59

In the final analysis, FDA’s decision whether to approve a new drug for marketing boils down to

two questions: ;

© Do the results of adequate and well-controlled studies provide substantial evidence of
effectiveness?

© Do the results show the product is safe under the conditions of use in the proposed
labeling? Safe, in this context, means that the benefits of the drug appear to outweigh its

risks, and that those risks are predictable.

Once a drug is approved for marketing, a sponsor (or manufacturer) may promote the use of that
drug for the approved indication or indications. This promotion can be to health care
practitioners, health maintenance organizations, health insurance plans, and directly to consumers.
After the initial approval, if a sponsor wants to change how its drug is manufactured or the
indications for which it is approved, a sponsor must submit an NDA supplement. Supplements
for approval of an additional use or indication are called efficacy supplements or supplemental
new drug applications. After review and approval by FDA, the new indication is added to the

approved labeling and can be promoted by the drug’s manufacturer.
THE IMPORTANCE OF THE EFFICACY STANDARD
The fundamental precept of drug regulation in this country is that drug products must be proven

safe and effective before they can be sold. The requirement that drug products be proven

effective, on the basis of adequate and well-controlled clinical studies, was first adopted by


123

Supplemental NDAs from companies when they know that “off-label” use is widespread.
The drug divisions at the FDA should work in tandem with the advertising division to
monitor the problem and find solutions. The acne medication, Retin-A, is an example of
how this could work. This year, the FDA approved the drug for the prevention of wrinkles,
but only after the agency prosecuted the manufacturer for unlawful promotional activities.
When the agency knows that dermatologists are regularly prescribing the drug for an
"off-label" use, a special division in charge of Supplemental NDAs should work with the
company to assure that they apply for the new indication -- especially, when a marketing
violation is well known.

“Off-Label"
Another quite devastating case involved companies that were subtly promoting the "off-
label" use of calcium channel blockers (approved to treat high blood pressure) for the
Prevention of heart attacks after a patient's first heart attack had occurred. This "off-label"
use became so pervasive, millions of heart attack victims were prescribed these drugs
until the NIH finally supported a controlled clinical trial proving to everyone's amazement
that the patients fared better on other approved drugs than those on the calcium channel
blockers. It has been suggested that this study alone proves the importance of FDA's
regulatory authority over “off-label” promotion, and the importance of supplemental
reviews and approvals. Thousands of people may have suffered unnecessary second
heart attacks because appropriate studies were not conducted with these drugs. if
doctors had only known that calcium channel blockers were ineffective in preventing
second heart attacks, they could have prescribed alternative, effective medicines.
Unfortunately, it was the American taxpayer who finally had to underwrite the research
that should have been done by the manufacturers.

Unsate “Ott-Label” Use
Even worse, tens of thousands of heart patients were killed by a family of drugs approved

to treat irregular heartbeats, known as antiarrhythmic drugs. Approved for the most
severely ill patients, these drugs were often prescribed "off-label" for patients with only
minor irregular heartbeats. Typically, the irregular heartbeats were so minor the patient


DiMasi - 2
times for new indications and compared them to the time spent to approve the applications for
the drugs’ original uses published over the last decade." The central hypothesis posited in
these studies was that, on average, new uses would be easier to review because most issues
and concerns regarding toxicology, chemistry, and manufacturing would have been addressed
in the original review. This reasonable hypothesis leads to the expectation that supplemental
indications would, on average, be reviewed more quickly than would the original uses.
Surprisingly, none of these studies have supported this expectation.

Although for some of the early periods analyzed in these studies average supplemental
new drug application (SNDA) approval times were less than the average times to approve the
original uses of these drugs, the differences were not statistically significant. For the more
recent periods analyzed, however, approval of SNDAs took longer on average than did the
original new drug applications (NDAs). As shown in Figure 1, the average approval time for
supplemental indications approved during 1984 to 1988 was 4.9 months longer than the
average approval time for the original indications of those drugs that had new uses approved
during this period. For the most recent period analyzed, 1989 to 1994, supplemental
indication approval times averaged 28.3 months, which was 3.7 months longer than the
average for the original indications. The differences between SNDA and NDA approval times
for these two periods were statistically significant.

A closer look at the data for the most recent period, however, does show some
improvement for the last two years. As shown in Figure 2, the average SNDA approval times
for 1993 and 1994 were 2.8 and 3.6 months shorter than the NDA approval times of the drugs

for which the new uses were approved. However, as was the case for earlier periods, the


149

pad that particular marketplace, we would not see that type of
ge.

The statement has also been made that there is a disincentive
to pursue additional indications at the end of a patent expiration.
The sad but true fact of life is that the same standard equation ap-
plies to loss of market share at the end of patent life whether
you've got one indication or whether you've got 20 indications. And
economics says that you want to build that base as large as pos-
sible so that when you only have half of it you are maximizing your
activities.

The third piece comes back to the incentive of companies to pur-
sue additional indications. I can speak from personal experience
when in 1989 we had a drug that was approved that had a state-
ment in it that it was not indicated for use in certain neurological
disorders. That was a significant incentive for us to do the work
and remove that statement from the package insert.

I assume that other manufacturers would have similar motiva-
tion if dissemination of information allowed for a statement in the
package insert that said the following are not indicated but they
have been found to be—there has been information found to be use-
ful.

Mr. Suays. It is such a strange term for me to get used to, “indi-
cated.” I come back from some of these hearings that I have, these
technical hearings, and I talk in front of my staff for a second, and
T'm not making sense to them. It is a funny term. How did the
term “indication” derive? It doesn’t seem funny to you, so it’s a
dumb question. Forget it. For me, it’s a very strange term.

Mr. KENNEDY. You would prefer approved for use?

Mr. Suays. No, you use the term “indication.”

Mr. KENNEDY. Yes.

Mr. Suays. And indication defined how?

Ms. MEvERs. A disease.

Mr. Suays. It’s a disease.

Mr. KENNEDY. For use in a particular disease, yes.

Mr. Suays. But why don’t we call it disease?

Mr. KENNEDY. Those of us who deal in the industry are guided
by FDA jargon, and that is how it is defined.

Mr. SHays. But we are going to give the FDA an opportunity to
defend itself on indication.

If you want to pick one question, you’ve got one question here.
In fact, I am going to let my staff member ask all three questions.
For our record, we would like these questions. And it is just an in-
dication I didn’t do my job well enough.

Ms. FINLEY. What actions has the pharmaceutical industry
taken, Dr. Kennedy, to update the labels of products where the
manufacturers are aware of extensive off-label use?

Mr. KENNEDY. Currently, the only option that is available to us
is to provide for supplemental indications, file for those, discuss
them with the FDA, and proceed to obtain them in any way we
can, either through doing the studies or using literature citations,
if allowed by the agency.

Ms. FINLEY. If the use in rare disease, cancer, and pediatric indi-
cations is 80 to 100 percent, as our other witnesses have testified,
clearly there must be some recognition on the part of the pharma-


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

BENJAMIN A. GILMAN, New York CARDISS COLLINS, Illinois

DAN BURTON, Indiana HENRY A. WAXMAN, California

J. DENNIS HASTERT, Illinois TOM LANTOS, California
CONSTANCE A. MORELLA, Maryland 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, Jr., 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 THURMAN,

DAVID M. McINTOSH, Indiana

jigan

GIL GUTKNECHT, Minnesota ELEANOR HOLMES NORTON, District of
MARK E. SOUDER, Indiana Columbia
WILLIAM J. MARTINI, New Jersey JAMES P. MORAN, Virginia
JOE SCARBOROUGH, Florida GENE GREEN, Texas
JOHN B. SHADEGG, Arizona CARRIE P. MEEK, Florida
MICHAEL PATRICK FLANAGAN, Illinois CHAKA FATTAH, Pennsylvania
CHARLES F. BASS, New Hampshire BILL BREWSTER,
STEVEN C. LATOURETTE, Ohio ‘TIM HOLDEN, Pennsylvania
MARSHALL “MARK” SANFORD, South ELIJAH E. CUMMINGS, Maryland

Carolina —
ROBERT “L. EHRLICH, Jr., Maryland BERNARD SANDERS, Vermont
SCOTT L. KLUG, Wisconsin (ndependent)

‘Jupita McCoy, Chief Clerk
Bup Myers, Minority Staff Director

SUBCOMMITTEE ON HUMAN RESOURCES AND INTERGOVERNMENTAL RELATIONS
CHRISTOPHER SHAYS, Connecticut, Chairman

MARK E. SOUDER, Ind Indiana EDOLPHUS TOWNS, New York
STEVEN SCHIFF, New Mexico TOM LANTOS, California
CONSTANCE A. MORELLA, Maryland BERNARD SANDERS, Vermont (Ind.)
THOMAS M. DAVIS, Virginia ‘THOMAS M. BARRETT, Wisconsin
DICK CHRYSLER, Michigan GENE GREEN, Texas
WILLIAM J. MARTINI, New Jersey CHAKA FATTAH, Pennsylvania
JOE SCARBOROUGH, Florida HENRY A. WAXMAN, California
MARSHALL “MARK” SANFORD, South
Carolina
Ex OFFICIO
WILLIAM F. CLINGER, Jr., Pennsylvania CARDISS COLLINS, Illinois
LAWRENCE J. HALLORAN, Director and


119

New Drug Application (SNDA). Therefore, pharmaceutical manufacturers have
determined that it doesn't make sense to spend such resources unless their market will
be substantially expanded by the new approval. Since the vast majority of
Pharmaceuticals are developed for common diseases with very large markets, few
manufacturers ever submit applications to the FDA for approval of new rare indications.

The National Organization for Rare Disorders (NORD) strongly believes that physicians
should continue to be permitted -- and, in some cases, even encouraged -- to prescribe
drugs for illnesses that are not on the label. Although, if the disease is not listed, then
physicians are not likely to know the proper dosage and possible side effects for the
secondary use. In fact, in the absence of any well-controlled clinical trials to prove
the safety and effectiveness for "off-label" indications, neither patients nor their
physicians can be assured that these drugs actually work and do not carry hidden
dangers.

Most rare diseases are without any treatment simply because they have not been studied
enough by the medical research community and knowledge of the underlying biochemical
or genetic defect that causes them is lacking; others are types of birth defects which have
irreversible symptoms (e.g. mental retardation). But increasingly, scientists are beginning
to understand the causes of some of these diseases, and their only weapons are drugs
that are already commercially available. Thus, discovery of treatments for orphan
diseases can be serendipitous through a "shotgun" approach of trying every drug in a
Class until you, hopefully, find one that works.

For example, scientists may know that a disease is caused by too much or not enough
of a chemical in the brain such as dopamine, so they experiment with drugs that were
designed to affect the level of dopamine (e.g. Parkinson's disease is linked to abnormally
low levels of dopamine, whereas schizophrenia is characterized by too much dopamine).
Every drug that affects dopamine levels may be examined and tried (the "shotgun
approach"), and if a drug is found to work on some patients, a paper will be published in
a medical journal. Thereafter, other doctors treating patients with the same rare disorder


68

‘on unlabeled uses and, where the data are sufficient to support a use, make the data
publicly available and invite potential sponsors, commercial or otherwise, to submit

applications based on that data.

© For products that are off-patent and require additional data to support an unlabeled use,

that the Agency explore ways to engender cooperative research efforts among interested

constituents to develop needed data.

Agency Accessibility and Guidance:

° To address uncertainty about the type and quantity of information that is needed to
establish safety and effectiveness for an efficacy supplement and the impression that data
requirements are very high, that the Agency publish guidance that makes clear the
scientific standards that are used in determining safety and effectiveness for efficacy

supplements.

© That the Agency take steps to assure that the case-specific guidance and support it
provides to sponsors and potential sponsors of supplemental indication applications is
comparable to the guidance that is afforded sponsors of new drug applications (first
approvals). This proposal would provide sponsors a ready means to clarify Agency data
expectations for unlabeled uses and thus help sponsors make better informed decisions as
to how to allocate their resources. Also, in conjunction with our commitment to adhere to

the Prescription Drug User Fee Act of 1992 (PDUFA) time frames, it will reinforce the

12


152

Mr. SHays. Donna Ferguson, thank you very much. I thank Tom
Costa, our clerk, for setting this up and Anne Marie Finley, who
has done a yeoman’s work in preparing for this hearing, as well as
minority counsel and help that we have received.

So thank you, and this hearing is adjourned.

(Whereupon, at 1:45 p.m., the subcommittee was adjourned.]

O°


19

information on the label about all conditions for which the drug is effective and how to use the
drug for that indication is important to public health. It is equally important to public health to
not have drugs being used for indications for which we have no assurance of safety and
effectiveness. We know there have been some problems and we are working on improved means
for getting well documented indications on the label. We are facilitating this by a number of
initiatives for all supplemental indications, including initiatives particularly geared to getting

oncology and pediatric indications on the label.

‘Our obligation to the public is to give physicians and other health care practitioners accurate
information in order for them to give patients the best care. An active medical and research
‘community means that uses of previously approved therapies will continue to be recognized.
While FDA generally does not sponsor these activities, we do want to ensure that their value is
fully applied for the public's benefit. The supplemental application and review process can help
‘ensure that the information generated by medical research is accurate, and in fact, does represent
a safe and effective new use for the public. The labeling of the drug for that new use, in turn,
assures that there is consistent and wide dissemination to practitioners about that new use and
proper dosing. With such information on the label, we can give practitioners the information they
need to get the correct therapy to their patients.

There are many constituencies interested in this issue, some of whom you heard from today. We
appreciate the Subcommittee’s interest in this important issue, and welcome the opportunity to

‘work with the Subcommittee and affected constituencies in developing ways to have drug

23


15

Two approaches exist for resolving the dilemma of whether and how
widely to allow promotion of off-label uses. One is to rely less
on the label as the determinant of what can and cannot be said
about a product. The other is to improve the process for
updating drug labels.

Change Restrictions Associated With the Label

Under one approach, promotion could be based partially or
entirely.on any of a variety of other sources of information, that.
are commonly accepted as reputable, such as the drug compendia
and refereed journals. The Congress used this strategy for
dealing with the previous off-label ‘crisis,* that of
reimbursement denials. In the Omnibus Budget Reconciliation Act
of 1993, the Congress defined the term ‘medically accepted
indication* to include not only the conditions incorporated in
the FDA-approved label but also uses

"supported by one or more citations which are included (or
approved for inclusion) in one-or more of the following
compendia: the American Hospital Formulary Service--Drug
Information, the American Medical Associations--Drug
Evaluation, the United States Pharmacopei:

-Drug

Page 9 GAO/T-HEHS-96-212


128

In conclusion, Mr. Chairman, | would like to commend the Subcommittee for caring about
the estimated 20 million Americans with rare "orphan diseases." In 1983, with passage
of the Orphan Drug Act, our nation only began to solve the problems associated with rare,
but serious health conditions. Today, there remains much more work to be done. The
1989 report of the National Commission on Orphan Diseases recommended that
Congress create a central "Office for Rare Diseases” that would coordinate the activities
of private industry with many federal rare disease programs which operate independently
now. This office would have saved time and resources by avoiding duplication and
waste. For example, if the offfice had been created as the Commission suggested, they
could have coordinated the FDA's "off-label" concerns with activities at the NIH, and
urged drug manufacturers to submit SNDAs on many marketed drugs. Today, however,
the federal government does not even obey its own mandates in the Orphan Drug Act for
regular meetings of the Orphan Products Board (OPB) nor its annual report to
Congress.

Clearly, in addition to the “off-label” use of drugs, other important issues persist.
Congress must turn a new corner and renew its commitment to people with orphan
diseases through a comprehensive, strategic action plan for rare disorders. Thank you
for your dedication to helping people with orphan diseases.


134

Mr. Towns. Thank you very much, Ms. Meyers. Dr. Kennedy.

Mr. KENNEDY. Thank you, Mr. Towns. I am William J. Kennedy,
vice president of drug regulatory affairs at Zeneca Pharmaceuticals
in Wilmington, DE. Zeneca is a research-based company that has
a distinguished record in providing innovative quality health care
products for patients and physicians.

Today, I appear before you on behalf of the Pharmaceutical Re-
search and Manufacturers of America, PhRMA, the trade associa-
tion for the research-based pharmaceutical industry. PhRMA com-
panies are world leaders in drug development, in discovery, respon-
sible for approximately 90 percent of the drugs that are discovered.

I greatly appreciate the chance to testify on supplemental new
drug applications, specifically applications for new indications of al-
ready approved drugs. I have submitted a complete written testi-
mony for the record and I will be very brief and will limit my com-
ments here to four major points.

There is a growing recognition that the supplemental NDA proc-
ess needs to be fixed. Industry has recognized this and has rec-
ommended changes for several years. Congress has identified this
as a problem. This hearing is proof of that.

In addition, legislation is pending in both the House and the Sen-
ate that acknowledges the need for changes in the review and the
approval of supplemental NDAs. Patient and medical groups, as
evidenced by their presence here today, want reform. And the FDA
has recognized this, as noted in the September 5th remarks by
Deputy Commissioner for Policy Bill Schultz to the Food and Drug
Law Institute.

We thank the FDA for recognizing that the supplemental NDA
process needs fixing and look forward to working with them to do
so. The problem, while serious, is not rampant within the FDA.
Some divisions have excellent records on reviewing and approving
supplemental NDAs, but other divisions have review times that are
considered unacceptable by all of the interested parties.

So the FDA has the solution to the review of supplemental NDAs
within its organization within the divisions that are working well.
FDA can and should be able to identify and formalize the best
practices in those divisions that are excelling.

FDA must then require these best practices be the standard in
all of the divisions and move the approval of supplemental NDAs
in all drug classes in a timely fashion. This goal must be articu-
lated and formalized in regulation, guidance and/or legislation.

But even when the supplemental NDA review process works effi-
ciently for all drugs, the need for dissemination of information on
off-label uses will continue because, as has been pointed out several
times this morning, state-of-the-art medicine will always be ahead
of the information that is in a drug’s package insert.

Dissemination of information is education. It is not promotion.
And the pharmaceutical industry plays a valid and a vital role in
providing that education.

I thank you for allowing me to testify and will answer any ques-
tions you might have.

[The prepared statement of Mr. Kennedy follows:]


14

children can be established. This regulation also explains about the need to submit additional
information supporting the pediatric use (e.g., postmarketing data, safety data, pharmacodynamic
data) in order to show that the drug can be used safely and effectively in children. A guidance
document has been published to assist sponsors in submitting these pediatric labeling supplements.

Also, CDER has begun focusing on the pediatric population throughout the clinical drug
development process, and we are integrating discussions of pediatric uses with sponsors
‘throughout the IND and NDA process. We also are working on more detailed guidances to

sponsors regarding early drug development, clinical trials and data review that may have pediatric

CDER also has been working with Pediatric Pharmacology Research Units (PPRU) in industry
regarding the development and conduct of clinical and pharmacokinetic studies of drugs in the
pediatric population, CDER has proposed clinical trials on specific drugs or pediatric
formulations without commercial sponsorship.

Office of Orphan Drug Development

‘As you can see, the Agency is committed to improving the way efficacy supplements are
reviewed; however, nothing points out the difficulties associated with efficacy supplements better
than drugs for rare diseases. While the Orphan Drug Act (ODA) has been called one of the most

successful pieces of legislation ever written, its effect on the number of supplements submitted has

18


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103

-4-
journals that report the results of the many ongoing clinical trials that are constantly
refining quality cancer care through new uses of approved drugs. Oncologists also

rely on continuing medical education programs, medical textbooks and other reliable

‘sources to keep current with quickly evolving cancer therapies.

Recognizing the possibly special circumstances of cancer drug development,
the American Society of Clinical Oncology has proposed a method for expediting
the supplemental new drug application (or SNDA) process, at least for anticancer
drugs. ASCO has suggested to FDA that it should permit pharmaceutical sponsors
to use reports of clinical trials in peer-reviewed medical journals as the basis for
SNDA approvals. These so-called literature-based SNDA’s (also known as “paper”
SNDA's) are authorized under current FDA law but are not routinely utilized. ASCO
believes that SNDA’s would be more widely pursued if FDA were receptive to
reports in the peer-reviewed literature as a basis for approval without insisting on
review of the raw data underlying those reports, which is generally perceived as the

agency's current policy.

However, even if the SNDA process is made more efficient by FDA, it still
will not be possible to keep pace with rapid developments in cancer research. For
this reason, ASCO has also urged FDA to relax its restrictions on dissemination of
reliable medical information by pharmaceutical sponsors. Among the types of

information that we believe are generally reliable are peer-reviewed medical


39

Mr. Towns. Well, then do you agree with Ms. Jaggar’s testimony
that with the passage of legislation in 1993, third party reimburse-
ment is no longer the problem it once was?

Mr. DIMasi. Third party reimbursement? I think that is still an
issue in this country.

Mr. Towns. A big issue, small issue, medium-sized issue?

Mr. DiMasi. I think it’s a fairly big issue. With the passage of
the User Fee Act, though I think that the supplemental indication
approval process has been improved.

Mr. Towns. Do you want to respond to that, Ms. Jaggar?

Mr. SILBERMAN. Our data were for cancer care and the 1993 leg-
islation was specifically for reimbursement for cancer chemo-
therapy. That is where our expertise lies. And in terms of the dimi-
nution of the reimbursement question, it is specifically for cancer.
We hear a lot less about those problems.

Reimbursement remains a constant problem and will probably
grow as a problem as insurers try to figure out what treatments
they will pay for and what treatments they won’t pay for. It isn’t
necessarily revolving around the label. There is a question of reim-
bursement for autologous bone marrow transplantation. There is
the question of reimbursement for length of hospital stay. There
are dozens of issues that surface every day about what insurers
will and won’t pay for, but in the cancer area the label has ceased
to be the limiting factor in terms of what insurers will or won't pay
for, almost entirely because of the 1993 OBRA legislation.

Mr. Towns. Thank you very much, and I yield back.

Mr. SOUDER [presiding]. Thank you. Mrs. Morella.

Mrs. MORELLA. I was, first of all, curious about GAO’s response
to the suggestions that you made when Mr. Souder asked in the
first question, Dr. DiMasi, because, again, they look like they make
some sense, the paper SNDA’s and submission by nonprofits. I
don’t know whether GAO has a comment on it. I am sure you have
probably explored it in conjunction with your report.

Ms. JAGGAR. We are aware that the FDA has a number of activi-
ties underway to work on the SNDA approval process. There are
draft guidance that they issued in December 1995. Comments have
been received in the interim. And my understanding is that in a
number of months they expect to finalize the guidance.

There have been improvements made in the process where they
have, in fact, accelerated approvals for certain drugs to remove
some of the bureaucratic barriers, if you will. This is an area that
we think further action should be taken.

Mrs. MorELLA. And the submissions by nonprofits, is that some-
thing that is relevant, appropriate?

Mr. SILBERMAN. There were five suggestions made by Dr. DiMasi
and they really mirror the issues that were discussed at length ear-
lier this year in terms of reform of the entire NDA process, which
is for the originals. Each has its attractions and each has its costs.

Third party review is really the question of in whose hands do
we want to place the responsibility for reviewing applications and
how much accountability should FDA have in that process. And
those issues have been debated at length and are similar here to
what they were for the original NDA’s.


64

WHAT WE ARE DOING TO ENCOURAGE EFFICACY SUPPLEMENTS

‘As previously mentioned, a subsequent indication is added to the labeling through the submission,
review and approval of an efficacy supplement. Once an efficacy supplement is approved, that

indication can be promoted by the drug's manufacturer.

There already are several good reasons for drug companies to submit efficacy supplements

These include the following:

© The manufacturer can promote the use, whether through the use of journal articles

or other means.

‘© Approval usually ensures that third-party payers will reimburse for the use, as

insurance companies virtually always pay for approved uses of drugs and devices

© Ashealth maintenance organizations (HMOs) continue to grow in size and
number, a sponsor's ability to get its drug included in the HMO's drug formulary

will be significantly enhanced.

© The physician, via the approved labeling, is given more complete information about
the drug's uses and proper dosing as well as its contraindications, adverse effects,

and other important information about the manufacturer's product.


148

But when you start looking at gastrointestinal drugs and drugs
for kidney disease and drugs for high blood pressure and drugs for
asthma and drugs for pain and drugs for anesthetics and so forth,
they don’t get labeled for children and infants typically because the
incremental market isn’t there to justify the investment.

Mr. Suays. Your point is, it is the same challenge that you have
for rare diseases.

Dr. KAUFFMAN. So our position has been that somehow we need
to address that economic disincentive by giving the company an in-
centive to be able to afford to develop it for children.

Mr. Suays. It is just kind of fascinating how, when the Govern-
ment sets up rules and regulations, that the marketplace finds
ways to adjust to the system. I’m getting the sense that the second-
ary use is the safety valve. It is compensating for the problem we
have of getting drugs in primary approval. I mean, that is the way
it strikes me.

So, I am going to put basically pediatrics and rare diseases in the
same economic challenge and I am going to put cancer in a dif-
ferent one. I realize we don’t have our witness there, but that is
where there is not a cure and so I am going to look everywhere to
find one.

Ms. MEyers. I mentioned, Congressman, before you came in that
there are approximately 200 different types of cancer and there are
only 4 or 5 of them that are prevalent. The rest are rare. They all
fit under the definition of an orphan disease. This entire problem
is really an orphan problem, whether it is children as orphans, or
cancer, or disease by disease, or all of them together.

Mr. SHAYS. Most cancers become an orphan problem?

Ms. MEYERS. That’s right.

Mr. Suays. Interesting.

Ms. MEYERS. Yes.

Mr. Suays. You are the only witness who represents the pharma-
ceutical industry here in terms of your presentation. en you
heard the dialog taking place between the first two panels and the
committee, what was your reaction? How did that relate to your
perspective?

Mr. KENNEDY. Well, I thought there was a lot of truth in it, but
there were a couple of misconceptions that kept coming through.
One is the misconception that if a company goes and gets approval
for a primary indication that there is no incentive—and they are
allowed to disseminate information on other uses—that there is no
incentive for them to pursue research. And that is certainly not the
case.

Mr. SHays. No incentive to be labeled—research to have second-
ary applications?

Mr. KENNEDY. Absolutely. And there are two sides of that
ment. One is with the ability or with the information available that
it is useful or has been tried and without that information.

Let me go to the first one. As a drug goes through the develop-
ment process, there are a series of activities that are laid out to
get these secondary indications. And as you monitor the success of
the drug in the marketplace, every time a new supplemental indi-
cation is approved, the use becomes wider. So that if we already



35

Mr. Suays. Doctor, thank you very much. It is a very interesting
issue and I look forward to hearing your response to some of the
questions. This is probably going to be more general in its focus
since this is the first hearing on this issue, and it is certainly some-
what of a new issue to me.

With that, Mr. Souder, I will have you start the questioning.

Mr. SoupER. Thank you. I wanted to first ask Dr. DiMasi, in the
different suggestions you had here—the third party review, the
paper SNDA’s, nonprofits, expansion of marketing exclusivity and
consistent reimbursement—what are some of the resistances, or
what would they be, to those changes? Is it going to be FDA? Is
it going to be the individual drug companies? Maybe you could go
through some of those because they sound like pretty reasonable

roposals.
p Mr. DiMasi. Well, with regard to paper SNDA’s, it should be
noted that it certainly would not be appropriate in all cases. It
would be appropriate in a limited number of cases.

Mr. SouDER. You say a greater use?

Mr. DiMasi. Pardon me?

Mr. SoupER. I think you said here a greater use of it.

Mr. DiMasi. Right.

Mr. SouDER. Not universal, but a greater use.

Mr. DiMasi. Right; absolutely.

Mr. SoupER. So is there a resistance to a greater use? Why
would there be any resistance to that? Are some of the studies
funded by certain companies? Is there a question on the accuracy
of the studies or just that that’s not the way it historically has been
done? What would be some of the reasons?

Mr. DIMasi. Well, historically, it has not been done very often.
The agency would naturally want to tread very carefully in this
area and not want to make mistakes and, indeed, would seek,
would desire, optimally definitive information. But, obviously, some
tradeoffs would have to be made.

Mr. SouDER. What would be some potential standards? Because
you said you wouldn’t have it universally be done. You would use
it greater; that they would like to, obviously, have complete control
of the experiments, which they wouldn’t have in this case. So what
would be some criteria to expand that use that would be reason-
able?

Mr. DIMasI. Well, I am perhaps, being an economist, not the best
person to discuss or establish criteria for acceptance of published
medical literature.

Mr. SoupER. OK, I was more looking for general. So you would
like to see it, but that would need to be researched and we would
need to have somebody else come in.

Mr. DIMAsl. Yes.

Mr. SOUDER. On the nonprofits, has that been done before where
people with a patient group have pulled together and petitioned?

Mr. DrMasi. Not to my knowledge.

Mr. SoupER. Has that ever been run by FDA or do you know if
that has ever been considered?

Mr. DiMast. I have never seen anything, formally put out in that
regard, either discussed or written.


67

Current proposals under discussion envision that we become: (1) more active in identifying
unlabeled uses, preliminarily assessing the data that support a use, and actively encouraging,
commercial sponsors and other interested parties to participate in pursuing approval of identified
uses; (2) more accessible and responsive to the broad array of constituents that have an interest in
whether uses are in labeling; and (3) more transparent in the standards we apply in making
decisions concerning safety and effectiveness. Proposals under consideration include the

following:

Identifying U .

© That the Agency take a leading role in coordinating with patient groups, commercial
sponsors, health care professional organizations, and health care purchasers to identify the
most important unlabeled uses and develop strategies as to how to get supplemental
applications submitted for those uses that seem to be supported by existing data, and to
develop needed data for uses that need to be more fully evaluated. Although off label use
is seen in all medical specialties, it is most widespread in certain areas, such as oncology
and pediatrics. Beginning with those specialties, we will work with practitioners and their
specialty associations to identify the off label uses that are most appropriate. We then will
present those findings to the sponsors of those drugs and urge them to work with us to get

the indications in the labeling.

. For products that are off-patent and for which there are likely adequate data to support an
unlabeled use, that the Agency explore ways independently to assemble and evaluate data

1


104

-5-
journals, standard medical textbooks and independently conducted educational
seminars. In the academic research environment in which | practice, obtaining the
latest data on new treatments is not usually a problem. Our colleagues in
nonacademic practice settings around the country may be less likely to have easy
and timely access to this potentially life-extending information. Oncologists are
trained to review such information with a critical eye, and we believe the risk that
they will be misled by independently derived medical data is much less than the risk
that they will not have access to it as quickly as possible for the benefit of their
patients. In general, then, ASCO supports regulatory policies that optimize the flow

of peer-reviewed, high quality, reliable medical information.

We note that most patient advocacy groups in the cancer community have
Positions that are consistent with ASCO’s on these issues, including the National
Coalition for Cancer Survivorship and various breast and prostate support groups as
well as the American Cancer Society. From my own experience as a patient, | can
attest to the intense desire of people with cancer to have access to as much
information as possible as quickly as possible. Knowing how much new
information about cancer therapy is being developed on a daily basis, | could not be
content with data that were accurate and up-to-date as of last year but perhaps

obsolete now.


126

One way to prioritize the review of supplemental indications, which consist primarily
of clinical data, would be to assign a small number of FDA reviewers to a separate
division or unit where review of Supplemental NDAs would be the priority. There
is no reason that supplemental applications should be put aside to await review
by division personnel who reviewed the original NDA. Once a drug is marketed,
a great deal is already known about its safety. Thus, a self-contained
Supplemental Review Division could review these applications more speedily
if they do not have to worry primarily about meeting deadlines for review of more
complicated New Chemical Entities (NCEs).

Administratively, the FDA should require centers and divisions to operate under the
same rules for review of Supplemental NDAs. Currently, we sense that some
areas within the FDA give a lower priority to Supplemental NDAs and they are
biased against them. Division directors should not be allowed to make judgements
based on their personal opinion of the importance or significance of a particular
drug. Supplemental applications should be categorized as "standard" or "priority"
reviews. SNDAs for "serious and life-threatening illnesses" should receive priority
Status, regardless of the condition's prevalence.

improve the supplemental review process. in general, companies should have
an easier, quicker application process for Supplemental NDAs than they do now.
However, modifications to the review process should not include an abandonment
of the efficacy standard nor bypass thorough, independent review of data and
information relevant to the new use. More rapid reviews will help reduce
disincentives for industry to submit applications seeking approval for "off-label"
uses, but only if unsolicited dissemination of information by the manufacturer
continues to be limited to FDA approved indications.


45

Mr. SILBERMAN. And in order to change the label. The use isn’t
completely consistent with the label. We know that to be the fact
through our data.

Mr. Says. And to what extent is it not reflective of all the use
of the drug? Some of these statistics boggle my mind.

Mr. SILBERMAN. What we showed was that more than half of the
cancer patients that we looked at were receiving at least one of
their drugs off-label.

Mr. SuHays. Yes. So it was off-label; it clearly wasn’t a primary
use. It wasn’t the original approval for that drug.

Mr. SILBERMAN. Right. That drug was typically approved for
some other form of cancer and was now being used for this form
of cancer.

Mr. Suays. So the bottom line is it is being used for something
that is not even on-label.

Mr. SILBERMAN. Right.

Mr. Suays. I don’t know quite what the end result is of it, but
that, to me, is a significant fact.

Mr. SILBERMAN. It says that the label will never, under the most
ideal circumstances, be able to keep up to date with the latest in
research. If you are a physician and I am your patient and an arti-
cle appears today that says that this drug might work against a
condition that I have that is necessarily fatal, I want you to give
me that drug.

Mr. Suays. I will tell you that if there is even the hint of a possi-
bility that it might be helpful, for someone who thinks they are
going to die with no hope in the world, they are going to contact
their doctor. The doctor is going to potentially prescribe it, maybe
not, and it is going to be used. And I understand. It is not a criti-
cism. I am just trying to understand the difference.

Mr. SILBERMAN. And there is no prohibition against that use.

