause might indeed increase the risks to the public from pesticide residues in their
food supply.


83

Mr. Fox. You are suggesting instead of the two large studies one
large study with confirmatory what?

Mr. Bots. Confirmatory data.

Mr. Fox. Data. Would that also include data from possibly other
foreign studies?

Mr. BLois. Yes. We do as a rule now, as I mentioned, a global
development program, which would have data from studies done
in—

Mr. Fox. Are there not international standards by which all
drugs must be made?

rT. BLots, I am sorry?

Mr. Fox. Are there international standards by which drugs must
be made?

Mr. BLOIs. Yes.

Mr. Fox. If I could ask that the chairman indulge me one more
moment?

If I may ask a question as well to Dr. Molt, you were talking
about incentives that we should provide for the FDA. What do you
mean by that? What kind of incentives? Do you mean a new proto-
col or a new goal or what?

Mr. Mott, I think right now the incentive system is one where
there is if they do something wrong, they hear about it. If they
hear something right, they do not. There is no retribution for no
action.

The incentive system seems to encourage caution. No one is
hauled before a Congress because they approved a drug. I think
that that is something that we need to change. I think that there
is a need to do something that rewards FDA for providing new
therapies faster.

Mr. Fox. Encouraging the innovation?

Mr. MOLT. Exactly.

Mr. Fox. I have no further questions. Thank you.

Mr. McINTOosH. Thank you very much, Mr. Fox.

I would like to now turn to Mr. Walker, who has to leave us
shortly.

Mr. WALKER. Thank you, Mr. Chairman. I have just a couple of
questions for this panel.

Primarily because all of you represent global companies doing
business beyond the borders of this country, do you know of any
other industrialized countries that have a more complicated drug
approval process than what we have?

Is that a no? Do I understand the consensus of the panel is that
amongst industrialized nations, we have the most complicated drug
approval process in the world?

Mr. MOLT. I think it is the most demanding.

Mr. WALKER. The most demanding. That is not necessarily a bad
thing in some people’s opinion.

The question is whether or not we are over complicated to the
point that we are not doing the right kind of thing in terms of the
global marketplace. That is what I am trying to get at.

Mr. Mott. I would say that we are over 4 cautious as a result
of all the information that FDA seeks. I think that they are asking
for maybe the right amount of information.


5

some reinvention plan which has some good points, but frankly I
am a little skeptical. I am not sure that it goes far enough.

I am looking forward to working with you, Mr. Chairman, and
Mr. Clinger and Mr. Fox, who is working on a bill that I would be
happy to help him with and see if we can untangle some of this.

Thank you for inviting me to the hearing.

Mr. McInTosH. Thank you very much, Mr. Peterson.

b Mr. Fox, thanks for setting this all up. We are delighted to be
ere.

Mr. Fox. Thank you, Mr. Chairman. I appreciate the opportunity
to speak about this issue and to have each of you be here today.

Frankly, as this committee is the one charged in this One Hun-
dred and Fourth Congress with regulatory review, I cannot think
of a more important area for us to work on than the review of the
FDA with regard to the accessibility of life extending and lifesaving
drugs here in the United States.

I extend a personal welcome to all who have joined us. I see that
Congressman Walker has also joined us. I am very pleased that the
chairman of the Science Committee is here. I welcome you to Mont-
gomery County, the 13th Congressional District of Pennsylvania,
which I am honored to represent.

Mr. Chairman, I am pleased that we have organized today’s
hearing on this issue of significance. As was aptly described in a
recent article by Carl B. Felbaum, president of the Biotech Indus-
try organization, lifesaving new drugs do take too long to reach the
people who need them.

In my district alone, I have heard many a compelling story from
constituents afflicted with cancer, Lou Gehrig’s disease, epilepsy or
AIDS who speak of the difficulties in accessing the medicines they
need because the approval process in our country is so prolonged
and in effect they have to turn to other countries where the prod-
ucts are available.

We are fortunate to have some of the individuals with us today.
I look forward to hearing their experiences, hopefully to bring
about the positive change they want and we want.

It is important to note that the Food and Drug Administration
serves a valuable purpose in maintaining high safety and efficacy
standards. However, it is also important to recognize that the
FDA’s actions directly effect the lives of patients and the ability of
physicians to provide state-of-the-art care for their patients.

As Chairman McIntosh eloquently commented previously, the pe-
riod beginning with the initial testing of a drug and continuing
until final approval by the FDA can require 7 or 12 years before
it reaches the shelves.

Furthermore, the FDA regulates businesses that produce 25 per-
cent of America’s gross national product, so the agency's actions
also impact our country’s well being. The pharmaceutical industry
is an excellent example. The United States leads the world in dis-
covery of new drugs, yet all too often these drugs are available
overseas first.

The United States is far and away the leader in biotechnology,
but many biotechnology firms are moving clinical trials overseas
because of the red tape imposed on them by the FDA. These are


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81

Mr. McINToSH. Thank you very much, Dr. Larkin.

I hope later we can hear from Chairman Walker, who has
worked a lot on the risk assessment bill.

I wanted to pursue a question with Dr. Molt on one of the two
drugs he mentioned as an example. It is the one that Ms. Gladis
had mentioned to treat Lou Gehrig’s disease.

I think she was indicating in her testimony that there may now
have to be another set of clinical trials for that drug. Is that the
case? What is the status of that application with FDA?

Mr. Mott. We have recently submitted to FDA a request for
them to grant us a treatment IND. That is currently under review.
We are optimistic that that will be approved, and then the drug
will be made available under the treatment IND. We also will be
filing a new drug application for the compound shortly, and FDA
will work to approve it so it will receive full approval.

There is no requirement now for additional data before the drug
is made available under the treatment IND, so we are optimistic
that it will be available shortly under the treatment IND program.

Mr. McINTosH. So currently it is not part of a treatment IND,
or has that lapsed under the first approval?

Mr. Mott. No. The drug is not approved in the United States.

Mr. McINTosH. Did you not have one treatment IND?

Mr. MOLT. No. This is our first treatment IND. We have an IND
under which some people are getting the drug in clinical trials.
Based on positive results, we submitted a treatment IND, which
will allow general access to the compound so that it will be avail-
able under a treatment IND.

Mr. McINTOSH. Would any patient whose doctor prescribes that
be able to receive access, or is there a numerical limit?

Mr. Mott. Again, it is somewhat limited by our production capa-
bilities. There has to be some sort of system for allocating it.

Mr. McINrTosu. Do you receive reimbursement when——

Mr. MOLT. You are allowed to receive reimbursement under a
treatment IND. Rhone-Poulenc Rorer is not going to seek reim-
bursement for its treatment IND.

Mr. McINTosH. So the company will be providing that drug at its
own expense until it is approved?

Mr. Mott. That is correct.

Mr. McInTosu. Thank you very much.

I will reserve the rest of the time for other members of the panel
who have questions.

Mr. Fox, do you have any questions?

Mr. Fox. Thank you, Mr. Chairman.

I guess my first question would go to Dr. Blois, if I could. We ap-
preciate all of you being here lay and contributing your vast.
knowledge on how we can improve the system.

I was interested to hear your testimony with regard to the bal-
ance we need between purity of the drugs and also the need for
being at the cutting edge of innovation and availability and access
to our patients.

I would ask you a question dealing with when your goal is to
refocus the agency to drug approval. Could you tell those of us who
are not in the drug field but who are here as representatives of the
people to try to move the process along, what are the different


107

We also looked at environmental requirements that pose
significant costs for drug and biologic manufacturers in getting
a new drug approved--complying with the National Environmental
Policy Act (NEPA). Pursuant to NEPA, the FDA for many years has
required pharmaceutical companies to submit with new drug
applications a formal environmental assessment of the impact of
approving the product. In virtually all cases, there has been
little or no significant impact on the environment. Yet these
evaluations each cost tens of thousands of dollars. In fact,
some companies estimate the cost to be several hundred thousand

dollars.

We intend to increase the number of categorical exclusions to the
requirements to prepare these assessments that will eliminate the
need for them, except in rare cases. This will free millions of
dollars of industry resources to be applied to other avenues of

drug development.

We also announced reforms in the regulation of antibiotics and
insulin, which have been subject to special controls since the
1940's. Today, these products can and should be regulated like

other drugs, and we will be asking Congress to repeal the special

a


92

a lot of the important issues that you have already begun to hear
about today from many of the witnesses who have already testified.

One of the points that I think people have brought up is this
issue of a mission statement and trying to define what the FDA’s
mission is. I can tell you that as far as the Center for Drugs is con-
cerned, in 1995 we realized that our statutory mission is to protect
and promote the public health of all Americans that have to do
with products that are under our jurisdiction.

I think we have to realize that this is really a multifaceted mis-
sion when you begin to think about it. It is not a simple mission,
and it is not one that one can hone down very easily.

Clearly this involves promoting public health. It involves insur-

ing that drugs are proven safe and effective before they are avail-
able for general marketing in our country. Clearly it means that we
assure that valiant, thorough information is available to healthcare
practitioners and to consumers to help assure that they make trul
informed decisions on the appropriate use of pharmaceutical prod.
ucts.
I think clearly it means that we have to have in place a process
whereby drugs that have good scientific data that demonstrate
their safety and effectiveness become available to Americans as
promptly as possible. This is a mission that clearly is as absolutely
vital today as it was 90 years ago when the first Food and Drug
Act was approved.

I think when you talk about standards of efficacy and safety, this
is not something that only benefits consumers. I think we have to
realize that this also benefits the medical profession, and it bene-
fits industry because it gives credibility to our pharmaceutical in-
dustry, and it is an industry that deserves the credibility that it
has in the world market today. It heightens competitiveness of our
product because people know that products that are available in
the United States have undergone very stringent safety and effi-
cacy testing.

I think the world has realized that indeed this general approach
to the overview and to the development of drugs has value because
I think we see in most modern countries, as people were pointing
out today, the basic standards are fairly similar. What is at issue
here is the process for how one gets through the independent eval-
uation of the data that people have.

Mr. Chairman, these are really very, very exciting times for
those of us at the Center for Drugs. As you are aware, we have a
new management team in at the ‘Genter for Drugs. Dr. Woodcock,
who is our Center director, and I have been in our positions for
about a year and a half.

I think when people really begin to look at the recent data on
the performance of what our Center has done and we begin to sep-
arate some of the rhetoric from the reality of what is going on
today compared to what went on in past years, to paraphrase a
commercial that is popular now, I think at least for the Center for
Drugs you will find that this is not your parents’ FDA.

Having said that and having said t that with pride in what I think
we have accomplished in the year and a half that the new manage-
ment team has been there, I will be very clear and forthright in
saying that we still have a long way to go, but we have a process


60

STATEMENT OF

ROBERT L. POWELL, Ph.D.
Vice President, Regulatory Affairs, North America
SmithKline Beecham Pharmaceuticals

to Special Field Hearing
House Government Reform and Oversight Committee
June 9, 1995
Norristown, PA

My name is Robert Powell, Vice President and Director, Regulatory Affairs, for
SmithKline Beecham Pharmaceuticals. On behalf of SB, I would like to thank you,
Representative Fox, for letting us take part in this hearing on FDA reform.
SmithKline Beecham is one of the world's largest health care companies; SB
discovers, develops, manufactures and markets human pharmaceuticals, including
innovative childhood and adult vaccines, over-the-counter medicines, health-related
consumer products and clinical laboratory testing services. We are a very large
employer in the Commonwealth of Pennsylvania, with over 6500 jobs. Our U.S.
headquarters, and the U.S. headquarters of all of our major businesses are located in
Pennsylvania, including over 1700 jobs in the 13th Congressional District.

I joined the Pharmaceutical industry almost 30 years ago, a time when things were
considerably less complicated than they are now. This is true not only from the
point of view of the “science” of drug development, but also from the point of view
of the complexity of the regulation of that drug development. The combination of
these two gradually changing environmental complexities has made the development

Page 1


And that is where we come to another problem. Because historically
the FDA is castigated in public if they underestimate the risk of a drug, they
seek to indemnify their decisions by using an Advisory Committee. In the
case of Taxotere®, the Advisory Committee was quick to point out the toxicity
profile of the compound without acknowledging the benefit; and the
Committee ultimately provided FDA with equivocal advice on whether or not
to make the drug available for women with advanced resistant breast cancer.
Without a strong vote of support, FDA was not able to act on their previous
conviction and Taxotere® remains unapproved today while FDA continues to
analyze the data we submitted to them. And, except for the strong voices
coming from the sufferers of breast cancer and their supporters, no one is
asking FDA how much potential benefit is being withheld from the patients
by their inaction.

It is clear that FDA and its Advisory Committees, because they both
appear to focus on risk at the expense of benefit, are in need of reform. We
must envision a system where there is a reward for approval of drugs that
are able to save the lives of Americans. FDA has to have less fear of public
retribution for a bad decision. Not making a decision, as in the case of
Taxotere®, can be more detrimental to the public health than the extremely

" rare bad decision. Likewise, if the present Advisory Committee system is to
remain intact, it too must place proper balance on the benefit to risk analysis
of high potency, life saving drugs. We must work to foster a system of drug
approval that will bring maximum benefit to patients while assuring that the
risk of use is acceptable. Until now the risk side of the equation has been of
paramount importance. Any FDA reform must include proper incentives not
to hold up approval of drugs deemed to provide clinical benefit when FDA
has decided that the benefits outweigh the risks.


18

on the market in six other industrialized countries.
I hope that as your consider proposals to change the drug
approval process, you will consider the needs of families like
ours and the needs of less fortunate families whose insurance
plans do not cover drugs from overseas. I am sure that if you
had someone close to you who suffered becau:
regulations, you would want to change them. That is why I am
sharing this story with you. Thank you very much for listening.

of government



at

Page 4

the development of new drugs and identify therapeutic combinations that will
significantly advance the treatment of HIV infection. Such studies are actually
underway.

INCREASED MARKET COMPETITION INCREASES THE RESEARCH STAKES

Clearly, to maintain our historic level of innovation, we must meet and master the
challenges confronting our industry today. These challenges include both unlocking
the mysteries of disease through science and adapting our discovery and business
objectives to an increasingly competitive marketplace.

It is no secret that the economics of health care have changed substantially over the
past decade. For example, just eight years ago, managed care customers, including
HMO's and the government, accounted for about 30 percent of Merck's sales; today
about 70 percent of our drugs go to that market. There has also been a consolidation
in the number of drug and biotechnology companies with scientists at work in
laboratories in America. In short, the new market environment places an even greater
premium on every promising lead.

FDA REFORM IS CRITICAL FOR INNOVATION

This is why FDA regulatory reform plays such a critical role in continued innovation by
U.S. industry. Streamlining the regulatory procedures and FDA management practices
to achieve even small improvements in the drug development and approval process
can pay off in enormous human and economic dividends. We can and should eliminate
unnecessary delays and bureaucratic procedures while maintaining high etandards for
safety and efficacy of new medicines and vaccines. Let me give you some illustretions
of the type of changes that could be made.

1. Refocus the Agency on drug approval

Redirecting the Agency's resources should begin with a statutory revision of its mission
statement to stress FDA's positive role in assuring the timely availability of new drugs
and therapies. As part of a revised mission statement, recognition and support should
be given to those at the FDA who play an important role in approving important new
medicines and vaccines.


51

Mr. McIntTosH. Thank you very much, Dr. Blois. I apologize for
mangling your name earlier.

Our second witness is Dr. James Molt, who is here today with
Rhone-Poulenc Rorer.

Dr. Molt.

Mr. Mott. My name is James Molt. I am the head of regulatory
affairs for Rhone-Poulenc Rorer or RPR. We are a research inten-
sive U.S. company located here in the 13th Congressional District
in Collegeville, PA.

Because RPR’s mission is the discovery and development of new
medicines, we have frequent interactions with the Food and Drug
Administration. We appreciate this opportunity to offer some ideas
that may help improve the drug approval process.

As _ you know, pharmaceutical research is a risky, costly and
lengthy process not only for us as companies, but also for the pa-
tients ‘who are waiting for these important new medicines. Today
I would like to use as examples two new medicines that we are de-
veloping to see where we may be able to improve FDA, but also to
show where we think FDA has some strengths.

The goal, of course, is to get new medicines to the patient faster.
Let me start with the example of Rilutek, where we have had some
positive interactions resulting from some recent FDA self-initia-
tives for reform.

As we heard early in the very poignant remarks from Mariah
Gladis, Rilutek is the first compound shown to prolong survival in
ALS. Since there is no approved treatment for ALS, RPR has asked
FDA to allow patient access before the drug is approved through
a treatment IND. The treatment IND is a mechanism put in place
by FDA to allow a patient access to promising new drugs before the
final approval is granted. We believe that this is a positive step to-
ward getting drugs to patients faster.

We hope that because the drug is available under a treatment.
IND there remains an incentive for FDA to provide full approval.
It is this concept of incentives that really brings me to my main
point today.

Until this system of incentives at FDA is modified, patients will
not have full access to all the medicines that could be available to
them. It is this concept of patient value—that is, the benefit to be
gained versus the risk associated with using the medicine—that I
would like to focus on.

As you are well aware, a drug is approved by FDA if they deter-
mine that the weight of the benefit outweighs the weight of the
risk. For a number of reasons, FDA has historically focused on the
risk side of the balance so that very little risk is able to pull down
a drug, even though there may be substantial balance.

One of the previous quéstions was whether Thalidomide had any-
thing to do with this, and I think the question is yes, it did. That
is one of the reasons that FDA does focus very intently on risk. We
see a little bit of risk being able to pull down a lot of benefit. We
really cannot fault FDA for this because I think it is we, the public,
who have placed on FDA an incentive system that really rewards
caution.

Let me give you an example using our new anticancer agent,
Taxotere. Faxotere has been shown to provide significant benefit in


80

. enhance the protection afforded infants and children as recommended by the
NAS in its 1993 report on “Pesticides in the Diets of Infants and Children”

« Streamline the cancellation provisions under FIFRA that will allow EPA to

take faster action, when warranted, against pesticide risks
. provide for uniform national tolerances for pesticide residues

. provide support for the registration of minor use pesticides - products
that are vital to the continued production of a varied and wholesome food

supply

Time does not permit me to go into detail on these other provisions. However,
while Delaney reform is the centerpiece of HR-1627, all of these otiver provisions

are an integral part of improving the laws governing pesticides in this country.

In conclusion, | would like to ask for your support in implementing the conclusions
of the National Academy of Sciences to establish a uniform standard for setting
tolerances for all food that will be more protective of the public hez|th than the
standards of the current Delaney Paradox through your support of HR 1627. itis
imperative that this legislation be enacted in this session of Congress in order to
insure Americans the continuation of a wholesome, plentiful and affordable food
supply.


142

Statement of Michael R. Sperling, M.D.

‘My name is Michael R. Sperling, and I am Chief of the Medical/Surgical Program of the
Comprehensive Epilepsy Center at Graduate Hospital in Philadelphia and Associate Professor of
Neurology at the University of Pennsylvania. I appreciate this opportunity to talk to you about
the needs of the approximately 1.6 million people in the United States with epilepsy.

