Prescription Drugs: Implications of Drug Labeling and Off-Label Use
(Testimony, 09/12/96, GAO/T-HEHS-96-212).

GAO discussed off-label drug use and its impact on drug promotion and
advertising. GAO noted that: (1) off-label drug use is a prevalent
phenomenon because the drug industry feels overly constrained by labels
in its ability to promote pharmaceutical products; (2) physicians can
use approved drugs for conditions or patients other than those listed on
the drugs' labels, but manufacturers cannot advertise or promote such
use; (3) the extent of off-label drug use has not been documented, but
there is evidence that off-label use is common among cancer, acquired
immunodeficiency syndrome, and pediatric populations; (4) in the past,
off-label use caused reimbursement problems, but 1993 legislation has
led insurers to rely on additional sources of information in making
their reimbursement decisions; (5) Congress is considering legislation
to allow manufacturers to base their advertising and promotion on
reputable sources of drug use information in addition to drug labels;
(6) the benefits of such an approach include avoiding the cost of
supplemental drug approval applications and allowing earlier promotion,
but some promising off-label drug uses have been ineffective or harmful
to patients; (7) the Food and Drug Administration (FDA) could expedite
its approval process by updating labels to list new drug uses; and (8)
FDA has improved its timeliness in processing drug applications and
efficacy supplements and has changed the evidence requirements for drug
use approval under certain circumstances.

--------------------------- Indexing Terms -----------------------------

 REPORTNUM:  T-HEHS-96-212
     TITLE:  Prescription Drugs: Implications of Drug Labeling and 
             Off-Label Use
      DATE:  09/12/96
   SUBJECT:  Drugs
             Pharmaceutical industry
             Physicians
             Health resources utilization
             Pharmacological research
             Therapy
             Food and drug law
             Product safety
             Consumer protection
             Advertising

             
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Cover
================================================================ COVER


Before the Subcommittee on Human Resources and Intergovernmental
Relations, Committee on Government Reform and Oversight, U.  S. 
House of Representatives

For Release on Delivery
Expected at 10:00 a.m.
September 12, 1996

PRESCRIPTION DRUGS - IMPLICATIONS
OF DRUG LABELING AND OFF-LABEL USE

Statement of Sarah F.  Jagger
Director of Health Services Quality and Public
 Health Issues
Health, Education, and Human Services Division

GAO/T-HEHS-96-212

GAO/HEHS-96-212T


(108292)


Abbreviations
=============================================================== ABBREV


============================================================ Chapter 0

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.\1

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 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. 


--------------------
\1 U.S.  General Accounting Office, Off-Label Drugs:  Reimbursement
Policies Constrain Physicians in Their Choice of Cancer Therapies,
GAO/PEMD-91-14 (Washington, D.C.:  September 1991). 


   DRUG LABELING AND OFF-LABEL
   DRUG USE
---------------------------------------------------------- Chapter 0:1

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 effectiveness. 

If, after FDA has approved a drug, evidence arises 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.\2 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 populations that are not
     listed on the FDA-approved labeling."\3


--------------------
\2 Other terms used to describe the use of medical products for
conditions other than those specified on the label include
"unapproved," "unlabeled," or "extra-label" use. 

\3 Statement by William B.  Schultz, Deputy Commissioner for Policy,
FDA, before the Committee on Labor and Human Resources, United States
Senate, February 22, 1996. 


   PATTERNS OF OFF-LABEL DRUG USE
---------------------------------------------------------- Chapter 0:2

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.\4
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. 

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.\6 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.\7


--------------------
\4 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. 

\5 Carol L.  Brosgart et al., "Off-Label Use in Human
Immunodeficiency Virus Disease," Journal of Acquired Immune
Deficiency Syndromes and Human Retrovirology, 12:1 (May 1, 1996),
56-62. 

\6 The 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," Journal of the American
Medical Association, 276:7 (August 21, 1996), 531-37. 

\7 For example, more than 1 million patients are diagnosed with
cancer each year. 


   PROBLEMS POSED BY OFF-LABEL
   DRUG USE
---------------------------------------------------------- Chapter 0:3

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 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 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 denials.  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.\10

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. 

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.\11 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 other 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


--------------------
\8 Efficacious 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. 

\9 Schultz, cited above. 

\10 Reimbursement 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. 

\11 The 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 A 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. 


   GENERAL APPROACHES TO ADDRESS
   THE PROMOTION DILEMMA
---------------------------------------------------------- Chapter 0:4

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
-------------------------------------------------------- Chapter 0:4.1

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 Pharmacopeia--Drug Information, and other
     authoritative compendia as identified by the Secretary."

Further, 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
-------------------------------------------------------- Chapter 0:4.2

Another approach to reducing the barriers to promotion faced by
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 resources 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 1995, we
reported that the time to reach decisions on new drug applications
had declined by more than 40 percent.\13 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

                                                                Averag
                                                Percen  Median       e
                                     Number of       t  approv  approv
                                    submission  approv      al      al
Year of submission                           s      ed    time    time
----------------------------------  ----------  ------  ------  ------
1993                                        69     57%      18      19
1994                                        67      63      14      14
1995                                        48      71      12      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. 

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


--------------------
\13 U.S.  General Accounting Office, FDA Drug Approval:  Review Time
Has Decreased in Recent Years, GAO/PEMD-96-1 (Washington, D.C.: 
October 1996). 

\14 For example, the expiration of a patent on a drug may well remove
much of the incentive that a sponsor might have for incurring the
costs of the research necessary to support an efficacy supplement for
that drug. 


-------------------------------------------------------- Chapter 0:4.3

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.
----------------------------------------------------------------------
----------------------------------------------------------------------

*** End of document. ***