Mr. SHays. OK. Why don’t we get to the information and pro-
motion, then we will get to you, Dr. DiMasi.

Mr. SILBERMAN. I will switch them around. I’ll talk about pro-
motion for a second.

Mr. Suays. OK.

Mr. SILBERMAN. In this environment, as Ms. Jaggar mentioned,
where pharmaceutical firms are really, for the first time, facing
enormous competition, the viability of the industry is, to some ex-
tent, at stake, and their ability to demonstrate the true utility of
their products. So, understandably, if they have some new use that
they think is worthwhile, they want to tell the world about it and
they want everybody to know about it. They want to be able to pro-
mote it.

Mr. Suays. Right.

Mr. SILBERMAN. On the other hand, the Food and Drug Adminis-
tration argues, legitimately, that in their responsibility through
FD&C to regulate promotion, they want to restrict promotion to
what they have already approved, to what FDA has already ap-
proved. And there is that dilemma. Do we allow use?

Mr. SHays. How is the dilemma resolved? By the way, to the
other committee members, we will do a second round, if you will,
because I would like to pursue this a little bit more so I am just
taking a little longer.


87

Mr. Suays. But I’m afraid we may be here all day. How does the
lack of efficacy and dosage information on products for which there
is extensive off-label use affect the quality of care for pediatric, can-
cer, and rare disease patients? That’s what I asked the first time
around.

Dr. FRIEDMAN. Well, I think each of those are different in com-
plex populations. If you take certain subgroups of patients, for ex-
ample, pediatric oncology patients, the amount of care that is given
to those patients is extraordinarily centralized into a relatively
small number of physicians and a relatively small number of insti-
tutions. The kind of information that they share with one another
with electronic data bases and others is really exceptional.

And, so, I think that for a group such as pediatric oncology pa-
tients, the majority of whom are treated in formal protocols and in
academic institutions or other tertiary care institutions, that there
is relatively little difference in the care of those Patients.

I believe that for other of the populations tt you have men-
tioned, it really becomes the quality of care that those individuals
are receiving, and I don’t think we have good data to say whether
or not those patients would benefit more or whether or not they
suffer.

Let me make a general statement, which is, leaving aside the in-
cidence of this and leaving aside what the theoretical concerns
might be, we think that there are powerful reasons to have the
label reflect as accurately as possible current care and, therefore,
we are moving to that. If this is a small problem, if it is a large
problem, we still think it is a problem which we can deal with not
100 percent, but that we can help in a very meaningful way. And
we are committed to that.

Mr. Suays. OK, question two: Why did the FDA take from April
27, 1993 to February 7, 1996, to compile a list of the most preva-
lent off-label uses of drugs after requesting this information for 10
academic r medical societies, and is i is delay a reflection of the low
priority the agency assigns to supplemental new drug applications
and the extent of offlabel u use? P

Dr. FRIEDMAN. I will be happy to deal with the second half of
that question.

Mr. Suays. Sure.

Dr. FRIEDMAN. I would ask Dr. Woodcock, please.

Dr. Woopcock. In 1993, the agency had a task force trying to
grapple with the prevalence of off-label use and requested informa-
tion from medical societies and other authoritative bodies on where
they thought the Problems were in off-label use. That information
was sent to us and we did compile it.

However, I think the question relates to the fact that our appli-
cation of that to each specific disease area and so it is hard for me
to answer the second part of the question. We did compile that in-
formation. We looked at it. We didn’t find it as helpful as we had
hoped at the time we received it. But now we are taking a second
I vk at that and we are attempting to go through disease by dis-
ease area and try to see if there is something we can target to
stimulate supplements in that area as part of Dr. Friedman’s work.

Dr. FRIEDMAN. But, I think what was surprising to the agency
was how few responses were gotten, that relatively few products


industry feels overly constrained by labels in its ability to
promote its products. This problem can be solved either by
relying on sources in addition to the label to define appropriate
promotion or by making improvements in the process for updating
the label. These two options are not necessarily mutually
exclusive and both have benefits and drawbacks.

DRUG LABELING AND OFP-LABEL DRUG USE

Amendments to the Federal Food, Drug, and Cosmetic (FD&C) Act of
1962 mandated that FDA evaluate the safety and effectiveness of
all new drugs. Before marketing a new drug in the United States,
the manufacturer (also called the "sponsor“) must obtain approval
from FDA by specifying both the medical conditions the drug is
effective against and the patients groups for whom the drug has
been shown to be effective. This information is contained in the
proposed "label" submitted by the sponsor. It is the sponsor's
responsibility to assemble all the evidence that would support
the uses proposed in the label.

When FDA reviews the sponsor's evidence for the drug's safety and
efficacy, it does so primarily for the conditions specified in
the sponsor's proposed label. Therefore, when FDA ‘approves* a
new drug application, this approval identifies only the uses for
which the manufacturer has demonstrated to FDA's satisfaction
substantial evidence of safety and effectivene:

Page 2 GAO/T-HEHS-96-212


OFF-LABEL DRUG USE AND FDA REVIEW OF
SUPPLEMENTAL DRUG APPLICATIONS

THURSDAY, SEPTEMBER 12, 1996

HOUSE OF REPRESENTATIVES,
SUBCOMMITTEE ON HUMAN RESOURCES AND
INTERGOVERNMENTAL RELATIONS,
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT,
Washington, DC.

The subcommittee met, pursuant to notice, at 10:05 a.m., in room
2247, Rayburn House fice Building, Hon. Christopher Shays
(chairman of the subcommittee) presiding.

Present: Representatives Shays, Souder, Morella, and Towns.

Staff present: Lawrence J. Halloran, staff director and counsel;
Anne Marie Finley, professional staff member; Thomas M. Costa,
clerk; Ronald Stroman, minority deputy staff director; and Michael
Kirby and Cheryl Phelps, minority professional staff members.

Mr. Suays. I would like to call this hearing to order and welcome
our panelists and our guests as well.

e convene this hearing to examine an important public health
issue: the extent and impact of what is known as off-label use of
prescription medications.

New drugs are approved or labeled, as safe and effective by the
Food and Drug Administration [FDA], for the treatment of certain
patients and diseases based on clinical studies conducted by the
drug sponsor. After approval, however, new research and the day-
to-day practice of medicine often result in the use of a drug for ad-
ditional indications, additional patients, or at different dosage lev-
els than originally approved.

How prevalent is off-label, or extra-label, drug use? For 50 mil-
lion children, 40 million cancer patients and 20 million Americans
suffering from rare, or orphan, diseases, most of their treatments
are off-label. In 1991, the General Accounting Office [GAO], found
off-label use of cancer drugs widespread, encompassing a third of
all drug dosages to those patients. More than half of the cancer pa-
tients in the GAO survey received at least one off-label drug.

As we will hear from our witnesses today, pediatric labeli:
also scarce, with up to 80 percent of drugs administered to children
prescribed for off-label or unapproved indications. It is estimated
that 90 percent of all rare disease treatments are off-label.

While a perfectly legal and necessary part of the healing arts, the
widespread off-label use of medicines raises significant public policy
and public health issues. Physicians need label information to treat
patients effectively. Patients need the same information to make
decisions about their own care. Both public and private health care

e})


150

ceutical manufacturers that those products are extensively used. If
the companies aren’t, as FDA testified, coming in with supple-
mental NDA’s, what is the proper role for the industry in that kind
of a situation?

Mr. KENNEDY. The industry is aware of the outside use. Surpris-
ingly, it doesn’t come in—I can only speak for my company. It
doesn’t come in to a significant degree to any type of market projec-
tions. It does come in to respect for stocking. You know, we cer-
tainly don’t want to have a drug that is going to be used for a lot
of off-label purposes and not have it available for its initial indica-

‘ion.

Ms. FINLEY. In your opinion, what is the a) propriate role of off-
label promotion in pediatric, rare disease, and. oncology situations?

Mr. KENNEDY. Our position has been very clear and we feel pro-
motion doesn’t have a role. Education has a very significant role in
providing the information to the physicians and the patients.

Ms. FINLEY. Would the other witnesses care to comment on that?

Ms. MEYERS. Well, I think that the testimony we had from the
physician who just left indicates that oncologists, in articular,
have to keep up with the medical literature. And they bb keep up
with the medical literature. They read these journals.

I don’t think that there is an issue. If doctors are reading the
medical journals, they are finding out this information without a
salesmen having to put it in front of their face. If you are treating
a rare type of cancer and you want to find out what is the very
latest treatment advance, you are going to find out the latest from
reading the latest journals.

So the question is promotion: whether a salesman has the right
to go into a doctor’s office and try to bring his attention to that
drug and try to sell it to him for an off-label use or whether they
freely can give the information when a physician asks for it.

Right now what the law says is, if the doctor asks for the infor-
mation, he can be given the information by the pharmaceutical
company. But the pharmaceutical company cannot go in there and
market the off-label use of a drug to the doctor without the invita-
tion. And that is the way it should stay.

Ms. FINLEY. Dr. Kauffman.

Dr. KAUFFMAN. I think it is important to recognize that physi-
cians access this information through multiple sources, and avail-
ability from a sponsor of a drug product is only one of many
sources. There are authoritative compendia out there that we ail
have on our desks which contain information on off-label uses, up-
dated information.

The database from the U.S. Pharmacopeia dispensing informa-
tion and the AMA drug evaluations is currently being merged and
will be available to physicians on CD-ROM as well as hard copy
in the near future. This is authoritative, peer-reviewed, annually
updated information which contains off-label information if you
want to access it there.

The American Hospital Formulary provides the same type of in-
formation, and then the current published periodical literature is
also available and continuing education courses and so forth.

So we shouldn’t be under the misconception that physicians are
totally dependent on this source for their education and informa-


42

Mr. Suays. Are you all set or do you have a few more questions?

Mrs. MorELLA. No, I’m all set. I think I interrupted you as you
were commenting on reimbursement issues in general from what
you found. I guess you would be looking at that too in the way of
research, what you hear, what the studies are indicating.

Mr. DIMasli. I really don’t have much to add to what the GAO
representatives have said. I think that while reimbursement may
have become less of a problem in the oncology area, it is still a
problem in other areas. And while the label may not be as impor-
tant in the oncology area, there are some related problems still as-
sociated with unlabeled uses in that area.

Mrs. MorELLA. And pharmaceutical companies, do you interact
with them or do they contact you in terms of the question that I
also asked regarding a role in promotion of off-label uses?

Mr. DiMast. Well, you have used the word “promotion.”

Mrs. MORELLA. As an economist, right?

Mr. DiMas1. Right. I do see a role for sort of loosening up restric-
tions on dissemination of information by manufacturers, although
that would not move into the realm of what is traditionally called
promotion.

Mr. Suays. Are you all set?

Mrs. MoRELLA. All set. Thank you, Mr. Chairman.

Mr. Suays. Let me just say I feel like we are beginning to speak
softer and softer and softer. I would like to get a little life in here.
This is a very serious issue.

The bottom line is, as I see it, and then I want you to respond.
The bottom line, as I see it, is this: You have drug companies that
basically have a drug tested at tremendous expense, and then once
it is on the market they and others find other uses for it. The ques-
tion is: Is there an incentive for them to find the least expensive
way to become a licensed drug? And then is there an incentive for
them to market and how would they do that, I would like to know,
the drug for other uses?

And, to me, what boggles my mind when I think about it, is we
test the drug and they have to go through extensive testing to see
that not only is the drug safe but it has efficacy, and then all the
secondary uses we have no testing that says that there is any effi-
cacy to it. And we don’t also know if it is safe. We don’t know at
what levels it is safe and not safe.

I am wondering if this isn’t just a big back door to enter into the
market. This is not a criticism of FDA. I mean, this committee has
not used either HCFA or FDA to be the whipping post. But is
there, because of the process, just a real incentive to find the easi-
est way to get on the market and then find all these other ways
to market the product to other people?

I mean, we have experts. You are all experts and we are really
getting into the general view of it, so we are not testing your ana-
lytical minds as much as I would like. But the bottom line is I
would like you to respond. First, my request is that you respond
to what I have just said. Put that into some perspective. I am going
to ask all three of you. Dr. Silberman, I am going to ask you to re-
spond as well.

Ms. Jaggar.


3

and applications for new uses of already approved products for cancer therapies to treat incurable,

advanced, or metastatic disease in patients without satisfactory alternative treatments.

This accelerated approval mechanism already has been used effectively. In June of this year, FDA
approved a supplemental new drug application, and the first therapy shown to improve
neurological recovery and decrease disability in adults following acuie ischemic stroke, the most
common type of stroke, caused by blood clots that block blood flow. FDA approved this
supplemental application for the stroke indication in less than three months. The drug, Activase
{altephase), a genetically engineered version of tissue plasminogen activator (t-PA), already was
approved as a blood clot dissolver to treat heart attacks and to dissolve clots in the artery going to
the lungs. The data supporting the approval of altephase as the first therapy for stroke came
primarily from a five-year clinical trial sponsored by the National Institute of Neurological

Disorders and Stroke (NINDS).

Pesiattic Label
‘We already are demonstrating how relatively limited data can be an adequate basis for pediatric
labeling. In December 1994, we promulgated new regulations that provide, in certain cases, for
pediatric uses to be included in the approved labeling without new clinical studies. Pursuant to
these regulations, when there is sufficient basis to conclude that the course of the disease and the
effects of the drug are sufficiently similar in children and adults, sponsors can rely on existing
studies in adults for evidence of effectiveness yet carry out studies of the drug's course through

the body (e.g, blood and tissue levels) so that the proper dosage for the use of that drug in

17


82

I think that behind all this is the 1962 efficacy standard where
Congress made a decision that when a drug goes on the market
and when a company promotes a drug, it must first prove that it
is effective. But at that time, Congress also had to grapple with the
question of how involved the Federal Government is going to get
in a doctor’s decision about prescribing a drug.

I think initially when one doesn’t think about it, it probably
seems like the doctor shouldn't prescribe the drug unless the drug
is proven to be effective. But, I think, as some of the panel discus-
sion reflected, that is just not realistic and it really does not ad-
vance the best practice of medicine.

A compromise was reached that we would be very rigorous in
terms of the label, but once the drug was on the market, we would
leave a lot of discretion to the doctor. That is not to say that we
are saying that the doctor should do anything he or she wants, but
the discretion is there.

And as we have gone around and around it, that may be a pretty
good place to be, even though it is not intellectually totally consist-
ent.

Mr. Suays. Mr. Schultz, I really appreciate that response be-
cause I think that is a very logical and clear explanation of why
we are here where we are today, and it may be a justification to
continue, given the alternatives may be not as good. And so I ap-
preciate you articulating it in that way.

I am struck by the fact that, in a sense, we do, obviously, have
two standards. It weights primarily more toward efficacy, I make
an assumption, than it does to safety because I make an assump-
tion that—and correct me if I am wrong—that for a drug to get on
the marketplace, for the most part, we really are pretty convinced
it is safe on the marketplace. But, obviously, you can misuse a drug
so I am now going to contradict myself. You could use it in a way
that could be totally destructive. But we make an assumption then
that it is unlikely we would use the drug that way.

The bigger question, and I am now making another assumption,
is it is really more an efficacy issue than a safety.

May I first just ask this question for the record? It is my under-
standing your primary statutory responsibility is to prove that a
drug is safe and to prove that it is effective for the purposes for
which it would be prescribed. Is that your primary statutory re-
sponsibility?

Mr. SCHULTZ. Or promoted.

Dr. FRIEDMAN. Labeled; yes.

Mr. Suays. Would Phas agree that the secondary use of drugs
tends to be more an efficacy issue than a safety issue?

Dr. FRIEDMAN. No, sir.

Mr. Suays. I saw, Dr. Woodcock, you shook your head the most,
so I am going to choose you first.

Dr. Woopcock. When FDA approves a drug, we approve it as
safe for its intended use. And that is a very different statement
than saying the drug is safe overall. Actually, no pharmacologically
active agent is totally safe.

And what we really do when we are approving a drug for an indi-
cation and a group of patients, is saying that the benefits, the dem-
onstrated benefits, outweigh the demonstrated risks. As you go fur-


OFF-LABEL DRUG USE AND FDA REVIEW OF
SUPPLEMENTAL DRUG APPLICATIONS

HEARING

BEFORE THE

SUBCOMMITTEE ON HUMAN RESOURCES
AND INTERGOVERNMENTAL RELATIONS

OF THE

COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES

ONE HUNDRED FOURTH CONGRESS
SECOND SESSION

SEPTEMBER 12, 1996

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

ae

U.S. GOVERNMENT PRINTING OFFICE
44-757 WASHINGTON : 1998

For sale by the U.S. Government Printing Office
‘Superintendent of Documents, Congressional Sales Office, Washington, DC 20402

ISBN 0-16-055961-8
3



108

Second, we recommend that Congress establish an independent
panel of experts in pediatric medicine composed of experts from, for
example, the Academy of Pediatrics, Pediatric Pharmacology Re-
sea: Unit Network, the U.S. Pharmacopeia, as well as other ex-
perts in pediatrics with authority to advise the FDA which new
drugs would have pediatric applications and the types of studies re-
quired in specific populations; to determine the need for studies of
specific marketed drugs in the pediatric population; and, advise the
FDA on the approvability of specific NDA’s for pediatric indica-
tions.

Third, we recommend that FDA establish age definitions for chil-
dren to be used for regulatory purposes as a standard throughout
the agency.

Fourth, the FDA, we feel should, in consultation with an inde-
pendent panel of experts in pediatric medicine, develop, prioritize,
and publish from the compendium of already approved patented
and off-patent drugs a list of drugs for which pediatric labeling is
necessary.

We would like to see the FDA authorized to fund studies re-
quired to accomplish pediatric labeling of off-patent drugs because
there is absolutely no economic incentive for a private sponsor to
do studies to Support labeling in off-patented drugs. Somehow, this
needs to be done because a number of drugs that are off-patent are
still not labeled for children and are used on a regular basis.

We recommend the FDA develop guidelines for the inclusion of
pregnant and/or lactating women in clinical trials of new drugs and
request such studies be performed when there is a high probability
the drug will be used in these populations.

And, last, the academy supports consideration of proposals to
provide economic incentives to companies who conduct pediatric
studies and who provide pediatric dosage formulations for new
drugs as well as already approved drugs. Consideration should be
given to patent extension for companies who complete pediatric
studies which lead to pediatric labeling.

Thank you, Mr. Towns, for the opportunity to present this impor-
tant health care issue to the committee. I have submitted a more
detailed written statement of my testimony for the record and I
would be happy to answer questions.

Mr. Towns. Your entire statement will be included in the record.
Let me just say to all of you it will.

[The prepared statement of Dr. Kauffman follows:]


131

On-label Indications: ‘Treatment of certain cancers including malignant lymphomas; multiple myeloma;
leukemias; mycosis fingoides (advanced disease); neuroblastoma (disseminated disease); adenocarcinoma of the
ovary; retinoblastoma; and carcinoma of the breast. Also indicated for the treatment of biopsy-proven “Minimal
Change” nephrotic syndrome in children.

Disease Name: Tourette Syndrome

Tourette Syndrome is a hereditary neurological movement disorder characterized by involuntary rapidly
repeated movements (tics and twitches) and uncontrollable vocalizations.

Drug Therapy: clonidine (Catapres)

‘On-label Indications: Indicated for the treatment of hypertension.

Drug Therapy: guanfacine hydrochloride (Tenex)
On-label Indications: Indicated for the treatment of hypertension.

Drug Therapy: fluphenazine hydrochloride (Prolixin)
On-label Indications: Indicated for the management of psychotic disorders.

Drug Therapy: imipramine hydrochloride (Tofranil)
‘On-label Indications: Indicated for relief of depression and childhood enuresis (bed wetting).

Drug Therapy: desipramine hydrochloride (Norpramin)
On-label Indications: Indicated for the treatment of depression.

Drug Therapy: nortriptyline hydrochloride (Pamelor)
On-label Indications: Indicated for the treatment of depression.

Drug Therapy: fluoxetine hydrochloride (Prozac)
On-label Indications: Indicated for the treatment of depression and obsessive-compulsive disorder (OCD).

Drug Therapy: clomipramine hydrochloride (Anafranil)
On-label Indications: Indicated for the treatment of obsessive-compulsive disorder (OCD).

Drug Therapy: sertraline hydrochloride (Zoloft)
‘On-label Indications: Indicated for the treatment of depression.

Disease Name: Tinnitus

Tinnitus is a condition characterized by the sensation of sound for which there is no external source.
Individuals with Tinnitus perceive sound when no environmental or external sounds are present. These sounds
have been described as clicking, buzzing, and/or ringing.

Drug Therapy: oxazepam (Serax)

On-label Indications: Indicated for the management of anxiety disorders. Alcoholics with acute
tremulousness, inebriation, or with anxiety associated with alcohol withdrawal.

Drug Therapy: clonazepam (Klonopin)
On-label Indications: Treatment of Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic
seizures, absence seizures (petit mal) who have failed to respond to succinimides.




109

Good Moming. I am Ralph Kauffman, MD, Professor of Pediatrics and Pharmacology at the
University of Missouri, Kansas City and Director of Medical Research at the Children’s Mercy
Hospital in Kansas City, Missouri. I am pleased to be here this morning on behalf of the American
Academy of Pediatrics, an organization representing 50,000 pediatricians dedicated to the health,
safety, and well-being of infants, children, adolescents, and young adults. I spent 16 years as either
amember of or consultant to the American Academy of Pediatrics Committee on Drugs, including
four years as Chairman. I should also add that 1 currently serve as a member of the Pediatric
Advisory Committee of the US Pharmacopoeia. I have devoted virtually my entire professional
career to the development of medications for the safe and effective treatment of diseases affecting
infants and children.

A critical issue and a high priority of pediatricians for the past 30 years has been the approval and
labeling of medications for use by infants, children and adolescents, It is shocking to note that few
drugs -- only approximately 20 percent of all drugs marketed in the United States ~- have been
labeled for use by infants and children. Eighty percent or more of drugs approved since 1962 have
been approved and labeled for use in adults with a disclaimer in the labeling that they are not
approved for use by children.

Approval of a drug for human use requires proof of efficacy and safety for its specific intended use
in human beings established by well controlled clinical trials. Once approved for specific
indications, the drug is labeled for interstate commerce. The labeling contains the approved
prescribing information including indications, contraindications, precautions, wamings, adverse
reactions, and dosage recommendations.

‘The Kefauver-Harris amendments to the Food and Drug Act passed in 1962 require that drugs be
demonstrated by well-controlled studies to be effective for their intended uses as well as safe. While
this provision has been applied to approval of drugs for use by adult patients it has not been extended
to use by infants and children in the labeling of a majority of drugs. This is particularly ironic since
several key Food and Drug statutes were passed in the aftermath of therapeutic catastrophes
involving children. The tragic deaths of 107 children from ingestion of elixir of sulfanilamide
brought about the passage of the Federal Food, Drug and Cosmetic Act of 1938, and later the tragic
malformations of infants caused by maternal use of thalidomide during pregnancy led to the 1962
Kefauver amendments to the Act.

Lack of pediatric labeling does not mean that the drugs are necessarily harmful, ineffective, or
contraindicated in children but simply that the clinical trials which satisfy the FDA requirements for
labeling were not conducted in children. Because of this, children have not shared in therapeutic
advances to the extent adult patients have nor have they been provided the same protections afforded
adult patients under the'1962 Kefauver-Harris amendments to the Food and Drug statutes. Though
there has been modest progress in the labeling of marketed drugs for pediatric use, it remains
sporadic and incompletely addressed.

Many reasons have been advanced for not studying and labeling drugs for use by children and
adolescents, but the leading issues are regulatory impediments, economic disincentives, and


30

DiMasi - 7
medical practice.
Educational Efforts. Programs organized by professional societies, such as the AMA,
can be developed to educate physicians about the optimal use of drugs for unlabeled

indications prior to labeling approval.

Conclusions

In conclusion, it is well accepted that some approved follow-on indications are more

medically important than the original indications, and that there is widespread use of already-

approved drugs for uses that are not on the product label. Optimal patient care requires that

physicians be informed about all of the effective treatments that are available for their patients.

It is imperative therefore that we have an efficient approval process for new indications and

that third-party payers recognize legitimate new uses even before they reach the label. Under

the user fee program, the FDA appears to have made substantial progress in achieving quicker

reviews of applications for both original and follow-on indications. The agency has also

recognized the problems associated with important off-label uses and has encouraged firms to

submit SNDAs for these uses. We need, however, to examine additional means to achieving

the ends that we all desire.
References

1.

Spivey RN, Lasagna L, Trimble AG. New indications for already-approved drugs:
time trends for the new drug application review phase. Clin Pharmacol Ther
1987;41(4):368-370.

DiMasi JA, Kaitin KI, Fernandez-Carol C, Lasagna L. New indications for already-
approved drugs: an analysis of regulatory review times. J Clin Pharmacol
1991;31(3):205-215.

DiMasi JA, Brown JS, Lasagna L. An analysis of regulatory review times of


89

and a more easy manner—allow a company to achieve a supple-
mental application.

Mr. SHAYS. So, the answer would be, yes; there is nothing that
restrains you from doing what you did with AIDS with other

Dr. FRIEDMAN. The answer is, we are in the process. That’s cor-
rect. Yes; we are in the process of doing it. I think we can do it
better and we are looking at ways of even further streamlining the
application process and simplifying it.

0, I don’t mean to sound arrogant and say we've already done
it and it’s fixed, but we are already moving in that direction. And
the numbers are very clear. The review times are dropping.

The problem is not so much the time it takes to review the appli-
cation; the problem is not enough applications are coming in. How
can we do our part to help create an environment to solicit or to
make it easier for companies or other interested parties to submit?
I think that is a challenge.

Mr. Suavs. You're talking about secondary labeling?

Dr. FRIEDMAN. Yes, sir.

Mr. SHAys. What prevents FDA from requiring pediatric studies
for NDA and SNDA submissions when drug sponsors do not in-
clude pediatric indications in their application?

Dr. Woopcock. What prevents us? It sounds like underlying
that is the suggestion that we should require for certain drugs that
there be pediatric data at the time of first approval of the drug. We
don’t have that requirement right now. That is true. And you
would have to imagine what sanctions we would impose if that
weren’t the case if we had that rule.

Mr. SCHULTZ. I just want to add though, this has been suggested
to us that we initially require it. And as Dr. Woodcock says, there
are some complexities in terms of what we would do if it weren’t
submitted. We have been asked to look at this, and we are doing
50.

Mr. Suays. The issue of literature-based information?

Mr. SCHULTZ. No; as I understand it, it is the issue of saying to
the companies when you submit a new drug application to us, that
if it is a drug that is likely to be used in children, particularly very
young children, one of the pieces that we want is a piece that
would allow us to evaluate it for children.

Mr. Suays. I am going on the assumption that more than three-
quarters of the drugs used for kids are unlabeled. I mean, maybe
I am starting with a false assumption, but I make that assumption.

Mr. ScHULTz. I think everybody agrees that it is a high percent-
age.

Mr. SHays. Close to that? I mean, am I unrealistic to say three-
quarters, basically?

Mr. Scuuttz. I don’t know the number. I believe that it is sub-
stantial.

Mr. Suays. The 80 percent, I think, came from studies, so I was
using three-quarters. I mean, isn’t it approximately 80 percent? I
would like to nail this one down. I mean, my understanding is that
the drugs used for kids, a lot of it is unlabeled and it is very, very

high.


84

Mr. SHays. Now, I then make an assumption that we would
more likely test something, if a human being is involved, that it is
going to be an adult before it is a child.

Dr. FRIEDMAN. In general, that is absolutely correct.

Mr. Suays. So, but for drug companies to bring a particular prod-
uct to the market that is supposedly directed at children, then
eventually it would be tested on children before it came to the mar-
ketplace, adults to children?

Dr. Woopcock. Do you want me to answer that?

Dr. FRIEDMAN. Please, go ahead.

Mr. Suays. What I am trying to understand is why we see a lot
of off-label use for children. And I am making an assumption that
I want to clarify that we are not as likely to utilize a drug on a
child in the protocol process.

Dr. Woopcock. Early in drug development, ordinarily, testing is
initiated in adults. And what you said is true for non-life-threaten-
ing diseases of children; that adults are tested and we have some
basic safety information or maybe quite a lot, or even the
might be approved and some efficacy information before testing it
in children.

But for diseases where children are targeted and for diseases
where children have life-threatening consequences, the pediatrician
community has really stood up and said these drugs for life-threat-
ening diseases in children should be tested early in children; chil-
dren have the same need for these kind of drugs. And so, ordi-
narily, they will be tested first with a very early safety testing in
adults and then childhood testing may start.

Mr. SHays. Now, this goes back to Mr. Schultz’s statement that
considering the extraordinary cost and time process of bringing a
drug into the marketplace, a rare disease is jst not going to get
attention, so it is logical to me that you would see off-label drugs
be more involved. I am not surprised by the statistic that it is close
to potentially 80 percent for rare diseases.

ut, what I would like to know is what is the protocol for a doc-
tor who has this interest in a rare disease looking at a drug and
then using it as off-label? What is the protocol and what is the po-
tential liability to that doctor?

Dr. FRIEDMAN. Perhaps I should have Dr. Haffner, who is in
charge of our orphan n products, answer that.

Mr. SHays. Sure. We welcome you to come up. You can just pick
up the mike if you like or you can just sit down a second. iy
don’t we bring an extra chair, Tom, and then we can do a musical
chair if someone else comes up.

Thank you, Doctor. Identify yourself again when you are sitting
down just so we know.

Dr. HAFFNER. Thank you. I am Marlene Haffner. I am director
of the Office of Orphan Products Development.

Mr. Suays. Did you hear what the question was?

Dr. HAFFNER. Would you restate it again, please?

Mr. Suays. I was hoping you would say yes, you heard what the
question was. I think the question involved the issue of rare dis-
eases, the issue of a doctor looking for a secondary use for this
drug, taking a drug on the marketplace and now having a second-
ary off-label use for it, and the question of protocol and also the


12

not necessarily inappropriate. In fact, a drug given off-label
may have been proven to be safer and more beneficial than any
drug labeled for that disease. This seemingly anomalous
situation can arise when research conducted subsequent to FDA
approval shows the drug's effectiveness in treating other
conditions, yet the label remains unrevised.8 For example, this
occurred with some frequency in the cancer area where drugs that
had been approved for one form of cancer were subsequently shown
to have efficacy against other cancers, yet the label remained
unchanged.

FDA acknowledges. the. potential benefits of off-label use. The
agency has stated that ‘under certain circumstances, off-label
uses of approved products are appropriate, rational, and accepted
medical practice.*9 FDA also recognizes that there are important
off-label uses of approved drugs and that physicians need to have
access to accurate information about these drugs. This being so,

why does evidence of extensive off-label use present a problem?

Our analysis shows that the nature of potential problems
associated with the drug label have changed. At the time we
collected the data on off-label drug use (spring 1990), the
SEfficacious uses of the drug can remain off the label for a
variety of reasons: (1) a supplemental application was not
submitted; (2) FDA did not feel the evidence in the application
was sufficient to warrant a change in the label; and (3) FDA is
still reviewing the supplemental application.

schultz, cited above.

Page 6 GAO/T-HEHS-96-212


54

STATEMENTS OF MICHAEL FRIEDMAN, DEPUTY COMMIS-
SIONER FOR OPERATIONS, FOOD AND DRUG ADMINISTRA-
TION, ACCOMPANIED BY WILLIAM SCHULTZ, DEPUTY COM-
MISSIONER FOR POLICY; DR. JANET WOODCOCK, DIRECTOR,
CENTER FOR DRUG EVALUATION AND RESEARCH; MARLENE
HAFFNER, DIRECTOR OF THE OFFICE OF ORPHAN PROD-
UCTS DEVELOPMENT; MURRAY LUMPKIN, DEPUTY CENTER
DIRECTOR, CENTER FOR DRUG EVALUATION AND RE-
SEARCH; AND SETH RAY, GENERAL COUNSEL'S OFFICE

Dr. FRIEDMAN. Thank you very much, sir. We will try and do
that. Let me recap, if I may, some of the important issues that
were previously mentioned.

The fundamental precept of drug regulation in this country is
that Praducts be proven safe and effective before they can be mar-
keted. The requirement that products be proven effective on the
basis of proper clinical studies was first adopted by the Congress
in 1962. In adding the concept of effectiveness to the Food, rug
and Cosmetic Act, Congress specifically intended that this require-
ment would apply not only to the initial indication for a drug, but
also to indications that come to light after that initial new drug ap-
plication has been approved.

The history of the Food, Drug and Cosmetic Act indicates that
Congress did not intend FDA to interfere with the practice of medi-
cine, and this is an issue that you were discussing just previously.
Thus, once a product is approved for marketing for a specific use,
FDA generally does not regulate how and for what purposes physi-
cians prescribe that product.

A licensed physician can prescribe a drug for other uses in treat-
ments, regimens, or patient populations that are not listed in the
FDA approved labeling, in keeping with appropriate standards of
medical practice. And these are the uses that are referred to as off-
label or unapproved or unlabeled or extra-labeled uses.

It is important to point out that there are two general situations
in which off-label use occurs, and you outlined those just pre-
viously. First, there is the situation in which strong scientific data
exist that support the off-label use and; second, there is the situa-
tion in which an off-label use exists but without sufficient support-
ing scientific data.

e FDA has an interest and ability to work with industry and
consumer groups to address the first situation where data exist.
We can clarify and simplify our processes so that industry will be
encouraged to submit the supportive data for an off-label use and,
thus, make it an on-label use.

The second situation where inadequate data, scientific data, to
support an off-label use exist is a more difficult one. It is not a situ-
ation that can be addressed specifically by FDA alone. All the in-
volved parties—and some of these constituencies have been de-
scribed. Before need to work together to identify incentives so that
industry and academia, patient groups and public groups and the
reimbursement industry, can work together to conduct the studies
necessary to know if an off-label use is effective and if it is appro-
priately safe and, therefore, should become part of the product
abel.