‘My neurology practice is largely devoted to treating people with epilepsy. Medications
that are currently approved by the FDA control the seizures of only 60-70% of patients,
Therefore, they are inadequate for 500-600,000 people, for whom epilepsy remains a serious
problem. People with epilepsy have a high incidence of associated mortality - the death rate
averages one in 200-300 per year. They are also prone to such problems as injuries, burns,
fractures, cognitive problems, and such social impairments as the inability to drive, with resulting
social isolation and limited occupational opportunities. Many are unemployed or underemployed.
The direct and indirect costs to the health care system and society are therefore enormous. Better
drugs are needed to treat this condition.

have treated thousands of patients with epilepsy who are inadequately controlled by the
currently approved medications. They continue to experience seizures, often with devastating
effects on themselves and their families. Family life is strained as people try to cope with the
illness, and sometimes a family member must devote much of his or her life to caring for a relative
with epilepsy. Some people resort to sending overseas for medicine approved in other countries
when approved medications in the U.S. fail, but most simply suffer with their symptoms and wait
for new medications to reach the U.S. market.

Medications that are currently approved for treating epilepsy have many side effects that
also make the development of new agents desirable. The drugs can produce symptoms that
diminish the quality of life, and none are ideal for pregnant women. The common drugs for
epilepsy also change the way our bodies metabolize other medicines, and therefore complicate the
treatment of other medical conditions.

‘Much has been learned sbout the physiological causes of epilepsy in recent years. We are
now in an unprecedented position to take advantage of basic research to design new drugs. These
could be more effective in treating epilepsy and have fewer side effects than the medications now
available. Their development should not be forestalled because of inappropriate and inordinately
expensive testing, Moreover, many of the new drugs might work on one specific mechanism to
prevent seizures and thus be useful for only a small subset of patients. The cost of development
might not justify the expenditure needed to bring it to market.

No new drugs were approved to treat epilepsy between 1979 and 1993. While three new
drugs were approved in 1993-1995, only two are currently in use, and they have limited
applicability. More than 20 compounds are currently being tested, and many more could be
developed. However, the regulatory system discourages development of new agents with limited
market potential due to enormous startup costs.

Let me mention some of the current problems preventing the development of new epilepsy
drugs and suggest some solutions.

‘New drugs take too long to reach the U.S. market, and some never make it. Lamotrigine


185

Last week, Pennsylvania State Representative, Elinor Taylor, ap-
peared with reference to the court-mandated coverage of dose in-
tensive chemo with autologous marrow transplant or peripheral
stem transplants as a treatment for metastatic breast cancer.

I figured rather than make myself responding to that, I would
look at the whole issue and suggest that they be merged, the clinic
with academics and research, along the line that that described.

I called for the creation of a seamless system designed to inte-
grate care, and I noted that some streamlined process would prob-
ably stimulate the composition of user friendly standardized stud-
ies. Large scale studies listing cardiology also, but there is really
no methodologic approach that would cover, for example,
neurologicals, as you heard earlier discussed.

Mr. McINTosH. If I could ask you, Dr. Sklaroff, to go ahead and
summarize your testimony?

Mr. SkLaRorr. That was the part of it. I suggest that this struc-
ture would have insurance coverage for the basic medical care and
additional coverage through either the academic institution or
through the pharmaceutical house promoting the drug to cover the
other aspects of it.

I close basically with the fact relating to tobacco and also relat-
ing to the recent information that came out from the FDA a couple
days ago. The coverage of tobacco, because it is a toxic issue,
should be maintained by the FDA. Similarly, when the FDA re-
quests reports on problems with blood vaccines, again this is a tox-
icity issue which I fee] belongs underneath the FDA, and these two
current samples do not undermine my major feeling that the FDA
has indeed denied this push.

Therefore, I am suggesting a national system for clinical research
benefiting the patients without jeopardizing their safety. I explain
why and a cost-effective level in the last paragraph.

Thank you.

[The prepared statement of Dr. Sklaroff follows:]


13

Mr. MCINTOSH. Our next scheduled witness is Faith Samowitz,
and her son, David, is here.
Faith, if you would like to start off?

STATEMENTS OF KIYOSHI KUROMIYA, DIRECTOR AND EDI-
TOR, CRITICAL PATH AIDS PROJECT; FAITH SAMOWITZ, CIT-
IZEN WITNESS; DAVID SAMOWITZ, CITIZEN WITNESS; AND
MARIAH GLADIS, CITIZEN WITNESS

Ms. SAMowiTz. Mr. Chairman and members of the committee,
my name is Faith Samowitz, and with me today is my son, David.
David and I want to thank you for this opportunity to talk directly
to lawmakers about the effects of Government regulations on our
ives.

David has epilepsy. When he was about 9 years old, he was first
diagnosed with a seizure disorder, and then it was labeled epilepsy.
We do not know what caused David’s epilepsy. There are several
possible causes for this order, including brain injuries, metabolic
disorders and infections.

Epilepsy is a neurological disorder affecting some 4,000,000
Americans with about 100,000 new cases reported each year. The
disorder is marked by recurring seizures. David has grand mal and
complex partial seizures.

In 1987, after we had exhausted all medications and combina-
tions of medications available in the United States, David’s neu-
rologist, Dr. Stanley Resor, suggested we try to some medications
that were having some success in England, but were not available
here. We did that, and now David is taking four medications. Until
recently, all four were imported from England. Now two have be-
come available in the United States.

With these medications, David’s seizures are not too severe, but
obtaining these medications has been a major problem. To get the
medication, David obtains a prescription from his neurologist, and
we send it to a London pharmacy that specializes in filling pre-
scriptions for people from the United States. The pharmacy must
then obtain a prescription from a local doctor, which is another ex-
pense.

The drug is shipped, and U.S. Customs must clear it. Then it
goes to our local post office, which notifies us to pick it up. If all
goes smoothly, we can get the drug in about 2 weeks, but life be-
comes very stressful. You hold your breath, you bite your nails, and
you count pills the whole time because David cannot do without
these medicines.

In 1991, U.S. Customs seized and burned a shipment of ours
without even notifying us. We only found out about it after we
wrote to the London pharmacy that we had not received the ship-
ment. The pharmacy put a tracer on it and was notified by British
postal authorities that the shipment had been seized by U.S. Cus-
toms as an illegal substance, an opiate.

The drug, Mogadan, is definitely not an opiate, and FDA regula-
tions clearly state that patients with a physician’s prescription
should be able tc import such drugs for their personal use.

Senator D'Amato kindiy intervened on our behalf, and after
about a year and many exchanges of letters, we were reimbursed


137

FDA Testimony 6/0/95

Rep. Jon Fox Page 2

In the past, such decisions have been justified by citing the absence of FDA
approval for the use of a given agent for a particular indication. It ie this
hurdle that costs the pharmaceutical houses such exhorbitant sums to overcome.

In the interim, patiente are denied access to agents that can help thi

Physicians prescribe drugs “off-label” routinely, drawing upon knowledge gained
from reading foreign literature and/or data recently presented at sectings.
For example, earlier this week, I prescribed ultra-bigh dosages of tasoxifen

for the treatment of widely-metastatic malignant melanoma, a type of aggressive

skin cancer. This decision was based upon information which had been presented
only a fortnight earlier during the annual meeting of the major world-wide
cancer organization, the American Society of Clinical Oncology. This decision
was also based upon my knowledge of the drug and its mechanism of action from
prior readings, thus underaining any claim that oncologists would merely engage
in "cookbook medicine.” We're patient advocates, and we're relucant to deay a
patient any treatment which could work in 1995, even if definitive data may not

be available until 1996 (or beyond). Life is too short!

Yet, as “restricted formularies” are generated by insurers, such alternatives
will be precluded regularly. Certainly, the FDA should disclaim responsibility
for determining if a new drug is “any better” than a related drug which has
already been marketed; this type of thinking blocked release of an anti-cancer

drug called Vindesine--desacety] vinblastine amide sulfate

decade ago,
despite the claim by some oncologists that it had greater efficacy than other
members of the family of “vinca alkaloids” (made from the periwinkle plant)

when treating lung and esophageal cancer. If the drug works, it should be

released, allowing it to “compete” freely in the open market with other agents.


Its this concept of net beneficial value, what we refer to as the
benefit/risk assessment, and what Deputy Commissioner Shultz called
"promoting the rapid availability of effective drugs" versus “protecting the
public", that I would like to focus on. It is our perception that for FDA the
benefit/risk assessment has historically focused on risk. We cannot fault
FDA for this because we, the public, have placed on FDA an incentive system
that rewards it for being cautious but does little to provide incentives to
increase the availability of beneficial medicines. Until the incentive system
changes, we should not expect FDA to act any differently than they do now.

Let me give you an example of our experience with FDA with regard to
this benefiv/risk assessment. For this example I will use our anti-cancer
agent Taxotere®. Taxotere® has been shown to provide significant benefit in
women with advanced breast cancer where other chemotherapies have failed.
And breast cancer is a disease where new therapies are sorely needed. Each
year in the U.S., more than 180,000 women are diagnosed as having breast
cancer, and this year 46,000 will die from the disease.

We submitted a New Drug Application for Taxotere® in July of last
year based on a developmental program devised in conjunction with FDA.
FDA reviewed the application in about 4 months, which is very fast and,
again, commendable. At the end of that review the Agency had arrived at
the conclusion that the considerable benefits of this drug for women with
resistant breast cancer outweighed its risks. This was a difficult decision
because, as with all highly active anticancer agents, the side effects are
substantial. As is usually the case the FDA decided to use an Advisory
Committee to obtain an independent opinion on the approvability of the

compound.


2

We have Randy Tate, who is a member of the committee from
Washington State, and Mr. Bob Walker is going to be joining us
later. He is chairman of the Science Committee, and I would ask
unanimous consent that he be allowed to participate as an ad hoc
member of this committee.

Seeing no objection, it will be so ruled.

Today the subject of our hearing is Food and Drug Administra-
tion regulations, particularly in the approval of new drugs and
pharmaceuticals. The Food and Drug Administration plays a criti-
cal role in the health and safety of the American people and one
that I believe all of us want to see continue and improve.

The FDA regulates more than $1 trillion worth of products every
year. That is about 25 cents on every dollar that is spent in Amer-
ica each year. The FDA regulates everything from the food we eat
to the drugs we take to the cosmetics that we wear. Because of this
critical role that FDA plays, it is appropriate that this new Con-
gress takes a hard look at the agency to insure that the American
people are receiving the best medical care with access to the latest

reakthrough lifesaving drugs and devices.

As chairman of the House Regulatory Affairs Subcommittee, I
have taken a look at that agency. I have reviewed very thoroughly
the drug approval process, and I can report to you today that it is
my opinion that the FDA is an agency that in many ways is out
of control. Its disregard for the health of Americans suffering from
treatable illnesses is in some ways shocking.

Today, thousands of Americans are needlessly suffering and
dying because the agency has prevented them from receiving the
latest, most effective medicines that are safe and effective for use.
Because of the needless red tape and bureaucratic snafus and in
some cases even intimidation, too many Americans are suffering
needlessly, and the evidence of this is overwhelming.

New drugs require on average 12 years for approval in the Unit-
ed States, 100,000 pages of paperwork, nearly $400 million in order
to receive approval from FDA. Doctors are effectively prohibited by
FDA from talking about the drug and the device manufacturers
and using it for certain needs that may not have received approval
by the agency even if they feel it is the best treatment for their pa-
tients.

American companies are moving overseas to countries like Ire-
land and the Netherlands to escape the heavy hand of FDA regula-
tions. Trial lawyers have pressured the agency to delay new drugs
and device approvals so they can profit from lawsuits, and special
interest groups enjoy special access to the agency’s inner circle that
the rest of us simply do not have.

In my home district, a doctor mentioned to me that he is aware
of a new insulin drug that has not been approved here in the Unit-
ed States which would greatly improve the treatment of diabetics,
but it has been approved in Russia. He found it ironic that as we
win the cold war, we cannot win the effort to get good, effective
drugs for our patients here in this country.

FDA has said that it performs its job relatively efficient]
and cheaply, only $3 per person per year, but I think today we will
hear from many witnesses who are patients and doctors working
with the drugs that they have approved, and we are indeed paying


163

and that the consumer and general population's safety is better maintained here than in
many foreign countries. However, there are frequently good studies that can be applied
to the approval process and we would benefit greatly by the ability to transfer data from

many of the studies done abroad.

‘On some occasions, pharmaceutical companies may be presented with a drug that is truly
innovative and perhaps lifesaving if patients were given the opportunity to benefit from
this product. A process must be put in place to expedite these drugs while at the same
time not losing the necessary data that one would need to analyze risk versus benefits,
‘Therefore, I would like to suggest that in these unique cases, a decision be made to switch
8 product from a close label double blinded protocol to a open-labeled protocol where the
drug can be more widely distributed and studied while it is contiming to be carefully

monitored.

In the same vein, I would like to suggest that we diligently purme the potential for long-
term phase IV studies (or those studies which take place post approval). As I stated earlier
in this report, it frequently takes at Icast a million doses of a drug to develop an adequate
side effect profile. We must, therefore, extend the monitoring process into the post
approval phase and establish good standardized criteria for doing so as well. This needs to
be done in the format of actual organized clinical trials demonstrating not only a side
effect profile but efficacy.


12

- Reform of FDA marketing procedures, The agency’s restrictions on marketing and
promotion have gone beyond the bounds of their original intent. Centocor, in its move toward
launch of ReoPro this year, found this out first hand. We believe that the industry’s marketing
practices must comply with FDA standards, but the current process is stow and bureaucratic,
Again, we endorse BIO’s proposal to curtail items such as exempting press releases involving SEC
requirements, and prohibiting prior FDA approval of advertising or sales literature for the first
120 days of a launch.

In closing, on behalf of Mr. Holveck and all of the employees at Centocor, I want to thank
the members for focusing on this crucial public policy issues. Mr. Holveck has stated numerous
limes that he believes a sensible, market-friendly, incremental approach lo FDA reform is the best
way to move forward. Wholesale restructuring of the agency is nut needed; common sense changes
are. We in the medical technology industry will drive ahead to innovate and create products that
meet unmet macdical needs, such as cancer, arthritis, and heart disease. We need a well-run and

market-driven regulatory process to make that happen,

Thank you,


27

4) AVOID THE USE OF PLACEBO IN FUTURE TRIALS — The
ALS Associadion has stated that "like cancer, once a drug is identified
as being effective in treating a particular disease (regardless of how
minimal), researchers commonly design future trials that compare
the reference drug versus a new drug or a combination of the
reference and new drug.” Basically, once we have a drug that works
in ALS, why should patients have totake a placebo? My next
statement is about such a drug.

5) | APPROVE NEW DRUGS AS FAST AS POSSIBLE — I have
been out to talk to.the people-at Rhone-Poulenc Rorer in Collegeville,
Pennsylvania and I've been following their drug development
program for Rilutek since 1992. | tried to get it then, but the FDA
system didn't allow for patients to find ways to gain access to it
beyond the Phase III trial. In the meantime, the existing wials
demonstrated that Rilutek is the first drug to prolong survival of
people with ALS, Today, I know the FDA is reviewing a treatment
protocol that will allow for access to this drug before approval. And,
I know the company is planning to provide FDA with the New Drug
Application this July. But the real question is how much longer do I
have to wait to get the drug?

can't afford to wait around for the conclusion of endless drug
tials and FDA review. My husband Ronn, myself and my sons, Luke
and Cole, simply don't have me. I didn’t have the speech or
physical impediments that I have now in 1992. Many of my friends
with ALS were still alive in 1992. Now, it's 1995 and we want, we
need the opportunity to get this drug.


10

Class THI products, which are critical to maintaining human health, our blood tests don't have the
potential to be intrinsically unsafe because they are never used in the body and are not used as the
sole basis for medical decision making. FDA approval of a Class IIL IVD requires submission of
data from extensive evaluations which, for products like ours, take many years to complete and

which often cost many times the annual expected revenues for the product.

‘As a partial remedy, Centocor recently filed a petition with the agency seeking reclassification
of a limited category of TVD products. And the agency has been very supportive of this initiative,
Unfortunately, the administrative procedures necessary to accomplish the reclassification have
historically taken many years to complete. We would welcome any assistance this comminee can

provide in improving the speed by which this process moves.

‘A more complete solution to the issue of unnecessarily strict regulation of new IVDs can be
accomplished through legislation. We encourage this subcommittee to consider legislation which
automatically places all new IVDs into Class If, while at the same time retaining FDA's discretion to

place new IVDs which raise significant new issues of safety and effectiveness, in Class IT.

‘One final note of interest regarding regulation of IVDs. We have studied the Citizens Petition
recently filed by the Indiana Medical Device Manufacturers Couneil regarding the FDA's
developraent of guidance and other similar documents. We would like to add our support to the
observation that guidance can play a most useful and valuable role when the FDA take the time to
involve the public in the initiation, development and implementation of those documents. Well-
developed guidance helps reduce industry's cost and time requirements when preparing premarket

submissions. They also speed the review and clearance by FDA reviewers of those submissions


146

ns alain

‘Thank you very much for the opportunity to testify before this committee. My name is Dr. Jack Cionci.
In 1988 | made a decision 10 devote my semi-retiremrent to helping people with AIDS. Ihave been
involved in many projeots both here and ebrosd since that time. One of these projects is the Community
Advisory Board of Philadelphia FIGHT, our local community research Initiative that sponsors clinical
research in AIDS in the primary care setting,

People living with HIV in the Philadelphia metropolitan are are very oonvcrned with the issue of FDA
regulation because many believe they are being denied access to potentiolly life saving therapies because
of the arrogance and paternalism of that agency. In most other areas involving medicine, the trend over
the past thirty years hes becn away from pstemnaliim, and toward the belief that adults are entitled to make
their own decisions about their own medical care. Only in the area of new drug development does this
trend move in the opposite direction. Only in the area of new drug development do we have an agency
that feels entitled to refuse to allow people facing a life-threatening illness Lo make their own decisions

about treatments.

The clearesi example of the heartlesmeas and arrogance of the FDA thet we have scen in Philadelphia has
come over the Salk Vaccine. Jonas Salk, one of the most ditinguithed scientists ofthe twentieth century,
developed an approach tha he felt might prevent people from getting sick, even ifthey had the AIDS
Views, In tests in California in the late 1980's the vaocine was shown to be safe. In wider tests in several
cities it was again showm to be safe, and there is some data that indicates it works, There are looal
physicians, and researchers in several academic centers, in addition to Jonas Salk, who believe this drug
might have some efficacy, and that it should be more widely tested. Yet for over two years now, the
FDA has refused to allow this drug into wider trial. We are particularly aware of this issue in
Philadelphia because many of the trials for Salk vaccine were conducted here. In 1992, over 1,000
people signed petition cirolated by ACT UP aking for acca to this drug. Many of those people are


63

1) To facilitate the timely availability of safe and effective drug products;
2) To encourage efficient drug development;

3) To take prompt action to avoid inappropriate health risks;

4) To assure global harmonization of safety and efficacy standards; and
5) To facilitate the flow of medical information.

However, the mere statement of a mission is not sufficient, since managers of FDA
come and go and with them enthusiasm for one or another of the individual mission
statements may wax or wane. Thus as a second initiative, equally important,
would be creation of a "Policy and Performance Review Commission" to oversee
the operation of the FDA. This commission would consist of persons not employed
by the government, but expert in drug development and drug use in the United
States. The commission would be responsible for review of policies created by
FDA and for the performance of the agency in the context of assuring the
implementation of its stated mission. The commission would have the power to
recommend policy changes within the agency as a result of an observed failure to
perform consistently in concert with the letter and the spirit of the mission
statement. Whilé such a commission would report directly to the Secretary of HHS,
an annual report to Congress of its findings and recommendations would enlist
appropriate Congressional oversight for further assurance that the commission is
effectively providing the necessary focus of the FDA on the availability of safe and
effective new therapies to American consumers.

A third proposal that I would like to make is that the agency should look into
utilization of outside experts to help speed up the review process. Use of qualified
extemal resources would help overcome FDA's difficulty in attracting and retaining

Page 4


DRAFT
STATEMENT OF DAVID SAMOWITZ
June 9. 1995
Good morning,

My name is David Samowitz. I am 24 years old, and as my
mother has told you, I was diagnosed with epilepsy when I was 9.

As you may know, many famous people and high achievers also
had epilepsy, including Napoleon Bonaparte, Julius Ceesar, George
Frederick Handel, Socrates, St, Paul, and Peter Tchaikovsky. I
am optimistic that, with access to the medicines I need, I can
algo achieve something in my life. 1 am now in # training
Program to be @ mail clerk, but I am most interested in
electronics. I enjoy filming with a Camcorder, and people have
said I do a very professional job.

My condition has improved with the medicines I am taking,
but it bothers me that products are available in England and
other countries before they are put on the market here. If
countries can work together to fight wars or to help other
countries, why can't they work together on helping people get the
medications they need?

The current situation 1s very hard on people like me.. I
hope you will do something to change it.

Thank you very much.


37

thousands of pages as compared to a few dozen pages for the same drug in order to fulfill
European requirements.

Although, | will not go into detail in this area, the FDA restricts the flow of information on
drugs. I also requires on off abel use and promotion, an approach which often beckfires
ang harms the very persons it Is Intended to protect: children with rarer forms of cancer to
give one example and off-label uses of drugs like aibendazole for treatment of persons with
AIDS who ere fighting microsporidiosis an intestinal tract infection for which there are no
good treatmonts. PWAs must resort to getting albendazole for this off-label use through
community “buyers” clubs,” from other countries such as Mexico, or the veterinary version
‘of the drug. Why go to such lengths? Because diarrhea trom microsporidiosic If
‘uncontrolled in a PWA can lead to death.

Medicinal marijuana is @ whole other istue which | will not go into detail today. It wes.
approved for use by persons with glaucoms and multiple sclerosis and AIDS in the 80s and
then in 1988 suddenly banned by President Bush. Persons with AIDS who get nausea from
‘the dozens of medications they take @ach day use it to contro! nausea. Mariiuana ig also.
effective for persons with AIDS and wasting syndrome. | have lost 30 lbs. weight in the
last 12 months but have stabilized my weight loss through contro! of my nausea and
appetite loss with marijuans, The reason my weight loss has been stabilized for the past six
months is because | have found access to marijuana through underground sources. Because
of the politicelly charged Issue. Phil Lee of HHS, Alan Leshner of NIDA, and David Kessler of
‘the FDA have not only deniad me access to an Important herbal modicine which has been
used world around for its medicinal properties for 5,000 yeass. There are people going blind
from glaucoma or dying trom AIDS-related wasting syndrome, and yet marijuana cannot
even be studied In a clinical trial such as the ona proposed by Donald Abrams of SFGH,
which compares smoked marijuana and marinol, a less effective medication containing THC.

The total costs of FDA's review and approval procedures have risen steadily and rapidly
since 1962. During that time neither Congross nor the FDA has ever conducted a thorough,
reputable study of FDA performance that justifies these rising costs either in terms of lives
‘saved, Improved medical practice, or identifiable benefits to the US economy.

Finally, as a person with AIDS, | find that my efforts to get promising new treatments to
persons who neod them almost always leads to the FDA where the process often comes to
a standstill. The situation for persons with AIDS has Improved with the innovative programs:


16

7

w

is

oTy

157

‘USA, which used to be first, with the Coulter counter in hematology, the automated Beckman
glucose analyzer, and the automated Technicon chemistry analyzer, is now the last, because of
the increased FDA regulation. | know that the FDA means well, but development and
acceptance of new technology is a scientific and medical decision Better to let the scientific
and medical commumity have a greater role in the decision to accept or reject. anew
technology. Scientific publications in peer reviewed journals by clinical laboratory scientists
reporting the performance of new products and technologies are more usefill to the clinical

Alto, the FDA should accept test devices that have been accepted by other
industrialized nations without requiring extensive retesting here. My experience recently in
doing clinical trial research has been one of making sure that the “i” is dotted and the “t" is
crossed, with no real scientific benefit. I have seen companies be much more cautious with
marketing and development of new tests in this country. It is not because they don’t bave
good ideas to develop, but they have to dedicate more of their financial and human resources
to get new tests through the FDA. Moreover, smaller companies may not be able to compete
‘stall. Remember that many of our breakthrough ideas belong to small companies.

I think that the FDA's efforts to help, will actually hurt more people because there will
be less rapid improvement and advancement than there could have been. I could give
mumerous examples to illustrate these points, but there is not time. 1 think it is time for the
FDA to return to a more appropriate level of regulation and allow the scientific and medical
community 8 greater role in determining which tests to use, and bow to use them to greatest
advantage.


57

‘Now the hard part. How do we bring this about? Certainly one
answer is to rewrite the laws under which FDA operates. Another answer is
to increase Congressional oversight, and perhaps to consolidate the
jurisdiction of those Congressional Committees that have control over FDA
into one Committee. Congress should focus on creating an environment
where inaction by FDA is as much a cause for an investigation as is a bad
action. And while we need to move, we need to do it in a way that will
provide lasting change. To use re-engineering terms, a few “quick hits" are
probably valuable, but meaningful change must take place at a pace where
it can be assimilated. We know that reforming FDA will not be easy, but we
are encouraged by efforts such as those made by Congressman Fox here
today. We at RPR thank you for this opportunity to share our concerns and
views regarding FDA reform with you today and are ready to help in
anyway.


23

‘TESTIMONY OF MARIAH GLADIS
U.S, HOUSE GOVERNMENT REFORM & OVERSIGHT COMMITTEE
June 9, 1995 — Norristown, PA

Good morning. I am Mariah Gladis, a resident of Malvern,
Pennsylvania. I am a mother of two handsome boys....the wife of
Ronn Gladis for 14 years and is the Founder and Director of the
Pennsylvania Gestalt Center for over 20 years. I also have a terminal
illness called amyotrophic lateral sclerosis, which is better known as
ALS or Lou Gehrig's disease.

Today, I would like to thank you -- Congressman Jon Fox - and
the other members of this Congressional Committee for the
opportunity to focus on a common goal.....to speed up the FDA
approval process for life-extending and life-saving drugs. We all
hope that through your efforts and others like this, that futute
meetings won't be needed.

Ihave certainly felt some confusion about the direction of the
FDA, which is perhaps best illustrated by two separate quotes from.
Dr. David Kessler, Commissioner of the FDA. Dr. Kessler stated in the
March 1, 1994 edition of New York Newsday that:

"When people are suffering and dying from a

devastating disease, we can not wait for all the

evidence to come in — for all the 1's to be dotted and

all the t's crossed. We must be prepared to accept

greater risks from a drug when greater benefits are

possible,”


144

Mr. McInrosu. I cannot resist, because there is a disagreement
between you and Dr. Fisher on that.

Would you, as a doctor, ever choose a drug that medical journals
were saying was 90-percent effective? Would you choose something
that was less effective?

Mr. SPERLING. No, I think not. I think the issue is—there are
two issues here. One is that these things are sometimes not ap-
proved by the FDA. Because the literature does show that it is ad-
vantageous, therefore we will use it, even though the FDA has not
approved it.

T am talking about drugs where there is really very little data
or no data at all to support it. A single trial or a single report
where several people got something and it seemed to be effective
really is not active scientific proof. I think the proof in the pudding
is that the vast majority of IND’s prove the policy of preliminary
data usually does not pan out, or it suggests a rigorous scientific
study.

Mr. MCINTOSH. Your concern then is not that people will ignore
the data, but that there will not be a sufficient incentive for the
companies to prove that their product works. Simply because of
marketplace you need the regulation in addition?

Mr. SPERLING. Precisely, and I think that is a very important
point that needs to be made.

Mr. McINTosuH. Thank you, Dr. Sperling. I appreciate it.

c Our next witness we would ask to participate in this is Dr. Jack

'ionci.

Dr. Cionci, thank you for joining us.

Mr. CIoncl. First of all, I would like to apologize for being a little
bit late this morning. My testimony is now at the door, so when
you leave you can pick up a copy.

I would like to thank Congressman Jon Fox for inviting me here,
and I would like to thank the distinguished panel and also every-
one that is in this room that is concerned about this issue that
really impacts public health for everyone.

I have been in general practice since 1950, and I never had a sin-
gle malpractice case brought against me. I have to owe a lot of that
to the FDA because the drugs that I prescribed, the FDA made
sure that they were safe and efficacious, thereby removing many
pitfalls of litigation. I consider the FDA one of my guardian angels.
This was in 1950 when I first went into practice.

Decades later, along comes AIDS. It is an entirely new ball game.
It is in a new arena, and we need new rules. The FDA must move
with the times. We must put aside our politics and put aside our
prejudices. We must open up our hearts to our brothers and sisters
who are HIV positive.

The paper that I wrote was written with a great deal of help
from members of Philadelphia FIGHT, of which I am proud to be
a member. The people who are HIV positive helped to write this
paper. It is an expression of their views of what they would like
to see done as far as new regulations from the administration.

We need the fast track, and we positively need the FDA to guar-
antee uniform dosage strength and quality assurance. We need doc-
umentation of side effects and efficacy.


90

Mr. PowELL. There are some down sides, particularly in terminal
diseases where you expect the patient to die if indeed you decrease
their lifespan with the drug. It would be difficult. You have to at
least guarantee that you are not hurting the patient before youn

Mr. CiinceR. First do no harm?

Mr. PowE LL. First do no harm. I think that is important. Never-
theless, I think that there could be and I think there is consider-
ably less conservatism for treatments of terminal diseases. I think
the FDA for the most part should be commended for their efforts
in this area.

Mr. McINTosH. In that case then you would argue that you only
need to test for safety and not for efficacy?

Mr. PowELt. If there is no other treatment, yes.

Mr. McINtTosu. Thank you. Thank you all.

Mr. Tate, did you have any questions?

Mr. Fox, you have an additional question?

Mr. Fox. Yes. Following the chairman’s question previously I
guess to Dr. Powell on the time period, I think you were talking
about the 10 or 12 years some drugs might take.

Can you quantify the number of years you thought how much
was for good science and how much was really for maybe over regu-

lation?

Mr. PowELL. I have never thought about it, but roughly I would
think we could reduce a couple of years off of the total Sevelopment
time just by improving the process. I could not give you the exact

letail.

Mr. Fox. I understand. Going back to your testimony on page 4,
how would you, briefly if you can, facilitate the timeliness of the
speed process? We have heard good testimony regarding the incen-
tives. What else would you do to speed it up?

Mr. PowELL. As I mentioned and as Dr. Blois pointed out, if you
can focus the resources on the issue of making drugs available
rather than focusing those resources on compliance and on data
verification, that alone would help speedup the process consider-
ably.
Mr. Fox. I have no further questions, Mr. Chairman.

Mr. McINTosH. Thank you very much, Mr. Fox.

Thank you all for participating today. We appreciate it, and we
appreciate your written testimony. There may be a few additional
questions that come up throughout the rest of the day.

If you all would not mind, if we could submit those to you if
there is any additional information we need? We will hold open the
record for that purpose.

Also let me urge you that if there are additional things you want-
ed to put in the record that you were not able to as part of your
verbal testimony, please make sure you submit those to us. We will
include them in the record.

Thank you.

We will move now to the third panel. Dr. Lumpkin, if you would
come forward?

One of the things we have asked is that the agencies, when we
are going through some of these regulatory issues, attend and par-
ticipate in these hearings, but also attend and listen to some of the
testimony.


44

STATEMENT OF OR. DAVID W. BLOIS
MERCK & CO., INC.

SUBCOMMITTEE ON NATIONAL ECONOMIC GROWTH
NATURAL RESOURCES AND REGULATORY AFFAIRS
OF THE
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
U.S. HOUSE OF REPRESENTATIVES
MONTGOMERY COUNTY COURTHOUSE, ROOM B
NORRISTOWN, PENNSYLVANIA

JUNE 8, 1995

Good moming, Congressman Fox and members of the Committee. My name is Dr.
David W. Blois. | am Vice President, Worldwide Regulatary Affairs of Marck Research
Laboratories. On behaif of the 4,325 Merck employees who live in your Congressional
District, Mr. Fox, | want to express our appreciation for the opportunity to testify here
today, and to share our excitement about pharmaceutical Innovation. | also want to
discuss ways in which the regulatory review process can be changed to facilitate and
encourage the rapid introduction of new medicines and vaccines to the American
public,

{t is important to state at the beginning that Merck supports a strong regulatory system,
one that assures the safety, efficacy, and prompt approval of medicines and vaccines.
We believe that the Food and Drug Administration (FDA) has an important role to play
in this process, and that the Agency has made many important contributions to public.
health. We have great respect and admiration for the many dedicated scientists in the
‘Agency.

A GROWING DISPARITY EXISTS BETWEEN SCIENCE AND REGULATION

However, there is a growing disparity between a rapidly expanding and increasingly
precise science of innovation towards the discovery of new medicines, versus the
number of regulations that dampen and restrict pharmaceutical development. The
‘science of drug discovery has led increasingly 1o more effective and safer medicines,
and yet there are regulations and regulatory practices built up over many years which
remain in place and which have outlived there usefulness.

Modem medicines ars very potent and very specialized compounds, pinpointing
specific targets in the body's metabolic pathways and thus attacking—or preventing—
diseases with a high degree of efficiency while minimizing side effects. Today's
vaccines and medicines are inherently safer than their equivalents of 20 years ago
because we have applied our increased knowledge about the fundamental mechanisms
of disease and chemistry to their development. Consequently we now can invent highly
targeted medicines with very precise mechanisms of action. Modem research focuses
‘on such mechanisms, at a molecular level, that might be involved In the disease


85

try, it cannot be manufactured here and sold in other countries. Is
that right?

Mr. PowELL. That is correct. We cannot export drugs to other
countries, even though they are approved in those countries, if they
are not approved here.

Mr. WALKER. So if we develop something here that gets throu;

a faster process in another country, you are almost forced to take
that manufacturing out of this country in order to offer that prod-
uct in the country where it is approved? Is that right?

Mr. PowELL. That is correct. When you investigate the drug in
another country, it is very difficult to export it as well. Quite often
we are forced to manufacture even clinical supplies for drug studies
outside the country.

Mr. WALKER. So chances are once you have manufactured a prod-
uct in another country, even once it gets approved here the likeli-
hood is you will continue to manufacture that product there and
ship it back here. We kind of lose the manufacturer of that drug
forever by that process. Is that correct?

Mr. CARROLL. That is the case for our drug, Mr. Walker.

Mr. CLINGER. Would the chairman yield for just a minute?

Mr. WALKER. Sure. I would be happy to.

Mr. CLINGER. Just a question. Does that apply to pesticides as
well, Dr. Larkin?

Mr. LaRKIN. It is not quite as black and white with pesticides,
but there are such stringent regulations about exporting pesticides
that are not registered in this country.

I do not think we, Rohm and Haas, would ever build another
manufacturing facility in the United States because, similar to the
drug industry, we almost always get registrations overseas first
and, therefore, locate our manufacturing facilities overseas first.

Mr. WALKER. One last point. Is there any nation in the world
that you would regard as having a regulatory process that you
think is a good model for us to look at as we are trying to deter-
mine what direction we should go?

Mr. POWELL. I would propose that the British system is probably
one you would want to look at.

Mr. WALKER. The British system?

Mr. Powe LL. Yes. It utilizes outside experts. It utilizes summary
data. It does not review all the raw data, as does the United
States. I think it has a lot of the benefits of the things we are pro-
posing.

Mr Fox. Is there a general agreement on the panel that that is
probably the better model?

Mr. WALKER. Thank you, Mr. Chairman. That was the extent of
my questions.

Mr. McINTosH. I wanted to have a followup on that one. Would
you think that we would be adequately protected here in this coun-
try if we acknowledged their approvals and just reciprocally said if
it is approved in Great Britain it could be marketed here in the
United States?

Mr. PowELt, I am not so sure I would go quite that far. I think
what should happen, though, is FDA should establish what the
standards are. There should be a harmonization of those standards
throughout the world so that that eventually can happen.


62

which is at least in part dependent on obtaining approval for marketing of the
resulting drug product from an ever more complicated, overworked and
understaffed bureaucracy which is the current Food and Drug Administration.

It is this aspect of the problem that I would like to address briefly today. In the
next few minutes, I would like to suggest some ideas that would improve the drug
development process in the United States without compromising the risk to
consumers. Let me assure you on this latter point. We, in the drug industry, are
fully aware of the important role played by FDA in protecting consumers in
matters of public health, and would in no way wish to see the FDA disbanded or
rendered impotent in carrying out this portion of its mission. But, there are other
aspects of the role of FDA in today's society which also need to be stressed.

Although the FDA traces its roots back to the 1830's, it has never had a
Congressionally approved mission statement.

Thus, my first recommendation for FDA reform consists of a legislative mandate.
that clearly describes the mission of FDA in terms of what it should do, and the
appropriate balance it should have between enforcement and assurance of the
availability of important new drugs. We would propose that the following be the
key elements of that “Mission Statement":

Page 3


86

Certainly there are some countries I think that you could propose
that we could accept approval of those countries as prima facie evi-
dence that it should be approved in the United States.

_ Mr. MCINTOSH. But only prima facie evidence and not conclu-
sive?

Mr. PowELL. Like I say, I think that FDA has the responsibility
to assure themselves that the country which is reviewing the data
has reviewed to their standards. I think the United Kingdom and
Germany and a lot of countries in Europe would meet those stand-
ards today.

Mr. McInTosu. Any other views on the reciprocity issue?

Mr. MOLT. There are some problems with that solution. Some
diseases are somewhat different in Europe than they are in the
United States, especially infectious diseases and things like that.
There would be a problem with some sort of blanket statement that
European acceptance would warrant United States acceptance.

Mr. McInrosu. So it may not be as effective here as it would
there?

Mr. MOLT. It could be a different strain of organism that is caus-
ing the disease. It might not work as well here. That is correct.

Mr. McINTosH. How about on the safety side? Would you antici-
pate any difference there?

Mr. MOLt. Again, it depends. I think it is more on the efficacy
side than the safety side. I think that safety probably is gen-
erally—except in some European countries, yes.

In Japan, for instance, there are different metabolisms and
things like that that may cause a different safety profile as well.
Looking at other areas for approvals may not hold the United
States both in efficacy and safety.

Mr. PETERSON. I know the Japanese claim they need to run the
tests over there on that basis.

Mr. McINTosH. Thank you.