96

Page 2 - The Honorable Christopher Shays

FDA has conducted additional outreach activities with other

Federal and non-Federal programs in support of orphan product
development.

Information about the orphan products program is widely
accessible across agencies, as well as to professional and

public audiences through a variety of publications and,
recently, the Internet.

We hope this information is helpful. If we may be of any
further assistance, please let us

Sincerely,

eas

Diane E. amoeba
Associate Commissioner
for Legislative affairs
cc: The Honorable Edolphus Towns
Ranking Minority Member
Subcommittee on Human Resources
and Intergovernmental Relations



xi)

been minimal. The ODA’s most powerful incentive is it’s marketing exclusivity clause. Once an
orphan drug is approved, exclusivity gives sponsors legal protection against introduction of an
identical competing product for seven years, In addition, FDA’s Office of Orphan Drug
Development (OPD) assists in protocol design, and the ODA allows a sponsor of an orphan drug
to claim 50 percent of clinical trial costs as a credit against taxes owed.

But, of the 131 drugs approved since the passage of the ODA in 1982, only two have been
supplements. Most of the approvals have been for new chemical entities which have taken
advantage of the exclusivity provided by the ODA. The tax provisions which allow a 50% tax
credit for clinical trials are used infrequently according to the Internal Revenue Service.

Grants for research on orphan drugs are available under the ODA. The grants provision is aimed
at academic researchers and at smaller companies. Approximately 25% (64/267) of OPD grants
have been for investigations on new indications for approved drugs. The grant program is used
almost exclusively by the academic community, and few pharmaceutical companies have been
willing to submit the results of these studies to change labeling. Therefore, for small populations,
neither tax credits nor completed studies seem to provide enough incentive for submission of
supplemental indications. ‘The one situation in which there is some activity by larger companies is
‘when a patent is about to expire. A manufacturer will occasionally attempt to preserve a portion

of the drug’s market by obtaining the seven years of exclusivity provided by the ODA.

19


36

Mr. SouDER. What percentage, knowing that I am asking you
specific questions that may be beyond your scope, but what per-
centage do you think would fall into—you suggest that some of
these drugs’ secondary uses don’t make enough money for the com-
panies to pursue, and that is why you suggested nonprofits. Others,
if they received a longer period of time, would change the financial
incentives, as opposed to those where there are currently financial
incentives enough that they would petition, but that is the group
that is taking a long time.

Of those three, do you have any idea what percentage falls in the
different categories?

Mr. DrMasi. I have no data on that. I couldn’t give you any fig-
ures.

Mr. Souper. Ms. Jaggar, in your testimony, you suggested that
the concern has moved from the reimbursement question more to
a health-related question and whether there are adequate and ac-
curate prescriptions being given; whether, in fact, with promotion
either from—you didn’t say this per se but it was certainly there—
that if a company promotes it aggressively to physicians, they may
use it more or use it in ways that may not necessarily be tested
because they don’t have an independent test and they are depend-
ent upon the combination of journals, word of mouth, and the peo-
ple who come in to promote the drugs to them, and, also, any pa-
tients who may have heard about it either from other patients or
another place and don’t want to be denied it, and so that may be
driving the prescription.

How serious a problem is that, both from a health risk and a
cost-driven?

Ms. JAGGAR. Mr. Souder, the reimbursement issue does seem to
have resolved itself in the past—given that legislation in late 1993
enabled the Medicare Program to consider drugs that had off-label
uses if there were reputable sources that they could base the cov-
erage and reimbursement decisions on. Medicaid also. And that is
one reason that the reimbursement issue has diminished a bit in
terms of its importance.

Mr. Souper. But that is reimbursement from the patient’s per-
spective?

Ms. JaGGar. Right.

Mr. Soupber. Not necessarily from the Government’s or from the
company’s perspective?

Ms. JaGGar. Right. The reason that was important from the pa-
tient’s perspective is that if you couldn’t get reimbursement for
something, then you have much less access to that drug.

Mr. Souper. Right; I understand.

Ms. JAGGAR. What we are seeing in the changing health environ-
ment today is that pharmaceutical companies usually, or much
more often, are marketing to a larger entity that is making a deci-
sion that affects many different physicians. For example, say that
a company is marketing to a managed care organization and that
managed care organization has established a formulary. In that
formulary, they may choose among the seven drugs that would be
acceptable to treat a particular disease.

For economic reasons, the formulary of the managed care organi-
zation may select a particular drug and, of course, the pharma-


48

But I have a feeling that nobody is really suggesting a solution,
like we are all kind of wrestling because we don’t have a solution.
And maybe, it is like let sleeping dogs lie. Someday we may find
that we regret that we haven’t come to grips with this. I mean,
that is my take on what I am hearing as I heard Mr. Souder ask
questions, and Mrs. Morella.

Mr. Souder.

Mr. Souper. I wanted to try to figure out a little bit of a scale
question and I am trying to figure out how best to do this. I
thought it was very interesting, Dr. Silberman, your earlier re-
sponse on the paper SNDA’s that the potential benefit, if it is great
and the cost is low, that is not a big deal because we would take
those risks.

Obviously, the key thing here is that from a patient perspective,
if I was in that situation I would want the best concerned. If I am
a doctor, I don’t want any hands tied. As an employer, I have con-
cern about my insurance. If I was an insurance company, I would
be concerned about it. And if we are the Government and we are
paying a lot of this through Medicare and Medicaid, we have a con-
cern. And as taxpayers, we have a concern.

So part of this is a question of scale. Let me ask first off, and
this may be more to Dr. DiMasi as an economist, when somebody
makes a movie, they estimate as a firm how much they are going
to get the first run, second run, foreign, videotape, television rights,
and the cost.

Do companies, depending on the drug—I realize it would be a
wide variation—but do they have built into their costs a factor that
there is going to be a secondary usage and what percentage of the
drug market do they think is a secondary usage? I mean, that
could cover a wide range of drugs but, nevertheless, you have bad
debt allowances can vary a lot too. Any kind of expense category.

I mean, are we talking about something that is 2 percent of their
business overall, a half a percent, or is it 20 or 30 percent? And
if it is 30 percent for some drug categories, what kind of dollar
scale are we talking about?

Mr. DIMasi. Well, I don’t know what the dollar figures are. I
think it varies substantially from drug to drug. In some cases, the
firms will know as they are developing the initial indication that
there is another indication or several other indications that look
very promising. In many other cases, new uses are not discovered,
if you will, until many years after initial approval and those new
uses will not have been factored into their thinking and their plan-
ning.

Mr. SouDER. So it would just be like a bonus profit?

Mr. DIMasi. Yes, yes, exactly.

Mr. SOUDER. It must not be that regular or that big or companies
would have to have some sort of an accounting method; otherwise,
it would screw up long-term planning. You wouldn’t have value
stock markets. There has got to be some predictability that you ex-
pect if you are Eli-Lilly, to use an Indiana example, that you are
going to hit something like that. Or if you have a series of experi-
mental drugs in the AIDS area or you are testing, it is not likely
that just all of a sudden there is a big hit.


117
Mr. Chairman and Members of the Committee:

Thank you for inviting me to speak with you today. My name is Abbey Meyers and | am
President of the National Organization for Rare Disorders (NORD), a unique federation
of more than 140 non-profit voluntary health agencies dedicated to the identification,
treatment and cure of rare "orphan diseases." We are the patient group that worked for
the passage of the Orphan Drug Act of 1983. We continue to advocate for and monitor
the development of treatments that would not be developed without the incentives of this
lifesaving legislation.

This morning, | would like to address the serious problems associated with the “off-label”
uses of prescription drugs for the treatment of rare "orphan" diseases. While policy-
makers often recognize this problem as peculiar to cancer treatment or the pediatric uses
of adult drugs, the probiems of rare disorders are usually ignored. Regretfully, most
people affected by these unusual diseases do not have therapies which have been
approved by the Food and Drug Administration (FDA).

Since very few treatments are developed solely for these small populations of patients,
a physician's armamentarium is quite often limited to drugs that were developed and
marketed for more prevalent health conditions. Unfortunately, when no clinical trials are
ever conducted to prove their effectiveness on rare diseases, health insurance companies
often claim that such treatments remain "experimental" and, therefore, refuse to
reimburse for their use. In addition, physicians concerned about liability matters may
avoid prescribing such drugs even though patients may need them.

The majority of orphan diseases remain totally without any treatment; however, for
those rare disorders which are to some degree “treated” with pharmaceuticals,
NORD estimates that probably 90 percent must rely on "off-label" uses of drugs.


53

Mr. SHays. The hearing is resumed. We call on Dr. Friedman,
who is the Deputy Commissioner for Operations, Food and Drug
Administration, accompanied by William Schultz. And are you also
accompanied by Janet Woodcock?

Dr. FRIEDMAN. Yes, sir; and she should be here. She was just
outside the door.

Mr. SHays. Thank you. I am going to wait to swear all of you
in at the same time. I appreciate you being here.

Dr. FRIEDMAN. Our pleasure.

h Mr. Suays. Thank you. Welcome. If you would all raise your
ands.

Dr. FRIEDMAN. Sir, there are other people accompanying me that,
should questions be asked that they can answer, would you like
them to be sworn as well?

Mr. SHays. Yes; and if they don’t mind standing up. And we
would identify you. It is very nice of you to do that now. Could the
both of you identify yourselves?

Dr. HAFFNER. Marlene Haffner. I am director of the Office of Or-
phan Products Development.

Mr. Suavs. It is nice to have you here.

Dr. LUMPKIN. I am Murray Lumpkin. I am the deputy center di-
rector at the Center for Drug Evaluation and Research.

Mr. Suays. Thank you very much.

Mr. Ray. And my name is Seth Ray. I am with the general coun-
sel’s office.

Mr. Suays. If you all have cards to give to our recorder, that
would be helpful to her, I think. Correct?

Court REPorRTER. Yes; thank you.

Mr. SHays. OK. Now, when you said, “Yes, thank you,” are you
also recording yourself now? Are we going to see you in this tran-
script?

CourT REporTER. I can take it out.

Mr. Suays. Oh, no; you can stay on. If you would raise your right
hands, please.

[Witnesses sworn.]

Mr. SHays. And I would like to note for the record that Dr.
Friedman did a yeoman’s job in trying to raise his injured right
arm. Thank you. I would have been a little more thoughtful of you
had I thought about it first.

My sense is that, Dr. Friedman, you are going to be giving testi-
mony and you are accompanied by William Schultz and Janet
Woodcock. And then there are other members who might respond
to a question, and we welcome that as well.

Dr. FRIEDMAN. That is correct, sir.

Mr. SHays. Let me just say that we welcome your testimony,
however long, however you feel you need to get your story out. We
welcome you here.

Dr. FRIEDMAN. Thank you very much, Mr. Chairman.

Mr. SHays. I’m sorry to interrupt just before you start. Given
that you have already heard questioning and dialog, anything you
want to interject about what you have heard, comments and so on,
feel free to amend your statement or whatever based on that. I wel-
come you responding to questions you have already heard before
we ask the second time, if you feel it is appropriate.


138

goals, SNDAs are being reviewed more rapidly, but in general, review of supplemental
applications has not been a priority at FDA.

There are examples where FDA has approved SNDAs with admirable efficiency, the
best that can be expected. In others, the time to approval is close to acceptable but could
be improved. Finally, as you’ve already heard from experts at Tufts University and the
GAO, there are approval times that are just unacceptable to the industry, to patients, to
you in Congress, and to FDA. What we should all work toward is helping the ageacy
identify the best practices that are providing the most efficient approvals so that the
standard time to approval in the future is as close as possible to the best times achieved
now.

Why is there this disparity in approval times? Because there are inconsistencies
from FDA division to FDA division in the requirements for an SNDA. There are even
inconsistencies within divisions regarding requirements. What is happening, what are the
‘consequences, and what can be done?

‘The worst case can be due to the strict requirement that efficacy be proven for each
new indication in the same way as it is in the original NDA ~ by two large, well-controlled,
double-blind clinical trials, The science of clinical research and study design has changed
greatly in recent years. One large, well-controlled clinical trial, supported by information
learned in other smaller supportive trials, can in most cases provide ample evidence to
prove efficacy. FDA reform legislation now before the Congress should reflect this current

scientific reality, But whatever the efficacy standard is for an NDA, requiring the same


49

Mr. DiMasi. True. And if you are a large enough company, if you
have a large enough portfolio of drugs in development, you can per-
haps be reasonably good in terms of predicting what you are going
to get from new indications.

It also depends a lot on what area you are working in. Our data
indicate that approved new uses tend to be concentrated in certain
therapeutic categories, relative to the way that original uses are
distributed. In particular, there are lots of approved new indica-
tions.

Mr. SoupeER. But I’m trying to get back to my question. You are
trying to explain the complexity, and that is difficult to do in the
limited timeframe we have here. But I think we are impressed that
it is complex, but we don’t have a feel for the scale here. Dollar-
wise, I mean, are most of these things medicines that cost $2 and
they are prescribing them here and there, or are we talking some-
thing that is potentially a significant percentage of all the drug
market? And that, indeed, as we discover new things, let me try
my second question. Do either of you have a comment on the first
part?

Mr. SILBERMAN. I think we actually have some data on that.

Mr. Souper. OK, I’d like that.

Mr. Suays. If the gentleman will yield, what we are really, I
think, trying to get—and correct me if I am wrong—is there a per-
cent of off-label use that comprises the market? I’m sure we can get
it from someone. And, if so, what is that? And is this unique to
some drugs or many drugs? Do most drugs that come on the mar-
ket end up having off-label use, or is it just some and then those
some have significant use?

Is that what you're getting at?

Mr. SOUDER. Yes.

Mr. SILBERMAN. The only two studies that I am familiar with
that put precise estimates on it are the study we did in cancer and
then another study that was published this year in AIDS. I think
that in the rare diseases area and the pediatric area there is such
widespread acknowledgment of the prevalence of this that no one
is going to bother to actually do the study because whether it is 85
percent or 89 percent, we know it’s very high.

Now, in the cancer area——

Mr. Souper. And pediatrics as well?

Mr. SILBERMAN. Pediatrics as well. I mean, everybody knows
that lots of drugs are not labeled for children that are given to chil-
dren for diseases that occur in children, like asthma. You know,
fairly common pediatric illnesses. °

In the cancer area, we are, I guess, cursed with the strange re-
ality that the most prevalent diseases are the ones that are least
susceptible to chemotherapy and the ones that take the longest
time to kill you. So we’re talking about the solid tumors—breast
cancer, lung cancer. There are the hematological disorders, dis-
eases of the blood, lymphoma and leukemia, that are very quick
and respond to chemotherapy.

Now, if I am going to do a clinical trial to demonstrate that my
drug has some efficacy against a cancer, I want to do it in a popu-
lation where I know the answer quickly. You know, if you don’t
have a response in a leukemia patient, that patient dies quickly.


18

efforts to facilitate getting more indications into product labeling when the indications are
‘supported by adequate data, we strongly oppose proposals that, in seeking to address the
unlabeled use problem, either directly or indirectly compromise the efficacy standard. We would
‘oppose any initiative to lessen the efficacy standard for supplemental indications. We also would
‘oppose any initiative that seeks to address this problem by allowing sponsors to promote
unlabeled uses. Such promotion diminishes the efficacy standard by reducing the incentive to
adequately study new product uses.

Adequate and well-controlled studies, as currently required, are a major part of ensuring the first-
Tate medical care that the health care system in this country provides. Consider some of the
additional uses that FDA has approved on the basis of such studies -- for example, timolol,
propranolol, metoprolol, and atenolol to improve the survival of heart attack patients, taxol for
breast cancer, and interferon-alpha 2b for chronic hepatitis B and C. Without the requirement to
submit clinical studies to prove that drugs are safe and effective for their intended uses, it is far
less likely that we would know the true value of these drugs in decreasing mortality in heart attack
patients, in delaying or preventing breast cancer recurrence, and in treating chronic hepatitis B and
Cc.

CONCLUSION

Public confidence in drug therapy has been built on the recognized rigor of FDA's approval

process. FDA recognizes that there are important uses of drugs that are not on the label. Having

22


88

were even suggested. When the blanket invitation was issued to
say what would you like us to consider, what do you think is
worthwhile, very few specific answers came back.

When queried—and this is not a scientific sampling. This is just
particular people being asked. When queried, some individuals said
we would prefer not to have things designated as supplemental ap-
plications because that will then call into question what is and
what it is not on the label and we prefer the ambiguity of the cur-
rent situation. Others said there isn’t a problem now and, there-
fore, we don’t want to do this.

Another part of this issue is—and I don’t mean to oversimplify
this and you need to ask industry directly--but, at least, two
things occur to us from an industry perspective as to why there is
less enthusiasm for submitting a supplemental indication.

One is that the penetration of the market is so complete and the
acceptance of the drug is so good right now that they don’t need—
there is no promotion. There is no other incentive that they would
have by submitting an application. This is a good product. Its use
is effective. People widely accept it. Therefore, why should they go
to the trouble to submit that paperwork?

Mr. Suays. Let me just ask you in other words, what I think I
hear you saying is that the two negatives for not being on label is
they can’t promote, but you’re saying they may not have to.

Dr. FRIEDMAN. At least one situation they may not have to be-
cause it is already widely recognized as a good treatment; every-
body likes it and uses it.

Mr. SHays. And then the only other incentive for them to do it
would be is if patients weren’t being reimbursed.

Dr. FRIEDMAN. There are others as well. But the second, as I see
it, major disincentive is that there is a small economic incentive.
The product may be useful. They may have some of the data.

But it may be near the expiration of whatever patent protection
they have or there are generic products for this very same applica-
tion, and that if a company spends the resources to get that supple-
mental application approved, generics may benefit from that, not
necessari ly themselves. And so they don’t see a vested interest in

loing it.

Again, there are many other incentives that companies have. I
am not being critical of companies. I am just saying these are two
of the disincentives that we can perceive.

Mr. Suays. Before I call on my colleague I just want to, for the
record, get these questions on. They really do deserve to be asked.

If the agency can use its discretion to evaluate applications for
AIDS with less initial clinical data and greater access for patients
during the review process, why can’t the agency utilize its discre-
tion to develop more expeditious review processes for oncology, pe-
diatric, and rare disease drugs, taking into account the special
challenges of clinical trial designs to demonstrate efficacy in these
populations? It’s a long question, but I think you get the gist of it.

ir. FRIEDMAN. And you are absolutely right. As I pointed out in
the initiatives that we announced in the springtime, we took a
major step in oncology of using objective response as a surrogate
endpoint to more rapidly allow—and with a smaller amount of data


43

Ms. JAGGaR. Mr. Shays, again, the issue is promotion, exactly as
you have framed it. What is key here is that when FDA approves
a drug, then the pharmaceutical company can promote it when it
is on-label. When something is off-label, there are substantial and
extensive restrictions and constraints on that promotion process.

Mr. Suays. But it is just limited to promotion; it is not limited
to use.

Ms. JaGGar. True.

Mr. Suays. I mean, reimbursement is a factor as well.

Ms. JAGGAR. True. You don’t want to limit use because the prac-
tice of medicine, as you know, is both science and art and involves
individuals and physicians looking at new ways to use drugs—
sometimes in combination, sometimes for purposes not used be-
fore—to see if they work.

Mr. Suays. But isn’t that a double standard? And I’m going to
get to all of you. Isn’t that an incredible double standard? We have
one test to get in the market and then—and you don’t use that
same argument to get in the market. You don’t say, well, a doctor
is just deciding if they want to use it. They have to have that drug
licensed. The sellers have to have it licensed before they can put
it in the marketplace. And so you are using two different stand-
ards.

Ms. Jaccar. I can see how it could look like a double standard,
and yet, if you look at the practicalities of what really is possible
in terms of clinical research and in terms of medicine and the con-
tributions that are made, the role of the FDA and the role of phar-
maceutical companies, if you were to put in place a standard that
required that kind of clinical research for every single use, you
would really constrain the availability of drugs.

Mr. Suays. I am not suggesting that. I am just suggesting it is
an amazing double standard. And if the argument applies to the
secondary uses, in your argument why doesn’t it apply to primary
uses? I’m sorry. Why don’t you finish.

Ms. JaGGarR. I would just say that one of the reasons that this
is of concern and that FDA is dealing with it very carefully is, they
don’t want to remove the incentive that the clinical trials be done.
In other words, when something is promoted, it is much more like-
ly to be used. It is widely known that the market increases. That
is definitely a driver.

_ So if, in order to promote, approval is required, that is an incen-
tive for pharmaceutical companies to seek that approval. And
FDA’s job is to make the process be expeditious, as cost-effective
as possible, so that we have accurate information and complete in-
formation.

Mr. Suays. Are you talking about primary use or secondary use?

Ms. JAGGaR. Secondary use, all uses.

Mr. Suays. Even primary?

Ms. JaGcar. Right.

Mr. Suays. Dr. Silberman.

Mr. SILBERMAN. If I could divide this into four issues; first of all,
the label, the use of the drug, the information available about the
drug, and then promotion of the drug. And I think that there is an
intersection of all those, and if I could just try and disaggregate
those.


129
Attachment “A”

A SAMPLE OF “OFF-LABEL” USES OF DRUGS
FOR TREATMENT OF RARE DISEASES

Disease Name: Aicardi Syndrome

Aicardi Syndrome is an extremely rare congenital disorder in which the structure linking the two cerebral
hemispheres of the brain (corpus callosum) fails to develop. Absence of the corpus callosum is associated with
frequent convulsive seizures, abnormalities of the retina and the thin membrane (choroid) that covers the retina
Of the eyes, and/or mental retardation.

Drug Therapy: adrenocorticotropic hormone (ACTH)

On-label Indications: West syndrome and certain seizure disorders, multiple sclerosis, endocrine disorders,
acute episodes of rheumatic disorders, collagen diseases, inflammatory dermatologic and eye diseases, certain
respiratory and hematologic disorders, leukemia and lymphomas, ulcerative colitis.

Drug Therapy: valproic acid (Depakene, Depakote)

‘On-label Indications: Indicated for use as sole and adjunctive therapy in the treatment of simple and complex
absence seizures and adjunctively in patients with multiple seizure types that include absence seizures (Note:
Many anticonvulsant medications are approved for one or two types of seizures, but are used for other types of
seizures that are not on the label).

Disease Name: Fibrosing Alveolitis

Fibrosing Alveolitis is a rare inflammatory disease of the lungs characterized by the abnormal formation of
Jibrous tissue between tiny air sacs (alveoli) or ducts in the lungs. Symptoms may include coughing, rapid,
shallow breathing occurring with moderate exercise, and an abnormal bluish skin coloration.

Drug Therapy: azathioprine (Imuran)

On-tabel Indications: Indicated as adjunct for the prevention of rejection in renal transplantation. Indicated for
the management of severe, active rheumatoid arthritis unresponsive to rest, aspirin or other nonsteroidal anti-
inflammatory drugs.

Disease Name: Alternating Hemiplegia of Childhood

Alternating Hemiplegia of Childhood (AHC) is a rare neurological disorder characterized by frequent,
temporary episodes of paralysis on one side of the body (hemiplegia), temporary paralysis of the muscles that
control eye movements (transient ocular palsies), sudden, involuntary movements of limbs and facial muscles
(choreoathetosis) and/or excessive sweating with changes in skin color and body temperature (autonomic
nervous system dysfunction).

Drug Therapy: calcium channel blockers (¢.g., Cardizem, Norvasc, Procardia)

On-label Indications: Treatment of hypertension and angina.

Disease Name: Acquired Agranulocytosis

Acquired Agramulocytosis is a rare drug-induced blood disorder characterized by a severe reduction in the
number of white blood cells (granulocytes) in the circulating blood. Symptoms may include increased
susceptibility to a variety of bacterial infections (causing flu-like symptoms) and painful ulcers in mucous
membranes that line the mouth and/or the gastrointestinal tract.

Drug Therapy: gammaglobulin (Immune Globulin [Human])

On-tabel Indications: Indicated for the treatment of Hepatitis A, measles, immunoglobulin deficiencies,
varicella and rubella.


118

RECOMMENDATIONS:

While we commend the efforts of the FDA at internally reforming the agency, we are concemed that
the regulations of December, 1994 meant to encourage the inclusion of pediatric data in FDA-
approved labeling, have failed to achieve their goal. The American Academy of Pediatrics believes
additional steps must be taken to augment the FDA initiatives and supports the following measures
to overcome some of the principal obstacles to labeling medications for children:

AAP recommends that Congress provide the FDA with specific statutory authority and
responsibility to make studies in appropriate pediatric populations a requirement during
clinical trials of each newdrug with potential use by children, unless it is determined by a
panel of experts in pediatric medicine that there will be no use of that drug in children and/or
adolescents.

The Congress should establish an independent panel of experts in pediatric medicine,
composed of experts from the American Academy of Pediatrics, the Pediatric Pharmacology
Research Unit Network, U.S. Pharmacopoeia, as well as other experts in pediatric research
with authority to:

- advise FDA which new drugs would have pediatric applications and the types of
studies required in specific pediatric populations;

= determine the need for studies of specific marketed drugs in the pediatric population;
- advise the FDA on the approvability of specific NDA’s;

FDA should establish age definitions for children to be used for regulatory purposes as the
standard throughout the Agency. The AAP recommends the following age breakdown:

= child means a neonate, infant, young child, or adolescent;

- neonate means a child from birth to the age of one month (30 days);

- infant means a child from the age of one month to the age of two years;

= young child means a child from the age of two years to the age of twelve years;

= adolescent means a child front the age of twelve to the age of eighteen years.
The FDA should, in consultation with the independent panel of experts in pediatric
medicine, develop, prioritize and publish from the compendium of already approved and
patented drugs, an initial list of drugs for which pediatric labeling is necessary.

‘The FDA should be authorized, in consultation with the independent panel of experts in
pediatric medicine, to identify, prioritize, and publish a list of off-patent drugs for which


122

‘The FDA and Supplemental New Drug Applications

The FDA may be aware that a drug or group of drugs has wide-ranging "off-label" uses,
but their jurisdiction ends at policing promotional and marketing activities. They cannot
approve a supplemental indication if no company applies for approval. Academic
‘scientists cannot apply for changes in labeling on a drug that is proprietary to a company.
In many cases, drugs that are considered standard therapy for a rare disease may be old
“off-patent" drugs manufactured by several generic companies. In these instances, no
company will invest funds nor manpower into seeking a supplemental approval for a drug
they do not own and cannot patent. Even when a company can get a "use patent" for
the new indication, when a patient fills a prescription the pharmacist usually fills it with the
lowest cost generic drug and does not look at the label. And even if a disease is listed
‘on one particular brand of generic drug, the pharmacist does not know the patients’
diagnosis and, therefore, cannot abide by the labeling.

On the other hand, when companies are willing to support the research necessary to add
a rare disease to the label of a patented drug, they often find the "Supplemental NDA"
Process too burdensome. In too many cases, the FDA appears to consider these
applications as a low priority and seems to take an inordinate amount of time to approve
them. While there is substantia! public and political pressure put on the agency to
approve new drugs, there is very little in the way of timely action on Supplemental
NDA's.

There seems to be no sense of urgency to do anything about this problem.
Unfortunately, for the American patients and families who find themselves deeply in debt
because their insurance will not reimburse them for an "unapproved" treatment, the day
arrives when they can no longer afford the medical care they need -- a sad predicament
for anyone with a serious or chronic disease.

it seems that no one at the FDA currently has responsibility for monitoring this problem,
although, they:do have the responsibility to police the market for "off-label" promotional
activities such as advertising. The agency should be in the practice of soliciting


127

Role for Congress:

. Congress should create incentives to entice manufacturers into adding new
indications to the labeling of marketed drugs for the treatment of serious and life-
threatening conditions, particularly rare diseases and pediatric uses. These
incentives should include a generous tax credit for the cost of well-controlled
clinical trials that are required by the FDA. if Congress removes the economic
disincentives that make companies hesitant to invest in supplemental research,
there would be no excuse for companies not to file a Supplemental NDA.

However, Congress should not create financial incentives that are disproportionate
to the amount of money a company must invest for a supplemental approval. The
amount of a tax credit should also have a direct relationship to the needs of
society. For example, getting a marketed drug approved as a diet, wrinkle or
baldness remedy is not as important as a supplemental approval for life-threatening
diseases such as Lou Gehrig's Disease, cystic fibrosis, cancer, or AIDS.

f dustry:

. The pharmaceutical industry must become more responsive to the needs of
medically disenfranchised Americans. For millions of men, women, and children
suffering with serious, chronic and life-threatening health problems, drug
companies often hold the key to their future. When a drug is known to have an
important "off-label" use, manufacturers should have a social responsibility
for the safety and effectiveness of their products. Only the industry has enough
resources to fund the necessary research to assure physicians and patients that
the treatment is safe and effective at appropriate doses in a target population.
Indeed, it is true that all companies must keep a close eye always focused
‘on the "bottom line," but they aiso have a responsibilty to assure American patients
that they will do no harm. ignoring “off-label" uses, which the industry knows is
pervasive, certainly causes harm.


151

tion, but it is one important source. And my only plea would be,
if this is done in the future, that the sources that are used to do
this are very carefully defined so that we can be sure that only
sources that are rigorously peer-reviewed and represent the best in
scientific information are used.

Ms. FINLEY. Thank you, Dr. Kauffman. Thank you, Mr. Chair-
man.

Mr. Suays. Thank you. I am happy you asked the questions. Let
me say we are all done. I don’t know if you all would like to make
a comment. I would love to invite the FDA if they would like to
come up just to make any observation they would like before we
leave. You don’t have to defend your concept on indication.

Dr. FRIEDMAN. No, nor will I defend our use of language because
that is treacherous as well.

Mr. Suays. You didn’t create it, did you?

Dr. FRIEDMAN. I would like to just make one very general and
simple comment. We very much appreciate the chance to partici-
pate in this discussion today. This is a very important issue, as all
the different constituencies have spoken in a thoughtful and re-
spectful and sensitive manner, recognizing that no one part of the
various interest groups has the whole answer nor is any one part
responsible for all the problem, and that by working together we
really can achieve something important.

What everybody has said, and what we certainly subscribe to, is
that information, good information, is absolutely essential. It is so
essential that it should be provided in the easiest, most accessible
way. How that is done and how patients can benefit from that is
the subject of ongoing discussions that you all have, and we very
much appreciate the chance to participate in that, sir.

Thank you.

Mr. SHays. Thank you. We look forward to working with the
FDA and the other interested parties. This is a very interesting
and important issue and we will tread carefully, but we think it is
important that we have this dialog and pursue it.

Do any of the three of you wish to make any closing comment?
Dr. Kauffman.

Dr. KAUFFMAN. I would just like to say on behalf of the Academy
of Pediatrics, we have worked closely over the past several decades
with PMA, which is now PhRMA, as well as the FDA to work on
this problem of getting drugs labeled for children. During the past
4 or 5 years we have made some major inroads into getting this
done. We have a long way to go and we need some help to get the
rest of the way.

But I want to commend the FDA as well as PhRMA for their sen-
sitivity to this issue and we will continue to work together to get
this done. Thank you.

Mr. SHays. Thank you very much. Let me, before closing here,
I would just like to recognize our recorder. I had your name down,
but for the record your name is?

Court ReporTER. Donna Ferguson.


CONTENTS

Hearing held on September 12, 1996
Statement of:

Friedman, Michael, Deputy Commissioner for Qnerations, Food and Drug
Administration, accompanied by William Schultz, Deputy Commis-
sioner for Policy; Dr. Janet ‘Woodcock, Director, Center for Drug Eval-
uation and Research; ; Marlene Hafthe,, Director of the of the Office of phan
Products Development; Murray Lumpkin, Deputy Center Director, Cen-
ter for for Drug Evaluation and Research: and Seth Ray General Counsel’s

issues, General rrscountin Office, accompanied by George Silberman,
Assistant Director; and Joseph Dim Tufts University Center for
Drug Development
Runowicz, American Society of Clinical Oncology; Ralph
Ieuan, American Academy of Pediatrics; Abbey Meyers, president,
National Organization for Rare Diseases; and William manedy, Phar-
maceutical and Research Manufacturers of America ...
Letters, statements, etc., submitted for the record by:
Dimasi, Joseph, Tufts University Center for Drug Development, prepared
statement Of .....s..00 essesesanscanscenssene
Friedman, Michael, Deputy Commissioner for Operations, Food and Drug
Administration, prepared statement :
daggar, Sarah, Director of Health Services Quality and Public Health
issues, General Accounting Office, prepared statement of ...
Kauffinan, Ralph, American Academy of Pediatrics, prepared statement

Kennedy, William, Pharmaceutical and Research Manufacturers of Amer-
ica, prepared statement of
Meyers, Abbey, President, National Organization for Rare Diseases, pre-
pared statement of
Runowica, Carolyn, American Society of Clinical Oncology, prepared
statement of...
Towns, Hon. Edoiphus, a Representative in Congress from the State
of New York, letter dated November 4, 1995 .

Ji

dib

54

24
57
7
109
135
117
100
95


145

Dr. KAUFFMAN. I don’t have a specific recommendation for that,
but I think they could be nominated by their respective profes-
sional groups from which they derived. They could be nominated
from a ni rv of sources.

But I think in response to the comments here, I think it is a lit-
tle different for children than it is for some of the other orphan
groups that we are talking about this morning. Children are the
only one of the three groups we are talking about here this morn-
ing that do not have drugs labeled for them solely on the basis of
their age. The others are based on the disease they have, but this
is based solely on the age. And approximately 25 percent of the
population in this country fall into the age group that we call chil-

n.

So I think that representation for children’s issues in FDA deci-
sions and considerations is very important. Currently, to my knowl-
edge, among the FDA advisory groups there is not one that is fo-
cused on pediatric issues. There may be a pediatrician on one of
the other advisory groups, but in terms of an advisory group to
focus solely on pediatric issues, to my knowledge, there is not such
a group.

ir. TOWNS. Did you want to add anything to that?