Mr. PETERSON. Dr. Molt, you said that you thought that the FDA
should have more incentive base in the system. Do you have a solu-
tion, or do you have a proposal other than adopting something like
the British? Has anybody thought that through?

Mr. MOLT. No. I mean, to change the incentive system at FDA
is a hard job. I think that we may be able to do it through legisla-
tion. I think that—

Mr. PETERSON. Excuse me. Do you think you could look at in the
proposal the reinvention of the MDA proposal? Have you seen that?
Have you seen that reinvention of the MDA proposal?

Mr. MOLT. Yes.

Mr. PETERSON. Do you think that does it?

Mr. MoLt. I think there are components of it that would help.

One thing that I mentioned when I was closing was that I think
that congressional oversight might want to be looked at in terms
of what we or what the public through Congress does to FDA, how
we view them, what their incentives are.

Again, I think that traditionally FDA is called before Congress
to be looking at decisions based on approving the drug where the
risk was perceived to be too high. They are extremely cautious not
to do that.


121

The populations that are being studied have to be applicable to
the American population because obviously at the end of the day
those are the people whom you have given us the responsibility for
approving drugs for. In most cases, as was pointed out, the popu-
lations where these drugs are studied are indeed applicable to the
American population.

There is the issue sometimes on antibiotic drugs because it is not
the populations that are different, but it is the microorganisms that
are different.

I think what you find in most of the larger clinical trials pro-
grams, as Dr. Blois was pointing out here earlier, is that the large,
multinational corporations are doing global development. We will
often end up getting pivotal studies both from the United States
and from Europe.

That is basically the standard. We do accept the trials that are
done in Europe that meet the caveats in our regulations as primary
efficacy data. That already exists.

Mr. Fox. I am still troubled by the fact that I think there are
probably AIDS patients and other patients waiting for drugs that
they would have lived longer had they had the chance to have some
of the drugs that are being held up by the procedures you are fol-
lowing that could be unfettered if you worked at it.

Dr. Lumpkin. Again, I would like to know some of the specifics
about which of —

Mr. Fox. The testimony we heard earlier from some of the wit-
nesses made it pretty clear that some of the FDA’s own over regu-
lations or duplications of their own trials and the length of time or
the number of trials required had caused delays in miracle drugs.

Do you need to have a waiver signed by patients or companies
in order to move forward? Would that help you? Is it lawsuits that
are concerning you?

Dr. LUMPKIN. No, sir. The concern that we see on particularly
the life threatening diseases, as I think we have already discussed
some previously, is that there are two needs that are having to be
met. One is the individual patient’s need to have access to a drug
that he or she believes is going to be helpful to them.

There is also the community need to be able to find out whether
indeed that drug does what it says it is going to do and can do it
in a way that there is more benefit to the patient than harm.

I think what we have tried to do is weigh the balance of both of
those through our accelerated approval, through our using the sur-
rogate endpoints that accelerated approval has. We get AIDS drugs
on the market in this country as quick as any other country for get-
ting the drugs there. It has been interesting. The—

Mr. Fox. I do not mean to cut you off, but I think we need to
accelerate the accelerated program.

Dr. LUMPKIN. OK.

Mr. Fox. I will be real clear about it. That is what they are try-
ing to say today, these people who have taken the time and effort
to be here. I appreciate that you are doing the same.

I think we really need to accelerate it geometrically. The fact is,
for the people who are dying or who could live a little longer, I
think we have to figure out a way. The community need comes sec-


124

of the problems and some of the good sides that people have to
think about on this.

One of the real problems that we have even with reviewers that
are in-house is the issue of consistency in the sense that you want
to make sure and we want to make sure as upper management
there that if Company A comes in with a marketing application to
use their drug to treat a certain disease and Company B comes in
with a marketing application for their drug to treat the same dis-
ease that there is as much as possible consistency in what the
standards are for those drugs because they are going to have to
compete in the same marketplace, and there needs to be consistent
standards on the inside.

One of the concerns that we have had and that we have seen in
some of our outside resources in the past is that when they are
spread throughout the country and are not part of the overall de-
velopment of the various policies and are not there during the re-
view process, we tend to get even wider swings in consistency than
we get with in-house representatives.

Other questions that have been brought up have to do with the
fact that when we have dealt with outside reviewers, the reviewers
that we have had the opportunity of dealing with have not been
able to review full-time. They have jobs on the outside that they
are also doing, whether they are academicians, whether they are
working at various other jobs. We only have them for a partial pe-
riod during the day, as opposed to a resource that we would have
in-house on a much more full-time basis.

One of the issues prior to the user fee problem—the user fee pro-
gram; it is hardly a problem—was that not having the resources
available, we had to look on the outside. What the user fee pro-
gram I think has done is provided us with in-house resources to do
our job.

One of the things that people have been talking about here that
I would like to put back to the panel is that from a management
perspective the beauty of the user fee Program is it gave us goals.
It said these are your performance goals that you are going to be
held to. The process for getting there is up to you. That is your
management job. We are not Boing to micromanage you, but we are
going to hold you to these performance goals.

TI think that is a very legitimate management tool to use perform-
ance goals as a method of saying this is your responsibility. If you
cannot do it, then your process is broken, and we need to go back
and look at the process. If we are able to use our process to meet.
those goals, then I think from a management perspective we have
done what has been asked of us.

Mr. McINTosu. Thank you, Mr. Clinger.

We are running somewhat short on time, but I want to make
sure Mr. Tate has a chance to ask questions.

You have to catch a train at 2 p.m.? Is that right?

Dr. LUMPKIN. Yes, sir.

Mr. TaTE. Then we will be leaving together.

Dr. LUMPKIN. Pardon?

Mr. TaTE. We will be leaving at the same time.

Dr. Lumpkin. OK. That is fine.

Mr. TATE. We are catching the same train.


31

point of view of persons with AIDS who feel lifesaving drugs are
being kept from them because of bureaucratic red tape.

Although I will not go into detail in this area, the FDA restricts
a flow of information on drugs. It penalizes drug manufacturers for
third party reports of off label uses of drugs. PWA’s, in other
words, people with AIDS, must resort to getting Algendazole for off
label use of treating microsporidiosis through community buyers
clubs, from other countries such as Mexico, or use the veterinary
version of this drug. Why go to such lengths? Because diarrhea
from GI tract microsporidiosis, if uncontrolled in a PWA, can lead
to death.

Medicinal marijuana is a whole other issue which I will not go
into detail today. It was approved for use by persons with glaucoma
and multiple sclerosis and AIDS in the 1980’s and then in 1988
suddenly banned by President Bush.

Persons with AIDS who get nausea from the dozens of medica-
tions they take each day, and I take about 25 or 30 separate pills
per day, use it to contro] nausea.

Manijuana is also effective for persons with AIDS and wasting
syndrome. I have lost 30 pounds of weight in the last 12 months,
but I have stabilized my weight loss through control of my nausea
and appetite loss with marijuana. The reason my weight loss has
been stabilized for the past 6 months is because I have found ac-
cess to marijuana through underground sources.

Because of the politically charged nature of this issue, Phil Lee
of HHS, Al Leshner of NIDA and David Kessler of the FDA have
independently not only denied me access to an important herbal
medicine which has been used safely world around for its medicinal
properties for 5,000 years.

There are people going blind from glaucoma or suffering need-
lessly from AIDS related wasting syndrome, and yet marijuana
cannot even be studied in a clinical trial, such as the one proposed
by Donald Abrams of San Francisco General Hospital, which com-
pared smoked marijuana and Marinol, a less effective medication
containing marijuana’s active ingredient, THC.

Marinol is approved for use in the United States and recently ap-
proved for coverage through AIDS drug assistance programs in the
State of Pennsylvania.

All this, when according to a recent survey over 80 percent of the
American public supports providing limited access to marijuana for
its proven medicinal value,

The total cost of FDA’s review and approval procedures has
steadily risen and risen rapidly since 1962. During that time, nei-
ther Congress nor the FDA has ever conducted a thorough, reputa-
ble study of FDA performance that justifies these rising costs ei-
ther in terms of lives saved, improved medical practice or identifi-
able benefits to the U.S. economy.

Finally, as a person with AIDS, I find that my efforts to get
promising new treatments to persons who need them the most al-
ways leads to the FDA, where the process often comes to a stand-
still. Accelerated approval programs need to be expanded to the
area of biotech products without setting a higher standard for
biologicals.


20

an

2

156

During the period of repid development in chemistry and hematology in previous
decades, the FDA approved devices and tests based upon equivalence. One aspect of in vitro
diagnostic testing thet sets it apart from other health care disciplines is thst clinics)
laboratories are expected to rigorously evaluate each new laboratory test (without any
possible patient ill-effects) versus their currest test system before implementing the use of the
of which are published in peer reviewed scientific journals of presented at scientific mectings,
ultimately determine the success of new diagnostic products. In effect, these srudies
performed by individual laboratories surpas in importence the studies performed by the
product's manufacturer for FDA spproval. FDA approved products can evolve by a process
of new discovery, improvement, and competition at a more rapid developmental pace due to
after FDA approval. Many of these evolutionary changes could never have been predicted and
incorporated into original FDA studies. Now, the new FDA regulations bold our country
back by changing the focus from equivalence and subsequent evolutionary improvements, to
simply trying to guess what the FDA wants and trying to meet their checklist and
expectations, which can be arbitrary and can change.

While most of the DNA amplification technologies were discovered and developed
here in the USA, Europe and Japan have more DNA amplification tests than the USA. We
have only one approved test. The rest ofthe world is airesdy benefiting from better tests for
TB, AIDS, and hepatitis C. They will be benefiting from the lower costs of automated test
‘systems at a tine when in the USA, we will not even have stasted our clinical trials. The


7

The thing that troubles me is many people are forced to go
abroad, spend more money and may not even have the opportunity
for the di at all because people are discouraged from investin;
their capital in the discovery of new drugs or medicines because 0:
the fact that it takes so long.

Many times I think we need to look at changing some of our laws
in regards to allowing drugs to be used for people that have life
threatening diseases or a terminal condition. We need to look at ex-
ceptions or change in those particular laws.

ie FDA has done a good job in some areas, but my local experi-
ence out in Kent, Washington, with Dr. Wright where the FDA had
worked and come in before hours and knocked the doors down and
came in and took things away such as vitamin B-12, which I can-
not see as any risk to anyone. To me, that is outrageous. Those are
the sorts of things that need to be investigated, and that is why
we need to take a closer look. That is my personal experience. We
need to change the process. We need more participation.

1 look forward to hearing the individuals that are going to testify
today. We truly can save more lives. I think we can save a lot of
money, and we can make this a country where people can have ac-
cess to the kind of medical treatment that they would prefer and
think is appropriate for them in a cost effective and safe manner.
I look forward to hearing from the public on this.

Mr. MCINTOSH. Thank you very much, Mr. Tate.

Let us turn now to our first panel of witnesses. Welcome. Let me
say at the outset that we have several people who are here to tes-
tify today, and we also want to have a time period where we have
an open microphone session to hear from additional witnesses. I
will be fairly strict about asking people to keep their remarks to
5 minutes.

I am going to ask the timekeeper to use this clock right here to
show a green light after about 3 minutes to give you time to start
thinking about a summary of your statement and then the red
light after 5 minutes.

‘Let me urge you to not use a prepared statement if you feel com-
fortable. It generally works better and you get your points across
in fact more effectively is what I have found in listening to wit-
nesses over the last few months. If you are at all comfortable with
that, let me urge you to summarize the written statement.

The full statement will become part of the official record, and the
written statement you have in addition to the 5 minutes will as
well.

It is the policy of the full committee to swear in all of our wit-
nesses, so if I could ask the first panel to please rise and raise your
right hand.

‘itnesses sworn.]

Mr. McIntosu. Let the record show the witnesses have answered
in the affirmative. .

Thank you all for coming today. I know in many cases it was
with some personal hardship. I look forward to hearing from you.

Our first scheduled witness was Beverly Zakarian, and she is not
able to make it today. She is suffering from cancer and had a
chemotherapy treatment yesterday and is not well enough to be
with us. Her statement will be put into the record.


139

FDA Testimony 6/9/95

Rep. Jon Fox page 4

Last week, I responded to PA State Representative Elinor Taylor's request for
data regarding the use of “dose intensive chemotherapy with autologous bone
marrow transplantation or peripheral stem cell transplanation as a treatment
for metastatic breast cancer." father than limiting myself to providing her
@ sunmary of the major studies being conducted in thia field, I emphasized the
need to merge academics and research with the clinic. I noted that the newest
cancer protocols are not routinely acceeible to the 85% of patients treated in

the community setting. Finally, I called for the creation of seamless syst

designed to integrate care, and I noted that this structure would probably
stimulate the composition of more “user-friendly” protocols for each cancer
patient. This would force « standardization process to occur, streamlining the

study of each tumor-type.

The structure you may wish to consider adopting is to identify prospectively
those facets of medical care which are basic--regardless of the type of therapy

--and those which would be necessary because of the specific characteristics

of the agent(s) or approach(es) to be employed. The former would be insurance-
covered and the latter would be divided between the research entity and the
pharmaceutical/industrial entity promoting the proposed innovation. Those who
would be composing the overall program would be able to base decision-making

onal organizations.

on relevant practice parameters generated by profe:
Thus, the “self-interest” of the advocate for the utility of a given treatment
would be subsumed by acts of those who would ensure that “the protocol should

be fit into the patient, rather than the patient fit into the protocol.”


147

now sick. or dead. ‘They have died waiting for this vaccine to be tested. No one has asked the FDA to
release the drug to the market without further tests, All that has been requested is we test the drug to see
if it works. Yet the FDA continues to refusc.

The Salk Vaccine illustrates the real problem with the FDA system when it has to deal with a life
threatening illness. Whether the drug is safe is not in question. There is a significant amount of data
indicoting that it is safe. The iswue is efficacy, whether the drug works. That is what we are trying to see
tented. The FLA is not yet satisfied, they claim. with the preliminary cfficecy data, Yet why should this
prevent the drug from being released for testing? Salk Vaccine won't hurt anyone, and it might help.

The effioaey issuc comes from « fundamental confusion, we believe, in the minds of the bureaucrats who
control the FDA. Much of this regulation is believed to stem from the Thalidomide incident in the 1960's,
where a drug that did cause major birth defects was kept off the American market by one FDA official
who prevented a potential tragedy. But Thalidomide was a sleeping pill, Thalidomide at that time was
not considered a drug with efficacy against « life threatoning illness. There is a difference between
‘Thalidomide and drugs, such as Salk Vaccine, The difference is the difference between a sleeping pill
and a potential treatment for a disease that will almost certainly kill you if left untrested Any system that
is unable to distinguish between these two categories should not be making its own rules.

‘Another way of putting this problem involves which risk we should take more seriously. The FDA rooms
to be fearful of making the mistake of allowing « drug to market that docs not work. The opposite risk, of
withholding from the market « drug that doss Work, does not sec as important to them. But for people

living with HIV, that rick is desperately important.

Finally, the FDA’s refusal to accept any foreign data further contributes to this problem. The result is that
drugs that are approved all over the world, including European countries are denied to people in the
United States while pharmaccutical companies jump through bureaucratic hoops, and people with AIDS


B

cy

1s

153

Comments
Donald Jungkind, Ph.D., MI(ASCP)
Diplomate, American Board of Medical Microbiology.
Professor of Microbiology and Pathology
Director of Clinical Microbiology.

Thave had extensive experience working with diagnostic devices used to perform
laboratory tests during my 22 years directing « clinical microbiology laboratory in a major
medical school hospital, My laboratory has done approximately 3.5 million laboratory tests in
that time. I have also been active in research, development, and clinical trials of diagnostic
devices (often called test kits). I have worked with numerous major manufacturers of these
devices. Much of this work bas been presented at national meetings, published, and submitted
to the FDA. My list of published presentations and scientific articles has approximately 85
entries, including two books. In short, ] know # lot sbout lab tests, how they work, and how
they get to market, As you know, this is one of the major areas that the FDA regulates. This
area is also one that has recently received increased regulation from the FDA.

‘Have these new efforts on the part of the FDA been constructive or destructive? They
certainly have fostered more attention to detail, but isi the right detail or is it. wasted effort?
History as usual is the best judge. I have seen most of the relevant history, and have seen lab
testing develop from manual methods in the three main lab areas, chemistry, hematology, and
microbiology, to a highly automated system in chemistry and hematology. Unforumately,
‘the science to automate microbiology was not discovered until recently. Noteworthy is the
fact that the high degree of sophistication and eutomation in chemistry and hematology
occurred during @ period when the FDA had 8 more appropriate approach with regard to


46

Pege3

Merck's own cancer research is both at an exciting and frustrating stage of drug
discovery. In the 1970's, researchers at the National Institutes of Health (NIH) and the
National Cancer institute (NCI) began te track down one of the genes that triggers the
runaway growth of human cells that we call cancer. They found that the gene, known
es ras, plays a critical role in signaling calls to divide uncontrollably and spread
cancerous tumors throughout the body.

At Merck, we've produced compounds that block the ras signal in test-tube experiments
‘and in just the past months we have made a further advance: we've been able to stop
growth of certain tumors in laboratory mice—thus far with none of the toxic side effects
of traditional cancer chemotherapy. Our research team continues to search for
‘compounds which are appropriate for tasting in humans in blocking the growth of
various human tumors.

We ara not yet ready to begin clinical trials and there is still a high risk of failure. But a
breakthrough could mark a major turning point in the war to help the 7 million victims
that cancer strikes annually and save some of the $104 billion we spend each year in
this country to treet it.

AIDS: Marck's AIDS Initiative, ongoing since 1986, is the largest research battle we
have ever waged. We have invested hundreds of millions of dollars in discovery
research and studied tens of thousands of compounds. Most have failed in the test
tube, others have failed in animal studies, and four, to date, have failed in human trials.

In March, however, we announced some very exciting developments about our current
sole remaining candidate, the HIV protease inhibitor, CRIXIVAN, formerly known as.
MK-639. Our ongoing Phase II trials show that MK-639 has significant antiviral effects
and clinical benefits and exhibits a good safety profile. Thus, wa have begun Phase iil
trials with about 3,000 patients.

At the same time, the manufacturing process for MK-639 has proven to be extremely
Jengthy and complicated. It is the most difficult manufacturing challenge ever faced by
Merck. Moreover, the volume requirements are great because the dose is large — more
than 2 pounds per patient per year, which is more than 100 times larger than the

of an average Rx medicine. Merck has allocated 125 engineers and more than
$100 million towards the manufacturing changes that will be needed to make this
Product in sufficient quantities. This is noteworthy because MK-639 has not been
‘approved, and the compound could still fail in Phase Il! studies.

‘So much is at stake here. in the U.S. alone, more than 1 million individuals are
estimated to be HIV positive; 450,000 have developed AIDS, well over half have died.
This tragic toll in human life is mirrored by as much as $50 to $70 billion in direct health
care expenses and indirect costs to our society every year,


6

very troubling trends that do not bode well for the economic future
of the United States or its health future.

In the 13th Congressional District of Pennsylvania alone, we
have many pharmaceutical and biotech companies. Together they
employ more than 11,000 people. We would not want to see any of
these constituents lose their jobs because the FDA regulation is
prompting companies to conduct much of their work overseas.