Ms. Meyers. Well, I think if anybody just walks into any drug
store in the country and just goes down the aisle that sells cold
medicines and cough syrups, if you read the labels on them, you
will find out they are not approved for children. It cautions parents
not to give them to children under 8 or under 12. And you could
probably take every single product off the shelf and find that same
warning on each label.

Mr. Towns. After this question I am going to yield back to you,
Mr. Chairman. Let me just ask Dr. Kennedy one thing.

You said something that really struck me. You said that SNDA
and the NDA needs to be fixed. Now, do you have any specific ideas
as to how that could be fixed?

Mr. KENNEDY. Well, yes, I do and they have been conveyed in a
number of different forms. As I noted in my testimony, the FDA
has some divisions which are working at an exceptional rate. They
are providing input to the sponsors before investigations start, be-
fore we start looking for supplemental indications. They work with
the sponsor while the development program is underway and they
work with the sponsor to expedite the review and the approval of
the supplemental NDA when it comes into the FDA.

The unfortunate thing, Mr. Towns, is that a lot of the informa-
tion that has been conveyed this morning is based upon informa-
tion at a cutoff of 1994. The regulatory reform that is being pro-
posed in Congress and the initiatives that have been taking place
under PDUFA have changed that picture considerably. And I think
it should be taken into consideration. The standard of best practice
does exist at the FDA. Identify it, formalize it, expand it, enforce
it.

Mr. Towns. Thank you very much. Mr. Chairman, I yield back.

Mr. SHays. What I would love to ask the three of you, and I am
sorry I didn’t hear your testimony, but I would like to know wheth-
er you think the status quo is better than a feared solution and/
or whether you think there are some definite solutions that we


106

Mr. Towns. Thank you. Dr. Kauffman.

Dr. KAUFFMAN. you, Mr. Towns. I am Dr. Ralph
Kauffman, professor of Pediatrics and Pharmacology at the Univer-
sity of Missouri and director of Medical Research at the Childrens
Mercy Hospital in Kansas City.

I am pleased for the opportunit to be here this morning on be-
half of the American Academy of Pediatrics. This is an organization
representing 50,000 pediatricians dedicated to the health, safety,
and well-being of infants, children, adolescents, and young adults.
I should also mention I have spent 16 years as a member of the
academy’s committee on drugs, including 4 years as chairman of
that committee.

A critical issue for pediatricians, as you have heard this morning,
over the past 30 years has been the lack of approval and labeling
of medications for use by infants, children and adolescents.

The question was asked from the previous panel, and I can give
you some numbers today. It is shocking that only 20 percent of all
drugs marketed in the United States have been labeled for use by
children. This is based on a survey of marketed drugs in 1977. The
survey was repeated in 1991, and nothing changed in that 20-year
peri

Eighty percent or more of drugs approved since 1962 have been
approved and labeled for use in adults with a disclaimer that they
are not approved for use by children. A related problem that needs
to be acknowledged is a lack of dosage formulations which can be
used in children, particularly infants and smaller children.

Let me give you an example. Asthma was mentioned by one of
the previous speakers this morning. This is the most common
chronic illness affecting several million children in the United
States today. It is so common that it is the most common reason
for hospital admission of children. Undoubtedly, many of you have,
or virtually all of you, have family members or friends who suffer
from asthma.

Albuterol, one of the drugs most frequently used to treat asthma,
must be prescribed off-label for children because the form of the
drug necessary to provide breathing treatments, the most effective
way of administering this drug, is labeled, “Safety and effectiveness
have not been established in children under 12 years of age.”

The Kefauver-Harris amendments of 1962 were mentioned ear-
lier. These were amendments to the Food and Drug Act that pro-
vided that drugs be demonstrated by well-controlled studies to be
effective for their intended uses, as well as safe. While this provi-
sion has been applied to the approval of drugs for adult use, it has
not been extended to use by children in the labeling of a majority
of drugs. Fully 25 percent of the population of the United States
has been disenfranchised from this statute.

This is particularly ironic since passage of the Federal Food,
Drug, and Cosmetic Act of 1938 and later in 1962 the Kefauver
amendments. Both of these were passed in the aftermath of thera-
peutic catastrophes involving administering drugs to children
based on adult information.

Absence of studies to support labeling of the majority of drugs for
children places a physician in the untenable position of either pre-
scribing without adequate labeling or denying the pediatric patient


66

submission of supplemental indications, and means to lower or eliminate identified barriers. The
Centers for Drugs, Biologics, Devices, and Veterinary Medicine are each represented on this task
force.

The Group is studying a variety of strategies to encourage the submission of supplemental
applications, and developing a clearer articulation of the scientific standards used by the Agency in
assessing the safety and effectiveness of new indications.

Certain general themes have emerged from the Group's deliberations. Traditionally, FDA has
perceived its role to be a somewhat passive one, reacting to data only when a sponsor submits it,
There is a growing recognition, however, that to address the problem of unlabeled uses
effectively, FDA should adopt a much more active role in identifying important supplemental
indications, facilitating their study and evaluation, and, if effective, incorporating those uses in the
labeling. There also is awareness that the best solutions to the problem will be achieved by
getting as many of the affected constituents as possible involved in creating strategies to get new
uses into labeling, It is apparent; however, that for products that lack marketing exclusivity and
for supplemental indications that benefit only small populations, no combination of strategies
reliably will induce commercial sponsors to pursue supplemental applications. To get these uses
into labeling likely will require allocation of public funds, particularly where additional data

would have to be developed to demonstrate that a use is safe and effective.

10


52

Mr. SuHays. OK. And as we will hear from our witnesses today,
we said pediatric labeling is also scarce, with up to 80 percent of
drugs administered to children prescribed for off-label or unap-
proved indications. True?

Mr. SILBERMAN. That was what we were told.

Mr. SHays. It is estimated that 90 percent of all rare disease
treatments are off-label.

Mr. SILBERMAN. The actual estimate was that we were given the
number of drugs that were approved through the orphan drug pro-
vision and the number of rare diseases, and just from those two
numbers you can see that there must be an enormous amount.

Mr. SHays. I mean, this is an enormous issue. I am just going
to ask you two questions that really are submitted for us when we
start to begin to do our report, and I just need to make sure this
is on the record.

I am going to ask you, Dr. Silberman, how does the lack of effi-
cacy and dosage information on products for which there is exten-
sive off-label use affect the quality of care for pediatric, cancer, and
rare disease patients? That is kind of a big answer so I am asking
you to do something I don’t ordinarily do; I am asking for not a 10-
minute response.

So how does the lack of efficacy and dosage information on prod-
ucts for which there is extensive off-label use affect the quality of
care for pediatric, cancer and rare disease patients?

Mr. SILBERMAN. I think that is the central question and we don’t
have an answer to that.

Mr. SHays. OK. Are we going to allow that one to stand or
should I pursue that a little bit? We'll have to ask other witnesses.

And what changes in the supplemental new drug application re-
view process would you recommend to facilitate more complete and
timely labeling of drugs?

Mr. SILBERMAN. I think the data that Dr. DiMasi presented
clearly show a process that took a long time, and perhaps an inor-
dinately long time. And yet the easiest thing we can do, the
quickest thing we can do, is just try and make it faster. Now, the
data we presented show that we may, in fact, be achieving that.
That is the FDA side.

Incentives for companies to submit applications need to be exam-
ined and the standard of evidence required needs to be examined.
But if we can make this process work better, it is in everybody’s
interest: reimbursers, FDA, the public, physicians.

Mr. Suays. You all have been very interesting and I appreciate
your patience with at least my learning knowledge of this issue. So
we will go to the next panel unless there is anything any of the
three of you want to say as a closing comment.

You have been very interesting, very helpful, and I am sure we
will have you back. Thank you very much.

We do have a vote, but I think what I would like to do is just
go then and vote. We are going to go vote and probably by the time
we are done it is going to ti us 15 minutes, but we are going
to try to hustle back here for our next witnesses. Sorry to hold you
UP nis committee is recessed for approximately 15 minutes.

CeSS.,


101

-2-
Progress in cancer treatment occurs rapidly but incrementally, often in small
steps that make a difference in survival or at least in quality of life. New products
are always welcome, and the Food and Drug Administration (FDA) is doing a much
better job than in the past to make therapeutic advances in the form of new
products available to the American people as quickly as possible. FDA has
responded to many of the demands of an increasingly vocal and effective cancer
patient advocacy movement. The agency now seems to give pending new drug
approvals for cancer the same priority that is given to AIDS therapies and that

should be accorded to products for any life-threatening disease.

In cancer, however, new drug approvals are only the beginning of the story.
Much of the incremental progress in cancer treatment requires finding new uses for
already approved drugs. Moreover, our most effective chemotherapy regimens are

combinations of two or more approved drugs.

Combination chemotherapy regimens are not usually reviewed or approved
by FDA and thus do not routinely appear on product labeling. In addition, for a
variety of reasons, FDA-approved labeling almost never keeps up with new uses of
products. As a result, there is a substantial disconnect between the FDA label and

the actual practice of cancer medicine.


DiMasi - 3
differences were not statistically significant. Overall, the evidence on approval times cannot
be used to support a case for quicker reviews of new indications.

Many new uses for old drugs offer significant advances in patient care, In some cases,
the follow-on indication is even more important than the original use. Our most recent study
of the supplemental indication approval process examined the approval times for new uses that
were recognized by the FDA as representing important advances. ‘These new uses include
AZT for pediatric patients with symptomatic HIV disease, tamoxifen for women with auxiliary
node-negative breast cancer, and pentostatin for untreated hairy cell leukemia.

For approvals through 1993, the FDA has indicated in its publications those new

indi

ion approvals that it considered to be significant improvements in patient care. Figure 3
shows the mean approval times by year from 1989 to 1993 for those follow-on indications that
were noted by the FDA to be important and compares them to the mean approval times for the
original indications of those drugs that had received the supplemental indication approvals.
Although our data indicate that, other things being equal, those new uses that the FDA had
noted were important were approved more quickly than other new uses, the approval times for
the important new uses averaged about 10 months longer than the average approval time for
the original indications. This difference was statistically significant.

The data that we analyzed in our studies did not allow us to definitively assess the
impact of the Prescription Drug User Fee Act of 19924 on the supplemental indication process.
Recent user fee statistics released by the FDA on efficacy supplements are encouraging.* The
reported statistics, however, are for FDA actions on applications, which include issuing not-

approvable and approvable letters. Thus, they do not measure the time from initial submission


22

safe and effective new uses. I will mention a few. And by a new
use, I mean here either a new indication or a new patient group.

Third party review. Although a formal report has never been is-
sued, by all appearances, the so-called MI’ experiment was a
success. This pilot project involved the outside expert review of five
efficacy supplements. The reviews were conducted expeditiously —
2to4 nonths per supplement for the biostatistical and medical re-
views. They were not excessively expensive and the quality of the
reviews was high, as judged by the fact that the FDA concurred
with MITRE’s recommendations for all five supplements. Addition-
ally, not all of the recommendations were favorable. The current
user fee legislation prohibits the use of user fee revenues for out-
side reviews, but this problem can be remedied legislatively. Faster
reviews will increase the incentives to pursue labeling approval.

Paper SNDA’s. Greater use and acceptance of so-called paper
SNDA’s should be encouraged. In some cases, the published Tit
erature can serve as the basis for approval of off-label uses. This
obviates the need for extensive and expensive additional clinical
testing and reduces the time needed to get new uses on the product
label.

Submissions by nonprofit organizations. In cases where the fi-
nancial incentives to pursue approval of paper SNDA’s are not suf-
ficient to induce firms to seek approval, nonprofit institutions such
as patient groups could conceivably put together the information
needed for a paper SNDA and petition for approval of the
unlabeled use. In these cases, marketing exclusivity would not be
granted to the manufacturer.

Expansion of marketing exclusivity. In cases where additional
clinical testing must be done but patent protection has been lost or
will soon be lost, an additional period of marketing exclusivity con-
ceivably could be granted to the firm that obtains the approval.
Currently, firms can acquire 3 years of marketing exclusivity for a
new use, a period during which only the firm that obtained the ap-
proval is allowed to promote its product for the approved new use.

With regard to reimbursement. To ameliorate access problems for
off-label uses, extra FDA expert panels could be set up by one or
more of the pharmaceutical compendia, distinguished professional
societies, or the Institute of Medicine, for example, to review
unlabeled uses that are supported by evidence. Third party payers
would then have a recognized basis for reimbursing off-label uses
that are viewed authoritatively as acceptable medical practice. Fi-
nally, programs organized by professional societies can be devel-
oped to educate physicians about the optimal use of drugs for
unlabeled indications prior to labeling approval.


105

-6-
Cancer may very well be a special case requiring special regulation from
FDA. None of the proposals advocated by ASCO and supported by the patients
requires legislation. Thus, FDA could, if it were so inclined, act immediately to
expedite SNDA’s by greater reliance on published reports and to lift restrictions on
dissemination of reliable medical information. Both people with cancer and the

physicians who treat them would benefit from such action.


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115

Mr. Towns. Thank you very much. Ms. Meyers.

Ms. Meyers. Thank you, Mr. Towns. I am Abbey Meyers. I rep-
resent the National Organization for Rare Disorders, which is a
nonprofit, voluntary health agency dedicated to the identification,
treatment, and cure of rare diseases. We are a consumer group who
advocated for passage of the Orphan Drug Act in 1983, and we con-
tinue to monitor its Progress.

The problem with off-label uses, I think, is it is not peculiar to
cancer. It is peculiar to many, many orphan indications. For exam-
ple, there are about 200 different types of cancer and there are only
4 or 5 or them that do not fit the basic definition of an orphan dis-
ease. Under the law, any disease or condition affecting fewer than
200,000 Americans is an orphan disease.

So beyond breast cancer and prostate cancer and lung cancer and
a couple of others, all the rest qualify for orphan drug status. In-
deed, Taxol was originally developed as an orphan drug because
ovarian cancer is an orphan indication, and they stepped back and
relinquished that designation.

Now, the question is: Why would any company want to invest the
money to get a drug approved for an off-label indication? If you
have a drug like TPA which is for heart attacks and it is a very
big-selling drug and you find out that there may be a market for
stroke which is going to add a few hundred thousand or a few mil-
lion people a year to that market, certainly it is worth developing
something for that large market of people. But for small markets
of people, rare diseases, there is no reason to do that. Most compa-
nies don’t see any reason to do it.

And so the off-label problem is very peculiar to all rare diseases,
including the cancers and including pediatric uses of many drugs,
because serious pediatric illness is quite rare in children. Most chil-
dren are healthy and they are going to take cough medicine and
antibiotics, but they are not going to need the kinds of drugs that
we are talking about unless their condition is rare.

So what we want is to find a way to get these off-label indica-
tions on the labels. There is enough evidence out there of compa-
nies promoting the use of drugs for off-label uses that didn’t work.
Some have been quite tragic. There are drugs that were for
antiarrhythmia, to normalize heart rhythm, that actually caused
heart attacks in many people. And I have cited some of those in
my written testimony which is being submitted for the record.

order to do this, who is going to fund the research? The com-
panies don’t want to fund the research. NIH says that they are in
the business of basic research; they don’t like to fund clinical re-
search. And Dr. Haffner’s office at the FDA has a tiny little appro-
priation each year of $12 million. Now, the scope of problem is
that we are talking about 5,000 rare diseases, and she has $12 mil-
lion a year to fund the clinical research on new treatments for
these diseases. That is just not going to fly.

Indeed, one of the drugs that I have submitted on the last page
of my testimony, or next to the last, is a drug called

droxyurea. T have listed it as an off-label use for a very com-

licated disease called essential thrombocythemia. However, this
Srug-it is very interesting—it is on the market as a cancer q
but about a year ago some papers were published saying that this


136

cancer, has changed the lives of countless women and their families. We also developed
Zoladex for the treatment of prostate cancer.

I feel well-placed to discuss regulatory reform at FDA as an employee of one of the
‘most successful pharmaceutical companies in the last 12 months. Against a background in
which the FDA approved an average of 25 New Chemical Entities (NCEs) per year, Zeneca
hhas received more than 10% of these approvals. These have been significant drugs:
Casodex, the first oral treatment for prostate cancer, approved in 10 months; Arimidex, a
member of a new class of breast cancer drugs, approved in 13 months; Merrem, one of only
three new anti-biotics approved in the last three years. We have also been involved with
our licensing partners in achieving approval of Sular, a cardiovascular drug, and Kadian, a
long-acting morphine product, specific for the management of cancer pain.

Germane to today’s hearing, we have also been successful in obtaining supplemental
NDA approvals, inclu

cancer treatment drug.

one for 2 long-acting formulation of Zoladex, our prostate

I am here today representing the Pharmaceutical Research and Manufacturers of
America (PhRMA), the trade association for the research-based pharmaceutical industry.
PhRMA companies are world leaders in drug development and discovery, responsible for
more than 90% of drugs discovered. I greatly. appreciate the chance to appear before you
and testify on the issue of Supplemental New Drug Applications (SNDAs). There are two
types of SNDAs — those for new indications and those for manufacturing changes. I will
focus today on new indications.


58

tested in humans; (2) there are adequate protections of the human subjects. including informed
consent; and (3) the clinical trials are adequately designed to permit an evaluation of the drug's

safety and effectiveness.

In order to market a drug in the United States, it must be the subject of an approved New Drug
Application (NDA). Once the IND clinical trials are completed and the data developed, if the
sponsor believes the data support the safety and effectiveness of the drug, the sponsor submits an
NDA. AnNDA includes all data on the safety and effectiveness of the drug for a particular
indication. The data include detailed results of clinical studies, information on how the drug is
made and how quality is maintained, and the results of animal studies. FDA also requires samples
of the drug and its proposed labeling. The reports of a drug’s clinical studies are provided in
detail so that FDA can evaluate the data. The data from controlled clinical trials are especially
important because they provide the only basis, under law, for demonstrating effectiveness. They
answer the question, “Does this drug work for the proposed use ?” The information derived from

the clinical trials also is used to determine any adverse effects.

At times, FDA asks for advice from outside experts on a particular drug application, These
experts are members of FDA's drug advisory committees and have specialized experience
involving the drugs under the purview of the specific committee. These expert advisers add to

FDA's understanding, so that final Agency decisions more likely will reflect a balanced evaluation.


112

5

antibiotic approved in 1995, has indicated a pediatric study is not needed or planned although it is
highly likely this antibiotic will be used by physicians to treat infections in children as well as adults.

LACK OF LABELING FOR USE OF DRUGS DURING PREGNANCY AND
LACTATION

‘Two other disenfranchised populations of patients with respect to drug labeling are women who are
pregnant and those who are breast feeding their infants. Pregnant and lactating women are routinely
excluded from clinical trials of new drugs. Consequently, the labeling for very few drugs includes
definitive information on or an assessment of risks associated with maternal use of the drug. This
impacts the health of children because of the unknown tisk to the unborn child and the unknown
effects on the nursing child when the mother uses medication.

FDA EFFORTS AT PEDIATRIC LABELING

In 1979 FDA published regulations pertaining to the specific content and format of prescription drug
labeling that stipulate that pediatric labeling be based on adequate, well-controlled studies involving
children. The intention of these regulations was to encourage drug labeling that would regularly
provide adequate information about the use of drugs in children. However, the result was not more
adequately labeled drugs; rather labels simply state that the drug’s safety and effectiveness in
children have not been established. Eighty percent of the prescription drugs currently marketed in
the United States are labeled with such disclaimers.

In an attempt to remedy this situation the FDA published regulations on December 13, 1994, aimed
at increasing pediatric information in drug labeling and facilitating addition of pediatric indications
to drug labeling. The 1994 regulations recognize several methods of establishing substantial
evidence to support pediatric labeling claims. These include 1) allowing inclusion of published
pediatric information in the labeling and 2) approval of pediatric use based on adult efficacy studies
where the disease for which the drug is to be used is substantially the same in children and adults
thereby allowing pediatric studies to focus on dosing and safety data for children. The regulations
Tespond to concems that current prescription drug labeling too often does not contain adequate
information about the uses of drugs in children and are meant to provide the physician with more
complete and useful information when prescribing for children. Though the new regulations have
been in effect for almost two years, it is not yet apparent that they have resulted in any increase in
new drug labeling for children.


76

PROBLEMS WITH OFF LABEL USES

With these initiatives we hope to get more off label uses that are well substantiated on the label.
FDA has found that the widespread use of unapproved indications of drugs raises significant
safety concerns. Even under current law, which prohibits the promotion of off label uses, we
know of a number of instances where physicians used drugs for off label uses that resulted in

disastrous consequences.

For example, the drugs encainide and flecainide were approved in 1985 and 1986 for life-
threatening and symptomatic arrhythmias, which are abnormal rhythms of the heart. In the
1980's, physicians prescribed these two drugs and other antiarrhythmic drugs for heart attack
‘victims who were experiencing ventricular premature complexes (VPCs), a type of asymptomatic
or minimally symptomatic arrhythmia. (Asymptomatic arrhythmias are arrhythmias that can be
detected by tests, but which the patients do not feel.) These two drugs were especially popular
because they were effective at suppressing VPCs and appeared to be well tolerated. These
patients were treated because it was known that patients with VPCs after a heart attack were
more likely to die suddenly. By suppressing the VPCs, physicians hoped to reduce the risk of
death. This off label use, which was supported by published peer-reviewed journal articles linking
high VPC rates to mortality, appeared "logical." After becoming aware of this widespread use,
the National Institutes of Health decided to study the effectiveness of encainide and flecainide in
these patients. Previously it had never been shown that treatment of VPCs was beneficial to these

patients. To the surprise of almost everybody, that study demonstrated not only that the drugs

20


28

DiMasi - 5
supported by the scientific literature. However, establishing sufficiently strong incentives for
firms to file supplements on some well-established off-label uses, while also encouraging
reimbursement for these uses, is a vexing problem. For a manufacturer to invest in the
expensive clinical trial work that is needed for many supplemental filings the perceived
benefits must exceed the costs. If a substantial period of patent protection for the drug
remains, then the weighing of benefits and costs may well be tipped in favor of pursuing FDA
approval. However, if patents have expired or are close to expiration, then the three years of
marketing exclusivity and the expansion of the market for the drug that will come with FDA
approval may not be enough to induce the firm to seek approval, since generic substitution can
be expected to capture a significant portion of the extra revenues that will be generated. Any
‘measures that reduce the costs or increase the benefits of getting new uses approved will
increase the incentives for manufacturers to pursue approval of new indications.
A number of process and legislative measures that potentially could facilitate the
development and use of safe and effective new indications should be considered.
© Third Party Review. Although a formal report has never been issued, by all
appearances the MITRE experiment was a success. This pilot project involved the
outside expert review of five efficacy supplements. The reviews were conducted
expeditiously (two to four months per supplement for the biostatistical and medical
review), they were not excessively expensive, and the quality of the reviews was high,
as judged by the fact that the FDA concurred with MITRE’s recommendations for all
five supplements.' Additionally, not all of the recommendations were favorable. The

current user fee legislation prohibits the use of user fee revenues for outside reviews,


94

Act that Congress passed in 1992. That act will expire next year
and there is broad support for it by the agency and by the industry,
and I think by consumers. It has been successful beyond anybody's
dreams. I think in that process there will be discussion about
whether the goals for reviewing supplements should be brought
down.

But that is a very important contribution that Congress made
and we are going to need to ask for your help in renewing it.

Mr. Towns. Thank you.

Dr. FRIEDMAN. That is an absolutely excellent point.

Mr. Towns. Do you have anything you want to add? You don’t
have anything you want to tell us todo? Let me thank all three
of you for your testimony. We certainly appreciate it. And, of
course, you have been extremely helpful. Thank you.

Dr. FRIEDMAN. Thank you.

(The letter referred to follows:]


If, after FDA has approved a drug, evidence ari: of its safety

and effectiveness in treating conditions or patient groups other

than those named in the label, then the drug's manufacturer (or
any other interested party) can submit a new application to have
the label changed. This application, known as an "efficacy
supplement," is similar to the original application in that it
must contain evidence demonstrating to FDA's satisfaction that
the product is both safe and effective for the treatment of the
new condition. If FDA agrees with the sponsor's claims in the
supplemental application, the agency changes the label to reflect
the expanded use that the applicant has requested.

Physicians use a drug ‘off-label* when they prescribe an FDA-
approved drug for treatments other than those specified on the
label.? According to FDA,

"the legislative history of the FD&C Act indicates that the
Congress did not intend FDA to interfere with the practice
of medicine. Thus, once a drug is approved for marketing,
FDA does not generally regulate how, and for what uses,
physicians prescribe that drug. A physician may prescribe a
drug for uses or in treatment regimens or patient

other texms used to describe the use of medical products for
conditions other than those specified on the label include
“unapproved,* ‘unlabeled, * or ‘extra-label* use.

Page 3 GAO/T-HEHS-96~-212


7

were ineffective in reducing the risk of death but that the drugs were actually harmful in patients
for whom it was being prescribed off label increasing the risk of death by two and one half
times compared to patients receiving the placebo. If these unapproved uses had been heavily
promoted by drug companies, it is estimated that thousands more unnecessary deaths would have
‘occurred each year. To compound this problem, there are other therapies that are known to be
effective for this condition. .

Another example relates to the widespread off label use of a class of drugs called calcium channel
blockers (CCBs). These drugs are effective for patients suffering from high blood pressure or
angina, which is chest pain caused by insufficient oxygen to the heart muscle. In addition to this
approved indication, CCBs have been widely prescribed for use in patients who have had a heart
attack, but have no symptoms. CCBs have no established role, however, in this patient
population despite publications that could be interpreted as supporting this use. These patients
do, however, benefit from another class of drugs, beta-blockers, which are known to reduce
mortality by 25-30% after heart attacks. Because CCBs and beta-blockers generally should not
be used simultaneously, patients are receiving CCBs in lieu of clearly life-saving beta blockers.
Many, probably thousands, of lives are lost each year because a drug with no known survival
benefit is being used for an unapproved use in place of a drug with known value. Widespread

promotion of this use would make the problem even worse.

Itis important that solutions to the problem of unlabeled uses not compromise either the efficacy

or safety standard, for such solutions would be tragically nearsighted, So, while we support

21


83

ther away from the target population and the indication, you have
less and less knowledge that the actual benefits are going to out-
weigh the risks because you haven’t quantitated them as well.

fe have instances of off-label uses that have occurred in the re-
cent past that actually caused mortality in the people they were
used in although, intuitively, those uses seemed very close to the
labeled use.

Dr. FRIEDMAN. May I?

Mr. Suays. Yes; thank you.

Dr. FRIEDMAN. Another example of that, to help put this in per-
spective, and it is a recent example. There is a drug which is cur-
rently marketed, tissue plasminogen activator,.which is a very pow-
erful biologic therapy for use in patients who have coronary artery
occlusions. So for patients who have a heart attack, there are some
of those patients who benefit very, very substantially from this

oduct.

P But it was also noted that there are some patients who have
strokes, vascular accidents in the brain, where this treatment
might be useful. There are not good treatments for patients who
have strokes and, therefore, this was a very high priority for the
agency to look at it, even though the drug was on the market. We
received an efficacy supplement for this, reviewed it in record time,
89 days even though it was a very large clinical trial, because we
were concerned to get it on the market.

The reason I point this out is if this drug is used in a certain
kind of stroke patient, the bleeding is much worse, the patients
have a devastating neurological consequence, and many of them
die. If it is used in the right kind of stroke patient who have cer-
tain characteristics, then the improvement in those patients is sta-
tistically significant and those patients benefit.

So that here is a drug that was on the market. It was clear what
the benefits and risks were for heart attack patients. It turned out
to be entirely different for another group of patients. And that is
why having that labeled information allowed the company to edu-
cate physicians how to use it meant that physicians would be using
it in a much more appropriate way.

there are a lot of instances where there is real risk as well
as real benefit in a supplemental indication.

Mr. SHays. I make an assumption that—I usually expose my ig-
norance but I do learn from it and, hopefully, it has some value
when we write our report. I make an assumption that we are first
likely to test something on an animal before we test it on a human
being. And then, we are going to test it on human beings under a
protocol that is fairly restrictive for those whom the drug is admin-
istered to. They know the risks and they accept the risks.

And I make the assumption again that this is a process that has
to through the FDA, this whole protocol process. Is that correct?

. FRIEDMAN. In terms of preclinical?
Mr. Suays. Yes; preclinical, before you bring it on the market-
place.

Dr. FRIEDMAN. There is a body of Areglinical data that is pre-
sented at the time the new product is filed.

Mr. Suays. And does it usually begin with animals before people?

Dr. FRIEDMAN. Almost always. Yes, sir.


5

changed, again demonstrating that the product is buth safe and ef-
fective for the treatment of the new condition. If FDA agrees, it
changes the label to reflect the expanded use.

Second, let me briefly discuss the extent of off-label drug use.
Evidence on the extent and types of off-label drug use is limited.
Hence, in 1989, we studied drug prescribing patterns among cancer
specialists. We found that one-third of all drugs oncologists admin-
istered were used off-label. We also found that more than half of
the cancer patients, 56 percent, were prescribed at least one drug
off-label as part of their chemotherapy regimen.

The extent to which off-label use is prevalent in all areas of med-
icine is not clear; however, there is evidence it is even more com-
mon with AIDS care than for cancer, and it is generally acknowl-
edged that off-label use is extensive for rare diseases and for pedi-
atric populations.

What are the problems posed by off-label drug use? Off-label use
is not necessarily inappropriate. FDA acknowledges the potential
benefits of off-label use and also recognizes that there are impor-
tant off-label uses of approved drugs and that physicians need to
have access to accurate information about these igs.

Our analysis shows that the nature of potential problems associ-
ated with the drug label has changed. Alt! ough in the past the pri-
inary concern was with reimbursement denials associated with off-
label use, today concern about the off-label use of drugs focuses on
the limiting role the label plays in defining appropriate boundaries
for drug Promotion and advertising. The concern with promotion
seems to have grown in direct relation to the increasing competi-
tiveness of the market for pharmaceuticals.

Finally, I would like to offer two general approaches to address
the promotion dilemma. Under the first approach, promotion could
be based partially or entirely on any of a variety of other sources
of information that are commonly accepted as reputable, such as
the drug compendia and refereed journals. Legislation currently
being considered proposes such an approach.

The benefits of this strategy are that it avoids many of the costs
needed to assemble a supplemental application for FDA approval,
and it also allows promotion earlier than would be likely if compa-
nies had to wait for FDA to approve an efficacy supplement. The
limitations, however, are evidenced by those past instances where
drugs shown to be effective in published research were later found
to be either ineffective or, in some cases, actually harmful for pa-
tients.

Another approach is to change the process for updating labels so
that it is more timely and more reasonable in its demands for in-
formation, thereby making it simpler and possibly less costly to up-
date the label. A concern, however, is the le: of time it takes
FDA to process drug applications.

Therefore, for this hearing, we looked at FDA’s timeliness in re-
sponding to efficacy supplements. We found that the average ap-
proval time for efficacy supplements has decreased from 19 months
in_ 1993 to 12 months in 1995.

FDA has also made changes in the evidence necessary to obtain
approval. FDA instituted a mechanism known as accelerated ap-
proval, whereby drugs can receive approval with considerably less


11

4

medications without the benefit of adequate studies to document safety and efficacy or establish
doses appropriate for their age.

A related problem is that medications not approved for use by children are not manufactured in
dosage forms which can be readily administered to children. For example, many medications are
provided in capsule or tablet forms which cannot be swallowed by small children and are not
available in small enough dosage increments to give the proper dose to children.

CHILDREN REMAIN THERAPEUTIC ORPHANS

Ina 1994 hearing before the House Subcommittee on Health and the Environment, Sumner J. Yaffe,
MD., Director of the Center for Research for Mothers and Children at the National Institutes of
Health, reported that only approximately 20 percent of all drugs marketed in the United States have
had clinical trials performed in children which satisfy the FDA requirements for being labeled as safe
and effective for use in infants and children, He further reported, “The FDA has suggested that of
the 80 drugs most frequently used to treat newboms and infants in U.S. hospitals, only five are
labeled for use by children. This does not imply that 80 percent of our drugs are contraindicated,
unsafe, or disapproved for use in infants and children. Rather, it means that necessary testing has not
‘been done to produce the data that would enable the Food and Drug Administration to grant approval
status for specific clinical indications and uses in pediatric populations',”

Drugs which need to be labeled for pediatric use may be divided into 3 categories based on their
position in the approval process and market place: 1) new drugs in clinical trials, not yet approved
for general marketing; 2)drugs approved for adult use but not labeled for children and still under
patent protection; and 3) drugs labeled for adult but not pediatric use which are off-patent and may
bbe marketed as generic products by multiple companies, There is at least some potential economic
incentive to include pediatric clinical trials in the premarketing development of new drugs.
However, once a drug is marketed for an adult indication, the economic incentive to do additional
studies to include pediatric labeling is markedly reduced because the drug may be prescribed off
label. In the case of drugs which are off patent, there is absolutely no economic incentive to invest
in studies to expand labeling because a single sponsor can no longer benefit from such an investment
due to lack of exclusivity protection of the drug.

An examination of new molecular entities, which represent the most innovative new medications,
approved by the FDA from 1984 through 1995 showed that approximately 80% of these medications
‘were approved without labeling for children, although many of them are widely used to treat illness
inchildren. An AAP survey of the 28 new drugs approved by the FDA in 1995, indicated that only
four have pediatric labeling. The sponsors of 10 have indicated pediatric studies are in progress or
will done in the future, and sponsors of the remaining 14 drugs have indicated studies are not needed,
since it is not likely that those drugs will be used in children. However, several of these 14 drugs
undoubtedly will be used in children. For example, the sponsor of dirithromycin, a new macrolide

*Statement by Summer Y. Jaffe, MD, Director, Center for Research for Mothers and Children, National Institute
of Child Health and Human Development, National Institute of Health, before the Subcommittee on Health and the
Environment, House Committee on Energy and Commerce, February 8, 1994.


81

Mr. Suays. Thank you, Dr. Friedman. Before I ask a specific one,
is there any comment you want to make? You were here for the
first panel, correct?

Dr. FRIEDMAN. Yes.

Mr. SHays. And I would also invite either Dr. Woodcock or Mr.
Schultz to respond as well. So any observations to start, because
it might save me asking the questions.

Dr. FRIEDMAN. If I might make just some general comments and
then—but I don’t want to waste your time either and want to make
sure that we get to your questions.

Mr. Suays. No; but we wouldn’t have asked the questions—the
questions we asked of the first panel are still on the table, and I
need observations.

Dr. FRIEDMAN. Good.

Mr. Suays. So I am relating it to the first panel and the ques-
tions we asked, whether it was Mrs. Morella or Mr. Towns or Mr.
Souder or myself. Any responses that you would have made that
you wanted to make when we were asking those questions?

Dr. FRIEDMAN. Thank you, sir. I see this problem of how to get
more information onto the label as much as anything an
epistemologic question of what is good data and how does one deal
with those data.

The fact is that for some supplemental applications the agency
can have a much simpler, a much more rapid, much less expensive
means of asking for the proper data and making good decisions.
There will, however, be some supplemental indications that are so
complicated or where the use entails such danger that they will, in
fact, be as large or even larger perhaps than the primary indica-
tion.

The agency is very committed to improving this system. We, as
you know, last spring announced in our oncology initiatives that we
were accelerating approvals not just for primary indications, but
we identified ways in which for cancer products supplemental indi-
cations could be approved through an accelerated mechanism. And
we have made some progress in that regard.

I think that in addition to the incentives and disincentives that
you noted, a very important one that was mentioned but perhaps
didn’t get enough attention was the increasing importance of
pharmacoeconomic considerations.

When a pharmaceutical industry makes certain presentations to
the pharmaceutical boards of HMO’s or managed care organiza-
tions, and we see a very powerful incentive that if the FDA has re-
viewed these supplemental indications for that product and has ap-

roved it, it makes that presentation to that pharmacy board or
formulary board that much stronger. And we see that as an impor-
tant new incentive as well.

I would be happy for Mr. Schultz or Dr. Woodcock to elaborate.

Mr. Suays. Sure. Any comments either of you would like to
make?

Mr. ScHULTz. I will make a comment. I think my general reac-
tion to the panel discussion was that it accurately and very capably
reflected a lot of the difficult issues that you are grappling with,
and, I think the questions did as well.


107

access to important therapeutic agents. When confronted with this
dilemma, the physician invariably prescribes the medication off-
label. As a result, off-label use of medications has, by default, be-
come established standard of care for children in the United States.

It is important to emphasize that off-label prescribing is neither
illegal nor improper; however, from the patient’s perspective, in-
fants and children frequently are exposed to medications without.
the benefit of adequate studies to document safety and efficacy or
to establish doses appropriate for their age.

Last week I was asked to see in consultation a 1-month-old in-
fant with a life-threatening infection which was resistant to all
antibiotics except one. The single antibiotic to which this infection
pas sensitive is not labeled for children, much less 1-month-old in-
fants.

We had to administer this medication to the infant with no infor-
mation regarding appropriate dose for this age patient or specific
information regarding possible side effects. Under the cir-
cumstances, we did the only thing we could, combining our knowl-

e of the physiology of an ill 1-month-old infant with knowledge
of how the drug is given to adults.

Fortunately, in this particular case, the infant improved and is
currently recovering; however, the outcome of this type of scenario,
which is repeated throughout the United States on a daily basis,
is not always so favorable.

Despite various attempts by the Food and Drug Administration,
which you have heard this morning, to address this problem, the
proportion of approved new drugs labeled for children has not
changed during the past decade.

An academy review of the 28 new drugs approved by the FDA
in 1995 indicated that only 4 were approved with pediatric label-
ing. The sponsors of 10 of these drugs have indicated pediatric
studies are in progress or will be done in the future, and sponsors
of the remaining 14 drugs have indicated studies are not needed
since, in their judgment, the drugs are unlikely to be used in chil-
dren. However, looking at that list, we know that several of these
14 drugs undoubtedly will be used in children.

While we commend the recent efforts of the FDA to encourage
the inclusion of pediatric data in FDA approved labeling, progress
to date has been modest and sporadic. Because of that, the Amer-
ican Academy of Pediatrics believes additional steps must be taken
to augment the FDA initiatives, and we have some very specific
recommendations to make.

First of all, we have been told consistently over the past 20 years
that the FDA does not have regulatory authority under the current
statute to require pediatric studies. They can request them, they
can encourage them, they can facilitate them to the extent they are
able, but they cannot require them.

Because of that, we recommend that Congress provide FDA with
specific statutory authority and responsibility to make studies in
appropriate pediatric populations a requirement during clinical
trials of each new drug which has anticipated use in children, un-
less it is determined by an independent panel of experts in pedi-
atric medicine that there is no anticipated use of that drug in chil-
dren.


92

your response to Mr. Towns. He is then going to call on the next
panel and I am going to get back.

I don’t expect everyone from the FDA staying, but I would like
someone who could respond to comments that are made. This is not
to position the FDA versus someone else. It is just to get clarifica-
tion and help us understand where we are going. We are just
touching our toes in the water this first hearing.

Dr. FRIEDMAN. This is of sufficient importance to me that I cer-
tainly will be staying, sir.

Mr. Suays. I thank you for doing that. And it may be that we
will just invite you to come back rwards if you want to make
an observation. It may be we won’t have a question and that is
why.

Dr. FRIEDMAN. I am going to stay under any circumstances.
Thank gon

Mr. Suays. That’s very nice. Mr. Towns has the floor and also
is in charge for a bit of time, and I'll be back.

Mr. Towns [presiding]. Thank you very much, Mr. Chairman.
Let me begin by saying that I a; with your testimony that if
drug companies can promote off-label drugs, the potential exists
that they would be less inclined to conduct or fund the required sci-
entific research to insure drug efficacy for new use.

Can you give circumstances where a manufacturer may seek to
avoid FDA review? Could you give sort of specific situations you
feel that might happen?

Mr. SCHULTZ. I can. One would be if there is an off-label use and
there is fairly preliminary data, maybe articles that have prelimi-
nary data, but doctors are using the drug widely. It may not be in
the company’s interest to do the full studies to find out whether it
works or not because there is a possibility that the study will show
it does not work. And so the company, under the current system,
is better off just leaving things as they are.

Mr. Towns. Do you want to add anything else to that?

Dr. FRIEDMAN. i'think it is always a matter of balance and that
companies are very, very frequently well-intentioned. They are in-
terested in promoting their products for the proper uses. And it is
a matter of the balance between incentives and disincentives. And
our goal is to try and help identify those factors which tip the scale
so that the company will want to pursue that research or to pursue
that application. And we can help in that regard.

Mr. Towns. How do you respond to the concerns that the cost of
pursuing FDA approval for supplements uses actually generally
outweigh the anticipated revenue?

Dr. FRIEDMAN. Well, I think there are some situations in which
that is true. I do think, and in our working group we have identi-
fied a number of areas, one of which is onco! , where there are
many instances in which we may be able to have a simpler, less
cumbersome, application process that would necessarily cost less
that companies would see as not such a great disincentive, even if
the use should be small.

I am not saying that this can always be done in all situations,
but we do think there are many situations. And people have men-
tioned paper applications as being at least part of the application
process. We think there are ways in which we can help to simplify


60

Congress in 1962, In adding the concept of effectiveness to the Federal Food, Drug, and
Cosmetic Act (FDC Act), Congress specifically intended that the efficacy requirement would
apply not only to the initial indication for a drug, but also to indications that come to light after
the initial new drug application has been approved. 108 Cong. Rec. $22044-46 (daily ed.
October 3, 1962), S. Rep. No. 1744, 87th Cong., 2d Sess. Part 2 at 267, 271 (1962).

The addition of the “efficacy standard" revolutionized drug development and approval, not only in
the United States, but worldwide as well. It clearly established that data from adequate and well-
controlled trials, independently evaluated by experts at FDA, were necessary to demonstrate
effectiveness. When FDA worked with the National Academy of Science’s National Research
Council to review the effectiveness of drugs marketed in the United States before the
effectiveness standard was established by Congress in 1962, 1,124 of the 3,443 drugs on the
market, being marketed for various claims, were pulled from the market because they were not
effective. Data of lesser quality, anecdotal reports, and poorly controlled observations do not
suffice because these data or reports may be wrong or may not be an adequate basis to reach a
sound conclusion. Even when such data or reports suggest efficacy, they fail to provide important
guidance in areas critical to the effective use of a therapy such as dosage and patient selection and
management, This in no way suggests that clinical observations are always wrong or are not of
value. Alert clinicians have been the source of hundreds, probably thousands, of insights about
the indications for which drugs may be useful and how best to use these drugs. But these

observations need evaluation in controlled trials.



56

It is also apparent that for products that lack marketing exclu-
sivity and for supplemental indications that may benefit only a
small population of patients, new and creative strategies are need-
ed to reliably induce commercial sponsors or other sponsors to pur-
sue these indications.

To get these uses onto the label likely will require the allocation
of public funds, particularly where additional research data would
have to be developed to demonstrate that a use is safe and effec-
tive.

Current proposals under discussion within our agency envision
that we will provide, first of all, much more clear, consistent, and
simple standards to be applied in making decisions concerning sup-
plemental safety and effectiveness reviews; second, to become more
accessible and responsive to the broad array of constituents who
have an interest in whether or not a use is on the label; and, third,
to more actively identify unlabeled uses preliminarily assessing the
data that support that use and actively encouraging commercial
sponsors and other interested parties to participate in pursuing the
approval of these uses.

Our obligation to the public is to help assure that physicians and
other health care practitioners have the best information available.
Patients deserve this information; physicians require this informa-
tion.

The supplemental applications and review process can help en-
sure that the information generated by medical research is accu-
rate and, in fact, does represent a safe and effective new use that
the public can benefit from. The labeling of a drug for a new use
assures that there is strong and reliable scientific information upon
which to base the use of the product and that that information is
widely available, as widely available as possible. With such infor-
mation on the label, we can give practitioners the information they
need to offer the best possible therapy to their patients.

We are committed to working with you, with industry, with pa-
tients, with physician groups, with research organizations, and a
variety of other constituencies, to assure that the best possible in-
formation is available as widely as possible. We are very seriously
committed to this important opportunity, as we see it.

I would be very happy, all of us would be happy, to answer any
questions you might have, Mr. Chairman.

[The prepared statement of Dr. Friedman follows:]


18

applications had declined by more than 40 percent.!3 in
Preparing for this hearing, we also looked at FDA's timeliness in

responding to efficacy supplements. Our findings are shown in
table 1.

Table 1: Approval Times for Efficacy Supplements in Months,
Fiscal Years 1993-95

Year of Number of | Percent Median Average
submission | submissions | approved approval approval
time time
1993 69 57% 18 19
1994 67 63 14 14
1995, s 48 71 12 kL. 12

As can be seen from the table, how long it takes for FDA to
approve efficacy supplements has been reduced considerably. This
improvement is consistent with that found for new drug
applications and with the goals established under the
Prescription Drug User Fee Act of 1992. Under this act, FDA is
held accountable for rapid action on efficacy supplements in the
same way that it is accountable for processing new drug
applications. The user fee legislation has the added dimension
of providing FDA with additional resources so that shorter action
times become more realistic goals.

33u.s. General Accounting Office, PRA Drug Approval: Review Time
i . GAO/PEMD-96-1 (Washington, D.C.:
October 1996).

Page 12 GAO/T-HEHS-96-212


AT

in the marketplace, but once you get in the marketplace there is
a whole different standard.

And so I am making this assumption, as a generalist who is not
a doctor, that we must have come to the conclusion that, boy, we
are really going to make it hard to get on the market because once
you get on the market, who knows how that drug is going to be
used. But once you are on the market, we have made a sense that,
you know, we have tested it on every conceivable animal, person,
and so on, so we know it is not going to kill him, but we can’t guar-
antee that there is efficacy involved, that it will be effective in an
off-label use. That is where my mindset is.

Mr. DIMasi. I think what is most important is that physicians
have the best and most up-to-date information available to them.
There are a number of ways we can work toward that goal. One
is to attempt to speed up the approval process and provide guide-
lines for firms in submitting supplemental applications so that they
can perhaps develop those new uses more quickly and less expen-
sively and submit applications that are in good order and will be
approved.

Second, though, I think a lot can be done in the area of edu-
cation. And that can perhaps involve a lot of the professional soci-
eties, as I have mentioned earlier, such as the Institute of Medicine
and other organizations, to assist in getting information to physi-
cians, practicing physicians, as quickly as possible on just what the
current state of knowledge is about the use of already approved
drugs for a variety of indications.

Mr. Says. I am going to call on Mr. Souder if he wants to re-
spond in just 1 second, but I gather I am making an assumption
that, somehow, if you can’t promote the drug, that is a negative for
the drug company.

But in this day and age, particularly as it relates to serious ill-
ness, I have a number of dear, precious constituents who have life-
threatening diseases that are on the Internet and they are commu-
nicating with a wide host of people. And it is almost like you could
subtly suggest this could be used and then people are going to use
that drug. And there is a lot of experimentation and you have pa-
tients who know more than some doctors, it seems, because they
have devoted their lives to trying to cure themselves.

And so what is in the back of my mind is that, in one sense, it
is a positive for a pharmaceutical company if they can just get on
the marketplace as cheaply and quickly as possible, then it is a
positive that they can expand its use. And I have a sense that is
happening.

And it is a negative, however, that they can’t promote it, but I
am not as impressed with that negative because there are a whole
host of ways to promote it without really, you know, advertising it
on .

And I am just stuck with then the only other negative is the re-
imbursement issue. If you can find ways to be reimbursed for the
drug without it being, you know, going to the hospital and gaming
the system. I mean, there are a lot of reasons why we want to re-
solve this. We want people to have knowledge so they use it well.
We don’t want to game the system. We don’t want people to spend
more when they shouldn’t.


51

Mr. SoupER. And it presents a real tough process. Having talked
to different individuals in the pharmaceutical field, if it costs $220
to $450 million to get a clearance, of course that is going to be an
expensive drug, given the number of cases, which is why you get
the off-label and we go right back into the cycle.

But thank you.

Mr. Suays. Mrs. Morella.

Mrs. MoRELLA. I know we've got several other panels that are
going to be shedding light on some of the questions that we posed,
and I think this panel has been excellent.

I wonder as a final shot, do you recommend that there should be
any furtherance of studies that FDA should be responsible for
thinking in terms of pediatric work, more that we need to know?
Is there an extended role in discerning needs and application, be-
cause of studies and collaboration, partnerships, that you can see
for FDA?

Ms. JaGcar. If I might respectfully urge you to inquire of FDA
and also the individuals from the American Academy of Pediatrics
who will be speaking later. I know that FDA is very aware of and
concerned about this issue and looking for ways to better discern
from the information that comes from clinical trials on adults, for
example, what the possible implications would be for pediatric
cases. I don’t think there is a simple answer to it.

Do you have anything to add?

Mr. SILBERMAN. I was hoping she wasn’t going to look at me. No,
really, nothing to add on that.

Mrs. MoRELLA. Dr. DiMasi.

Mr. DIMasti. Nothing to add either.

Mrs. MORELLA. Nobody wants to touch it. OK, Mr. Chairman, I
yield back.

Mr. Suays. Dr. Silberman, in my statement we basically, I think,
took from your work. We said for 50 million children, 40 million
cancer patients and 20 million Americans suffering from rare or or-
phan diseases, most of their treatments are off-label.

Is that correct?

Mr. SILBERMAN. From our work on cancer, we know the exact
amount. From the information we have gotten from the various
groups representing those other patient populations, there is such
widespread acknowledgment of the prevalence of this use that I
feel fairly certain that it is correct.

Mr. SHAYS. Are you comfortable with what I just read then?

Mr. SILBERMAN. That there is widespread use?

Mr. Suays. I said, “For 50 million children, 40 million cancer pa-
tients and 20 million Americans.” Some of them could be all the
same.

Mr. SILBERMAN. For cancer patients it is a little tricky because
some cancer patients are not candidates for chemotherapy and I
don’t have a precise estimate of the number.

Mr. SHays. In 1991, the General Accounting Office—that was
your study—found off-label use of cancer drugs widespread—that’s
true—encompassing a third of all drug dosages to those patients.
True? More than half the cancer patients that GAO surveyed re-
ceived at least one off-label drug?

Mr. SILBERMAN. That’s true.


80

products’ labels more completely and accurately reflect clinical usage that is safe and effective.

All of us will benefit from such an effort.

I would be happy to answer any questions.

24


142

and I will conclude my statement with a few remarks about off-jabel use and information
dissemination. .

‘It must be recognized that off-label use is common in medicine — as the new GAO
report states, 80-100% of cancer, pediatric and rare disease treatment is off-label, and off-
label use is the norm in treating many other diseases.

Dissemination of information about off-label use to medical professionals is not
Promotion of off-label use — it is education by facilitating the availability of third-party
information that has already been published, particularly in peer-reviewed journals. There
are more than 3,000 medical journals published, and no practicing physician has time to
read every one. The FDA currently prohibits dissemination of information on unapproved
uses by no one other than pharmaceutical manufacturers, meaning that a drug company
that may be uniquely informed about a particular drug may not send out reprints of
Journal articles to doctors unless the doctor specifically calls and requests the article.

PhRMA believes, as do I, that education of physicians does not stop when they leave
medical school and dissemination of information on all meaningful uses is necessary to
make the most up-to-date medical information available to doctors, so that patients can
receive the most effective treatment. Please remember that a physician cannot request
information that he does not know exists.

In the debate over dissemination of information, some have suggested that

manufacturers would limit disseminated information to positive studies on their drugs.

This is not consistent with the principles expressed and supported by PhRMA members.

We have always supported and encouraged dissemination of balanced information —


185

P Statement Rd AN

‘TESTIMONY OF WILLIAM J. KENNEDY, PH.D.
BEFORE THE HUMAN RESOURCES AND INTERGOVERNMENTAL AFFAIRS SUBCOMMITTEE
(GOVERNMENT REFORM AND OVERSIGHT COMMITTEE
‘SEPTEMBER 12, 1996

Good morning, Chairman Shays and members of the Subcommittee. I am Dr.

William J. Kennedy, Vice President for Drug Ri ry Affairs at Z

Pharmaceuticals, Wilmington, De Zeneca Inc. is $2.8 billion

with approximately 6,000 employees at 53 locations in 24 states. Zeneca Inc. is » wholly-
owned subsidiary of the UK-based Zeneca Group PLC, a major $7.6 billion international
bioscience business engaged in the research, development, manufacture and marketing of
ethical (prescription) pharmaceutical, agriculture, and specialty products and the supply of
healthcare services.

Zeneca has a distinguished record in providing innovative quality health care
products for physicians and patients. This began when Sir James Black, working in our
laboratories, gave the world receptor-based research. For this, he won the Nobel prize in
‘medicine. Our laboratories have also produced Diprivan, an injectable anesthetic with
rapid onset and rapid recovery. We are probably most proud of our contribution to the
treatment of cancer. Nolvader, the most widely used drug in the treatment of breast

Pharmaceutical Research and Ma 3 of America
7700 Fiteenth Street, NW. Washington, 0.. 20005 (202) 835-3400



13

primary concern was with reimbursement denials associated with
off-label use. We found that denials made because the FDA label
did not include the specific drug were certainly prevalent. More
than half of all the cancer physicians we surveyed reported
problems with reimbursement for off-label use, and most indicated
that the problems had gotten worse in recent years. Most
troubling was that many respondents said they altered what they
believed to be optimal therapy in response to these reimbursement
Genials. In fact, 62 percent of physicians responding to our
survey said that they had admitted to hospitals patients who did
not require hospitalization solely as a way to circumvent

problems with reimbursement. denials .!? -

While reimbursement concerns were the primary ones associated
with the drug label in the earlier part of this decade, this
issue seems to have declined significantly since that time. This
decline has been attributed to legislation in 1993 that required
Medicare carriers to rely on sources in addition to the FDA-
approved label in making reimbursement decisions for cancer
therapy. Subsequently, the insurance industry generally followed
suit. This is to say not that there are no longer any
reimbursement problems with off-label drug use--just that they

seem to be more isolated.

10Reimbursement for a hospital stay is based on the condition for
which the patient is admitted and not on the basis of which drugs
are given.

Page 7 GAO/T-HEHS-96-212


137

The drug discovery, development, and approval process is time-consuming and
expensive. It has taken as long as 15 years and $500 million to secure approval for a new
drug in the U.S. FDA initiatives, including the Prescription Drug User Fee Act (PDUFA)
and others similar to those proposed in several pieces of legislation are shortening the time
frame but there is still room for improvement in these areas. The drug business is a high-
risk endeavor, but it is also a high-reward endeavor. In recent months, pharmaceutical
companies have introduced the new protease inhibitors that are showing great success
agaiost the virus that causes AIDS, as well as new drugs for cancer, Lou Gehrig’s disease
and multiple sclerosis.

Because what we do is so expensive, time-consuming, and important to patients, we
in the industry believe that the process of making new drugs available must be as efficient
as possible, and we are hopeful that legislation will be passed this Congress to assist the
FDA as it prepares for the 21st century.

‘New Indications

Equally important, as evidenced by this Subcommittee hearing today, is the
continued development of these new drugs, and the approval of Supplemental New Drug
Applications (SNDAs) for new indications, There appear to be numerous obstacles to the
rapid approval of SNDAs. A report from the Labor and Human Resources Committee
mark-up of June 20, 1996 noted that “it takes as long or longer for the FDA to review
supplemental applications as it does to review applications for initial product approvals.
These lengthy review times serve as a disincentive to drug [..] manufacturers to file

supplemental applications.” Because of user fees and FDA’s efforts to meet its user fee


55

There are many off-label uses of approved drugs and there are
already many good reasons for drug companies to submit efficac
supplements. One of these is the physician, via the approved label-
ing, is given more complete information about the drug’s use, prop-
er dosage, and other important information. And, ultimately, of
course, it is that physician’s patients who benefit from that infor-
mation.

Second, as has been pointed out, manufacturers can promote the
use of that product. Third, approval is often considered by third
party payers, the reimbursement industry, in making a reimburse-
ment decision for drugs or products.

Fourth, a sponsor’s ability to get its drug included in an HMO’s
drug formulary or other sort of managed practice formulary can be
significantly enhanced. And as was pointed out previously, this is
an enormous and growing economic incentive for the pharma-
ceutical industry.

And another point to be mentioned is that drug companies can
present the FDA findings to drug approval bodies in other coun-
tries and, thus, perhaps enhance their ability to gain approval and
perhaps reimbursement for use in other markets.

Now, so far today you have heard that there have been meaning-
ful improvements in the efficiency in which the agency processes
its supplemental applications. Data has been presented to you, and
I can present more, should you like.

While we are gratified with this trend, we are not satisfied. The
FDA is undertaking initiatives to encourage and expedite still fur-
ther efficacy supplements for these unapproved uses. We are doing
a number of things and have several plans for additional progress
in this area. Our goal is to have the product’s label more com-
pletely and more accurately reflect clinical usage that is safe and
effective.

There are many constituencies interested in this issue. You will
hear from some of them today. And all these constituencies will
benefit from this overall effort.

Now, earlier this year, the Food and Drug Administration assem-
bled an internal working group to examine in some depth the range
of issues that influence whether a supplemental indication makes
it onto a product’s label. This supplemental indications working
group is focused on identifying barriers to sponsor submission,
some of the very same questions that you raised this morning, Mr.
Chairman, of these supplemental indications, and to try and iden-
tify means to lower or eliminate disincentives or barriers.

The group is considering a variety of strategies to encourage the
submission of supplemental applications and developing a clear ar-
ticulation of the scientific standards, level of evidence, and so forth,
used by the agency in assessing the safety and effectiveness of a
new indication for that product.

To address the problem of unlabeled uses effectively, FDA must
adopt a much more active role in identifying important supple-
mental indications, facilitating their study and evaluation and, if
effective, incorporating these uses onto the label. The best solution
to the problem will be achieved by getting as many of the affected
constituents as possible involved in creating strategies that will get
new uses onto the label.


2

pairs need safety and efficacy data upon which to base reimburse-
ment policies.

Pervasive off-label use can blur the distinction between medical
information and drug promotion, as pharmaceutical developers,
with neither financial nor regulatory incentives to undertake costly
supplemental studies, find ways to spread the word on off-label
uses of their products.

In considering the impact of off-label use, the need for supple-
mentary efficacy information, at least in the form of an FDA ap-
proved label, must be balanced against the ability of independent
studies and peer-reviewed journals to provide the same data more
quickly and effectively than the current FDA supplemental new

4g application [SNDA], review process.

e necessity of off-label uses in the private practice of medicine
must be balanced against the public health benefits of clinically
tested treatment and dosage information for significant patient
populations, including children and those suffering from cancers
and rare diseases.

The benefits of dissemination of supplemental efficacy and drug
use information must be balanced against the need to regulate
drug promotion, so treatment decisions are determined by medical,
not marketplace, considerations.

We asked our witnesses today to help us gauge the scope and im-
plications of off-label use and to discuss the role of FDA’s review
of supplemental new drug applications in maintaining the nec-
essary balance between regulation and innovation, between infor-
mation and promotion, and between individual patient care and
public health.

We welcome all our witnesses and look forward to this testimony.
I think this is going to be a very interesting hearing and a good
introduction for this committee to this very important issue. And
whether it is Mr. Towns or I that chair this committee next year,
this issue will be pursued.

And now I welcome my ranking member, who has been an equal
artner in these hearings over the last 2 years. This is the 49th
earing this committee has held.

Mr. Towns. Thank you very much, Mr. Chairman. Let me begin
by first thanking you for having this hearing and also to say to you
that we really appreciate your leadership over the past 2 years.
And, of course, I want to let you know a lot of the things you have
done, I will do them next year.

The regulation of drug products is an important function of the
Food and Drug Administration due to the efforts of the FDA that
drugs are safe and effective and that physicians, pharmacists,
nurses, and patients are uniformly aware of their appropriate use.
Even so, the use of off-label drugs is extraordinarily high. In many
instances, these drugs have significant, sometimes life-preserving,
value,

There are four principal issues that stem from the use of drugs
approved for one purpose but prescribed for another: First, FDA
procedures for reviewing supplemental new drug applications have
been characterized as necessarily time-consuming and also costly;
second, the therapeutic benefits of an off-label drug may be pre-
sumed before its safety and efficacy are established; third, reim-


12

timeframe on those remaining in this group that are not yet overdue, the final performance for
‘NDAs in this group will be 99% on time. In addition, the Agency has reviewed and acted upon
90% of the efficacy supplements for NDAs within the determined time frame, The agreed
performance goal was only 70%, If we continue this trend in reviewing efficacy supplements that

are not yet overdue, we will be 95% on time.
‘We should continue our efforts to reduce review times for all applications and to improve upon
them. We are working on mechanisms and policies that should decrease the number of months

for review.

RECENT ONCOLOGY INITIATIVES HAVE IMPLICATIONS FOR ONCOLOGY
DRUG SUPPLEMENTAL INDICATIONS

In March of this year, as part of its Reinventing the Regulation of Cancer Drugs initiative, the

Agency indicated that it intended to make greater use of the accelerated approval mechanism for
cancer drugs. This mechanism facilitates earlier approval of drugs for serious or life threatening
conditions by allowing the Agency to base approval on well established surrogate endpoints that
reasonably predict clinical benefit, such as evidence of tumor shrinkage in solid tumor disease and
meaningful remission in hematologic disease, rather than requiring demonstration of actual
clinical benefit, such as improved survival or quality of life. Companies more quickly can
demonstrate tumor regression than increased survival time, Clinical benefit is established in post-

approval studies. This accelerated approval mechanism is available for new product applications

16


DiMasi - 4
of an SNDA to approval. The category of efficacy supplements is also much broader than the
types of applications that we have analyzed (new indications and new patient groups).

Efficacy supplements include, for example, new dosage regimens and new routes of
administration, as well as new indications, new patient groups, and other types of
supplements. The FDA data and our results suggest that there have been improvements in
recent years in approval times for follow-on uses, but the need for further improvement

remains.

Why has approval of follow-on indications generally taken so long? A likely

explanation for our results is that historically the agency had effectively placed a low priority
on supplemental filings, because the drugs were available in the marketplace and physicians
can, and often do, prescribe for off-label uses. Such a perspective would not be problematic if
the information available to all physicians were sufficiently complete to allow their prescribing
to be optimal and if reimbursement were never conditioned on whether an indication is FDA-
approved. However, the restrictions placed on manufacturers on dissemination of information
about off-label uses suggest that there will be some underuse or misuse of drugs. For
example, a recent study found that approved new indications appeared in one of the major
pharmaceutical compendia (United States Pharmacopeia - Drug Information), on average, 2.5
years prior to FDA approval.* Optimal use of drugs is also impaired when third-party payers
refuse to reimburse for uses of a drug that are not included in an FDA-approved label.”
Patient care can be enhanced when applications for supplemental indications are

approved expeditiously and when reimbursement is routinely allowed for off-label uses that are


10

For example, for an oncology drug that has shown anti-tumor activity against one type of tumor,
there is a strong presumption that it could be active against other types of tumors. Thus, a single
well-controlled trial might support its use for another type of tumor. Similarly, for an antibiotic
that has demonstrated activity against one type of infection caused by a particular organism, a
single well-controlled trial of the drug in another infection caused by the same organism, in
conjunction with evidence showing that the antibiotic achieves adequate blood levels at the site of

the other infection, might support its use for the other infection.

° When the Agency does not have access to full reports of data, but there are multiple

published reports in the literature of studies of adequate design and consistent results:

It is the Agency’s belief, based on substantial experience, that full access to study data is very
important, and journal peer reviewers rarely have full access to the raw data that are the bases for
the manuscripts they review. Nonetheless, when there are multiple published trials of good design
and consistent results, the consistency of results may overcome FDA concerns about not having
access to underlying data to verify results or analyses. However, it is probably more common that
easily available selected critical data (e.g., the protocol, data tapes, etc.) might be sufficient to

allow review.

There are many more examples that illustrate when existing data may obviate the need to exactly
replicate a study finding and there is an effort underway to compile these examples in a useful

guidance document. It is hoped that, by explaining the relevance of data that may already exist,

14


146

should take, and then I would like each of you to outline as suc-
cinctly as possible. I mean, we have already set the stage for the
last two panels, so I will just start with each of you.

t First, 1. Kauffman, do you fear the solution more than the sta-
us quo?

Dr. KAUFFMAN. No.

Mr. Suays. Ms. Meyers.

Ms. MEYERS. We need a solution.

Mr. KENNEDY. No, we don’t fear it.

Mr. Suays. Pardon me. You don’t fear it?

Mr. KENNEDY. No, we don’t fear a solution.

Mr. Suays. OK. So each of you, you have made it in your state-
ments, but state as succinctly as possible what you think the par-
ticular solution is or a step that we should consider.

Dr. KAUFFMAN. I think from the perspective of the care of chil-
dren, there are two critical issues: One is to provide the FDA with
the regulatory authority to require pediatric studies when it is ap-
propriate; and, second, to deal with the economic disincentives for
the industry to be able to afford to develop drug products for chil-

ren.

Mr. Suays. I want to come back to the economic incentives be-
cause I am not quite sure what that means, but I would like to just
pursue this line.

Ms. Meyers.

Ms. Meyers. Well, we think that the economic solutions are very
important and we are suggesting tax credits for the clinical trials,
dollar for dollar, but not to give companies an incentive that is
larger than the amount of money that they should be investing in
the research to get these things re-labeled.

But there are also some other adjustments that have to be made
at FDA to make this a quicker and easier application process.

Mr. Suays. So you're talking about not just for secondary use;
you're talking in general for all.

Ms. MEYERS. To get any off-label—

Mr. Suays. But are you saying—I just want to clarify we are just
talking off-label, to be on-label? We are not talking the primary
entry into the marketplace?

Ms. MEYERS. No.

Mr. SHays. Do you think that needs to be changed there as well?

Ms. MEYERS. No, orphan drugs already get the tax credits and
other incentives.

Mr. SuHays. I wasn’t talking about the credits. I’m sorry, I
thought you were talking about the regulatory process to be ap-
proved on the label.

Ms. MEyeERs. I think FDA has been doing an excellent job on get-
ting new drugs approved very, very quickly for serious and life-
threatening diseases in the last year or two. And I would rather
that we continue to have the FDA be the gold standard for the rest
of the world. We are not willing to sacrifice safety or efficacy to get
a drug on the market.

Mr. Says. I need to clarify because I thought you had two
points: one, you needed the economic incentives; and I thought the
second was you needed reform of the process to be approved.

Ms. MEYERS. Of the supplemental NDA process.


63

label, we can be better assured that wide dissemination of that information is made to everyone

who could benefit from such information.

Unlike with the practice of medicine, the FDC Act specifically directs FDA to regulate the
promotion of drugs. Promotional materials are considered unlawful if they promote an
unapproved use for the product; contain claims relating to the dosing, safety or effectiveness of
the product that are inconsistent with the approved labeling; or if they lack a fair and balanced
presentation of information, i.e., of benefits and risks. Were companies allowed to promote uses
of drugs that have not been proven effective, they might promote uses that do not work or are
dangerous. In addition, they would have no incentive to conduct or fund the necessary scientific
research and to present data to FDA to verify the safety and effectiveness of those off label uses.
In fact, because the Agency might determine that the new use is not supported by the evidence,
there would be an incentive to avoid FDA review. A question could be asked as to why a drug
company would undergo the expense of actually studying whether a cancer drug works for
crippling arthritis if it could promote the drug for arthritis based on preliminary evidence,

particularly since a thorough study might fail to establish efficacy for arthritis?