Americans want safe medicines. They want a strong FDA that
will keep unsafe products off the market, but I believe—we be-
lieve—they want to see more emphasis on the value of giving pa-
tients quicker access to safe and effective new medicines.

Those with life threatening diseases want to take control of their
own illness. We need to break down the barriers to experimental
drugs, to approve new drugs as fast as possible, to have free flow
of information about those drugs. We want to make sure we correct,
the regulatory spiral which has caused us to have restrictive proce-

lures.

We need to revise the Food and Drug Administration’s mission
statement and eliminate unnecessary paperwork. We need to pro-
vide the FDA the incentives to increase the availability of new life
extending and lifesaving drugs. We need to protect Americans
without unduly restricting innovation. To some, the FDA has been
Fostering Delay of Approvals. We need to change that to Facilitat-
ing Drug Access.

say to you, Mr. Chairman, that I appreciate the opportunity to
have these hearings hopefully to move ahead to a system that is
going to improve access to our consumers, while still maintaining
quality. I thank you for this opportunity.

Mr. McINTOSH. My pleasure. Thank you very much, Mr. Fox.

Chairman Walker has arrived. Thanks very much for coming
over, Mr. Walker. I appreciate you dni us today. Earlier we
passed a resolution making you an ad hoc member of this commit-
tee.

Mr. WALKER. I am delighted by that, Mr. Chairman. I am actu-
ally on a leave of absence from the committee as it is.

Mr. McINTOSH. Welcome back.

Mr. WALKER. I am glad to be back, and I am delighted to be with
you here in Montgomery County today. We thank you for coming.

Mr. McINTosH. Thank you.

Mr. Tate or Mr. Walker, do you have any opening statement?

Mr. WALKER. I have no opening statement. That was opening
statement enough.

Mr. TaTE. I would like to start by saying I would like to thank
the chairman as well of this committee, Mr. McIntosh, and Mr.
Clinger of the full committee and Mr. Fox with whom I have had
the pleasure to work with as a fellow freshman. It has just really
been an honor to work with him. He has been an aggressive, asser-
tive, hard-working member of the committee, and he has done a
phenomenal job.

I will keep my comments very brief because we are here to hear
from the public and not the politicians, and that is what is so im-
portant about these public Rearings. A number of the concerns
have been brought up. We are going to hear from consumers, from
industry, from the agency and some experts.


40

be helpful. I think you have been very persuasive witnesses, and
we thank you for your testimony.

Mr. McINTosu. Mr. Peterson, do you have any questions?

Mr. PETERSON. I want to also thank the panel, and hopefully we
can put some of their questions to the agency. Thank you.

Mr. McINTOosH. Mr. Fox indicated he has one further question.

Mr. Fox. Mr. Samowitz, your testimony was quite compelling, as
were the others, especially with regard to the fact that you ha:
to get your medicines from England. Are you still getting them
from England as well?

Mr. SAMow!Tz. Yes.

Mr. Fox. They are not available in the United States?

Mr. SamowiITz. Correct.

Mr. Fox. What does it cost for you a year, if you know, approxi-
mately or a month?

Mr. SaMowiTz. You would have to ask my mother. You will have
to wait until she comes back.

Mr. Fox. Your mother is coming forward. Mrs. Samowitz, could
you help illuminate us on the question of the cost?

Ms. Samowitz. As I said, my union plan covers my medication,
but the Lamictal, which until recently I was getting from England,
would have cost roughly $6,000 a year. It is a little over $500 a
month. That is just for the one medicine. One of the others is about
$500, but that lasts 3 months. Mogadan is about $250. That lasts
about——

Mr. Fox. And there were some months you did not get receipt
of them?

Ms. SaMowiITz. Pardon?

Mr. Fox. Did you ever have to go any time where you did not
get them because of a delay in the mail?

Ms. SamMowiITz. Dr. Resor has a list of patients, and when we are
really running short we call. They will Express Mail it to us, and
then when we get our shipment, we Express Mail it back.

Mr. Fox. As you expressed in your testimony and in your son’s,
I guess some people actually cannot afford it. They, of course, do
not get it.

Ms. SamowI!Tz. They cannot even bother with it because of the
enormous expense.

Mr. Fox. I thank you.

Mr. MCcINTosH. Thank you very much.

Mr. Tate?

Mr. TATE. I would like to followup with that as well, that whole
issue. How do you come in contact or get the knowledge of these
drugs in other countries? If they are not approved in the United
States but you are allowed to do them thro direct mail of some
sort, how do you come in contact? Does your doctor suggest that
you do this?

Ms. SaMOwITZ. My doctor, I guess through the journals and the
research, is aware of all the drugs being tested in other countries.
He has followed them and when they become available in the other
countries.

If all else fails—I mean, he was just having no success with the
medicines available. He would have four to five seizures a week.
We are talking about grand mal. He just falls. I do not want to tell


120

Dr. LUMPKIN. In simple terms, I think some of the things that
have already been pointed out as far as the issue of exports, as far
as the old regulations on antibiotics and insulin, a lot of things that.
the RICOH initiatives have already begun to deal with. Most of
these are going to take statutory reform in order to free us from
some of the shackles that the FD&C Act has on us in those particu-
jar areas.

I think, though, getting really to the heart of the problem that
you bring out, I think all of us who have looked at this problem
realize that this is not a simple blueprint plan. There are a lot of
different elements that play into this.

Clearly there is the issue of resources and having the people
available, but I think the Congress and the industry—we have al-
ready taken that step. We have the user fee Program that is well
underway. Thus far, it has been very successful in meeting our
needs and I think the needs of the country and the needs of the
industry on that particular issue.

There is the issue, as the members of the pharmaceutical indus-
try were talking about here, of looking at the overall timing of the
development. You talk about this 12-year period of time. As was
pointed out earlier, there is a part of that—the synthesis of the
drug initially, the preclinical animal testing—that FDA has no reg-
ulation over per se. It is not under any kind you may start—you
have to stop oversight of the FDA.

People have talked about dealing with getting in to people when
you believe you have the data that you need. I think there are
many of us that agree with what the people from the industry have
been saying and who have been working with industry to try to
highlight what are those areas within our regulations as far as
formatting, as far as the data that need to be looked at that would
allow them to get in to people more quickly in what we call phase
I

Mr. Fox. Let me ask you a question. What about the foreign test-
ing? Can you take that? I mean, right now we are hearing from
company after company and patient after patient that the foreign
testing that is done by qualified companies in countries that have
good standards like the United Kingdom. Can we without regula-
tion make that change in your procedures?

Dr. LUMPKIN. I am not sure if I understand. Are you asking if
we accept foreign data?

Mr. Fox. Yes.

Dr. LUMPKIN. Yes, sir, we do.

Mr. Fox. In all cases?

Dr. LUMPKIN. What is in our regulations, and I think it is a vei
good approach to foreign data, is a standard approach that I thin
Most countries take as far as foreign data is concerned. We are
willing to take foreign data as primary data of efficacy, provided
there are several caveats on that data.

No. 1, the data have to be done under what is called the Declara-
tion of Helsinki, which has to deal with the protection of human
subjects. This is not for most companies a big issue. Most of the
companies clearly are very ethical. They are doing the trials that
way, and that is not a particular problem.


19

Mr. McINTosH. Thank you very much. I appreciate your coming
today.
David, do you also have a statement? We appreciate your coming.
Mr. SaMowiTz. Good morning, Mr. Chairman, members of the
committee. My name is David Samowitz. I am 24 years old, and as
my mother has told you, I was diagnosed with epilepsy with I was
9.

As you may know, many famous people and high achievers also
had. epilepsy, including Napoleon Bonaparte, Julius Caesar, George
Frederick Handel, Socrates, St. Paul and Peter Tchaikovsky. I am
optimistic that with access to the medicines I need, I can also
achieve something in my life.

I am now in a training program to be a mail clerk, but I am most
interested in electronics. 1 enjoy filming with a camcorder, and peo-
ple have said I do a very professional Sob.

My condition has improved with the medicines I am taking, but
it bothers me that products are available in England and other
countries before they are put on the market here.

Mogadan, generic name Nitrospan, has also been available in
England about 5 years. I have heard that it may never be approved
in the United States. I have been using Mogadan for approximately
4¥e to 5 years,

If countries can work together to fight wars or to help other
countries, why can they not work together on helping people get
the medicines they need? The current situation is very hard on peo-
ple like me. I hope you will do something to change it.

Thank you very much for your attention.

[The prepared statement of Mr. Samowitz follows:]


14

by the Customs agency under the Federal Tort Claims Act in the
amount of $209.65.

Since 1991, our shipments have not been seized, but we still
must pay import duties on these medicines. It strikes me as wrong
that the Government is taxing what is really a necessity to David’s
physical well being. This is not a luxury.

David and I are fortunate in several ways. We are fortunate to
have Dr. Stanley Resor of Columbia-Presbyterian Hospital as Da-
vid’s neurologist. He is a renown authority on epilepsy. As a teach-
er in the New York City public school system, T am fortunate that
my union’s health plan reimburses me for the cost of these drugs,
minus a $5 deductible. Otherwise, Lamictal alone would have cost
about $6,000 last year. That is only for one medication.

Many people cannot get the drugs they need since most insur-
ance plans do not cover drugs that are not available in the United
States because they are not approved by the FDA. It is important
to note that as the dollar suffers, so does the patient who buys
medication abroad.

I believe that once medicines are approved in Europe or else-
where and there have been sufficient trials and the medicines have
been found somewhat successful, we should either rely on the for-
eign testing or work jointly with the other countries in order to
have the drugs approved in a quicker fashion in the United States.

Compared to other countries, we seem to take forever to get
drugs on the market. For example, one of the drugs David needs,
Lamictal, was only approved here in December 1994. In December
1993, Dr. Resor told me it was going to be available, but it was not.

I would just like to have you consider Proposing the changes in
the drug approval process and to take into consideration families
that are less fortunate than I am.

Thank you very much for listening.

[The prepared statement of Ms. Samowitz follows:]


3

a much higher price. In fact, too many Americans are paying a
higher price of sacrificing the access to the best possible medical
treatment that they may get.

I look forward to hearing the testimony today. Our panels will
be first citizen witnesses and then a representative of the agency.
We will get a chance to inquire into many of these regulatory prob.
lems.

Before beginning the hearing, let me turn to Mr. Clinger for any
opening statement that he may have.

Mr. CLINGER. Thank you very much, Chairman McIntosh. At the
outset, I would like to wish you a belated happy birthday. I under-
stand you had a birthday yesterday.

Mr. McINTOSH. Thank you.

Mr. CLINGER. I also commend you for coming to Pennsylvania
and specifically coming to Congressman Fox’s district because this
is certainly a district that has a great interest in the whole ques-
tion of regulatory reform, particularly as it relates to FDA because
there is a very substantial presence of companies that are involved
in producing drugs and other things for the industry which obvi-
ously has to bear a lot of these problems.

so, I want to commend Mr. Fox for bringing the committee to

your district and for your great concern for the problems that you.

ave identified with regard to the issues that we are going to be
looking at here today.

lam really pleased to join with you and Congressman Peterson
and Congressman Tate to examine a host of FDA regulatory reform
issues, including drug and medical device approval.

In the past few weeks, I have had an opportunity to talk with
a number of Washington representatives about FDA regulatory re-
form, but today, and I think this is why these field hearings are
so important, we have an opportunity to hear directly from some
of those that are most impacted, such as the patients, doctors and
companies, by the fact that we have these inordinate delays. All of
these constituencies are trying to provide care for those who need
it in an expedient and effective fashion.

The FDA, by its own estimates regulates one quarter of the
consumer products—one quarter of the consumer products—in the
United States. With over 9,500 employees and a budget of $975
million annually, there are indeed serious concerns about the agen-
cy’s ability to get the job done.

Despite frequent reform recommendations, it seems that most of
the changes over the past 20 years have resulted not in a decrease,
but in an increase in the agency’s regulatory responsibilities.

There seems to be considerable delay in the drug approval proc-
ess, which we are going to hear about this morning. During the
1970's, the average time for approval was 5 to 7 years. Today it is
averaging somewhere between 10 and 12 years. We are going in
the wrong direction in terms of product approval.

The time and the cost of development discourages companies
from producing new and innovative drugs that may be beneficial to
patients. It becomes an extraordinarily expensive proposition to do
the research and bring to market these products. Excessive regula-
tion, inconsistencies in regulations, too high costs and a lack of


a?

3

‘would be stricdy limited to articles in peer-reviewed journals, available only

the medical profession. 1 would not object to some sort of licensing process for
such peer-reviewed journals, jing 8 way to revoke the license if the
journal strayed from scientific rigor. In summary, I propose a stage in drug

unwilling to release drugs into that limbo.

This sort of subsidlary question leads me to the thought that Congress needs to
creat some sort of oversight or FDA evaluation commission to report yearly on the
evolving complexities of drug evahuation, availability

inclusion on {t of representatives of the American Medical Association and the
Pharmaceutical

Association of Recail Druggists. mamsfacturing representatives are
valuable, but they may feel constrained to blunt their criticism of an agency
which can them. Similarly, academic medical centers are so dependent on

medical
federal grants and the overhead allowances attached to then, that they, too, may
fear to speak out with the opinions Congress would want to be aware of.


110

some cases, patients were disadvantaged by these delays.

Whatever the truth of those allegations, they are not true today.
Today drugs that offer significant improvement over existing
therapies are approved as fast, and often faster, in the U.S.
than in other countries with comparable standards. As a result
of the Prescription Drug User Fee Act of 1992, we anticipate that
drug review time will continue to improve further during the

coming years.

We have proven--and will continue to prove--our commitment to
making FDA more efficient and responsive, while maintaining our
high quality of work and the independence and scientific
expertise that makes that work possible. In the end, it is FDA's
independence that gives the American consumer confidence in the
Agency's decisions. Our ability to meet our mission--to protect
and promote the public health--should not be allowed to be

compromised in the name of "reform".

14


69

aan extraordinarily speedy manner with final approval coming just one year after initial application,

In addition to therapeutic products, Centocor is the world’s leading producer of in vitro
diagnostic tests -- or IVDs -- used in the management of cancer patients. TVDs are the routine blood
and urine tesis which all of you have experienced as part of a physical exarnination. It is in the area
of regulating IVDs that we feel substantial changes should take place at the FDA. Because, after
investing nearly 10 years and 20 million dollars seeking FDA approval for these products, only one
Centocor product has ever heen approved for use in the United States. Accordingly, the vast
majority of our commercial activity and a significant portion of our high-skill manufacturing base is

located abroad where these products have been used successfully for many years.

Centocor’s tests are used in the management of ovarian, pancreatic, breast, lung, and other
types of cancers. FDA regulates cancer diagnostics under its premarket approval (PMA) authority
the most stringent regulatory control. Medical device and diagnostic products, like Centocor's blood
tests, are the building blocks in the search for therapeutic products. As these diagnostic tools are
researched and developed, clues surface in the ultimatc hunt ~ the cures for cancer, AIDS and other
killer diseases. ‘That is why it is critical that regulatory reform focuses on this area of medical
technology. What we are developing today in the-area of blood tests has a direct impact on

providing health therapies in the coming years.

However, these blood tests are regulated by the FDA in a category of medical device known
as “Class I" -- which is designed for high-risk devices such as heart valves, pacemakers, certain
devices implanted into the body and devices which are used for life-sustaining or life-saving

purposes. These products are also subject to the highest levels of regulatory contol. Unlike other


24

Congressman Fox and Cormmittee members, we clearly agree
with this statement. If the FDA adhered to this philosophy, I would
be up here providing a testimonial to their work.

However, we often see contradictory statements and.actions
that leave us wondering what are their real goals? An example of
this type of conflicting statement can be found in the January 30,
1995 issue of Business Week, where Dr. Kessler also stated that:

"There is a clash between the right of the individual

{to get any drug) and the duty of government to

Prevent harm."

Congressmen, we certainly believe that safety is important, but
we often wonder what we are being protected from! What is the
harm that we are being prevented from?

Dr. Kessler's last statement tells me that FDA may be missing a
central point of battling a terminal illness. Taking control of one's
illness is incredibly important. Making a drug available or increasing
the options to obtain a new therapy or even providing new
educational materials is so critical because it yields hope which is life
giving in and of itself. We shouldn’t worry about false hope because
hope is often the only life giving force that we have. We need an
FDA that places less emphasis on preventing harm and more
emphasis on making changes that provide a way to rally around a
drug or new trial to generate even more health and hope.


143

was available in Europe for many years before FDA approval, and vigabatrin has been used in
Europe for years and has yet to arrive. Other drugs, for various reasons, may never be available
here.

‘The paperwork required for clinical trials is enormous, adding costs and thereby
discouraging the development of new drugs.

Sometimes, the FDA approves a drug for such a specific use that it discourages wider use
of potentially beneficial drugs for others with the same condition. Some of the medicines
approved for “adjunctive” therapy could be given alone, for example.

‘Inappropriate cautions are sometimes added to labeling by the FDA for no logical reason.
This discourages appropriate use of the drug. FDA approval is sometimes delayed for an .
inordinate time after FDA advisory panels have recommended approval.

Pharmaceutical companies are often discouraged from testing new medications in many of
the people who might need a new drug, such as children or the elderly, because it makes
regulatory approval more difficult and complicated, Consequently, wider use is discouraged after
a new drug is approved.

Suggestions

‘There must be an incentive for FDA personnel to approve drugs. Now, all the incentives
favor delay.

The FDA should issue annual reports regarding the number of completed evaluations,
including approvals and disapprovals, and should specify how much time the process took.

The natural course of illness must be considered in the regulatory process. A two-year
delay from submission of documents to approval is excessive, particularly when that might mean
thousands of unnecessary deaths. The FDA should have a defined time period in which to accept
or reject a new drug.

‘The amount of paperwork must be reduced, but reforms should not allow ineffective or
inappropriately risky drugs to reach the market,

Some testing protocols should be allowed to measure new drugs against conventional

py, rather than requiring some patients to take no therapy at all.


10

CAN ACT 2
And why not? Because too many true-believers are entrenched in the agency. It's not
so simple a matter as rewriting regulations: there's a mindset against approval on the part of
career employees and people who have been hand-selected to sit on Advisory Committees.
Nothing but an entirely new structure, and new people, will make any difference.

So I would like to offer some directions for reform. Some of them are mutually
exclusionary, but I present them as concepts for thought and discussion, not as carefully.
wrought legislation.

First, that you separate the FDA from any functions in the area of drugs for life-
threatening illness.

‘The FDA has amply demonstrated that its heart is buried deep in consumer protection.
Some of what it has done is of benefit to consumers: Food labeling is more informative;
fresh orange juice is either fresh or it's not. This is where the real interests of the
Commissioner and his agency lie, and the need is there.

So be it. Change the FDA into the FA, and let us be protected zealously from
contamination of our food supply by pesticides and herbicides; protected from rampant
adulteration by food coloring and unnecessary cosmetic additives; from excessively hasty
introductions into our food supply of genetically-engineered products that all carry with them
the seed of penicillin-resistance, a time-bomb in the making for the health of the American
people.

Then formulate # new, sensible, responsive agency for the D, on which so many lives

depend.

Second, if that is not possible, separate the functions of the FDA so that it cannot
both approve and regulate drugs.

‘When I was in the advertising industry in the seventies, it was mocked as “the league
of frightened men.” I would say that the advertising industry has nothing on the
pharmaceutical industry. Why? Because there is so very much money at stake, and only one
‘boss to answer to.

Let me tell you that drug companies were afraid to support educational material
published by CAN ACT about clinical trils, about patient empowerment, about news of


141

Mr. MCINTOSH. Thank you very much.

Let me ask you, Doctor. Are you able to see David holding up the
time remaining?

Mr. SKtaRoFF. I did not. I was looking around. I did not see him.

Mr. McIntosu. David, apparently the witnesses cannot see you
keeping the time. Can you do it in a way that they can do that?

Our next witness is Michael Sperling. Are you able to see David,
Dr. Sperling?

Mr. SPERLING. Yes, I can. Thank you.

Mr. McINTOSH. You might stand somewhere where they can rec-
ognize you.

Mr. SPERLING. I will be very brief. My name is Michael Sperling.
I am a neurologist specializing in the treatment of epilepsy. I have
extensive experience in treating patients with professionally ap-
proved drugs and also with investigational drug trial tests. That is
testimony that I will not reiterate for the panel.

I have a couple of general comments after listening to all of the
statements made this morning, and that is that I think we would
all agree, those of us working in the field, that new drugs are ex-
pensive and come to the market very slowly or do not come at all.
It would be most helpful if the cost could be brought down and the
efficiency improved.

I think the paperwork issue is an important one that needs to
be addressed and that specific goals be given to the FDA for reduc-
ing paperwork and time. Each patient has a booklet about this
thick, two or three inches, that we have to fill out for each individ-
ual person undergoing a trial for 3 months. That just snowballs. It
is not surprising to hear of hundreds of thousands of pages being
developed.

My overall conclusions would be to advise that the FDA be given
incentives to approve drugs, that they need to issue some sort of
annual reports regarding the number of completions, how many
completions and how many rejections.

One other comment I think I have to make now which I was not
planning on making, but from past testimony I will make it, is in

ds to the efficacy and safety issue. I think it is going to be ab-
solutely key for efficacy to be maintained. That is why the FDA
mandates it. Otherwise patients will suffer in the long term.

If I as a doctor and other people as doctors knew that a patient
could choose whatever we want, no matter how ineffective it may
be without any evidence, over the long run many people will suffer.

There is a form of leukemia now that has a 1 in 90 percent cure
rate. If-we could give whatever we thought over the last 20 years
without insisting upon these kinds of trials, we would still probably
have a 90-percent fatality rate.

To jump in and say I know what is best for you and I want to
take a long shot is reasonable under certain circumstances, but
there needs to be efficacy or else society in the long run will suffer,
which means individuals like you and I will suffer over the long
run,

(The prepared statement of Dr. Sperling follows:]


29

Mr. MCINTOSH. Thank you for coming here. You are a very brave
woman, and we all really appreciate you testifying here today.

We will hear later from the FDA, and we will put your questions
to them on how we can speed that up.

Ms. GLapIs. All right.

Mr. McInTOosH. Thank you very, very much.

Ms. Guapis. Thank you.

Mr. McINTOSH. Our next witness is an advocate for AIDS pa-
tients, Mr. Kiyoshi Kuromiya. Thank you, Mr. Kuromiya, for com-

ing.

Ser. Kuromiya. Thank you, Chairman McIntosh and panel mem-
bers for this opportunity to testify for myself and on behalf of my
community.

As a Philadelphian with full-blown AIDS and a vocal advocate
for my community, I must preface my remarks by saying that I ap-
preciate the fact that the FDA over the last 5 years has imple-
mented accelerated approval programs for AIDS drugs under com-
munity and activist pressure.

Further, I want to say that I do not support congressional micro-
management of regulatory agencies and do not believe Congress
should set the scientific agenda for this country, but we have come
to a time when it may be possible to improve an agency, the FDA,
which in some regards has lost sight of its mandate.

My concern as a person with AIDS and a treatment activist who
has worked as a community representative since 1991 in the ACTG
and CPCRA clinical trials programs of the NIH, my concern is that.
conspicuously absent from Kessler’s recent presentation to the Sen-
ate Labor and Human Resources Committee were any new effort
to speed approval of drugs for AIDS.

Since the drive for faster drug approval was spearheaded by
AIDS activists and one of the areas where the FDA has made
progress is in accelerated approval of drugs for persons with AIDS,
we were surprised and disturbed that Kessler neglected to high-
light this area in his proposed FDA reforms.

Perhaps a clue to Kessler’s snub of AIDS drugs can be found in
his article in the March, 1995, Scientific American in which he
claimed ACT UP members have undergone a change of heart, and
now AIDS activists want the FDA to slow down.

This is not true. Kessler failed to mention in his article that the
activists to whom he referred were not really ACT UP members.
They were from Treatment Action Group, a group that broke from
ACT UP a couple years ago primarily because of disagreement over
the pace of drug approval.

During 2 days of hearings that took place last September, he lis-
tened to scores of angry persons with AIDS and treatment activ-
ists, including myself, representing 100 AIDS organizations de-
manding that he approve AIDS drugs faster, not slower. Kessler’s
cynical and even dishonest manipulation of the community’s posi-
tion in this matter shows a real contempt for people with AIDS.

Many of us who have HIV infection or AIDS owe our present
good health to the drugs we get through such innovative programs
as expanded access, treatment IND’s, accelerated approval, com-
passionate use and parallel track.


166

We have over 30 patents as a small company in the fields that
we work in. I can almost say it is easier to deal with the Patent
Office than it is with the FDA. I am the last person in the world
that wants to ship an unsafe or a nonefficacious product to my cus-
tomers. That is as a human being and also as a businessman. I
really do not need the FDA to discharge that responsibility for me.

I would like to make four recommendations, if I could. One: Long
ago in quality control manufacturing we learned that some vendors
are safer and better than others, and we relaxed inspection on
those vendors. Ford, Chrysler and GM even have approved vendor
lists that they accept the vendor’s certification for what they are
receiving.

There are so many of us with an absolutely clean record with the
FDA that it seems to me that they could ease the inspection cri-
teria on our companies for new product approval based on the fact
that we have clean records.

They typically have what I call “an organized for the gangster”
mentality. The rules are set for the absolute worst felons in our so-
ciety, and then the other 95 percent of us who are trying to do a
good job as human beings and citizens are governed by that “gang-
ster mentality” rule. I would say let us use a graduated approval
process that recognizes 25 years of safe operation.

The second thing that I would like to see is an enforced time and
clock accountability so that they cannot reset the clock from resub-
mission. When a product submission goes in, they should share
some of the responsibility for the backlog and delay that they are
forcing on us. They should start measuring from day one instead
of from each resubmission.

The third thing I would like to see is a mission written into the
law that says the FDA has a responsibility to assist U.S. manufac-
turers. They look on us right now I think as someone they have to
enforce against. I really believe that they feel very little respon-
sibility for the health and safety of the industry that they are regu-
lating.

The fourth thing that is a most dangerous thing that we see in
devices which the previous gentleman referred to is the application
of drug law mentality enforcement to device manufacturing.

I wrote to the FDA and helped write the good manufacturing
practices back in 1976-77, which I am happy to say many of the
suggestions I made were incorporated. They wanted us to save one
instrument out of every lot that we made just as they asked
SmithKline to save one pill out of every lot that they made. The
only difference is the pill costs $5. A spirometer costs $950. Merg-
ing the two mentalities leads to dangerous policy.

ne of the things that we are being asked to do now is report
and document the invention process. That is poing to lead us right
down the route of the AEC and NASA and all the other innovation
areas that have been killed in the United States. By the time you
get around to documenting an invention as a device manufacturer,
you may have more money in the invention than the gross sales
of that device will be for a year or two.

I am proposing those four things.

Mr. Fox. Thank you for your commonsense suggestions, as well
as the other doctors who testified.


98

The FDA's consumer protection mission is absolutely vital--as
vital today as it was the day the Pure Food and Drug Act was
Passed 90 years ago. The assurance that FDA is there, every day,
doing its job, is fundamental to what the American public knows
and expects as public health protection. The standards for
safety and effectiveness of drugs not only protect consumers, but
also give credibility to industry and bolster consumer confidence
in its products. The world has recognized the benefits of these
standards; most modern countries, alone and in groups like the
European Union, have developed principles of drug development and

evaluation that are very similar to the ones we have.

But high standards alone are not enough. Promoting public health
also means making timely decisions about the safety and
effectiveness of important new drugs. During recent years the
Agency has made significant strides in making important drugs
available to people in need more quickly. It is time to dispel
the myth that the United States lags behind other nations. The
truth is that today the United States often outperforms other
countries in terms of product availability. This is particularly
the case for products that either provide treatment for life-
threatening diseases for which there is no other therapy or offer

important therapeutic gains over existing U.S. products for any


140

FDA Testimony 6/9/95

Rep. Jon Fox page &

The FDA would be involved in the above proposed processes, to the degree
determined by how enabling legislation sight control its oversight functions.

Illustrative of the national implications of FDA approval-

cited in the
Physicians’ Desk Reference--is the appended AMA resolution; it cites a rejected
claim by HCFA (in the third "Whereas" paragraph) ascribed to a PDR reference.

‘These same approaches could be applied to the tobacco product, inasmuch as the
cigarette serves as a nicotine-delivery device. Regardless of whether it is

felt to be “addictive,” this drug shouldn't be exeapted from FDA-ove!

ight.

This isn't a tangential consideration, for smoking remains "Public Health Enemy
Number One,” and the PDA shouldn't shirk its power to fight the pandemic of
diseases caused by cigarettes, . .which, indeed, the above scenario would not
preclude. This scourge on the world society--as well as our own--wouldn't
receive "PDA approval” were it introduced today, and the necessity to acquire a

prescription for its acquiaition would surely curtail a lot of its use.

To summarize, I endorse both the insertion of a new stage in drug-development,

ght, as detailed

and the development of a Congreseional Committee for FDA Ove:
by Dr. Fisher, Further, I suggest consideration be given to creation of a

rch, whereby the cost incurred when providing

national system for clinical rei
basic medical care could not be ignored by insurers, and whereby the cost
incurred when providing a new therapy could not be ignored by academiciane and
by private industry. The former idea would prove cost-effective, for it would
ensure the FDA would work to facilitate development of new drugs; enacting the

latter idea would cost the coveroment nothing. And both would benefit natiantn

without Jeopardizing their safety. Thank you for the opportunity to speak with

you thia morning. If there are any questions, please do not hesitate to ask.


91

Our next witness is a representative from the Food and Drug Ad-
ministration, Dr. Mike Lumpkin. Actually, Mike, I will let you give
your title so I do not get it incorrectly. I appreciate you coming up

ere from Washington with us today. As you can expect, there are
a lot of questions that we will have for you.

If you could give us your opening statement? Before we do that,
let us swear you in.

(Witness sworn.]

Mr. McInTosu. Let the record show the witness answered in the
affirmative.

Dr. Lumpkin.

STATEMENTS OF DR. MURRAY M. LUMPKIN, DEPUTY DIREC-
TOR FOR REVIEW MANAGEMENT, CENTER FOR DRUG EVAL-
UATION AND RESEARCH, FOOD AND DRUG ADMINISTRA-
TION; ACCOMPANIED BY DR. GEORGE ROSS FISHER, TRUST-
EE (PHILADELPHIA), PENNSYLVANIA MEDICAL SOCIETY; DR.
ROBERT B. SKLAROFF, MEDICAL COLLEGE HOSPITAL-ELK-
INS PARK; DR. MICHAEL R. SPERLING, CHIEF OF MEDICAL/
SURGICAL PROGRAM, COMPREHENSIVE EPILEPSY CENTER,
GRADUATE HOSPITAL; DR. JACK CIONCI, CHAIR, MONTGOM-
ERY COUNTY AIDS TASK FORCE; DONALD JUNGKIND, THOM-
AS JEFFERSON UNIVERSITY; DR. DAVID O. GINSBERG,
PRESIDENT, CONCORDE CLINICAL RESEARCH, INC.; JOHN
BOEHRINGER, PRESIDENT, BOEHRINGER LABORATORIES;
AND BARBARA DELUCA, EXECUTIVE DIRECTOR, LINDA
CREED BREAST CANCER FOUNDATION

Dr. LuMPKIN. Thank you, Mr. Chairman. As a way of introduc-
tion to the committee, since I have not had the opportunity of ap-
pearing before you, let me first tell you that I am a physician, and

am not a political appointee at the FDA.

I actually have had a bit of I think a very fortunate career as
far as drug development goes in that I have only been with the
FDA for approximately 5 years. I came to the FDA in 1989 as the
director of the division of anti-infectious drug products. This is the
division that deals with antibiotics. After 3 years in that position,
I was asked to assume my present position at the FDA, which is
the deputy director of the Center for Drug Evaluation and Re-
search.

Prior to my time at the FDA, I was employed by Abbott Labora-
tories in Chicago, IL, and I was head of one of their antimicrobial
development programs that led to the worldwide registration of one
of their new antibiotics.

Prior to that I was a practicing physician. I was head of the pedi-
atric infectious disease department at East Tennessee Children’s
Hospital in Knoxville, TN. I did my training at the Mayo Clinic,
and I was a Fulbright Fellow at the University of London.

As I say, I think I have had a very fortunate career in that I
have seen drug development from the practicing physician, from
the patient, from the pharmaceutical industry, and now I am hav-
ing the opportunity of seeing it inside a regulatory agency.

really am very pleased to be here today to have this oppor-
tunity to discuss with you and with the people here in Norristown


1

CAN ACT 3
newly-released anti-nausea drugs~- because they were afraid to be associated with me or my
organization in the FDA's mind. Is that ludicrous? Yes, sadly, and all too believable. You and
1 both know the capacity of the FDA to punish a pharmaceutical compeny by sitting on their
neat drug application, by slow-tracking it. No matter that people who are sick might need the
drug; this is how the FDA operates.

‘Third, force public accountability.

Advisory Committees are supposed to have e non-voting representative of the public, a
‘consumer, participate in approval deliberations. That person should be sent to the FDA by the
public, and must consult with her or his constituents, advising them of the issues and keeping
people informed of the process.

‘Six years ago, I applied to become such a representative. What I learned was that
public representation was a sham; the well-intended mechanism had been easily manipulated
so the FDA could appoint “consumer representatives” that would parrot the party line, just as
it appointed like-minded doctors to its panels. Two doctors and a lawyer have been
“consumer representatives,” each of them from the same Washington coterie. The two doctots
had cancer, at least; the lawyer did not even that.

‘Thanks in part to my efforts, but mostly thanks to the much greater force of AIDS
activism, ad hoc consumer representatives are now being seated, although Thear that this is a
source of grest anxiety and bitterness at the FDA. The current cancer representative
(appointed) is ~ did you guess? ~- « doctor! 4

Fourth, force the FDA to change its label designation structure.

This is « critically important issue that goes to the heart of the most important problem
confronting people with cancer today: the issue of “off label” use, Because the FDA
approves --"labels--drugs for use only in a very defined way, as to type and even stage of
disease, dose, route of administration, and other characteristics, health insurers and managed
‘care companies have found an opportunity to restrict patient access to new therapies.

‘At the very least, $0% of all cancer chemotherapy involves the use of drugs used in
ways other than that for which they are approved. That is called “off-label” use. Until the
present Commissioner undermined the credibility of his own agency, it patticipated in a
“gentlemen's agreement” with the medical establishment about the validity and even


9

I am pleased to be here today to have this opportunity to discuss
important issues concerning the Center for Drug Evaluation and
Research (CDER) at the Food and Drug Administration (FDA). The
FOA's primary mission is to protect and promote the public health
of all Americans. Promoting public health means ensuring that
drugs are safe and effective, and that information is available
to health care practitioners and consumers to help assure
appropriate use of pharmaceutical products. It also means making
every effort to assure that drugs that have scientific data
demonstrating their safety and effectiveness become available

promptly.

Under our law, drug companies are required to test drugs for
safety and effectiveness. Once that testing is complete, they
submit a new drug application to one of two centers at FDA. CDER
is responsible for ensuring the safety and effectiveness of drugs
made from chemical substances. The Center for Biologics
Evaluation and Research (CBER) is responsible for the regulation
of biological products. Traditionally, biological products
included vaccines, therapeutic sera, allergenic products, and
blood and blood products. In recent years, biologicals have come
to include products produced by recombinant DNA technology,

monoclonal antibodies, and certain types of gene therapy.


102

As a result of these programs, since 1987 more than 75,000
patients, not in formal clinical trials, have received access to

promising new drugs while the drugs were being studied.

PRESCRIPTION DRUG USER FEE PROGRAM

The third program is one that is particularly important to the
health of the drug industry and it is the one for which Congress
deserves substantial credit. I am referring to the program
established under the Prescription Drug User Fee Act of 1992
(PDUFA). The bill was endorsed and agreed to by the two lead
trade associations for the drug industry--the Pharmaceutical
Manufacturers Association, now the Pharmaceutical Research and
Manufacturers of America and the Biotechnology Industry
Organization. It was passed unanimously by both the House of
Representatives and the Senate and signed into law by President

Bush.

The theory of the bill was that FDA would be able to review drugs
in a timely manner if it had sufficient resources. An FDA-

industry work group studied FDA's programs and identified the


118

ed States. There is a communicative process that is well underway
there.

Mr. PETERSON. I think that there is that situation going on, but,
as I understood it, the reason they were doing this is because they
could not get done what they needed here and that they did not.
really want to ban it in the United States. This was some kind of
interim step. I do not know. Maybe they just have not seen this
new data.

Dr. LUMPKIN. That could be.

Mr, PETERSON. I apologize. I am going to have to leave to catch
my plane. I appreciated being with you.

ir. McINTosH. I thank you very much, Mr. Peterson. I appre-
ciate you coming.

Let me ask one followup question on this chart. How many drugs
not shown there were approved in those other countries, but not
approved in the United States?

yr, LUMPKIN. I can get you the data for the other countries. 1
have the data available for the United Kingdom, if that would be
helpful to you here today. The data I have is 1990 to 1994.

If we take that 4-year period, in that period of time there were
104 drugs that were approved either in the United States, in Great
Britain or both. Fifty-eight of those drugs during that period of
time have been approved in both countries.

There are 28 drugs that have been approved in Britain that have
not yet been approved in this country, and there are 18 drugs that
have been approved in this country that have not been approved
in Great Britain.

[Chart.]

Dr. LuMpKIN. Let me show you a little bit about those drugs. If
you look at the drugs, there are 28 drugs that were available in
the United Kingdom that are not available in the United States.

We went back and said well, what is the status of these drugs
as far as the American market is concerned? There are eight of
these drugs that have pending NDA’s at the FDA, but all of those
NDA’s have been classified as standard, meaning that there are al-
ready approved alternatives to that drug in the United States to
meet that particular disease need.

There is one NDA that has already been approved. It was ap-
proved in 1995 after this data was put together. There are two
that, interestingly, the NDA’s were withdrawn by the company
while they were under review here in the United States because of
safety problems that developed after their approval in Great Brit-
ain. Interestingly, both of those drugs were rated priority drugs for
the American Population, but because of the safety data in Great
Britain, they withdrew them in this country.