Ina world where off label uses can be promoted legally, manufacturers would have an incentive
to do the minimal amount of studies necessary to obtain approval for the first, narrowest/easiest
indication and then heavily promote the product for other broader (and possibly more speculative)
uses. This is precisely the scenario that Congress sought to prevent when it added the

effectiveness requirement to the FDC Act.


20

Mr. Chairman, this concludes my statement. I would be happy to
answer any questions that the Subcommittee might have.

For more information about this testimony, please call George
Silberman, Assistant Director, at 202-512-9226. other major
contributors include Michele J. Orza and Thomas J. Laetz.

(108292)

Page 14 GAO/T-HEHS-96-212


37

ceutical company would like it to be their drug. So there is addi-
tional pressure on the competitiveness of the health industry now
as a result. Most formularies have an “out clause” in case a par-
ticular drug that is selected doesn’t work well for an individual pa-
tient, but it requires some additional effort.

That can have an influence on individual patients. If a patient
for years has been receiving a particular kind of drug, joins an
HMO, and now the formulary doesn’t cover that particular drug,
there can be some need for adjustment. I think that is a char-
acteristic now of our industry in that there are so many more deci-
sions being made by insurers that affect many people, rather than
individual physicians making those drug choice decisions.

Mr. SouDER. Thank you.

Ms. JAGGAR. You're welcome.

Mr. Suays. I thank the gentleman. Mr. Towns.

Mr. Towns. Thank you very much, Mr. Chairman. Ms. Jaggar,
if drug companies can promote off-label drugs, what incentive
would they have to conduct or fund scientific research to ensure the
drug efficacy for the new use?

Ms. JaGGAR. Mr. Towns, that really is the question, I think,
which underlies the debate here and why the word “promote” is the
key one under discussion.

e FDA’s position, of course, is that it has a responsibility to
assure the safety and efficacy of the drugs. When an application is
submitted for a drug to be approved, it may be or it is likely to in-
volve only one, or maybe in some instances, particular application
of that drug, one particular reason for it to be approved.

If there are additional areas where the drug can be useful, what
I think everyone would really like to have happen is, that the clini-
cal testing be done so that we have confidence that the side effects
or the negative effects from that additional use may not be det-
rimental to the individual.

When off-label drug use occurs, there has not been the approval
process so that there is not the clinically proven circumstances that
gives the user confidence. However, it doesn’t mean that in many
instances there haven’t been studies that prove that there is value
to that drug. This is why we suggest that the process of improvin;
and making simpler and faster the approvals of these supplemental
applications is a very important one.

ir. SILBERMAN. If I might.

Mr. Towns. Go ahead.

Mr. SILBERMAN. There is no suggestion that promotion be al-
lowed without any research. The suggestion is that promotion be
allowed on the basis of research published in refereed journals or
in compendia. The incentive remains to do that research; it’s just
a question of how much information needs to be gathered: enough
to get into a refereed journal or enough to submit an efficacy sup-
plement to FDA? The incentive is always going to be there to do
something to gather information to serve as a basis for promotion.

Mr. Towns. Dr. DiMasi, I would like to hear your comments on
that issue.

Mr. DiMast. I think Mr. Silberman summed it up quite well. No
one is certainly suggesting that off-label uses be used or reim-
bursed without sufficient scientific background and evidence. So,


57

INTRODUCTION

Mr. Chairman and Members of the Committee. My name is Dr. Michael Friedman. I am the
Deputy Commissioner for Operations at the Food and Drug Administration (FDA or “the
Agency”). With me today is Mr. William Schultz, Deputy Commissioner for Policy, and

Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research (CDER).

I appreciate the opportunity to testify on the important issue of supplemental indications for
approved prescription drugs. FDA supports and encourages the labeling of new indications for
approved drugs. We have been working actively to encourage the industry's submissions of

efficacy supplements and to ensure that such supplements are reviewed in as timely a manner as

possible.

THE NDA PROCESS

Let me start with a brief discussion of the process for approving new drugs in the United States.
When a sponsor has completed and evaluated its initial research on a drug, including animal
research, and has determined that a drug appears to be a promising treatment for a medical
condition, the sponsor then proceeds to study the drug in humans. At that time, the sponsor
submits to FDA an Investigational New Drug Application (IND). An IND includes protocols for
studying and collecting data on the safety and effectiveness of a drug in humans, The initial
clinical studies of a new drug often only include studies for one or a discrete few uses of the

Product. FDA reviews the IND to help ensure that: (1) the product is reasonably safe to be


23

In conclusion, it is imperative that we have an efficient approval
process for new indications and that third party payers recognize
legitimate new uses even before they reach the label. Under the
user fee program, the FDA appears to have made substantial

ss in achieving quicker reviews of applications for both origi-
nal and follow-on indications. The agency also recognized the
problems associated with important off-label uses and has encour-
aged firms to submit SNDA’s for these uses. We need, however, I
believe, to examine additional means to achieving the ends that we
all desire.

Thank you.

{The prepared statement of Mr. DiMasi follows:]


144

Mr. Towns. Thank you very much, Dr. Kennedy. Dr. Runowicz,
I know you have to leave, so let me just ask you a couple questions
and then you may depart.

You indicate that because of the FDA approval rate cannot keep
pace with the practice of cancer medicine, a number of accommoda-
tions should be made in FDA regulatory procedures. Is your pri-
mary recommendation that the FDA restrictions on off-label pro-
motions, including information-sharing, should be lifted?

Dr. RuNowicz. Well, I think that the word promotion is pejo-
rative and misleading. I think that dissemination can be education.
When there is a new drug that has been shown to be effective in
other cancers and then clinical trials show it to be effective in, say,
another cancer like ovary cancer, it is very important that that in-
formation be disseminated to the medical community so that pa-
tients can benefit from that new information.

I think just as an aside that what I have heard this morning,
and I think is very misleading, is that these secondary applications
are as if they are pulled out of thin air when, in fact, ii you look
at the research that is done on these secondary applications, this
is very stringent research. And doctors look at this research very
critically and that is how a secondary indication develops. It is not
that we just sit down and say, well, I would like to try this drug
on this patient because it has just been released. It is based on
good, scientific data. And that data needs to get out quickly to the
community through dissemination and education.

Mr. Towns. Should we be concerned about any negative impact
on patients’ health because of off-label drug use?

Dr. RuNnowicz. I would turn that around the other way and I
would say that the standard of practice in cancer is that these sec-
ondary uses benefit the patients. Not to focus entirely on cancer,
but if you look at the issue of hormone replacement, for example,
estrogen is not approved for the prevention of heart disease; yet we
know from good prospective trials that there is very strong evi-
dence of heart prevention, heart disease prevention.

And yet that is an off-label indication that I would say most phy-
sicians, primary care providers, are now using to persuade women.
And I can assure you that they are not signing informed consent
because this is based on very good clinical evidence.

Mr. Towns. Let me just ask you one other thing and then I will
be delighted to say to you thank you very much for your participa
tion. Of course, it was suggested here, I think, by Dr. Kauffman
that the Congress should come up with a panel that would sort of
approve, look at, and help to expedite.

What is your reaction to that?

Dr. RUNOWICcz. Well, I think that legislative action may not be
necessary. I think that already the FDA has a lot of these pro-
grams available to them to expedite review and that they can do
this internally without further regulations.

Mr. Towns. Well, let me thank you very much for your testi-
mony, and I know you have to leave. So thank you very, very
much. We appreciate your participation.

Let me just move to you, Dr. Kauffman, on that note. You indi-
cated that, first of all, if the Congress decided to do that, I mean,
how would these people be appointed?


90

Mr. SCHULTZ. We’ve seen those numbers and we don’t have a
basis to question them. We don’t know. We can’t affirm them, but
we don’t have inconsistent data.

Mr. SHays. I am going to accept that the basic argument is you
are not necessarily disputing that number.

Dr. FRIEDMAN. The problem is the typical analysis——

Mr. Suays. Let me just tell you that the challenge we have—and
I am sorry to interrupt you—we really wanted you to come third.
And we are happy to have you be second, but the reason we want-
ed to have you third is that we have testimony from witnesses that
will follow you that will make basically that claim and, therefore,
it would be good. That is why we are now trying to have to adjust
the question based on something we haven’t had on the record.

OK, so we'll get it on the record you are not necessarily disputing
it but you don’t have anything that affirms it.

Dr. FRIEDMAN. That’s right.

Mr. SHays. And we will let others testify. I’m sorry, I did inter-
rupt you.

ir. SCHULTZ. I was going to say, typically, under our statute,
when a company comes in, it comes in to have a drug approved for
a particular use, and it chooses what use it wants. it use could
be for a disease and it can be for a disease population.

The question that you are raising is whether we require the com-
pany to add a new component to that application? I want to tell
you that we are looking very hard at that. It is not easy, but it is
certainly something that needs to be looked at.

Dr. FRIEDMAN. There are a variety of special populations—
women, the elderly, other populations—to whom these questions
have been asked.

Can I spend just 30 seconds in case? You probably are fully
aware of this but in case you are not, the steps the agency has gone
to in offering guidance for getting pediatric labeling to simplify ——

Mr. Suays. I have no awareness, so you can have a comfort level
that this will be helpful information.

Dr. FRIEDMAN. I think it will because it is one thing to say that
there is a substantial off-label use in pediatric. It would be dif-
ferent to say has the agency done anything to try and remedy that
situation.

And I can let Dr. Woodcock or Dr. Lumpkin speak to it in greater
detail, but suffice it to say what this guidance does is to indicate
that when a body of information exists in adult patients, that rel-
atively little information is needed in children, Perhaps only
pharmacologic information to say do children metabolize the drug
differently or do they have different toxicities or do you use it in
different dosage form.

So, it may be quite a limited data set. You don’t have to recreate
all the studies that were used to get the first approval. You might
have dozens or hundreds or thousands of patients in the first ap-
proval. You might have a much, much smaller number in the pedi-
atric supplemental labeling.

Dr. Woodcock or others can speak more to that, but I just wanted
to give Ride that.

Mr. Suays. I make an assumption, though, that a child growing
up is a lot different than an adult.


44

The standards for what goes on the label, to the best of our un-
derstanding, are consistent for primary and secondary indications;
that is, you have to demonstrate to FDA’s satisfaction that the
drug has substantial safety and effectiveness for the condition it is
supposed to have.

Mr. Suays. Only for the primary use.

Mr. SILBERMAN. For the secondary as well, you have to dem-
onstrate. So that if a drug is approved as an antihypertensive in
an elderly population and then you want to show that it has effi-
cacy in a younger population, you have to convince FDA through
your research that is of the same standard as the original.

Mr. Suays. Who is they? The drug company?

Mr. SILBERMAN. The drug company has to convince.

Mr. SHays. What is to prevent a doctor from prescribing that
drug for a use unrelated to the label?

Mr. SILBERMAN. That is use. That is the second question.

Mr. Says. OK.

Mr. SILBERMAN. So the first issue is the label. The standards of
evidence to get on the label are supposedly consistent for all uses.

Mr. Suays. Being new at this, I am just going to clarify one thing
so I don’t lose it. I made an assumption that the label could only
be focused on primary use. You are making the point to me that
once they have primary use, they can make a claim on the label
for secondary use and begin to back it up. They haven’t yet had to
document it.

Mr. SILBERMAN. The label is changed by the Food and Drug Ad-
ministration, and the way that is done is that you submit evidence
for a supplemental application.

Mr. SuHays. OK, you answered the question.

Mr. SILBERMAN, So the label is for whatever evidence you submit
originally. And then if you want to change it, you have to submit
more evidence. The FDA reviews that, and that is the data that Dr.
DiMasi and we presented on how long that review takes.

In terms of use, I think it was very wisely determined that physi-
cians should have considerable discretion in what they prescribe for
patients. Now, they can only prescribe—that is actually a little bit
of an overstatement—they can mostly prescribe drugs that have al-
ready been approved for at least one indication. There is, in fact,
the ability in recent years to provide drugs to patients that have
not yet been approved, through a compassionate IND.

Mr. Suays. Being a skeptic here, particularly since I see so much
of it in cancer use where people are really desperate, I have to be-
lieve that if a doctor feels that this drug has some efficacy without
it being labeled, that they will prescribe it and a patient will will-
ingly use it.

Mr. SILBERMAN. And that is what our results show; that that, in
fact, was occurring.

Mr. Suays. OK. And so I am having a hard time reconciling your
previous statement which was, in essence, that there had to be
shown a secondary use.

Mr. SILBERMAN. That is for the label.

Mr. Suays. Right; OK.


85

question of potential liability to that doctor if he or she misused
that drug.

Dr. HAFFNER. As has been stated many times already today, cer-
tainly a physician that thinks for good reason that a product that
is available to him or her may work in a particular disease may
use it in that disease. And they will think that from literature re-
ports, from reading the journals, from courses, et cetera, and may
well try it in that situation.

Mr. Suays. As to the protocol, do they have to tell the patient
that this is an off-label drug and so on? Do they have that kind
of requirement?

Dr. HAFFNER. They don’t have that requirement. They may well
do that.

Dr. Woopcock. It depends on the institution. Some academic in-
stitutions may have those requirements but, generally, in the prac-
tice of medicine informed consent for an off-label use isn’t nec-
essary.

Mr. Suays. I’m not looking for more regulations and so on. I
mean, but it would seem to me that this is one area that there
could be some common ground because, obviously, if we are using
something in an area where, Dr. Woodcock, you pointed out a drug
is safe for the use it is intended, it would seem to me that, at least,
for the safety issue if not for the efficacy issue, there would be
some protocol that said this is a drug that is not labeled for this
use, but based on my belief, I think it may be effective in your case.

Dr. FRIEDMAN. Maybe I should just add one other thing. And I
don’t mean to overstate this, but there is real concentration of re-
search at certain institutions for certain kinds of diseases, as you
well recognize.

And because academic centers may be devoted to the study of un-
usual metabolic diseases, unusual neurologic diseases and so forth,
rare diseases often are studied at institutions that have very for-
mal research structures in place and may be supported by grants,
sometimes given by us and sometimes given by NIH. Under those
circumstances, there is a protocol. There is informed consent and
so forth.

Mr. Suays. I hear you. I hear you. That would seem logical, I
mean, for a variety of reasons.

Dr. FRIEDMAN. Sure.

Mr. Suays. But I’m just saying, you know, our weighing in on
this, and we may decide to say in our report, and it wouldn’t be
based on one hearing, let me assure everyone here, that we should
just not deal with this issue; that, you know, the recommended so-
lution may be worse than the present circumstances. But it would
strike me that if we got into any area, this might be one that we
would.

Dr. HAFFNER. The treatment of one patient by a physician sel-
dom is reflected in a protocol; on the other hand, our office has a
grants program wherein we publish in the Federal Register annu-
ally requesting clinical trials for certain rare diseases. And under
certain circumstances, we have even said we would like clinical
trials for certain drugs for certain diseases if we know that a drug
is being used, if we know that there is a particular need for a dos-


62

great value, Some off label uses have been of great historical importance. Use of beta blockers in
hypertension and angina preceded labeling for these uses by many years. It is inevitable that there
will be preliminary support for off label uses before definitive information becomes available.
Physicians confronted with patient needs, may choose to act on such data, especially where there

are no good alternatives.

Physicians have extensive access to information about off label uses through compendia,
textbooks, journal articles, continuing medical education program symposia, and professional
meetings. Physicians also have access to a number of data bases that provide information about
off label uses. For example, the National Cancer Institute's Physician Data Query (PDQ) system
is an excellent source for oncologists to obtain information about current oncologic therapies.
The National Library of Medicine (NLM) offers a Medical Literature Analysis and Retrieval
‘System (MEDLARS), which is a computerized system of databases and databanks pertinent to
biomedical research and patients. Also, NLM currently offers free access to three databases:
related to AIDS. FDA does not regulate a physician's access to any of these sources of
independent off label use information ~ no matter how preliminary the data may be. Also, FDA.
does not prohibit a manufacturer from providing a physician with information about off label uses
if the physician makes a specific unsolicited request for the information. It is important to good
medical practice, however, that physicians have access to accurate information about drugs and
how to use them. Without accurate information, physicians cannot help ensure their patients

obtain the correct therapy in the correct dose. By seeing to it that such information gets on the


86

age form of a particular drug. That is not the usual, but it has been
done.

Mr. Suays. Thank you. Yes.

Dr. Woopcock. I would like to make a clarifying comment about
off-label use. Off-label use is certainly very prevalent in orphan
drugs and cancer and so on, but I don’t think you can estimate the
use across general medical practice.

As Dr. Haffner said, for the single patient, if someone has a mi-
graine and they have exhausted the conventional therapies that
are approved for the prevention of migraine attacks, a doctor may
well go onto other kinds of blood pressure medicines or other medi-
cines that are approved for something else to try in that patient.
We don’t know the extent of this. There are no good studies. But
we believe it is fairly widespread.

Mr. Suays. Thank you, Doctor. I am beginning to realize that
maybe when I use protocol I should have used the word “ethics”.

Dr. Woopcock. Informed consent, I believe is what you meant.

Mr. SHays. Yes; OK. And just make a reference again to what
your view is on informed consent. I'm sorry. You triggered some-
thing and then I began to get off your message.

Dr. Woopcock. You asked, I believe, that if in rare diseases pa-
tients had informed consent.

Mr. Suays. In any disease where the drug is used for an off-label
use that hasn’t even been established—I mean, they are going into
new territory—is there any requirement that a patient be told that
this is a recommendation, and should there be, is my question. And
I would welcome any of the three of you responding.

Dr. Woopcock. There is no recommendation but, as I said ear-
lier, certain institutions may.

Mr. Suays. I understand that.

Dr. Woopcock. There is no Federal regulatory requirement.

Mr. Suays. I understand that. If I was a large institution, I
would have more protocols and more ethical standards to make
sure I covered every base. That’s not what I’m asking.

yr.

Dr. FRIEDMAN. Excluding formal studies, it is considered to be
medical practice and physicians inform patients about side effects
of treatment as they usually do. But in terms of formally signing
an informed consent document, I think that’s a rarity. I think it is
very uncommon.

Mr. SHays. OK. And the question is: Should there be? You know,
I realize that if you don’t know the answer, I am not going to—
I wouldn’t want you to respond to a question like that unless you
have given it a lot of thought, but I would think that you have
given it some thought.

Dr. FRIEDMAN. I don’t think we've given it sufficient thought. It
is a very good question and a very complex question. I don’t feel
that I have given it enough thought.

Mr. SHays. OK. I’ve having a little debate with my col-
league here on five questions that she wants me to ask for the
record. And I have never asked five questions written, but I am
going to do it. You better be t.

Dr. FRIEDMAN. We'll do our best to answer them, sir.


121

approved for Parkinson's Disease, dopamine-depleting agents such as Reserpine and
Tetrabenazine (antipsychotic drugs) and dopamine-blocking agents such as Haldol
(haloperidol) and Orap (pimozide). While haloperidol is labeled for schizophrenia and
Tourette Syndrome, and pimozide is also labeled for Tourette syndrome, both are used
for a wide variety of hyperkinetic movement disorders such as myoclonus, tardive
dyskinesia and the Dystonias. Moreover, clonazepam, Valium, baclofen, and
carbamazine are also used for the Dystonias even though they have only been approved
for other conditions.

Myocionus, another movement disorder, is treated "off-label" with a wide variety of
pharmaceutical agents ranging from anticonvulsant therapies to high blood pressure
drugs, including sodium valproate, clonazepam, primidone, vigabatrin, methysergide and
propranolol (Inderal). Tourette Syndrome is treated with a wide variety of drugs from
antidepressants to antihypertensives and anticonvulsants that are not labeled for this
condition. Essential tremor, which is a common movement disorder in the elderly, is
treated “off-label” with primidone and meythysergide in addition to clonazepam and
alprazolam. For the rare paroxysmal dyskinesias, anticonvulsants are commonly used
as well as anticholinergics and neuroleptics. Additionally, Dr. Brin points out, many of the
agents used to control pain are not labeled for pain management, and some drugs
commonly used to ease spasticity are not labeled for this indication.

“Off-t i nm if

Why should a pharmaceutical manufacturer spend millions of dollars and several long
years developing a drug for a rare disease with a limited market if another company that
has spent no money on research, is allowed to make claims that their drug is effective
‘on the same rare indication? The exclusivity provisions of the Orphan Drug Act are
seriously undermined unless the FDA strictly enforces its "off-label" marketing regulations
and demands proof of safety and efficacy.


124

couldn't even detect them. It took special 24-hour heart monitoring to identify the irregular
beats. Researchers believed these very mild irregular heartbeats could without warning
blossom into lethal irregular beats and death. It thus seemed perfectly reasonable to
treat these mild cases. Papers supporting this theory were repeatedly published in all the
best medical journals, but nobody had done the proper clinical testing. Unfortunately, the
theory was wrong. Again, the NIH finally performed a clinical trial which proved
Conclusively that these drugs caused cardiac arrest instead of preventing it.

Pediatric “Off-Label” Drug Use

Regarding pediatric uses, most drugs sold in the U.S. are not approved for use by
children because they have not been tested in pediatric populations. Except for a few
common childhood diseases such as asthma, attention deficit disorder, infections, etc.,
serious and chronic diseases in children are quite rare. Pharmaceutical companies would
Not ordinarily spend the money, for example, to study a hypertension drug used in a
childhood disease when everyone thinks that hypertension is an adult disease. However,
there are many pediatric rare diseases that are treated with hypertension drugs not only
for high blood pressure but for heart abnormalities, neurological disorders, etc. It is
important that pediatric uses be studied for these drugs so that appropriate dosages and
possible side effects are known to physicians.

Insurance Reimbursement

The reimbursement problem associated with "off-label" uses of certain drugs for the
elderly has been somewhat solved in the Medicare population by the "Three Compendia
Rule." That is, Medicare will reimburse for a drug that is being used for an “off-label”
indication, if that use is recognized as effective in one of three medical compendia: the
AMA Drug Evaluations, the American Hospital Formulary Service's Drug Information, and
the United States Pharmacopeia Dispensing Information (USPDI). Unfortunately,
problems remain because a) the AMA's Drug Evaluations is no longer published, and b)
the private health insurance market is not compelled to follow this Medicare rule. Some
insurers will reimburse for some compendia uses, but they ignore others.


31

DiMasi - 8

supplemental indications for already-approved drugs: 1989-1994. Drug Inf J
1996;30(2):315-337.

Shulman SR, Kaitin KI. The Prescription Drug User Fee Act of 1992: a 5-year
experiment for industry and the FDA. PharmacoEconomics 1996;9(2):121-133.

Third annual performance report -- Prescription Drug User Fee Act of 1992: fiscal
year 1995 report to Congress. (Rockville, MD]: Food and Drug Administration, Dec
1, 1995.

Beales JH III. Marketing information and pharmaceuticals: new uses for old drugs.
In: Competitive strategies in the pharmaceutical industry. Washington, DC: American
Enterprise Institute; 1996.

Raiford DS, Shulman SR, Lasagna L. Determining appropriate reimbursement for
prescription drugs: off-label uses and investigational therapies. Food Drug Law J
1994;49(1):37-76.

Walker P. Testimony of Pamela Walker before the Committee on labor and Human
Resources, United States Senate. 104th Congress 2nd Session. Hearing 21 February,
1996.


Mr. Chairman and Members of the Subcommittee:

We are pleased to appear before you this morning to discuss the
general area of off-label drug use and the more specific problem
off-label use poses for drug promotion and advertising. This
area is critically important in ensuring the quality of health
care, controlling expenditures, and maintaining a viable
pharmaceutical industry.

My statement will set this important policy issue in context, by
covering four points: (1) what ‘off-label" use is; (2) the

existing evidence on the prevalence and nature of off-label. use;
(3) the dilemmas posed by off-label use, including the question
of whether or not to allow promotion for off-label uses; and (4)

two general approaches for how these dilemmas may be resolved.

My comments today are based on our study of off-label drug use
among physicians who specialize in cancer care that was published
in 1991 and on new analyses of FDA performance that we conducted
expressly for this hearing.

In sum, we found that off-label use is a prevalent phenomenon
that has presented different problems for policy-makers at
different times. As it stands now, the problem is that the drug

4

General Accounting Offic

Off-Label Drugs: Reimbursement
Therapies, GAO/PEMD-91-14 (Washington, D.C.: September 1991).
Page 1 sO GAO/T-HEHS-96-212



139

stringent standard in an efficacy supplement is not efficient or practical, and it slows down
the SNDA process, especially when safety has already been established.

This is totally unacceptable in the treatment of cancer. Upon approval by FDA, 2
cancer drug is seldom labeled for use in all cancers, It is usually labeled for use in one type
or sub-type of cancer, but oncologists often prescribe the drug for cancer patients not in the
approved type. In fact, such cutting-edge organizations as the National Cancer Institute
(NCI) and the National Institutes of Health (NIH) routinely include drugs with unapproved
indications in their recommended standard protocols for the treatment of cancers.

‘Once a drug is on an NCI or NIH protocol, many, but not all, oncologists begin
using the drug, and 2 wealth of information becomes available. This expertise should be
considered in the approval for new indications. This has been the norm rather than the
exception in the approval of additional indications for cancer drugs, but has not been the
case for other drug classes. We owe just as much attention to drugs in other classes, which
may help patients suffering from other devastating diseases.

‘Solution to the Problem

The solution — in all drug classes, not just in those for politically correct diseases —
is simple, When a drug becomes the standard of treatment, it should be included in the
Package insert so that correct and appropriate information can be provided to all
Practitioners to safely and effectively treat patients.

FDA has recently recognized that the current SNDA process also hampers effective
treatment for children and has moved to remove these obstacles. For a number of reasons,

including more stringent regulatory requirements, ethical questions and lack of incentives,


147

Mr. Suays. OK. Explain that a little bit better.

Ms. Meyers. I think FDA should look at the amount of informa-
tion that they already have on a drug that has been on the market
for a period of time and make some choices. For example, perhaps
they could pass a rule that says only one well-controlled clinical
trial might be needed on a drug that has been on the market for
some time and a great deal is already known about it.

Those types of options need to be looked at to make it an easier
process so that companies aren’t worried about putting so many
people from their regulatory affairs staff aside for so many months
just to create the application.

Mr. SHays. OK. Dr. Kennedy, the issue of positive steps that
would make a contribution toward improving the system, what
would they be?

Mr. KENNEDY. Well, I think we are talking really three different
points here. One is if our objective is to fet information on drugs
to patients, information to physicians and drugs to patients as ex-
peditiously as possible, we can do that by loosening up on the dis-
semination of information in considering it an education.

One of the proposals that has been made was to have the inclu-
sion of these unapproved uses provided for in the package insert
with the approved uses, very clearly identified that these are unap-
proved uses for which the drug has been found useful. In looking
at what Ms. Meyers was talking about with hydroxyurea, that
would be something that could be very easily accomplished. It
would provide the information to the physician so that he could
make the correct choice as to whether or not his patient fit that.

The supplemental review process, I think I have already pro-
vided for that in my testimony. And as far as pediatric use is con-
cerned, one thing that has not come out in testimony this morning
is the current procedures that are required to get approval for a
drug in children in pediatric use.

Mr. Suays. What I don’t understand—and we will get to your
economic incentive. And let me have you respond to that and then
let me just ask the next question. You said economic incentives
were important. What would they be?

Dr. KAUFFMAN. Well, may I give you a little background?

Mr. Suays. Sure.

Dr. KAUFFMAN. The fact of life is that for most drugs the use in
pediatrics or the market in pediatrics is fairly small relative to the
adult population, so that the incremental market to spend the re-
sources to get the SNDA for pediatric indication doesn’t pay.
nas Suays. So, it is almost the same problem that rare diseases

ve?

Dr. KAUFFMAN. Well, to an extent, it is because in its simplest
form it can be stated that the marketplace isn’t large enough to
carry the load for the investment to develop the indication.

Mr. Suays. That is a surprising statistic.

Dr. KAUFFMAN. That is reality in our world for most drugs. But
for vaccines, for antibiotics, for example, the marketplace is fairly
large in children because they tend to have infectious diseases
more than any other type of disease, so the marketplace is there.
And because of that, antibiotics typically are studied and developed
for use and labeled for children.


46

So what is the bottom line to it?

Mr. SILBERMAN. The bottom line is that we need some policy
that, on the one hand——

Mr. SHays. OK, so that is one answer. I’m sorry I interrupted
you. Tl let you finish your statement and then I will interrupt
here.

Mr. SILBERMAN. We want physicians to know as much as they
can about every possible use of the drugs.

Mr. Suays. So it is an unresolved issue of gigantic proportions.

Mr. SILBERMAN. Yes.

Mr. Suays. The question is: Do we allow them to promote a drug
that is not the primary use but is on-label and we allow them to
promote any part that is labeled? Is that correct?

Mr. SILBERMAN. Do we allow pharmaceutical firms to promote on
the basis of research that is of a certain quality and stature.

Mr. SHays. No. I want to know, if it is on-label, are they allowed
to promote it?

Mr. SILBERMAN. Yes.

Mr. Suays. If it is not on-label, are they allowed to promote it?

Mr. SILBERMAN. No.

Mr. Suays. OK. And then the issue is?

b Mr, SILBERMAN. Should we allow them to promote it on that
asis?

Mr. Suays. Well, I think I know my answer. Dr. DiMasi, any-
thing of the comments I made and observations? I’m just trying to
get some’bottom line senses of where the real battle lines are.

I mean, for all of you this is old hat. For us, it’s not, but we bring
a fresh look to this and we also may bring some impetus to resolve
it because I have a feeling that this is the kind of issue that will
never get resolved unless someone pushes it. And yet I can see
some really gigantic potential problems if we don’t.

Mr. DiMast. OK. I believe that it is important to have high
standards for efficacy and safety for product labels and there is a
benefit to establishing that—establishing an initial indication and
establishing that a drug is safe and effective.

That tells you a good deal about the drug, usually, in potential
secondary uses. You know a good deal about the safety of the drug
in many cases, although the standards, as Mr. Silberman said, are
the same for supplemental indications as they are for original indi-
cations.

Mr. Suays. Just to make sure I’m hearing you, are you saying
that if a drug gets in the market we have achieved one basic
threshold that that’s safe and that the off-label issue is really
whether there is efficacy, or is there even still a safety question on
off-label?

Mr. DIMasi. There are some safety questions.

Mr. SHays. But just so you know what is in my mind here, I
mean, a physician always has the right to prescribe any drug for
any disease, whether or not the disease indication is on the label.
We know that. And I am not suggesting a change there.

But what is interesting is if a drug hasn’t been labeled at all and
it’s not on the market, that physician doesn’t have a right to use
that drug. And so it is like we have one standard for how you get


6

evidence than was traditionally necessary. FDA has already made
some changes in the evidence required for certain efficacy supple-
ments and has the discretion to use the same authority to make
changes to reviews for other purposes.

In sum, Mr. Chairman, in a 1991 study of physicians who spe-
cialize in cancer care, we found that off-label use was a prevalent
phenomenon. Currently, the drug industry feels overly constrained

y labels in their ability to promote their products. We suggest two
general solutions to this problem: Relying on sources in addition to
the labels to define appropriate promotion and/or making improve-
ments in the process for updating the label.

This concludes my statement. We will be happy to answer any
questions you or the subcommittee may have.

[The prepared statement of Ms. Jaggar follows:]


40

In terms of the interesting question about paper NDA’s, I think
paper NDA’s become a much more feasible alternative the greater
the difference between the benefits and the costs. In other words,
as we move to supplemental indications where the benefit is enor-
mous and the costs are minimal, then the standard of evidence in
terms of paper NDA’s becomes a much more reasonable alternative;
that is, lifesaving drugs for indications where we currently don’t
have therapies where there is little cost associated with it, paper
NDA is fine. But it is at the edges where it becomes more difficult.

In terms of the nonprofits, there is a cost of submission, and how
do you motivate nonprofits to incur that cost? Especially, if it isn’t
a paper NDA, it is something more substantial than that. As you
all know, the cost of submitting applications, original applications,
is estimated at anywhere between $220 and $470 million. That is
a significant amount relative to the profits.

Market exclusivity, we haven’t explored the legal aspects of this
and so I don’t think we have a comment.

And, finally, the whole notion about some independent tech-
nology assessment function, either at IOM or through some other
reputable body, gets back to the question of where we want to cen-
ter this authority and the ability of organizations really structured
to perform one role to take on additional responsibilities that are
considerable.

Mrs. MorELLA. You also posed a question that I can see emanat-
ing from this, too. Is there an appropriate response that you would
suggest from pharmaceutical manufacturers to extensive off-label
use in those instances that have been cited—pediatric, rare disease,
oncology indications?

Some patient groups are concerned that the prevalence of off-
label use for pediatric, rare disease, and oncology indications serves
as a disincentive to conduct clinical trials. I wondered, is there a
responsibility? Does this tie into cost?

Ms. Jaccar. I think clinical trials for pediatric uses are some-
thing that will be a thorny issue for us, perhaps forever, because
the notion of doing clinical trials on children is a difficult one.

Mrs. MORELLA. It is rarely done, too.

Ms. JAGGAR. Yes; and that is why.

Mrs. MoRELLA. Jim Moran has a bill that deals with that.

Ms. JAGGER. Yes; indeed. So it is a difficult issue and probably
will not be one that is readily resolved. I think for rare diseases,
the cost of doing clinical trials is something that, again, becomes
an issue. You have pharmaceutical companies making substantial
investments in developing new drugs because they expect to be
able to make a return. They are for-profit companies. And so off-
label use becomes more important in those instances. But that is
why the notion of orphan drugs is an important one.

I think there will remain in pharmaceutical research and clinical
trials some difficult issues when the cost is great, as it is for clini-
cal trials, and the reward or the ethical sensitivity of it remains
problematic.