There are eight that we have not received a marketing applica-
tion for, i.e., an NDA, but they are under IND in this country, and
there are nine of those drugs that we have neither an IND to s'
them in this country nor a marketing application for them in this
country.

[Chart.]

Dr. LUMPKIN. If you also look at the next chart on the drugs that
we have during that period of time that the British do not have,
I think it is kind of an interesting group because of these 18 drugs,


65

A switching to such certified summary submission — as is the practice in many other
sophisticated countries — would add great efficiency to the FDA review process,
whether done "in house" or by an outside consultant under contract to the agency.

There are, of course, several other initiatives that would provide incremental
improvement in the function of the FDA, which are being thoroughly discussed and
considered by us and others in healthcare. We at SmithKline Beecham are
Participating in these discussions, and will comment on other proposals in due
course, But for today, I would suggest that if only these four initiatives were
implemented (The Mission Statement; The Policy and Performance Review
Commission, Use of Outside Experts in the Review Process, and Elimination of
Detailed Data Verification by the Reviewer), the entire process would be vastly
improved to the great benefit of, and with no additional risk to, the American
public.

Thank you for your kind attention. If there are any questions, I would be happy to

attempt to answer them.

Page 6


1

because they establish clear criteria (ur decision-making during scientific review. For guidance
documents to play that role, however, they public nceds to contribute to the process by which they

are created so that the FDA decisions are well-informed.

‘Obviously, IVD over-regulation is a specific problem that the diagnostic component of the
medical technology industry faces. We also fully support HIMA and the Biotechnology Indusuy
Organization (BIO) in their efforts to move forward on FDA reform proposals. Some arcas which
we feel are most important include:

~ Restructuring the overlapping procedures between the Center for Biologic Evaluation
and Review and the Center for Drug Evaluation and Review (CBER and CDER). There are
many confusing and contradictory regulations which biologic companies must maneuver through on
the way t0 product application and approval. Those regulatory hoops are putting biologic companies
at a competitive disadvantage. We fully endorse the proposal by BIO to merge biologic regulations
under the Public Health and Service Act into the Food, Drug and Cosmetic Act. This proposal also

addresses the differing manufacturing standards between drugs and biologic therapies.

- Reforming the FDA regulations on exporting. Current FDA exporting regulations are
driving manufacoaring jobs and live-saving medical products overseas. Changing these regulations is
essential for keeping American medical technology in this nation, and not forcing companies to move
operations overseas, Centocor supports HR 1300, introduced by Congressman Fred Upton, which
‘would eliminate the FDA-approval of exporting products going to GATT Treaty nations. T would
also like to thank Chairman McIntosh for his support of this legistation as well.


16

severe. But obtaining these medications has been a major
problem,

To get these medicines, David obtains a prescription from
his neurologist, and we send it to a London pharmacy thet
specializes in filling prescriptions for people from the. U.S.
‘The pharmacy must then obtain a prescription from a.local doctor
(another expense). The drug ig shipped, and U.5. customs must
clear it. Then it goes to our local post office, which notifies
us to pick it up.

If all goes smoothly, we can get the drug in about two
weeks. But life becomes very stressful. You hold your breath,

you bite your nails, and you count pills the whole time, becau:
David cannot do without these medicines.

In 1991, U.S. Customs seized and burned a shipment of ours
without even notifying us. We only found out after we wrote to
the London pharmacy that we had not received the shipment. The
pharmacy put a tracer on it and was notified by British postal
authorities that the shipment had been seized by U.S. customs as
an illegal substance (opium). The drug, mogadan, is definitely

not an opiate, and FDA regulations clearly state that patients,

with a physician's prescription, should be able to import such
drugs for their personal use, Senator D'Amato kindly intervened
on our behalf and, after about a year and many exchanges of
letters, the government reimbursed us for the §209.65 cost of the
medication ‘under the Federal Tort Claims Act.

Since 1991, our shipments have not been seized, but we still


160

that almost any drug can, at some point in time, demonstrate new side effects and dangers.
Therefore, understanding these considerations, the job that we ask the FDA to perform is
almost an impossible task in that it is incredibly difficult to predict how chemical moieties
are going to effect a complicated biological entity such as a human being and on the other
hand delays in approving effective medicine may certainly cause people to suffer or die.

It is with the previous comments in mind and with the application of my thirteen year
history in doing drug development that I would, however, like to make certain suggestions

as to techniques that I believe will make the drug approval process more expeditious.

1 would like firstly to suggest that we must do everything as # society to encourage the
development of new and innovative pharmacological weapons in our on-going battles with
disease. To this end, 1 would suggest, that for any product which is considered the first
of a new class of drugs, the company which worked to develop it be given and extension
of the exchusive period in which they have to market it. I would like to see the developing
company given an increased opportunity to recoup its developmental cost. So, for
example, if it’s normal to give a seventeen year patent on a new chemical modality, I
would like to suggest that it be extended to twenty-one years in cases of unique or
innovative drugs. This, of course, does not keep other drugs of the same class from being
developed, but it will encourage the chance that unique or innovative drugs be
preferentially explored.


disease.

There are four separate initiatives we have undertaken to
accomplish twin goals of protecting the public and promoting the
rapid availability of effective drugs. These four initiatives,
along with ongoing management efforts to streamline and improve
the drug review process, will guarantee that safe and effective
therapies continue to be available as rapidly as possible. I

would like to tell you about each of these initiatives.

EXPEDITING AVAILABILITY

First, years ago FDA established a fast-track procedure for drugs
representing real gains, including breakthrough drugs--drugs to
treat persons with life-threatening and severely debilitating
illnesses, and for which there is no other treatment available,
as well as other drugs that have significant advantages over
drugs already on the market. The Agency has long worked very
closely with companies throughout the drug development and review
period, even before anything is submitted to the Agency, so as
not to waste any precious time. Many drugs have been made
rapidly available because of these steps. A conspicuous example

came in 1987, when FDA reviewed and approved AZT, the first drug


21

Mr. McINTosH. Thank you very much, David. I think your state-
ment of aspiration is one we should all strive for in working to-
gether for that purpose.

Our next witness is Ms. Mariah Gladis. Mariah, we appreciate
your coming today. Please share with us your testimony.

Ms. GLADIS. Good morning. Let me begin my story here. I am not.
deaf. I have ALS or Lou Gehrig’s disease. I am a resident of Mal-
vern, PA. I am a mom with two wonderful sons, ages 11 and 19.
I am the wife of Ronn, here in the room. I am the founder and di-
rector of the Pennsylvania Gestalt Center for over 20 years.

I would like to thank you, Congressman Fox, and other members
of this committee.

I have felt some confusion about the direction of the FDA. Dr.
Kessler, Commissioner of the FDA, said in a 1994 edition of
Newsday, “When people are suffering and dying from a devastating
disease, we cannot wait for all the evidence to come in—for all the
i’s to be dotted and all the t’s crossed. We must be prepared to ac-
cept greater risks from a drug when greater benefits are possible.”
If the FDA adhered to this, I would not be here today.

Later in 1994, he said, “There is a clash between the right of the
individual—to get any drug—and the duty of the Government to
prevent harm.”

We certainly believe that safety is important, but we wonder
what are we being protected from and prevented from?

Dr. Kessler’s last statement tells me that the FDA may be miss-
ing a central point of battling a terminal illness. Taking control of
one’s illness is incredibly important. Making a drug available or in-
creasing the options to obtain a new therapy or even providing new
educational materials is so critical because it yields hope.

Hope is life giving in and of itself. Hope is based partly on the
knowledge of your disease and the support that you receive from
the healthcare system.

Let me tell you about me. On June 30, 1981, I received a termi-
nal diagnosis and a marriage proposal. Eventually I was first diag-
nosed with a brain tumor and later on with ALS. I was given a 10-
percent chance of surviving a half a year to 2 years.

I searched for public information. There was very, very little.
Doctors did not know what caused this, nor did they have any
drugs or treatment at all. Ronn and I knew that we were faced
with moving toward life or death. Had I listened, I would not be
here today.

In many respects, we have had to create our own hope. I began
seeing a nutritionist and started an aggressive antioxidants pro-
gram with exercise.

Let me state the key issues that can help save or at least maxi-
mize time for ALS patients. Start combination drug trials now. Im-

rove the expanded access program. People with life threatening
illness want access and the choice to take experimental drugs when
they have reached or completed phase III. How can the FDA expe-
dite and facilitate this access? What are they going to do to stream-
line this process to help save lives?

Breakdown barriers to experimental drugs. Avoid the use of pla-
cebos in future trials. The ALS Association has stated that, “Like
cancer, once a drug is identified as being effective in treating a par-


Page 7

allow for mutual recognition of the inspections of clinical investigators and
manufacturing. This would help free FDA employees from conducting costly and time
conauming inspactions overseas.

CONCLUSION

The American public should expect standards for safety and efficacy for new medicines
and vaccines that are the most stringent of any nation's. Merck has always accepted
this responsibility and demands from our employees the best science and the best
scientific practices. We do not want reform to lower standards for the approval of
important medicines and vaccines. Rather, reform should improve management
practices and streamline the review process so that we can provide innovative
medicines and vaccines to the patients who need them as quickly as possible.

Today, | have presented some examples of change that the Congress needs te ensure
‘are made to the FDA. We are working with our research colleagues from companies in
the Pharmaceutical Research and Manufacturers of America (PhRMA) to develop more
comprehensive and specific recommendations. We are also eager to consider the
ideas and work with others in the public and private sectors who are currently
developing reform proposals.

Again, | thank you for the opportunity to be here today and look forward to your
questions.


95

The administration has proposed various reinvention types of
ideas that have already been discussed. We are very active in what
is called the International Conference on Harmonization.

This is a Process by which the regulatory authorities for drugs
in the United States, in the European Union and in Japan, in con-
junction with the pharmaceutical manufacturers in those three
areas, work together in an organized process to try to harmonize
as much as we can on the standards, not only the clinical stand-
ards, but the manufacturing standards, the animal preclinical test-
ing standards, to try to come up with as best we can dealing with
some of the time elements in the development process that have al-
ready been talked about.

In conclusion, Mr. Chairman, I would just like to say that this
is obviously an era of change. There is a lot going on in the
healthcare system of which all of us are aware, there is a lot goin;
on in the pharmaceutical industry of which all of us are aware, an
there is a lot going on at the FDA of which I am trying to make
more and more of us aware because I think it is important that
what we are trying to accomplish there is discussed in our open po-
litical debate situation.

I think in the end it is FDA’s independence that gives American
consumers confidence in our agency's decisions. I think that now
our challenge is to continue to build a track record on efficiency
that will give Americans a confidence in the agency’s processes.

I thank you for your time, and I am happy to answer any ques-
tions that you happen to have.

Thank you, Mr. Chairman.

(The prepared statement of Dr. Lumpkin follows:]


33

INC

4
2667 LOMUARD STACET, PRILADELTHIA."PA. «0846

FDA Regulatory Reforms

Statement of Kiyoshl Kuromlya
Director/Editor

Critical Poth AIDS Project

June 9, 1995, Noristown, Pennsylvania
Phone: (216) 845.2212

Fox: (216) 735-2762

Emalt: klyount@erlipetn.org

‘Asa perron with AIDS pnd a vocal advocate for my comnrunity, I must preface my’ remarks by saying
that I appreciate the fact that the FDA ovcr the last five yenrs has implemented accelerated approval
programs for AIDS drugs under community and activist pressure. And further, ] want (o say that I do not
support Congressional micromanagement of regulatory agencies, and de nol believe Congress should ect.
the scientific agenda for this country. But, we have come to a timc when it may be possible to improve an
agency-the FDA--which in some regards has lost sight of ils mission.

Last month at the GOP summiit cgislation to reform the FDA was presumably one of the unanounced
topics of discussion facing lawmakers, This legislation seems even more certain since FDA
‘Commissioner David Kessler gave the Sonate Labor and Human Resources Commitiee an outline of the
Clinton Administration’s proposed FDA reforms,

My concern as a person with AIDS ends treatment activist who has worked as a
Community representative since 1991 in the AIDS Clinical Trials Group program of the NIH
ts that conspicuously absent trom Kessier’s presentation were any now efforts to speed
approval of drugs for AIDS. Since the drive for faster drug epproval wes spesrheaded by
AIDS activists and one of the areas where the FDA has made progress is In accelerated


168

Ms. DeLuca. Yes, and I know Beverly well from our National
Breast Cancer Coalition.

Mr. Fox. I appreciate your testimony.

Ms. DeLuca. I thank you for your help, and I hope everyone will
continue to fight for this funding.

Mr. Fox, That is our hope, too. If you have anything in writing
that you want to submit to us beyond your oral testimony which
has been transcribed, we would love to receive it.

We will make sure that you get our address so that we can in-
clude it in the record because this is the very reason why we have
created this hearing so we can change the FDA law.

Ms. DeLuca. I certainly shall. Thank you.

Mr. Fox. Thank you, Barbara.

Are there other witnesses who wish to come forward to testify at
this hearing at this time?

Chairman Clinger, do you have questions you want to ask of any
members of the panel who just finished?

Mr. CLINGER. No, Mr. Chairman. I would inst again commend
you for being the instigator for this hearing. I think we have had
a very thorough hearing. As you say, we have had some very com-
pelling testimony. I think it is going to be enormously helpful to
us as we go back and begin to deal with legislation in these areas.

One of the functions of this committee which I chair, which is the
Government Reform and Oversight Committee of which this is a
subcommittee, is to really figure out how we can make the Govern-
ment work better and work more efficiently instead of being sort
of a mindless, senseless bureaucracy responsive to our customers.
Our customers are the people who depend upon these agencies.

Certainly FDA is a prime example of where we can do so much
more to provide help for people who are in desperate need of that
help. I think we all will leave this hearing rededicated to making
this thing work better and work more efficiently.

Again, I just commend you for bringing us to Pennsylvania and
holding this hearing.

Mr. Fox. Thank you, Mr. Chairman.

1 just wanted to say to all of our doctor witnesses, Dr. Jungkind,
Dr. Cionci, Dr. Sperling, Dr. Sklaroff and Dr. Fisher, that each of
you has given to us very poignant testimony which I think goes to
the heart of the fact that we need to make sure that patient con-
cern, especially those who need the life extending drugs and the
lifesaving drugs, in fact do receive those drugs as soon as possible.
We need to accelerate the acceleration process, if I can say so.

It is the work of the many advocates here for healthcare that
have caused us to draft the proposal, which will be known as, after
we receive your testimony and we have had a chance to digest it,
the Life Extending and Lifesaving Drug Act of 1995, which will in
fact be, from our perspective, an improvement on the existing Food
and Drug Administration law.

We need to breakdown the barriers to experimental drugs. We
need to approve new drugs as fast as possible. We need to increase
the flow of information to consumers about drugs. We need to re-
duce the number of duplicative regulations that have restrained us
in serving our patients and constituents, and we need to make sure


133

Mr. McINTosH. Thank you.

Any questions for Dr. Fisher?

Mr. Fox. If the six doctors that are coming up, Mr. Chairman,
could remain for questions after the group has spoken, or do you
need to leave right away?

Mr. FISHER. No.

Mr. McINTOsH. Do you want to do it that way? OK. I would be
glad to schedule it that way.

Mr. Fox. We will ask you questions after we finish the other doc-
tors. Thank you, Doctor.

Mr. McINTosH. There were several other doctors who wanted to
be included in this section.

Dr. Robert Sklaroff I think, was the next one.

Mr. SKLAROFF. You have my typewritten testimony. Mr. Chair-
man, thank you for the opportunity to discuss the impact of the
FDA upon the daily experience of a practicing oncologist.

You have already heard from Dr. Fisher. He encourages the FDA
to focus its work upon toxicity of drugs, products and devices rath-
er than just on their utility.

I had opposed former President Reagan in terms of how some of
his ideas may have had an impact on the first 100 days contract.

The key point here is to see how the Government can be stream-
lined in order to achieve freedom and in fairness. Government
should guide the citizenry. It should neither dictate its activities
nor engage in “laissez faire.” At least in my opinion, removing the
efficacy requirement would unleash the FDA, allowing it to protect
without unduly restricting innovation.

I found it quite startling to listen to a defense, if not an apology
for the 150,000 to 200,000 page application with justification that
the applicant entity wants that length because otherwise the drug
will not be marketable such as the antibiotic. I found that to be dis-
ingenuous.

st week a colleague told me that the HMO created by Travel-
ers Insurance Co. for Medicare patients had decided not to finance
the use of Taxol against lung cancer. You heard about Taxotere
here earlier today.

Taxol, or powdered Taxotere, is a first-line therapy for ovarian
cancer, although you did not hear that mentioned with respect to
ovarian cancer earlier today. This is based on that major knowl-
edge that we have.

jung cancer is the major cancer because of cigarette smoking.

Although this affords few therapeutic options, particularly in re-
sponse to Taxol, thus is access to an active drug effectively banned.

Doctors are acutely aware of the limits of this, so we often test
a series of agents until we find one which works for a given pa-
tient. Being patient advocates, we cannot ignore anything which
would help in 1995, despite the absence of definitive data.

The advent of restricted formularies which are generated by in- -
surers are regularly precluding the ability to entertain such alter-
natives. We would invite you to share receiving the gratitude of a
patient who has acheived. tumor regression, or alleviation of her
ailment symptoms, from chemotherapy or any other treatment if
she felt therapies were required which would enable legislation


17

medicins

must pay import duties on th + Tt strikes me as
wrong that the government is taxing what is really a necessity to
David's physical well-being. This is not a luxury.

David and I are fortunate in s al ways. We are fortunate

to have Dr. Stanley Resor of Columbia-Presbyterian Hospital as
David's neurologist. He is a renowned authority on spilepsy.. As
a teacher in the New York City public school system, I am

fortunate that my union's health plan reimburses me for. the cost

of these drugs, minus a 85 co-payment. Otherwise, Lamictal alone
would have cost about $6,000 per year. Many people cannot get
the drugs they need since most insurance plans do not cover drugs
that aren't available in the U.S. because they aren't approved by
the FDA. It is important to note that as the dollar suffers, so
does the patient who buys medicines abroad.

I believe that once medicines are approved in Europe and
there have been sufficient trials and the medicines have been
found somewhat successful, we should either rely on the foreign
testing or work jointly with the other countries in order to have
the drugs approved in a quicker fashion in the 0 Compared to
we seem to take forever to get drugs on the

other countrit

market. For example, one of the drugs David needs -- Lamictal --

was only approved here in December 1994, after almost three years
of review by the FDA. It was already available in more than 40
other countries and is available over the counter in Mexico.
Another drug David needs, Sabril, is still waiting for FDA
approval but has been available in England since 1989 and is also


61

of useful new drugs an extremely formidable task, and has added considerable
expense and time in getting useful new therapies to the American public.

In fact, it now takes, on average, well over 10 years from the time a drug is
"discovered" until it becomes available for general use by patients. During this
time, the agency is directly involved with every aspect of the development.
Nevertheless, it took 19 months for the agency to evaluate the average New Drug
Application in 1994, This is not to say that the FDA has been totally unresponsive
to the growing problems of complexity in the development of drugs. As a result of
the implementation of user fees and the specific performance goals associated with
them, this 19 month review average represents a reduction of review time from the
approximately 30 to 33 months that was standard review time for the 12 years prior
to 1994.