Mrs. MoRELLA. Is there an appropriate role of off-label promotion
in pediatric, rare disease, and oncology treatment, if any of you
want to address that?


120

will also use that drug. In time, the treatment will become standard medical therapy for
that particular illness even though it has not been studied in well-controlled clinical trials
and serious questions about proper dosage and side effects in a unique patient
population remain unanswered.

When academic scientists want to study the drug to answer these questions, the
manufacturer is usually not interested in funding the research. Furthermore, publicly
funded research sponsored by the National Institutes of Health (NIH) tends to favor
“pasic" research rather than "clinical" research on humans. According to the National
Commission on Orphan Diseases' 1989 Report to Congress, there are few other
options for funding of clinical studies on rare diseases. The small amount of funds
appropriated to the FDA's Orphan Products Grants Program each year to fund clinical
trials on treatments for rare diseases cannot possibly address the “off-label” dilemma for
5,000 rare diseases.

To illustrate how pervasive this problem is for rare diseases, NORD reviewed just a small
sample of diseases included in our Rare Disease Database (Internet address,
http://www.nord-rdb.com/~orphan). We chose 25 diseases alphabetically from "A," and
25 from “T." A list of some of these diseases and their commonly prescribed drugs is
attached for your perusal (Attachment A). Please note that out of 50 diseases only 14
are listed because: a) most of the 50 diseases remain totally untreatable, b) some
diseases are treated with surgery and/or blood products, and c) some diseases (such as
Tetralogy of Fallot) have symptoms that are controlled by drugs labeled for those
symptoms (€.g. abnormal heart rhythm) even if the disease is not named.

In addition, | asked Mitchell Brin, M.D., a leading neurologist from Mt. Sinai School of
Medicine in New York City, to explain the “off-label” use of pharmaceuticals in the
treatment of neurological movement disorders. Dr. Brin is the Director of the Movement
Disorder Center at Mt. Sinai Medical Center. He noted that a group of movement
disorders known as the Dystonias are ordinarily treated with anticholinergic drugs


19

FDA has also made changes in the evidence necessary to obtain
approval since the time of our off-label drug study. Largely in
response to pressures from patient groups eager to have
potentially life-saving drugs available as quickly as possible,
FDA has instituted “accelerated approval,* a means by which drugs
can receive approval with considerably less evidence than was
traditionally necessary. FDA has already made some changes in
the evidence required for certain efficacy supplements and is

considering more far-reaching changes.

Although the changes in FDA review time and in the evidence
requested by the agency are promising indicators that labels will
become more reflective of a drug's true benefit, the process of
updating a label is a collaborative one that involves the sponsor
of the application as well as FDA. Therefore, a major limitation
of relying on changes in the way FDA reviews efficacy supplements
as the solution to the off-label promotion problem is that the
agency cannot act on drugs for which supplemental applications
are not submitted. If companies remain hesitant to submit
supplemental applications, changes in the process at FDA would
have little effect on the utility of the label.14

por example, the expiration of a patent on a drug may well
renove much of the incentive that a sponsor might nave for

incurring the costs of the research necessary to support an
efficacy supplement for that drug.

Page 13 GAO/T-HEHS-96-212


14

In recent years concern about the off-label use of drugs has
resurfaced. This time the focus is on the limiting role the
label plays in defining appropriate boundaries for drug promotion
and advertising.1} although definitive evidence of a cause-and-
effect relationship is difficult to obtain, the concern with
promotion seems to have grown in direct relation to the
increasing competitiveness of the market for pharmaceuticals. As
changes in health care brought on by managed care and oth

attempts at cost containment have accelerated, pharmaceutical
manufacturers have faced a more competitive environment. With
increasing competition, it is in the interest of manufacturers to
demonstrate as many benefits for their products as possible. The
need to impress prospective clients of the value of drugs may be
especially true with respect to pharmacoeconomic benefits, in
which formulary managers are understandably interested. 12

1lgne issue has alternatively been discussed as the desire to
promote products more broadly and the need to inform physicians
more fully about drugs. Physicians currently gain access to
information about off-label uses through compendia, journal
articles, continuing medical education programs, symposia, and
professional meetings. They also have access to a number of
databases that provide information about off-label uses. None of
these sources of information is limited by what is contained on
the FDA-approved label. Further, a manufacturer can supply
physicians with information about off-label uses if the physician
specifically requests such information. However, the
manufacturer cannot provide information on off-label uses without
such a request.

12, formulary is a list of drug products. The basic types are
‘open" formularies, which list the drugs that are recommended but
do not restrict physicians in their prescribing behavior, and
"closed" formularies, which specify the drugs that physicians can
prescribe and, by omission, drugs that they cannot provide to
patients.

Page 8 GAO/T-HEHS-96-212


3

bursement denials for off-label use may prevent patients from re-
ceiving the best care available; fourth, pharmaceutical manufactur-
ers cannot promote a drug regardless of its benefits if its use isn’t
consistent with the FDA-approved label.

This hearing will help us establish the prevalence and implica-
tions of off-label drug use. It also provides us an opportunity to as-
sess the efficacy of the FDA’s supplemental new drug application
review procedures.

The General Accounting Office indicates that the FDA has im-
proved its response to supplemental applications hy 71 percent. I
would like to know what impact this progress has had on the will-
ingness of the pharmaceutical manufacturers to submit supple-
mental applications.

I welcome today’s witnesses and look forward to hearing their
views. Mr. Chairman, I am committed to working with you on this
issue and again thank you very much for convening this hearing.

Mr. Says. You are welcome, and I thank my colleague. I under-
stand Mr. Souder doesn’t have an opening statement. I would like
to say, however, that as vice chairman of this committee, his par-
ticipation has been extensive throughout the last 2 years and I
have learned a lot from his questions. He is really an outstanding
member. I know that is what chairmen say about their members,
but he is truly an outstanding member.

I understand Mrs. Morella, who has been active on the very issue
that we have been involved in and so many others, would like to
make a statement.

Mrs. MORELLA. And a truly outstanding member.

Mr. SHays. Depends what you say, young lady.

Mrs. MorELLA. Thank you. I don’t have an opening statement ex-
cept to say that, Mr. Chairman, I appreciate your scheduling this
very important oversight hearing on FDA reviews of supplemental
new drug applications and off-label use of prescription drugs. You
are right, I am very interested in it, having the FDA in my district
in such a biomedical area, including NIH, National Naval Medical
and other medical facilities. Bethesda is truly well named for the
“Pool of Bethesda”, which had curing qualities.

Off-label use of drugs is increasing and, as we know, the GAO
now estimates that between 80 and 100 percent of cancer, pedi-
atric, and rare disease patients use off-label drugs. There are a
number of critical questions that need to be addressed today, in-
cluding the effect of off-label use on public health and the relation-
ship between the FDA approval process for SNDA’s and the preva-
lence of off-label use.

So, Mr. Chairman, these issues need to be addressed. I look for-
ward to hearing the testimony and learning from our witnesses
today. Thank you.

Mr. Suays. I thank you very much. The only reason why you
didn’t get an introduction is I think you are pretty well known in
this area.

So let me call on our first panel. It is Sarah Jaggar, who is Direc-
tor of Health Services Quality and Public Health Issues, General
Accounting Office [GAO], accompanied by George Silberman, who
will also be sworn in and respond to questions if we have them.


182

Drug Therapy: sodium amylobarbitone
On-label Indications: Hypnotic drug.

Drug Therapy: flunarizine hydrochloride
On-label Indications: A calcium channel blocker used to treat hypertension and angina.

Drug Therapy: eperisone hydrochloride
On-label Indications: Centrally-acting muscle relaxer.

Disease Name: Essential Thrombocytopenia

Essential Thrombocytopenia is a rare blood disease characterized by abnormally low levels of circulating
blood platelets and a shorter than normal platelet survival time (i.e., 10 days). Symptoms may include a
tendency to bleed excessively into the skin or mucous membranes, especially during menstruation.

Drug Therapy: immune globulin

On-label Indications: Indicated for the maintenance treatment of patients with immunodeficiencies, Treatment
of acute and chronic idiopathic thrombocytopenic purpura (ITP).

Disease Name: Essential Thrombocythemia

Essential Thrombocythemia is a rare disorder of blood platelet production characterized by abnormally
elevated levels of circulating blood platelets. Major symptoms may include active bleeding, the formation of
blood clots (thrombosis) and/or abnormai enlargement of the spleen (splenomegaly).

Drug Therapy: hydroxyurea (Hydrea)

On-label Indications: Significant tumor response to Hydrea has been demonstrated in melanoma, resistant
chronic myelocytic leukemia and recurrent, metastatic, or inoperable carcinoma of the ovary. Hydrea used
concomitantly with irradiation therapy is intended for use in the local control of primary squamous cell
(epidermoid) carcinomas of the head and neck, excluding the lip.

Drug Therapy: melphalan (Alkeran)

On-label Indications: Indicated for the palliative treatment of multiple myeloma and for the palliation of non-
resectable epithelial carcinoma of the ovary.

Drug Therapy: busulfan (Myleran)
‘On-label Indications: Indicated for the palliative treatment of chronic myelogenous (myeloid, myelocytic,
granulocytic) leukemia.

Disease Name: Thomsen Disease

Thomsen Disease is a rare inherited neuromuscular disorder characterized by difficulty in initiating voluntary
movements, followed by prolonged muscle contraction. Symptoms may include muscle stiffness (affecting the
entire body), muscular rigidity, uncontrolled involuntary muscle movements (spasms) and slowness in chewing,
swallowing, talking, and walking.

Drug Therapy: tocainide hydrochloride (Tonocard)

On-label Indications: Treatment of documented ventricular arrhythmias, such as sustained ventricular
tachycardia, that, in the judgment of the physician, are life-threatening.

Disease Name: Tardive Dyskinesia
Tardive Dyskinesia (TD) is a neurological movement disorder resulting from use of neuroleptic drugs used to
control psychiatric or gastrointestinal disorders. Tardive Dyskinesia is characterized by involuntary and

4


110

3

reluctance on the part of the FDA to make studies in children a requirement for a new drug unless
the primary use of the drug will be in children. With the exception of antibiotics, medications for
fever, vaccines, and a few other therapeutic categories, pediatric use represents a relatively small
segment of the total market for a drug. Companies frequently are reluctant to expend the additional
time and resources to do pediatric studies with little promise of additional market potential,

CHILDREN ARE NOT SIMPLY SMALL ADULTS

It is important to understand why drugs must be studied in children to establish their safe and
effective use in children. In other words, why can’t studies in adults provide sufficient information
for use of a drug in children? No animal model or study in adults adequately predicts the effect of
drugs on children of various ages and stages of development. The dynamics of growth and
maturation of various organs, the changes in metabolism throughout infancy and childhood, changes
in body proportions, and other developmental changes result in significant differences between
children and adults. As a result, the elimination of drugs from a child's system, the dosage required
and the safety and effectiveness of a pharmacologic agent need to be studied at critical
developmental stages in the pediatric population.

Even within the pediatric population there is great diversity. There may be a need to study the same
drug in several pediatric groups (i.e., neonates, infants, young children and adolescents) in order to
determine drug efficacy, dosing, toxicity, and appropriate formulations for each subpopulation.

OFF-LABEL USES OF DRUGS IN CHILDREN AND ADOLESCENTS

‘An off-label use, also known as an "unapproved" use of an approved drug, refers to a use that is not
included or that is disclaimed in the approved labeling. It is important to emphasize that
“unapproved use” or "off-label" use does not imply an improper or illegal use. Indeed, this off-label
use may represent the only, or best, treatment available for a specific illness in a child.

As mentioned, only a minority of currently marketed drugs have undergone pediatric clinical trials
and have approved labeling for use in children. These include common antimicrobial agents,
medications for fever, vaccines and some asthma and allergy medications. However, most drugs
used to treat illnesses in children have never been formally tested or approved for pediatric use and
lack even basic dosage recommendations for children in their labeling. These include such routinely
used medications as dopamine (used to treat shock), cisapride (used to treat abnormal regurgitation
of stomach contents in infants and small children), ketorolac (the only available injectable non-
narcotic pain reliever), midazolam (used as a sedative and to treat convulsions), and adenosine (used
to treat life threatening abnormal heart beats).and the list is much longer.

Lack of studies to support labeling of the majority of drugs for use by children places the physician
caring for children in the untenable position of either prescribing without adequate labeling or
denying pediatric patients access to important therapeutic agents. When confronted with this
dilemma the physician invariably elects to prescribe a medication without adequate pediatric
labeling. As a result, off-label use of medications has, by default, become an established standard
of care for children, From the patient's perspective, infants and children frequently are exposed to


69

Agency's commitment to not treat supplemental indication applications as lesser priority

applications.

‘The goal is to describe in a guidance document situations where different data submissions than
the standard data (i.¢., two adequate and well controlled studies of the same use with full data
available) are sufficient to establish safety and effectiveness for a new indication. This in no way
Teflects a retreat from existing safety and effectiveness standards, but, rather, describes a sound
scientific basis for when data, other than data that exactly replicates a finding, are nonetheless
adequate to establish the validity of a finding. Examples of situations where different data
submissions than the standard data may support a safety and efficacy determination include the
following:

. ‘When the drug has been studied in other disease phases:

For example, some oncology products are first studied and approved for use in late stage,
refractory cancers, i.e., those that have not responded to other available therapies. A single well-
controlled study of a drug in an earlier stage of the same tumor, together with the studies of the

later stage of the disease, might support a new indication.

. ‘When the drug has been studied in a closely related disease:

13


24

Written Testimony of Joseph A. DiMasi, Ph.D.

Director of Economic Analysis

Tufts Center for the Study of Drug Development
Tufts University, Boston, Massachusetts

House Subcommittee on Human Resources and Intergovernmental Affairs

‘Mr. Chairman and Members of the Subcommittee:

‘Thank you for the opportunity to speak to the Committee. My name is Joseph DiMasi.
I am Director of Economic Analysis at the Tufts Center for the Study of Drug Development, a
non-profit, policy research group affiliated with Tufts University. ‘The opinions that I express
here are my own and do not necessarily reflect the views of the Tufts Center for the Study of
Drug Development.

In this testimony I will present historical data on the length of the supplemental
indication approval process and discuss potential solutions for getting off-label uses approved
expeditiously. The information relied upon in this testimony was obtained from Tufts Center
for the Study of Drug Development (CSDD) databases that track drug development and

approval times for new chemical entities (NCEs) approved in the United States since 1963.

‘The time that it takes to get new uses for old drugs approved is an important topic for
analysis for at least two reasons. The longer the approval process, the longer some patients
will wait for treatment simply because not all physicians will be aware of the effectiveness of
the drug in its new use. Secondly, use of a drug for an off-label use may be curtailed if third-
party payers refuse to reimburse for unapproved uses.

In.a number of studies published over the last decade, the CSDD has tracked approval


143

Positive, negative, and neutral, with the goal being that fully educated physicians will make
the right choices for their patients.

‘Thank you for allowing me to testify and I would be happy to answer any questions.


10

populations that are not listed on the FDA-approved

labeling. *?
PATTERNS OF OFF-LABEL DRUG USE

The evidence on the extent and types of off-label drug use has
not been extensive. Almost a decade ago, a University of
Washington Family Medicare Center study found that off-label use
was relatively rare: only 46 drugs of the 500 that were
evaluated were being used in an off-label context. However,
assertions by a group representing community cancer care centers
presented a very. different picture. In 1989, in an_effort..to
document the amount and types of off-label use, we initiated a
study of drug-prescribing patterns among cancer specialists. By
examining the drugs oncologists prescribed for specific types of
cancer, we determined that one third of all drugs they
administered were used off-label. Further, of the 46 approved
anticancer drugs and hormonal agents prescribed by oncologists at
the time, 44 were prescribed at least once to treat an off-label
indication. Perhaps most significant was our finding that more
than half of the cancer patients (56 percent) were prescribed at
least one drug off-label as part of their chemotherapy regimen.
3statement by William B. Schultz, Deputy Commissioner for Policy,
FDA, before the Committee on Labor and Human Resources, United
States Senate, February 22, 1996.

‘throughout the late 1980s, the Association of Community Cancer
Centers issued a series of reports saying that off-label use was
prevalent among its participating institutions.

Page 4 GAO/T-HEHS-96-212


M41

Current Legistative Proposals

Both House and Senate FDA reform bills would address the need to reform the
SNDA process. H.R. 3199, the House bill, would require the Secretary of Health and
Human Services to consider clinical practice, as reported in studies in scientific journals or
in information included in compendia. The Senate bill, S. 1477, would require the FDA to
establish performance standards for review of supplemental applications and clarify the
data requirements for an SNDA. The Senate bill would designate a person within each
FDA center, like the Center for Drug Evaluation and Research, who would be responsible
for ensuring timely action on supplemental applications. The Senate bill also mandates
creation of programs to foster collaboration between FDA, NIH and medical groups. The
Purpose of this collaboration would be to identify studies that could be used to support an
SNDA and encourage the submission of SNDAs based on this information. All of these
provisions would go far to improving the SNDA process and I hope that they pass as part
of FDA reform legislation. The Senate bill would also offer incentives for conducting the
clinical trials necessary to support pediatric indications in a drug’s label, and this provision
should be supported.
Dissemination of Information

Until approval of an SNDA, use of the product for a non-approved indication is
considered “off-label.” Off-label use is not prohibited — doctors may prescribe an FDA-
approved drug for any condition. As a result, supplemental approvals for new indications

are inextricably linked to off-label use and dissemination of information about off-label use,


DiMasi - 6
but this problem can be remedied legislatively. Faster reviews will increase the
incentives to pursue labeling approval.

Paper SNDAs. Greater use and acceptance of so-called paper SNDAs should be
encouraged. In some cases, the published literature can serve as the basis for approval
of off-label uses. This obviates the need for extensive and expensive clinical testing
and reduces the time needed to get new uses on the product label.

Submissions by Non-Profits. In cases where the financial incentives to pursue
approval of paper SNDAs are not sufficient to induce firms to seek approval, non-
profit institutions, such as patient groups, could put together the information needed for
a paper SNDA and petition for approval of the unlabeled use. In these cases,
marketing exclusivity would not be granted to the manufacturer.

Expansion of Marketing Exclusivity. In cases where additional clinical testing must
be done but patent protection has been lost or will soon be lost, an additional period of
marketing exclusivity can be granted to the firm that obtains the approval. Currently
firms can acquire three years of marketing exclusivity for a new use, a period during
which only the firm that obtained the approval is allowed to promote its product for the
approved new use.

Consistent Reimbursement. To ameliorate access problems for off-label uses, extra~
FDA expert panels can be set up by one or more of the pharmaceutical compendia,
distinguished professional societies, or the Institute of Medicine to review unlabeled
uses that are supported by evidence. Third-party payers would then have a recognized

basis for reimbursing off-label uses that are viewed authoritatively as acceptable


98

our most effective chemotherapy regimens are combinations of two
or more approved drugs. .

Combination chemotherapy regimens are not usually reviewed or
approved by FDA and, thus, do not routinely appear on product la-
beling In addition, for a variety of reasons, FDA-approved labeling
almost never keeps up with new uses of products. As a result, there
is a substantial Risconnect between the FDA label and the actual
practice of cancer medicine.

For virtually every anti-cancer drug, appropriate medical usage
differs from the terms of the product labeling.

Consider cisplatin, a mainstay of modern chemotherapy. It is ap-
proved for treatment of bladder, ovarian, and testicular cancer. But
over the last decade, it has been found useful in 10 or more other
distinct tumors, including breast, cervical, endometrial, lung, and
prostate cancer, none of which is reflected in the cisplatin labeling.
Cisplatin is also most effective in combination with other drugs,
but these combination regimens are generally not noted in the
label.

A newer product that is being developed in a similar fashion is
Taxol, which was originally approved in 1992 for treatment of
metastatic ovarian cancer after failure of first-line or subsequent
chemotherapy. Very quickly, Taxol became part of the standar pri-
mary treatment of ovarian cancer where, combined with cisplatin
or a related drug, it has improved response rates and extended sur-
vival as off-label. I have brought a copy of the published research,
a New England Journal of Medicine article by McGuire establish.
ing Taxol as primary therapy off-label.

'axol is now widely used to treat breast, bladder, esophageal,
head and neck and lung cancer, but its labeling reflects approval
only for second-line treatment of ovarian cancer, the origi ap-
Proval, id for treatment of breast cancer after failure of first-line
therapy.

Oncologists are well aware of the inadequacies of the FDA-ap-
proved label as a guide to treatment and they adapt their practice
accordingly. Instead of relying on drug labeling for the requisite
data, we look to peer-reviewed medical journals that report the re-
sults of many ongoing clinical trials that are constantly refining
quality cancer care through new uses of approved drugs.
Oncologists also rely on continuing medical educational programs,
medical textbooks, and other reliable sources to keep current with
quickly evolving cancer therapies.

Recognizing the possibly special circumstances of cancer drug de-
velopment, the American Society of Clinical Oncology [ASCO] has
proposed a method for expediting the supplemental new drug appli-
cation, or SNDA, at least for cancer drugs. ASCO has suggested to
FDA that it should permit pharmaceutical sponsors to use reports
of clinical trials and peer-reviewed medical journals as the basis for
SNDA approvals. These so-called literature-based SNDA’s, or paper
SNDA’s, are authorized under current FDA law but are not rou-
tinely utilized. ASCO believes that SNDA’s would be more widely
pursued if FDA were receptive to reports in the peer-reviewed lit-
erature as a basis for approval without insisting on reviewing the
raw data underlying those reports, which is generally perceived as
the agency’s current policy.


140

drugs intended for adults are seldom tested on children, even though those drugs may
commonly be used in children. In much the same way that limitations once existed for the
evaluation of drugs in women, FDA is evaluating the requirements and considering
incentives to sponsors that will encourage the earlier evaluation of a new drug in children.
The industry applauds this action by FDA and encourages the rapid conclusion of this
exercise. Until that is accomplished, trials in children will remain technically more difficult,
and the child will have to endure the blood sampling, urine collections and other
unpleasant procedures that are part of the current process.

‘There is anecdotal information that health care providers and hospitals recognize
the inadequacy of the current system. It used to be that health care providers would deny
Payment for uses that were not approved. The reason — economics. They are now
beginning to rethink their policies for the same reason. They used to feel that money could
be saved by limiting use of newer, generally more expensive drugs. Now they are starting
to recognize that the cost effective treatment of a disease should include the best treatment.
How are leaders in health care and hospitals doing this? They are reviewing the literature,
attending scientific and medical meetings, and making their own decisions through their
formulary committees. In addition to the older drugs that have wider ranges of
indications, they are adding to their formularies newer drugs that have limited indications,
allowing physicians to make the correct choice, Shouldn’t all patients, not just those
covered by enlightened health care providers, have the same standard of care provided to

them? They can if SNDAs are offered a higher, more consistent priority and review.


91

Dr. FRIEDMAN. For some drugs that is true; for some it is not.
But it’s not a bad assumption.

Mr. Suays. OK; that was a very gracious comment.

Dr. FRIEDMAN. I guess there is no such thing as a bad assump-
tion by the chairman, so it is probably unnecessary.

Mr. SHays. OK, thank you. Do you want to make a comment?

Dr. Woopcock. Sure. Actually, we made that assumption for a
long time because it is a rational assumption, and separate trials
of efficacy in children were required to get pediatric labeling on the

But what we have determined in consultation with all the pedia-
tricians is that, for many diseases, the disease in children is the
same disease in adults, and what you really need is childhood dos-
age information and childhood safety information.

So for many diseases, we don’t require formal trials of the effec-
tiveness in children. What we want is directions for pediatricians
to use that drug safely at the right dose in the children, and we
basically can extrapolate that it works.

So we have been working very closely with sponsors who are now
in drug development to try and bring this into effect. And we work
with them at each phase of their clinical trials and ask them when
are you going to start studying children. You know, are you ready
to ge Where is your pediatric development program?

ir. FRIEDMAN. But for those drugs that are off-patent or those
where generics exist, you understand the economic disincentive.

Mr. Suays. Sure. And because of that, it may be that the way
we deal with secondary uses is a logical response to the challe:
of bringing a drug into the marketplace. I mean, that seems to
the only hope for some who have particularly rare diseases.

You were looking like you were about to say something. My last
question really involves the issue of the Orphan Products Board.
My understanding is it hasn’t met since—and when I use orphan
products, these are rare disease issues.

Mr. SCHULTZ. Yes, sir.

Mr. Suays. It hasn’t met since December 1994. I don’t know if
you have knowledge of that. And, if so, is there an explanation of
why that might be the case? And I don’t even know how significant
it is, but I want it for the record.

Dr. FRIEDMAN. I do not have an explanation for the interim
meeting that hasn’t been held. I can tell you that there is planning
underway for the meeting to occur this winter.

Mr. Suays. But, I mean, that’s not 1995 and 1996, so it’s a 2-
year lapse. Our understanding is it hasn’t met all of 1995 at all
and during 1996.

Dr. FRIEDMAN. And it’s going to be meeting this winter—I’m
sorry, before the end of the year.

Mr. Suays. But that’s about a 24-month gap. Does that just say
to us that it’s not a very important board?

Dr. FRIEDMAN. I would like to be able to get you a better answer
for that. I don’t have a good enough answer.

Mr. Suays. You all have been very helpful. We do have another
panel and Mr. Towns is going to be pursuing some questions.

I have a meeting that I am going to go to. I missed half of it and
I am just going to try to get to part of it, so I am going to miss


W

The extent to which off-label use is prevalent in all areas of
medicine is not clear. However, there is evidence that it is
even more common within AIDS care than for cancer. In a study
published earlier this year, researchers from California reported
that more than 80 percent of AIDS patients received at least one
drug off-label as part of their treatment and that 40 percent of
all drugs that were given were provided off-label.5 Further, it
is generally acknowledged that off-label use is also extensive
for pediatric populations. ‘This may well stem from a hesitancy
to conduct medical experiments on children. Even if these were
the only areas where off-label use was common, the number of
patients affected would be considerable.”

PROBLEMS POSED BY OFF-LABEL DRUG USE

While it may appear to be problematic that many physicians
prescribe medications for conditions for which there has been no
official determination of safety and benefit, off-label use is

Scarol L. Brosgart et al., ‘Off-Label Use in Human
Immunodeficiency Virus Disease, *
Defici , 12:1 (May 1, 1996),

Sthe American Academy of Pediatrics claims that 80 percent of
drugs administered to children are given off-label. The latest
evidence supporting this claim was recently published: Leona
Cuttler et al., "Short Stature and Growth Hormone Therapy, *

i i jation, 276:7 (August 21,
1996), 531-37.

Tror example, more than 1 million patients are diagnosed with
cancer each year.

Page 5 GAO/T-HEHS-96-212


97

Mr. Towns. Let me call up our next panel. Dr. Runowicz, Dr.
Kauffman, Abbey Meyers and Dr. William Kennedy, please come
forward. We always swear in all of our witnesses, even Members
of Congress.

[Witnesses sworn.]

Mr. Towns. Thank you. Let the record reflect that they all an-
swered in the affirmative. Why don’t I begin with you, Dr.
Runowicz. I understand that you have a scheduli

ing problem.
STATEMENTS OF CAROLYN RUNOWICZ, AMERICAN SOCIETY
OF CLINICAL ONCOLOGY; RALPH KAUFFMAN, AMERICAN
ACADEMY OF PEDIATRICS; ABBEY MEYERS, PRESIDENT, NA-
TIONAL ORGANIZATION FOR RARE DISEASES; AND WILLIAM
KENNEDY, PHARMACEUTICAL AND RESEARCH MANUFAC-
TURERS OF AMERICA

Dr. RuNowicz. Thank you, Mr. Towns. I am Dr. Carolyn
Runowicz. I am here today on behalf of the American Society of
Clinical Oncology. With more than 10,000 members, ASCO is the
national medical specialty society for cancer physicians and physi-
cian researchers. I am also representing the Society of Gynecologic
Oncologists, with approximately 800 physician members who ad-
minister comprehensive cancer care for women.

As a board-certified specialist in gynecologic oncology, I treat
women with cancer, primarily cancer of the ovary or other
gynecologic tumors. As a survivor of breast cancer, I also know per-
sonally the disease and the perspective of the patient. I am pleased
to address the subcommittee today in both capacities concerning
the topic of off-label usage of FDA approved drugs. There may be
no other therapeutic area in which FDA approved drugs are used
more extensively in ways other than those set forth in FDA ap-
proved labeling. In light of the fact that most anti-cancer therap:
involves a combination of drugs not referenced on labels, almost all
cancer patients treated with drugs will receive off-label treatment.

Over the past two decades, a number of new anti-cancer agents
have been introduced. Because of these and other advances in can-
cer therapy, many cancers are now curable. These include a signifi-
cant percentage of childhood leukemias, Hodgkin disease and tes-
ticular cancers. For the most commonly occurring cancers—pros-
tate, breast, lung and colo-rectal—progress is less substantial but,
nonetheless, measurable.

Progress in cancer treatment occurs rapidly but incrementally,
often in small steps that make a difference in survival or quality
of life. New products are always welcome and the FDA is doing a
much better job than in the past to make therapeutic advances in
the form of new products available to the American people as
quickly as possible. FDA has responded to many of the demands
of an increasingly vocal and effective cancer patient advocacy move-
ment. The agency now seems to give pending new drug approvals
for cancer the same priority that is given to AIDS therapies and
that should be accorded to products for any. life-threatening dis-
ease.

In cancer, however, new drug approvals are only the beginning
of the story. Much of the incremental progress in cancer treatment
requires finding new uses for already approved drugs. Moreover,


102

-3-
For virtually every anticancer drug, appropriate medical usage differs from
‘the terms of the product labeling. Consider cisplatin, a mainstay of modern
chemotherapy. It is approved for treatment of bladder, ovarian and testicular
cancer, but over the last decade it has been found useful in ten or more other
distinct tumors--including breast, cervical, endometrial, lung and prostate cancer--
none of which is reflected in the cisplatin labeling. Cisplatin is also most effective

in combination with other drugs, but those combination regimens are generally not
noted in the label.

‘A newer product that is being developed in a similar fashion is Taxol, which
was originally approved in 1992 for treatment of metastatic ovarian cancer after
failure of first-line or subsequent chemotherapy. Very quickly, Taxol became part
of the standard primary treatment of ovarian cancer, where, combined with
cisplatin or a related drug, it has improved response rates and extended survival.
Taxol is now widely used to treat breast, bladder, esophageal, head and neck, and
lung cancer, but its labeling reflects approval only for second-line treatment of
ovarian cancer (the original approval) and for treatment of breast cancer after failure

of first-line therapy.

Oncologists are well aware of the inadequacies of the FDA-approved label as
a guide to treatment, and they adapt their practice accordingly. Instead of relying
‘on the drug labeling for the requisite data, we look to peer-reviewed medical


118

To put the problem in perspective, an "orphan disease" is defined under federal law as
a disease or condition that affects fewer than 200,000 Americans. Most of these illnesses
are unfamiliar to the public, as well as many medical professionals. However, some are
quite well known such as cystic fibrosis (20,000 -30,000 Americans), Duchenne muscular
dystrophy (10,000 Americans) and Amyotrophic Lateral Sclerosis, commonly known as
Lou Gehrig's Disease (30,000 Americans). There are over 5,000 rare disorders, most of
which are genetic. Cumulatively affecting an estimated 20 million Americans,
orphan diseases represent a major health problem.

‘The Orphan Drug Act... . Justa first step?

Because each rare disorder affects a small number of people, pharmaceutical companies
did not develop drugs to treat them until 1983 when the Orphan Drug Act became law.
This federal statute assures manufacturers that they will not lose money, and will actually
have a chance to make a profit, if they develop a drug for a very limited market. The law
contains several financial incentives designed to entice manufacturers into this field of
research and development, including tax credits and a seven-year period of exclusive
marketing rights.

Since 1983, over 130 orphan drugs have been approved for marketing in the United
States, and approximately 650 designated orphan drugs are in the research pipeline.
This law is undoubtedly one of the most successful pieces of legislation that Congress
has enacted in recent decades. Subsequently, Japan and Singapore have passed similar
laws and the European Union is formulating their own orphan drug legislation right now.

While the Orphan Drug Act spurred development of new treatments for rare
diseases, it did not address the problem of "off-label" usage -- it remains very
difficult to get rare diseases "on-label." There is simply little reason and no incentive
for a company to study the use of a drug on a rare disease if the compound is already
approved and on the market for a more prevalent and, thus, more lucrative health
condition. It costs money to fund clinical trials, and manpower to submit a Supplemental


65

© And, drug companies can present the FDA findings to drug approval bodies in
other countries, thus enhancing their ability to gain approval (and reimbursement)
for uses in other markets.

Despite such incentives, however, many indications remain unlabeled, presumably because the
incentives are not perceived to offset the resources that would be required to obtain approval for
‘anew indication. There appear to be two primary reasons for the failure of the sponsors to
pursue approval of new indications . First is the concern that millions of additional dollars will be
required to conduct new clinical studies to establish the safety and effectiveness of a use. Second
is the concern that efficacy supplements are a lesser priority for FDA than applications for new
products, and, as a result, the review process is very lengthy and is likely to erode much of a
sponsor's market exclusivity. These concems may exist in part because FDA has not been as
clear as it could be about its data requirements for efficacy supplements. FDA is now engaged
actively in efforts to address these concerns to encourage and expedite efficacy supplements for
unapproved uses. We are doing a number of things and have several ideas for ad

ional progress
in this area. I will outline them for you:

‘New Initiatives at FDA

Earlier this year FDA assembled a task force to examine, in depth, the broad range of issues that

influence whether a supplemental indication makes it into a product’s labeling, The Supplemental
Indications Working Group (“the Group”) has focused on identifying barriers to sponsors’


1

this document will clarify that the Agency's data expectations for new indications of already

approved products are perhaps not nearly as great as some sponsors perceive them to be.

FDA also is examining mechanisms and resource requirements for implementing the strategies

which ultimately are decided upon.

Expediting Review of Efficacy Supplements

‘As you know, PDUFA is helping resolve the problem of timely reviews for drugs and biologics.
Under PDUFA, for the applications submitted in FY 1997, the Agency will perform a complete
review and take an action on all drug and biologic applications (NDAs and PLAs) within 12
months of submission for standard applications and within 6 months for priority applications
These review performance goals apply to efficacy supplements as well. In fact, under PDUFA,
for NDAs, PLAs, and efficacy supplements, the Agency has exceeded the interim goals
established by Congress. For applications submitted in FY 1994, the Agency reviewed and acted
upon 96% of the NDAs and 77% of the efficacy supplements on time. The interim “on time”

performance goal, agreed by Congress and industry, for this group of applications was 55%.

For those applications submitted in FY 1995, FDA continues to far exceed the goals established
under the user fee program. The established performance goal for the group of applications
submitted in FY 1995 was to be “on-time” at least 70% of the time. In fact, already we have

reviewed and acted upon 89% of the NDAs in this group and if we act within the PDUFA

15


16

Information, and other authoritative compendia as identified
by the Secretary."

Purther, reimbursement could also be based on supportive clinical
evidence in peer-reviewed medical literature appearing in
publications that have been identified by the Secretary of Health
and Human Services. Legislation currently being considered (H.R.
3199) proposes a conceptually similar approach with respect to
promotion of off-label drug uses.

This strategy has both benefits and limitations. The benefits.
are that (1) it avoids many of the costs needed to assemble a
supplemental application for FDA approval and (2) it allows
promotion earlier than would be likely if companies had to wait

for FDA to approve an efficacy supplement.

However, relying on sources other than the label for defining
appropriate promotion also has its drawbacks. Most importantly,
in instances in the past, drugs that had been shown to be
effective in research that was published in respected peer-
reviewed journals were later found to be either ineffective or,

in some cases, actually harmful for patients.

Change the Process for Updating the Label

Another approach to reducing the barriers to promotion faced by

Page 10 GAO/T-HEHS-96-212


99

However, even if the SNDA process is made more efficient by
FDA, it still will not be possible to keep pace with rapid develop-
ments in cancer research. For this reason, ASCO has also urged
FDA to relax its restrictions on dissemination, not promotion, of re-
liable medical information by pharmaceutical I sponsors, Among the
types of information that we believe are generally reliable are peer-
reviewed medical journals, standard medical textbooks, and inde-
pendently conducted educational seminars. In the academic re-
search environment in which I practice, obtaining the latest data
on new treatments is not usually a problem; however, our col-
leagues in non-academic practice settings around the country may
be less likely to have easy and timely access to this potentially life-
extending information. Oncologists are trained to review such infor-
mation with a critical eye and we believe the risk that they will
be misled by independently derived medical data is much less than
the risk that they will not have access to it as quickly as possible
for the benefit of the patient. In general then, ASCO supports regu-
latory policies that optimize the flow of peer-reviewed, high quality,
reliable medical information.

We note that most patient advocacy groups in the cancer commu-
nity have positions that are consistent with ASCO’s policies, includ-
ing the National Coalition for Cancer Survivorship and various
breast and prostate support groups, as well as the erican Can-
cer Society. From my own experience as a patient, I can attest to
the intense desire of patients with cancer to have access to as much
information as quickly as possible. Knowing how much new infor-
mation about cancer therapy is developed on a daily basis, I would
not be content with data that may have been accurate a year ago
and is perhaps obsolete now.

Cancer may very well be a special case requiring special regula-
tion from FDA. None of the proposals advocated by ASCO and sup-
ported by the patients require legislation; thus, FDA, if it were so
inclined, could act immediately to expedite SNDA’s by greater reli-
ance on published reports and to lift restrictions on the dissemina-
tion of reliable medical information. Both patients with cancer and
the physicians who treat them would benefit from such action.

Thank you.

[The prepared statement of Dr. Runowicz follows:]


21

Mr. SHays. Thank you very much. Dr. DiMasi.

Mr. DiMasi. Mr. Chairman and members of the subcommittee,
thank you for the opportunity to speak today. In a number of stud-
ies published over the last decade, my center has tracked approval
times for new indications and compared them to the time spent to
approve the applications for the drugs’ original uses.

The central hypothesis posited in these studies was that, on av-
erage, new uses would be easier to review because most issues or
concerns regarding toxicology, chemistry and manufacturing would
have been addressed in the original review. This reasonable hy-
pothesis leads to the expectation that supplemental indications
would, on average, be approved more quickly than the original
uses.

Surprisingly, none of these studies supported this expectation.
For the most recent period analyzed, 1989 to 1994, supplemental
indication approval times averaged 28.3 months, which was 3.7
months longer than the average for the original indications. The
difference between the SNDA and NDA approval times was statis-
tically significant.

A closer look at the data for this period, however, does show
some improvement for the last 2 years. The average SNDA ap-
proval times for 1993 and 1994 were 2.8 and 3.6 months shorter,
respectively, than the NDA approval times for the drugs for which
the new uses were approved. The differences, however, were not
statistically significant. Overall, the evidence on approval times
cannot be used to support a case for quicker approval of new indi-
cations relative to the original indications.

Many new uses for old drugs offer significant advances in patient
care. In some cases, the follow-on indication is even more impor-
tant than the original use. In our most recent study of the supple-
mental indication approval process, we also examined the approval
times for new uses that were recognized by the FDA as represent-
ing important advances. Although our data indicate that, other
things being equal, those new uses that the FDA had noted were
important were approved more quickly than other new uses, the
approval times for the important new uses averaged about 10
months longer than the average approval time for the original indi-
cations. This difference was statistically significant.

The data that we analyzed in our studies did not allow us to de-
finitively assess the impact of the User Fee Act on the supple-
mental indication process. Recent user fee statistics released by the
FDA on efficacy supplements, though, are encouraging. The re-
ported statistics are, however, for FDA actions on applications
which include issuing not-approvable and approvable letters; thus,
they do not measure the time from initial submission of an SNDA
to approval. The category of efficacy supplements is also much
broader than the types of applications that we have analyzed in the
past, which were those for new indications and new patient groups.

Providing sufficiently strong incentives for firms that file supple-
ments on some well-established off-label uses while also encourag-
ing reimbursement for these uses is a difficult problem to resolve.
A number of process and legislative measures can, however, be con-
sidered that potentially could facilitate the development and use of


50

If you don’t have a response in a colon cancer patient, that patient
could still live for 15 years. So there is a natural incentive to test
your drugs against hematological disorders and chemotherapy
works better against those.

But the real market is in the solid tumors. You don’t have 6,000
patients; you have 60,000 patients. Just in terms of dollar figures,
of the most widely used drugs that we found, carboplatin was used
off-label frequently. The cost per patient was $5,500 in 1990 dollars
in terms of one regimen of this, six cycles. Our cost ranged from
a low of a few hundred dollars to a high of about $10,000 per pa-
tient, though a lot of the money is being used off-label.

What we found, and this should come as no surprise, is that re-
imbursement denials were not for all off-label uses but for the off-
label uses that were expensive.

Mr. SoupER. Can I ask one other variation of the same question?
In trying to gauge what impact this has, in particular on the Gov-
ernment, if the ones that are denied are often the most expensive,
I would assume that particularly for anything that really pushes
past $5,500 a year, you start to get into the phenomena that we
see with Ricky Ray and others where, in effect, you can push fami-
lies into financial a situation where they go into Medicaid and
Medicare.

Do you have any what kind of Government reimbursement costs
we have in these areas and what percentage, and do you expect
this to grow? In other words, as we come up with more miracle-
type drugs that deal with really devastating diseases and every-
body wants access to those, isn’t this a potential large growth ele-
ment of our Medicaid and Medicare budget?

Mr. SILBERMAN. The specific answer for cancer is that we allowed
reimbursement for other issues, so the off-label has disappeared for
that. But the general statement is exactly on the mark: every day
we can do more and more for more and more patients and we can’t
pay for everything, so the decision about what we reimburse is crit-
ical. That is, I think, the central dilemma of health care: what we
are going to pay for and what we are not. So you're right on the
mark.

Mr. SouDER. And that partly requires us to know costs.

Mr. SILBERMAN. And how well things work.

Mr. SOUDER. And what the costs are.

Ms. JAGGaR. Mr. Souder, perhaps I would bring to your mind an
article I know you've seen recently in the paper about the high cost
of the new AIDS drugs. So many people are aware that they offer
great hope, new hope for extended life or even better than that;
however, the cost is extremely high.

Many AIDS patients achieve their coverage through Medicaid
and so there are State programs that are in the process of making
some very difficult decisions. Can they add additional money to pay
for these expensive drugs? Do they have to ration the coverage in
some way? Can they not cover the new expensive drugs and only
continue to cover the old drugs that were less expensive?

I think that is an example of a very real dilemma that many
States are facing right now. And, of course, Medicaid is partially
funded by the Federal Government, so it has Federal implications.


95

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

‘The Honorable Christopher shays

Chairman, Subcommittee on Human Resources
and Intergovernmental Relations

Committee on Government Reform and oversight

‘of Representatives

ington, D.C. 2051!

Dear Chairman Shays:

‘This is in follow-up to your September 12, 1996 hearing on
‘off-Label Drug Use and Food and Drug Administration (FDA)
Review of Supplemental New Drug Applications (SNDAs).” You had
asked about the Orphan Products Board meetings. We have
scheduled a meeting for this fall and will continue to hold
meetings at least once a year as required by the Board’
charter.

The Orphan Products Board last met in December 1994. Its last
Public Meeting was held in June 1994. The 1994 Public Meeting
was attended by only five non-Government individua.
representing groups with which Board members already met
frequently. At that time, the Board's coordination and
information exchange functions were proceeding very smoothly
without the need for routine formal meetings. Given the lack
of public interest in the Board meetings, it was agreed that
FDA and Office of the Assistant Secretary of Health (OASH)
staff would arrange to call future meetings at such times as
they were needed.

Since our last Board meeting, FDA, the National Institutes of
Health (NIH), and the Centers for Disease Control (CDC)
personnel involved with orphan products issues have been in
Rearly constant contact on issues of mutual concern. Topics
included development of the rare disease database at NIH,
research funding priorities, product availability, grant’ review
methods, and numerous other subjects. Other Board members,
including the Department of Defense representative, have been
consulted as needed on important issues where that’ agency was
involved, including collaborative development of botulinum
toxin products.

The promotion of orphan product development has continued, our
designation and grant programs are working extremely well, and
more and more products are reaching the market. As previously
mentioned, collaboration among the Federal agencies ha
continued’ without interruption, where and when most needed.



33

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133

abnormal movements of the jaw, lips and tongue including grimacing, sticking out the tongue, sucking or “fish
like” movements of the mouth.

Drug Therapy: lithium carbonate (e.g Lithonate)

On-label Indications: Treatment of manic-depressive illness.

Drug Therapy: bromocriptine mesylate (Parlodel)

On-label Indications: Treatment of hyperprolactinemia-associated dysfunctions including amenorshea with or
without galactorrhea, infertility or hypogonadism. ‘Treatment of patients with prolactin-secreting adenomas,
acromegaly and Parkinson’s disease.

Drug Therapy: baclofen (Lioresal)
On-label Indications: Treatment of spasticity resulting from multiple sclerosis, particularly for the relief of
flexor spasms and concomitant pain, clonus and muscular rigidity.

Drug Therapy: methyldopa (e.g., Aldomet)
On-label Indications: Treatment of

Drug Therapy: valproic acid (Depakene, Depakote)
On-label Indications: Treatment of simple and complex absence seizures and adjunctively in patients with
multiple seizure types that include absence seizures.

Drug Therapy: clonidine (Catapres)
On-label Indications: Indicated for the treatment of hypertension.

Drug Therapy: propranolol hydrochloride (Inderal)

On-label Indications: Indicated in the management of hypertension, the long-term management of angina
pectoris due to coronary atherosclerosis, cardiac arrhythmias, reduction of cardiovascular mortality in patients
who have survived the acute phase of myocardial infarction and are clinically stable. Also indicated for the
prophylaxis of common migraine headache, the management of familial or hereditary essential tremor, and
management of hypertrophic subaortic stenosis, especially the treatment of exertional or other stress-induced
angina, palpitations, and syncope. In patients with Pheochromocytoma, may be useful as adjunctive therapy if
the control of tachycardia becomes necessary before or during surgery.

Drug Therapy: amantadine hydrochloride (e.g., Symmetrel)

On-label Indications: Prophylaxis and treatment of infection caused by various strains of influenza A.
Treatment of parkinsonism (idiopathic Parkinson's disease {paralysis agitans), postencephalitic parkinsonism, and
symptomatic parkinsonism) and drug-induced and extrapyramidal reactions.

Drug Therapy: clonazepam (Klonopin)
On-label Indications: Treatment of Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic
seizures, and absence seizures (petit mal).

Drug Therapy: nifedipine (e.g., Adalat)
‘On-label Indications: Management of vasospastic angina and chronic stable angina (classical effort-associated
angina).


Ww

pharmaceutical companies is to encourage changes in the process
for updating labels so that it is more timely and more reasonable
in its demands for information. Expediting the review process
for efficacy supplements would make the information on labels
more reflective of the most current understanding of a drug's
benefits, while modifying the information needed to obtain a
supplemental approval, could well reduce the costs and
disincentives of submitting an application for approval. A
Process that produced an up-to-date label would benefit all who
sell, buy, prescribe, and use drugs.

Although there are benefits to changing the process, the Congress
did not choose to do so in response to the problems created when
insurers refused to reimburse for off-label uses. This may be
the result of the perception that FDA takes an inordinate amount
of time to process applications and is unwilling to adapt to an
increasingly dynamic environment. Also, any demands that FDA
reduce the amount of time it takes to make decisions might result

in increased resourc

for the agency in an era of growing
sensitivity about the costs of government.

However, since the time of our work on off-label drugs, much has.
changed at FDA. One change is that the agency has improved its
performance in processing drug applications. In October 1996, we
reported that the time to reach decisions on new drug

Page 11 GAO/T-HEHS-96-212


61

The wisdom of the efficacy requirement has been borne out repeatedly. For example, many drugs
approved before 1962 turned out to be ineffective when, after 1962, they were studied for
effectiveness. The solid foundation that is laid down by the efficacy standard is one of the main
reasons that there is such a strong sense of confidence in the drug products that are on the United
States market today. Recognition of the critical value of controlled trials is not confined to those
in the United States. It is a world-wide regulatory standard and is the standard expressed
repeatedly in scientific assessments and reports of all kinds -- clinical reports, editorials, and in

academic and government evaluations.

OFF LABEL USES

‘The history of the FDC Act indicates that Congress did not intend FDA to interfere with the
practice of medicine. Thus, once a product is approved for marketing for a specific use, FDA
generally does not regulate how, and for what uses, physicians prescribe that drug. A licensed
physician may prescribe a drug for other uses, or in treatments, regimens, or patient populations,
that are not listed in the FDA-approved labeling, Uses that are not approved by FDA are referred

to as “off label", “unapproved”, "unlabeled," or “extra-labeled" uses.

The extent of off label use varies from one drug class to another. For example, off label use is
very high for oncology drugs, yet much lower for many other drugs. FDA recognizes that, in
certain circumstances, off label uses of approved products are appropriate, rational, and accepted

medical practice. Off label uses, particularly for oncology, rare diseases, and pediatrics, can be of


130

Disease Name: Ahumada-Del Castillo Syndrome |

Ahumada-Del Castillo Syndrome is a rare endocrine disorder that affects females and is characterized by
impaired function of the pituitary and hypothalamus glands. ‘Symptoms may include abnormal production of
breast milk (galactorrhea) without childbirth and nursing, lack of normal ovulation (amovulation) and the lack
of regular menstrual periods (amenorrhea).

Drug Therapy: pergolide mesilate (Permax)

On-label Indications: Indicated as adjunctive treatment to levodopa/carbidopa in the management of
Parkinson's disease.

Disease Name: Amyloidosis
Amyloidosis is a group of metabolic disorders characterized by the abnormal accumulation of a certain fibrous
protein (amyloid) in many tissues of the body. Amyloid accumulations, which may be localized, general, or
Pathan ae te aifecied organs) e.., intestinal tract, heart, liver, spleen, kidneys, etc.) to

tion,
Drug Therapy: colchicine
On-label Indications: Indicated for the treatment of chronic gouty arthritis when complicated by frequent,
recurrent acute attacks of gout.

Disease Name: Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neuromuscular disease of the nerves that control the function and
‘movements of skeletal muscles (motor neurons). Symptoms, which typically affect both upper and lower motor
neurons, include muscle weakness, clumsy movements, difficulty swallowing (dysphagia) and speaking
(dysarthria), and progressive wasting of muscles that have lost their nerve supply.

Drug Therapy: diazepam (Valium)

On-label Indications: Indicated for the management of anxiety disorders or the short-term relief of symptoms
of anxiety. In acute alcohol withdrawal, may be useful in symptomatic relief of acute agitation, tremor,
impending or acute delirium tremens and hallucinosis. Relief of skeletal muscle spasm due to local pathology;
atheosis and stiff man syndrome. May be used adjunctively in convulsive disorders although it has not proved
useful as the sole therapy.

Drug Therapy: pyridostigmine bromide (Mestinon)
On-label Indications: Treatment of Myasthenia Gravis.

Drug Therapy: gabapentin (Neurontin)
On-label Indications: Indicated as adjunctive therapy for the treatment of partial seizures with and without
secondary generalization in adults with epilepsy.

Disease Name: Aplastic Anemia

Aplastic Anemia is a rare blood disorder characterized by decreased function of the bone marrow that results
in abnormally low levels of all the cellular elements of the blood (pancytopenia). In some cases, the disorder
‘may affect primarily single cell lines (i.e., red blood cells, white cells, or platelets). The initial symptoms may
include increasing weakness, fatigue, recurrent or persistent infections, and/or lethargy.

Drug Therapy: cyclosporin (Neoral, Sandimmune)

On-label Indications: Indicated for the prophylaxis of organ rejection in kidney, liver and heart allogenic
transplants,

Drug Therapy: cyclophosphamide (Cytoxan)


114

7

pediatric labeling is necessary and be authorized to fund studies required to accomplish
pediatric labeling of those drugs.

+ The FDA should develop guidelines for the inclusion of pregnant and/or lactating women
in clinical trials of new drugs and request such studies be performed when there is a high
probability the drug will be used in these populations.

‘The Academy supports consideration of proposals to provide economic incentives, if
necessary, to companies who conduct pediatric studies and who provide pediatric dosage
formulations for new drugs as well as already approved and off-patent drugs. Consideration
should be given to patent extension for companies who complete pediatric studies which lead
to pediatric labeling.

‘The American Academy of Pediatrics is anxious to work with Members of Congress to develop the
best and most far-reaching protections for infants, children, adolescents and young adults. We
welcome the opportunity to continue this dialogue.


116

is the most effective drug for sickle cell anemia. This drug should
probably be approved for sickle cell anemia as soon as possible. Not
only isn’t the company supporting the research on it for sickle cell
anemia, but Dr. Haffner’s office under that $12 million appropria-
tion is supporting the clinical trials to someday get this ig ap-
proved for sickle cell anemia.

It is wrong. It is wrong that this is happening and that compa-
nies are not stepping forward, especially when there was such an
excellent paper published in the New England Journal of Medicine
saying that this is a very important breakthrough.

0 what we think should be done is a number of things. First of
all, to raise the priority of supplemental applications at FDA. Re-
move the gag rule, because right now if you call up FDA and ask
why isn’t my drug labeled for my disease, they say “we're not al-
lowed to tell you; it’s a trade secret.” Well, the secrecy under which
FDA operates is horrendous because even if they know the com-
pany submitted the data for that drug and they found out that the
drug was unsafe or ineffective, consumers and doctors can’t find
out. So the agency, must be allowed to talk to the public.

Require the FDA to identify these candidate drugs, create a sup-
plemental review division that would look at these drugs individ-
ually and get them out of the divisions that are so bogged down
with reviewing new NDA’s.

And Congress should consider financial incentives to the industry
to support these clinical trials. If they gave them a tax credit for
every $1 that they invest in the clinical trials to get supplemental
NDA’s approved, I think there wouldn’t be so much resistance to
performing the research.

And, finally, drug companies must understand that they have a
social responsibility to do no harm, and to know that their drugs
are being prescribed off-label without being able to tell people what
dose or what the side effects are is doing harm. Thank you.

[The prepared statement of Ms. Meyers follows:]


4

And also testifying will be Dr. Joseph DiMasi, who is from Tufts
University Center for Drug Development.

We invite all three panelists to come up. We would like to swear
you in. If you could remain standing, we will swear you in.

[Witnesses sworn.]

Mr. Suays. For the record, our witnesses have responded in the
affirmative. I would just like to take care of some housekeeping for
the committee.

I ask unanimous consent that all members of the subcommittee
be permitted to place any opening statements in the record and
that the record remain open for 3 days for that purpose. And with-
out objection, so ordered.

I ask unanimous consent that our witnesses be permitted to in-
clude their written statements in the record. Without objection, so
ordered.

We will start with the GAO and then we will go to you, Dr.
DiMasi. Thank you. We welcome your testimony.

STATEMENTS OF SARAH JAGGAR, DIRECTOR OF HEALTH
SERVICES QUALITY AND PUBLIC HEALTH ISSUES, GENERAL
ACCOUNTING OFFICE, ACCOMPANIED BY GEORGE SILBER-
MAN, ASSISTANT DIRECTOR; AND JOSEPH DIMASI, TUFTS
UNIVERSITY CENTER FOR DRUG DEVELOPMENT

Ms. JaGGaR. Thank you. Good morning, Mr. Chairman and mem-
bers of the subcommittee. I am pleased to be here to appear before
you this morning to discuss off-label drug use and the problems off-
label use pose for drug promotion and for advertising. With me is
George Silberman, the assistant director who has led our work in
this area.

My statement today will cover four points: what off-label use is;
the existing evidence on the prevalence and nature of off-label use;
the dilemmas posed by off-label use, including the question of
whether or not to allow promotion for off-label uses; and two gen-
eral approaches for how these dilemmas may be resolved.

My comments today are based on our 1991 study of off-label drug
use among physicians who specialize in cancer care and on new
analyses of FDA performance that we conducted for this hearing.
We also interviewed representatives from the American Society of
Clinical Oncology, the American Academy of Pediatrics, and the
National Organization of Rare Diseases.

To my first point: What is off-label drug use? Physicians use a
drug off-label when they prescribe an FDA-approved drug for treat-
ments other than those specified on the label, So-that goes to:
What is the label? Before marketing a new drug in the United
States, the manufacturer must obtain approval from FDA by speci-
fying both the medical conditions the drug is effective against and
the patient groups for whom the drug has been shown to be effec-
tive. This information is contained in the proposed label submitted
by the sponsor.

When FDA approves a new drug application, this approval iden-
tifies only the uses for which the manufacturer has demonstrated
to FDA’s satisfaction substantial evidence of safety and effective-
ness. If, later, evidence arises of other safe uses, then the drug’s
manufacturer can submit a new application to have the label


93

and make less expensive that process, again as another way of tip-
ping the scales in that direction.

ir. TOWNS. What financial incentives to pharmaceutical manu-
facturers currently receive to meet the FDA requirements for ap-
proval of supplemental applications? Do they receive any at this
point?

Mr. SCHULTZ. These aren’t actual dollars but the main incentive
is that if they get approval of a use through the supplement proc-
ess, they can put it on the label and they can promote the drug for
that use. That is the big financial incentive. In addition, for orphan
drugs, a specific category of drugs, there are some tax credits and
grants that are available.

Dr. FRIEDMAN. And exclusivity.

Mr. SCHULTZ. Exclusivity is available for orphan drugs. Also, and
this hasn’t been totally successful, but for supplements there is,
even if the patent is expired, a 3-year exclusivity where the com-
pany can have a 3-year right solely to do the labeling and advertis-
ing for that new use. The problem is if the patent is expired, a ge-
neric drug or another drug can be prescribed for the use even
though it wouldn’t be labeled.

Mr. Towns. Now, most off-labels do require FDA approval?

Mr. ScHuLtTz. If the company wants to promote the drug for a
use, it has to have FDA approval. But as long as a drug is ap-
proved for the first use, a doctor is free to prescribe it for another
use based on his or her opinion, based on journal articles or what-
ever, without FDA approval.

Mr. Towns. Let me ask this and sort of reverse roles here. What
can Congress do to continue to facilitate your efforts to improve
drug approval rates? What can we do on this side?

Dr. FRIEDMAN. Let me start, if I may. I think as we look at this
there are three areas that one can divide the responsibilities up in.
One are those areas in which the Food and Drug Administration
has the authority and the responsibility, and we think that we
must work very hard to improve our own systems to make it sim-
pler, more clear, more efficient, and to work with other constitu-
encies. That is something that we can control and we can do, and
we are working on that very hard right now.

There is a second area in which we don’t have the full authority
or responsibility, but we can sort of help move the system along.
And a third area, obviously, or that component that we don’t have
any responsibility for or any authority and where Congress or other
bodies has a real role to play. I think that identifying the economic
and the patent incentives and disincentives that currently exist for
pharmaceutical companies for other parts of even the reimburse-
ment industry may be a very relevant role for congressional inquiry
and, perhaps, remedy.

We don’t have specific solutions that we would offer in that re-
gard, but we think those are complicated areas. They are sensitive
areas, and they are areas where the pharmaceutical industry might
really benefit or see additional benefits from some remedies that
you all could think about. I think that would be my simple answer.

Mr. SCHULTZ. I just want to add one thing. I think probably the
biggest reason that the story we have to tell about drug approvals,
and to some extent supplements, is the Prescription Drug User Fee



38

indeed, there are incentives for someone to do that research,
whether it be the manufacturer or private medical investigators,
Government agencies, and so forth.

So there certainly will always be incentives to conduct research
into new uses. The real question is; How much is acceptable?

Mr. Towns. You are saying that somebody should do it. What do
you mean by that? I just want to make certain I understand you
clearly. You didn’t say FDA; you said somebody. Is there a reason
for that somebody? I guess I’m listening maybe too closely.

Mr. DIMasi. Well, the research, clinical research, will be done
not by the FDA but by the manufacturer or other parties—inde-
pendent medical investigators, nonprofit institutions, Government
agencies—who are interested in pursuing or investigating a par-
ticular use.

Mr. Towns. Right. So it leads me to this question: If there is less
reliance on an FDA-approved label for supplemental use, wouldn't
the credibility of the label be undermined by new drugs as well?

Mr. DIMasl. I don’t think the credibility of the label would be un-
dermined. There, obviously, would be some questions in the minds
of some practitioners and patients about uses which are being used
and reimbursed but have not found their way onto the product

label.

Mr. Towns. If FDA approval become unnecessary for supple-
mental use, what criteria would we require or should we require?
I just want to hold onto this a little while longer.

Mr. DiMasi. Well, I'm certainly not suggesting removing FDA’s
authority here in approving supplemental indications. But in terms
of use in the marketplace and appropriate reimbursement, there
certainly is the possibility of referring to organizations which can
be set up by members of the compendia or professional societies to
review in some sense what is out there in terms of off-label use and
render opinions as to not what should be on the product label but
what appears to be acceptable medical practice.

Mr. Towns. GAO, did you want to respond to that?

Ms. Jaccar. Yes, sir. Mr. Towns, I think the desire is actually
to have things in the opposite direction: Not to remove FDA’s
role in approval for supplemental purposes, but to expedite that
and make that more effective.

The FDA “Good Housekeeping Seal of Approval” is a very impor-
tant one to consumers around the world, to patients and physi-
cians, to purchasers, to insurers around the world because of what
it says about the best information that can be gotten about the
safety and efficacy of the drug that has been under consideration—
for which the application is being submitted.

And yet what you don’t want to do is put in place a situation or
a system which denies further experimentation of and use of drugs
for purposes other than the original one for which approval has
been sought. And, I think the key is to make the process work bet-
ter so you have the incentive for the pharmaceutical companies to
do the research to get more uses on the label.

Mr. Towns. Thank you. Let me just sort of hold on for a minute
longer. Dr. DiMasi, how current is your data?

ir. DrMast. Our last published study covered supplemental indi-
cation approvals through 1994.


125

Mr. Chairman, patients are getting the short end of the stick. We are creating a two-
tiered system when some patients who are rich enough to pay for their prescriptions
themselves, or are lucky enough to have a compassionate insurance company, can
obtain treatment while those who are unlucky or poor cannot. Understanding that this
Subcommittee does not have jurisdiction over the insurance industry, we simply want to
point out that in the absence of a ground swell of supplemental new drug applications,
further reform of the health insurance industry is absolutely necessary.

Solutions to the Problem

The ultimate solution -- what American patients and their doctors really need -- is to put
“off-label” diseases on the labels of marketed drugs. Of course, this would require that
appropriate research has to be conducted to prove the drug is safe and effective and
proper doses for the secondary condition are clearly delineated on the label. But this will
not happen without 1) raising the priority of Supplemental NDA reviews inside of the
FDA, and 2) financial incentives to the pharmaceutical industry. NORD suggests the
following solutions:

for Fe ind Dri Talk mn:

° Remove the "gag rule" that prevents the FDA from talking honestly with the public
about the mere status of supplemental applications. Right now, if a consumer or
physician inquires about why their disease is not included on a drug's label, the
FDA is not allowed to say whether or not the manufacturer has applied for a
Supplemental NDA, nor give the status of the review process. Even if the FDA has
disapproved an application because they know a drug is not safe or not effective,
they are not allowed to tell the American public the truth. The silence of the FDA
‘endangers the public health. Congress should remove unreasonable restrictions
on information.

° Require the FDA to monitor and identify "candidate" drugs with substantial
“off-label” uses. A special unit for "off-label" surveillance should be created to
coordinate with the Advertising and Labeling Division to "red flag" these products.


100

Mr. Chairman, | am Dr. Carolyn Runowicz. | am here today on behalf of the
American Society of Clinical Oncology (or ASCO). With more than 10,000
members, ASCO is the national medical specialty society for cancer physicians and
physician researchers. | am also representing the Society of Gynecologic

Oncologists.

As a board-certified specialist in gynecologic oncology, | treat women with
cancer, primarily cancer of the ovary or other gynecologic tumors. As a survivor of
breast cancer, | also know the disease from the perspective of a patient. | am
pleased to address the Subcommittee today in both capacities concerning the topic
of off-label usage of FDA-approved drugs. There may be no other therapeutic area
in which FDA-approved drugs are used more extensively in ways other than those
set forth in FDA-approved labeling. In light of the fact that most anticancer therapy
involves combinations of drugs not referenced on labels, almost all cancer patients

treated with drugs will receive off-label treatment.

Over the past two decades, a number of new anticancer agents have been
introduced. Because of these and other advances in cancer therapy, many cancers
are now considered curable. These include a significant percentage of childhood
leukemias, Hodgkin's disease and testicular cancers. For the most commonly

occurring cancer:

prostate, breast, lung and colorectal - - progress is less

substantial but nonetheless measurable.


41

Ms. JaGcar. I think there is an appropriate role for off-label
drugs, but the issue of promotion is, again, what a lot of this turns
on. On what basis do you promote?

And, again, for pediatric diseases, you want as much confidence
as you can that the drugs that you are going to be using are going
to be effective and not dangerous for that particular population.
The incentive is to have trials and to use other indicators—reputa-
ble studies or studies that are reported in refereed journals or
other reputable sources as guidance for that, and go with that as
decisionmaking assistance.

Mrs. MORELLA. One of the issues I see here from the GAO report
has to do with reimbursement. About half the cancer physicians re-
ported having been denied reimbursement for off-label treatment in
the last 12 months, and then 23 percent reported that reimburse-
ment problems influenced them to alter preferred treatments.

I would like to hear from you, Ms. Jaggar. And then you might
want to comment on that, Dr. DiMasi, from your experience.

Ms. JAGGAR. Mrs. Morella, those results were from the study
that we published in 1991 and the data were collected in 1989 and
1990, so they are, I think, old information. As we mentioned a little
bit earlier, there was legislation enacted in 1993 that specifically
went to coverage for cancer drugs, and reimbursement at this point
for those particular drugs seems to be less an issue.

Mrs. MORELLA. Good.

Mr. SILBERMAN. There are other areas where off-label reimburse-
ment remains a problem, and I think one of the ironies was pointed
out by our finding where oncologists, as a way of circumventing the
problems with reimbursement, were admitting their patients who
didn’t need hospitalization into a hospital simply because the ac-
tual drugs given in a hospital weren’t examined by reimbursement.
So you wind up paying more.

And we know that the same is true for other drugs. There is a
published article in the New England Journal of Medicine docu-
menting that for antidepressants. And so in an effort to save
money, we may wind up actually spending more money because of
shortsighted decisions.

Mrs. MORELLA. Did you want to comment on it, Dr. DiMasi?

Mr. DIMasI. No; really just to say that I concur.

Mrs. MoRELLA. What do you do, research at Tufts? Tell us some-
thing about your background.

Mr. DiMasi. I am economist in a multidisciplinary research cen-
ter at Tufts, called the Tufts Center for the Study of Drug Develop-
ment. We are devoted to studying issues related to drug develop-
ment and regulation and innovation and the economics of the phar-
maceutical industry.

As I said, it isa multidisciplinary up. I am an economist. We
have a pharmacologist, a molecular biologist, an attorney, and an
M.D., Dr. Lasagna, is the director of the center.

Mr. Suays. Basically, it would be fair to say, Doctor, you are
pretty much an observer of this process fulfilling, in some ways, the
same kind of analytical role that the GAO has functioned in this.
I mean, that is the reason why we invited you to be on this panel
as opposed to the third one.

Mr. DIMasi. Yes.