Nevertheless, other sophisticated regulatory agencies are able to review the safety
and efficacy of new drugs considerably more rapidly. (For example, the United
Kingdom approves new drugs based on essentially the same data base as the U.S.,
following an average of 6 months of review. This difference alone accounts for
over a 12 month *drug-lag," on average.) It is the consumer, of course, who
ultimately must bear not only the economic cost of drug development but also the
social cost of delays in the availability of useful new therapies because of the system
that has evolved over the past 33 years since the 1962 Drug amendments.

But there is, perhaps, an even greater price to be paid for this increasing complexity
and cost of drug development. Some drugs may never be developed at all because
of the inability to obtain capital to support such an expensive process, the retum on

Page 2


130

GEORGE ROSS FISHER, M.D.
29 BPAUCE STREET
PHILADELPHIA, PA. 19107

Improvemenss in the Regulation of Drugs
‘Testimony, June 9, 1995.

Rass Plsher,
Trustee iphia), Yeanryivenia Medial Soctty

Mr. Chairman, let me thank you for the opportunity to comment on possible
legislation for the inproved regulation of the Food and Drug Administration.

To begin, let me submit a photocopy of a resolution to the American Medical
Association of which I am an author. It will be considered by the House of
Delegates of that organization on Jane 18, and is subject to their amendment and
deliberation. My testimony today is therefore as an individual. For the purpose of
today’s testimony, attention is best directed to live 16 of page 2 of the

federal government
ther the drug was safe for physicians to use. What they used it for, was a matter
of professional determination.

The late Senator Estes Kefauver then spousored the current additional

responsibility of the FDA that it assure that a new drug tae at least one proven
medical use before it is released for prescription, Senator Kefauver might not
have phrased it just \ike that, and J am uncertain what combination of regulation,

professional Judgement, ts you can see in'the sppendod phorocoy of a from
the PDR (Phivisans Deck Reference), ¥ pa

Pharmaceutical manufacturers would summarize the Kefauver Amendment quite
differently. The manufacturers are strictly limited to advertising only the

official uses Which have passed the elaborate tet of efficacy specified by the
FDA. On many occasions, I have asked drug representatives about uses not
specified in the approved package intext. They prove extremely uncomfortable
about such questions, and refuse to comment. Nevertheless, the medical literature


114

Mr. McINtosH. Thank you very much, Dr. Lumpkin. We appre-
ciate your coming and testifying.

I have several questions, although I want to really address two,
and then I will pass on to other members. If they do not get raised,
I will come back at the end.

The first is related to something that came to us as we were put-
ting together this particular hearing. Mr. Fox received a letter from
one of the witnesses or people we had invited to become witnesses
who had declined to come because, and I will read briefly from
their letter:

“We have made the difficult decision as a result of our concern
that our testimony may risk undue scrutiny and intimidation by
the FDA and would cause severe stress, interruption of business
and financial hardship to our small company.”

Essentially we have been hearing from a lot of people that they
are reluctant to talk about the agency because they fear retribu-
tion. When I held our first hearing of this subcommittee, I made
it very clear that we would aggressively intervene in any case
where we determined that somebody had. been subject to retribu-
tion as a result of our efforts.

I wanted to not only ask you about that, but also ask if you
would undertake a personal commitment to review that in the
agency and, if cases come up, insure that appropriate action is
taken to discipline the employees who may have overstepped the
bounds in a way that does intimidate people from coming forward
here in Congress.

There have been other examples. I think in the biologic area
there was a newspaper report of somebody who has been calling up
CEO’s and saying do not bad mouth FDA. Remember, we are the
one who approve your products.

I wanted to open that question generally, but also to get your
ersonal assurances that you will do everything to prevent that
from happening.

Dr. LUMPKIN. I think you bring up an absolutely critical point.
Let me say at the vei ginning that when I talk about having
a process in which alf Americans can be confident, part of that
process is that it is an open, fair process.

The kind of things you are talking about—any kind of retribution
or threats of retribution—clearly would not be consistent with an

open, fair process. Let me make it clear that we will not tolerate
that kind of behavior.

Now, I think we have to look at the realities of some of the types
of allegations that are being made. I would like to say that we hear
them also, and we are very concerned about them. I can assure you
that if we have specifics on that kind of conduct, we will prosecute
it to the absolute limits that we are able to do that because we do
not want that kind of system.

I thought it was interesting at the oversight hearing with Mr.
Bardin about 2% weeks ago when that question was put to the
CEO of Amgen, | believe. When he answered he said that he had
not been personally involved. He knew of no personal knowledge of
that going on, but he, too, had heard the rumors.

I think I am in the same kind of position he is in. I, too, have
heard the rumors, but I have not had people bring forward to me


116

point in time, to enroll in a program that allows them access to the
drug while it is still not approved for general use here in this coun-
h

Ty.

‘As to the specific that you brought up of that particular drug, as
the representative from the sponsor has already said, they admit-
ted here in the open that they have put in a treatment IND. Under
our regulations, the agency has 30 days to review the treatment
IND and get back to the company. If the agency does not say there
are any objections to it, it automatically goes into effect on day 31.

Beyond talking about the specifics because of the trade secret
laws that I am bound under that Congress passed in the FD&C
Act, I cannot tell you any more specifics about that review at this
point in time, but I would be happy to give the committee and the
Chair of the committee any information they would want on that
in a nonpublic situation.

Mr. McINToSH. And so that 30-day clock has not lapsed in this
case?

Dr. LUMPKIN. Not to my knowledge.

Mr. McINTOSH. Good. Well, hopefully there will be good news
coming on that question.

Dr. Lumpxin. Yes.

Mr. McIntosh. Let me just put it another way, though. You have
the treatment IND that requires the company to go through a fair-
ly extensive process to apply for that and the possibility that it
would be denied.

What would be the problem with changing the law to say look,
ifa physician wants to give a treatment to somebody who is suffer-
ing from a terminal disease that they will be able to give any type
of treatment, as long as it does not cause their condition to worsen
or shorten their life?

Dr. LUMPKIN. Actually, there is a provision in our present regula-
tions that basically allows that to happen under the single patient
IND. The treatment IND is kind of a generalized IND that would
allow this to be done over a large population in the country.

Physicians can get their own individual IND, and it is not a par-
ticularly paper intensive process. J think it is one that we could
make less intensive, but it is one that many physicians in this
country avail themselves of in order to get unapproved drugs for
their patients and to use them on an individual patient basis.

Mr. McINTosH. Are the companies allowed to notify them of the
potential drugs?

Dr. LumpKIN. I think there is within the scientific literature

lenty of information. I mean, that is what people use to get the
information out to physicians about drugs that are under develop-
ment. You see it in all of the medical journals that come out during
the months and during the development.

Mr. McINTOSH. Which leads me to a whole other area of ques-
tioning, but I will defer that to some of the other members.

Mr. Peterson needs to catch his plane. I will call on him.

Mr. PETERSON. Thank you, Mr. Chairman. I will not take a lot
of time.

You had two other charts in your testimony, Doctor, that you did
not get to. I think I understand the second to the last one, but this
last chart you have in there that has these graphs——


4

focus by the FDA are all apparently stifling innovation and tech-
nolo;

Tne addition to regulatory concerns, we need to look at how we
can harness the private sector in the approval process using out-
side resources of experts for review. I think that would be perhaps
a direction we could go that would perhaps do the most to expedite
the procedures. By using private sector resources, we may be able
to expedite the review processes at less cost.

I believe it would also be useful to look at how other countries
are conducting drug approvals—as Chairman McIntosh mentioned,
some are obviously moving faster, and we could do as well—and
whether we should continue to apply our standards to other coun-
tries.

Clearly a top to bottom review of FDA’s missions, goals and regu-
latory processes is sorely needed and long overdue. The status quo
is fostin us jobs, dollars and, most importantly, lives.

airman, I look forward to hearing the testimony from our
wit today as an important part of the re-examination process
and in your ongoing efforts to bring some sanity to the whole regu-
latory processes in this country.

I commend you again for holding the hearing, and I also am de-
lighted that you came to Pennsylvania.

Mr. McINTosH. Thank you very much, Chairman Clinger. I
greatly appreciate you participating in this hearing with us today.

Let me turn now to Mr. Peterson for any opening statement.

Mr. PETERSON. Thank you, Mr. Chairman. I will be brief so we
can get on with the witnesses.

1 again want to commend you and Chairman Clinger for your
leadership on these regulatory issues. I think we are making a lit-
tle progress, but I think it will be quite a battle.

In the district that I represent, we do not get involved too often
with the FDA, which I think is fortunate, given some of the slow-
ness of the process. There has been some talk of them giving more
power to the FDA over food inspection, which I shudder to think
about, given how some of this works.

I do not know a whole lot about the FDA. From what I read
about it, it is similar to what I do know something about, and that
is the bureaucracy that we have in the House and in the Govern-
ment on computers where you cannot get the leading technology
because the bureaucracy is in the way. It seems like we had kind
of a similar situation here with the FDA on some of these issues.

T have kind of taken this philosophy the longer I am in Congress.
I have decided that I am not going to believe anything unless I see
it firsthand.

I had an opportunity to go over to Israel. As part of that trip we
got to go to some businesses. What I was really struck by in that
tour was how many medical companies we have in Israel because
they could not get approval for their products here in the United
States. These were American companies, American scientists that
have gone to Israel because they are completely frustrated by the
situation that is going on here in the United States.

Clearly, this is something that we have to deal with. What is
going on is unacceptable. As I understand it, the Department has



93

that has been negotiated with Congress. It has been negotiated
with the pharmaceutical industry. I think it is a process that we
at the Center are very committed to. I want to talk about that for
just a few minutes.

That process is the Prescription Drug User Fee Act. As many of
you know and it has already been talked about today, the Prescrip-
tion Drug User Fee Act, as far as I am concerned, is an act that
in all of my experience, both on the industrial side and on the regu-
latory side, has been the first real catalyst for culture change at
the Center for Drugs because for the first time it has made very
real to our reviewers and to our management that accountability
is something that matters.

It is not only good decisionmaking, but it is good decisionmaking
in a timely manner and that people will be held accountable for
that. I think that was the idea when people from FDA, people from
the pharmaceutical industry and those of you here in Congress put
together the basic premise for the Prescription Drug User Fee Act.

Now as you are well aware, this is an act that started in 1992.
It has a 5-year implementation to it. It ends in 1997. It has a sun-
set provision. If Congress does not re-up it in 1997, it will go out
of existence at that point in time.

During this 5-year period, there are interim goals that were
mandated in the exchange of letters between the commissioner and
the Congress when this act was put into place. I can tell you and
it is public record. We have our records that are available on a
monthly basis. We have met all of the interim goals that were set
in that program.

I think we are already beginning to see the effects of the pro-
gram and having a process by which you have an expedited, effi-
cient review process such that when you have an application that
has good scientific data in it that if it can be reviewed in a timely
manner, then obviously it is going to be approved in a timely man-

ner.

If I could have the first chart there?

[{Chart.]}

Dr. LUMPKIN. These are the same kind of numbers that I think
some of the representatives from industry were just talking about.
Tf you look back in 1992 at the beginning of this program, the me-
dian time for drug approval for all NDA’s at the Center for Drugs
was around 26.7 months. Last year, when you look at all NDA’s
that were approved, the median time was 19 months.

If you look at those applications that came in under the user fee
program, the median time for their approval was 13.5 months. For
those user fee applications that we call priority applications—these
indeed were for drugs that were for lifesaving illnesses—their
meeting an approval time was 10.4 months.

Clearly this has not yet reached the goals that were set in the
user fee program, but those goals are not in place until 1997. There
are interim goals on the percentages of applications that have to
meet the performance goals in there, and we have met those per-
centages.

I think what you will begin to see and what the whole idea be-
hind the user fee program was is that because we want to develop


38

for socelerated approval, but these programs nead wo be expanded, not scrapped. For
example, they need to be expanded to the area of biotech products, without setting @
higher standard for biologicals. We fee! reforms of the FDA are needed, but we must not
scrap the hard-tought-for Improvements in the AIDS drug approval process that have been
made under pressure from the AIDS community. If the FDA tums its back on persons with
AIDS the way much of the rest of the Federal bureaucracy has, we will suffer the
consequences of the human as wall as monetary expense of such short-sighted planning.
Persons wiith AIDS will be hospitalized sooner and kept there longer.

Our goal is an improved FDA that will oxpedite spproval of drugs that will keep persons like
myself, who has never been in the hospital for HIV-related infections, out of the hospital for
many more years of productive life. We can do it, with your help. Thank you for listening.


158

Mr. McInrosux. Thank you very much, Doctor. Actually, it is fas-
cinating. I think we have had three views on the question of effi-
cacy and very helpful insight.

I, unfortunately, must depart at this point, but I am going to
turn over the gavel to the vice chairman, Mr. Fox. There were some
questions he had for the doctors who participated, and if there are
any other people, Mr. Fox, if you could let them also contribute
their testimony.

Mr. Fox. Absolutely.

Mr. MCINTOSH. I appreciate it. Let me repeat that it is an honor
for the subcommittee to be here, and everybody from Montgome
County should be particularly proud of Jon. He is doing a ‘eat jo)
on our subcommittee and the hearings we have had in Washington.
It is an honor to have him as our vice chairman.

Thank you very much, and thank you, Jon, for completing this.

Mr. Fox. I just wanted to thank Mr. McIntosh before he leaves.

[The prepared statement of Dr. Ginsberg follows:]


125

Dr. LUMPKIN. All right.

. Mr. TaTE. I, too, would like to thank you, Dr. Lumpkin for com-
ing by.

You may have mentioned this, and maybe I did not catch it in
your testimony. What are you folks doing in regards to reduction
of paperwork in Tegards to new drug applications?

Dr. Lumpkin. I think the biggest thing that we have in reducing
paperwork is the use of our electronic submissions. People have
talked about in the past these 100,000 page documents that come
in. Indeed, we do have 100,000 page documents that come in, and
they are a tremendous problem to us if for no other reason than
finding a storage place to put them.

I think what we have been working with, and industry has been
absolutely wonderful in working with us on this, is trying to come
up with electronic ways of submitting. Most of our larger applica-
tions now are submitted in an electronic format.

It clearly helps us on the review process of being able to use elec-
tronically formatted NDA’s to go through the review and evaluation
process. That is one of the biggest things that we have at this point
in time.

Mr. TATE. What would you say would be the average number of
pages for a new drug application like 3TC, for example?

r. LUMPKIN. For what? I am sorry.

Mr. TaTE. For example, like 3TC. How many pages would they
have to fill out?

Dr. LUMPKIN. It really varies, depending on what the disease en-
tity is. Let me give you the extremes, for example.

ur experience has been if you are developing a new, general use
antimicrobial and you know that in order to be a competitor in the
antibiotic marketplace you have to have five, six or seven indica-
tions approved with your drug at the time that you go to market
here not so much because the FDA requires it, which we do not,
but because in order for you to be competitive with the buyers that
are out there, you have to have a good product, those particular
NDA’s usually will run somewhere between 100,000, 150,000 or
200,000 pages when you talk about manufacturing procedures to
preclinical to clinical data, all the data put together.

There are then other products that are called, for example, line
extensions. If you have a dermatological product that is already ap-
proved as a cream and you want to now make it as a lotion, those
things will often only have several hundred pages, if that many, in
them. They will be clearly much, much smaller.

We do see a very large differentiation there, depending on what
they are going for.

ir. TATE. If they are filling out 150,000 pages, for example or
200,000 or 100,000 or whatever, are every one of those necessary?
If so, for example, like on 3TC are there any that you suggest that
are not necessary?

Dr. LUMPKIN. From what I have seen from my experience as a
reviewer, the pages that we ask for for the most part are necessary.

I am sure there are things in there that we could think about
doing without. Particularly, for example, one of the initiatives that
has been put forth was the one dealing with the environmental as-
sessment. I think, for example, we know those are very costly for


100

for the treatment of AIDS, in 3-1/2 months. Today, AIDS and
cancer drugs for which adequate data are presented typically are
reviewed and approved in a year or less, sometimes much less, and
other important drugs are also often approved in this amount of

time.

In December 1992, FDA established a program, called "accelerated

approval

which allows approval of drugs for serious or life-
threatening illness based on the drug's effect on a surrogate
endpoint. A surrogate endpoint is an effect that is not a
clinical benefit itself but is reasonably likely to correspond to
or predict a clinical benefit. For example, under this program
the AIDS drug a4T was approved on the basis of data that the drug
raises T-Cell counts. While there is reason to believe that
increased T-Cell counts in an AIDS patient will prolong life
there was no actual evidence that d4T produced a clinical benefit
such as prolonging life. Nevertheless, the Agency approved d4T
less than six months after the application was submitted on the
condition that studies demonstrating a clinical benefit be
completed after approval. When approval is based on a surrogate
endpoint under the accelerated approval rule, the sponsor is
required to conduct postmarketing studies to verify and describe

the drug's clinical benefit.


4l

ou how many times I have gone to the emergency room, to the po-
ice station. I get calls from people in the street.

That is an unfortunate part that David has, but he has had a
lot more success with the medicines from England.

Mr. TaTE. Are you familiar, and I do not know if you mentioned
it, with Colpizone?

Ms. SAMOwITZz. Yes.

Mr. Tate. Is it my understanding that their patent is about to
expire in the United States. It is my understanding that there is
no company that is willing to go through the FDA approval in the
United States just because the expense is so much——

Ms. SAMOWITZ. Yes.

Mr. TaTE [continuing]. That they are going to continue to have
to get it overseas.

Ms. SAMowlIrTz. Yes, I am familiar, and we still do get it.

Mr. TaTE. I would also like to add that I just appreciate your
openness and your willingness. I know it is difficult to talk about
these issues, but I sure appreciate your honesty and your willing-
ness to take the time to come here. It has really been moving testi-
mony for me personally. I just want to say thank you.

Mr. McInTosH. Thank you very much, Mr. Tate.

Mr. Walker, do you have any questions?

Mr. WALKER. I have no questions, but I, too, want to thank the
panel. I think it is very important from time to time to take what
is essentially regulatory reform issues and put a human dimension
on them.

What we have had here this morning is a very, very important
buman dimension to the decisionmaking that we are going to try
to do.

Thank you very much for being here.

Mr. McIntosH. Thank you, Mr. Walker.

Thank you all very, very much for coming here. We all appreciate
it. This will be enormously helpful to us, and we will take this in-
formation back with us. It will become part of the record and the
process in Washington as to move to speedup this drug approval
process.

We appreciate all of you coming. We may in fact from time to
time be in touch with you as we get new information or have addi-
tional questions.

Thank you.

Let us move now to the second panel of today’s schedule. This
is a panel of representatives of several of the drug and pharma-
ceutical companies here in the district. We will hear from their ex-
perts on suggestions they have for speeding the drug approval proc-
ess, which will be helpful to us as we go forward in this inquiry.

Let me say that this clock with the lights apparently is not worl
ing, so I have asked one of the staff members to hold up a little
sign at 3 minutes and then at 5 minutes. We will try to keep the
schedule going.

If you could all rise and please raise your right hand?

‘itnesses sworn.]

Mr. McINTosH. Let the record show the witnesses answered in

the affirmative.