Laurie B. Burke, RPh, MPH
Tokyo, Japan
April 23, 1998


(Slide 1)
　The opinions expressed in this presentation are my own. They are not to be interpreted as FDA’s official position with respect to regulatory policy for prescription drugs.

(Slide 2)
　A fundamental precept of drug regulation in the United States is that drug products must be proven safe and effective for a particular use before they can be sold. The FDA reviews carefully the evidence that is submitted to determine whether there is an adequate basis for approval. The evidence must demonstrate substantial evidence of drug effect, safety for the intended use (meaning that the drug’s benefit outweighs the drug’s risks under that use), and adequate directions for use, including information about important differences in subsets of the overall population.

(Slide 3)
　The requirement that drugs must be proven effective, on the basis of adequate and well-controlled clinical studies, was first adopted by Congress in 1962. Congress specifically added the concept of effectiveness to the definition of ‘new drug’ in order to ensure that the efficacy requirement would apply not only to initial claims made for a drug, but also to claims made after the initial new drug application had been approved.
　The Federal Food, Drug, and Cosmetic Act was amended to state: “substantial evidence (of drug effect) means evidence consisting of adequate and well-controlled investigations...by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.”
　The addition of the evidentiary standard for effectiveness revolutionized drug development and approval. This became obvious when many drugs approved before 1962 turned out not to work when, after 1962, they had to be studied. Since that time, once FDA makes a determination of effectiveness, there can be a high degree of confidence that the drug will work for the particular disease or condition claimed by the manufacturer.

　The determination of whether the submitted evidence represents ‘adequate and well-controlled investigations’ requires FDA to review the full reports of all the studies supporting the conclusion of effectiveness. An adequate and well-controlled trial has the following three characteristics: a design that permits a valid comparison with a control to provide a quantitative assessment of treatment effect; the use of methods to minimize bias in the allocation of patients to treatment groups and in the measurement of response to treatment; and an analysis of results appropriate to the design to assess the effects of treatment. FDA evaluates the study protocol in conjunction with all the data, examines critical details of the design, conduct and analysis of the studies, asks, as necessary for additional details, and searches for potentially serious adverse effects of the drug that may not have been recognized. Once a drug meets these tests and standards, it is approved for marketing.

(Slide 4)
　There has been much discussion and controversy around FDA’s legal standard for >1 adequate and well-controlled investigation to demonstrate effectiveness. However, there is a scientific basis for this requirement based on the real possibility that a single study can produce erroneous results. For example, it is quite possible that the results from a single study are not generalizable to the intended population, but rather site or investigator specific. It is also quite possible that undetected systematic bias is present or that there may be a chance occurrence of an erroneous conclusion.

(Slide 5)
　However, precise repetition of the same experiment may sometimes be less than optimal because of systematic biases inherent to the particular study design. Results from studies that are independent in both design and execution may be more convincing. But certainly there is no controversy over the fact that a single favorable study among several failed attempts to show effectiveness would not represent persuasive evidence of effectiveness.

(Slide 6)
　You will hear me refer several times to the FDA Modernization Act of 1997 which our President signed into law last November. It invoked many changes to FDA regulatory policy. Section 115, entitled ‘Clinical Investigations’ states:, “If ’data from one [adequate and well-controlled study] and confirmatory evidence’ are sufficient to establish effectiveness, such data and evidence [may] constitute substantial evidence....”

(Slide 7)
　What this means for the drug approval process is that, in some cases, even though an adequate and well-controlled study is still needed, but there may not be a need more than one such study. For example, a controlled study of a particular use or claim could be supported by other controlled trial data that may not represent an exact replication. Instead the study may use different doses, a closely related disease state, different populations, or a different clinical endpoint. And of course, another example of a situation where only one adequate and well-controlled study is needed is a very persuasive study that involves a mortality or major morbidity endpoint in which case it becomes ethically impossible to repeat the experiment.

(Slide 8)
　A guidance FDA will use to implement this new law has been finalized.
　It clarifies what is needed to support claims. It is intended to encourage study of important off-label uses, and it is especially relevant for claims that extend effectiveness to new patient subsets or new uses, for example, comparisons with other drugs and quality of life claims, which have become more valuable with the changing health care environment in the U.S. It is also important for claims that extend effectiveness to new patient subsets or new uses.

(Slide 9)
　FDA pays careful attention to claims that represent extension of effectiveness. Our legal basis for doing so comes from the Code of Federal Regulations that states: “No implied claims or suggestions of drug use may be made if there is inadequate evidence of safety or if there is lack of substantial evidence of effectiveness” [21 C.F.R. 201.56(c)] The regulation of such off-label claims is important from a public health viewpoint. Without this requirement for the demonstration of efficacy for new uses, we would be far less likely to know that marketed drugs work for important uses discovered after approval. Patients would be exposed to the risk of drug use without knowing whether the drug is effective for the disease or condition they are treating. Furthermore, companies would have no incentive to conduct the scientific research necessary and to submit the data to FDA to verify the safety and efficacy of the drug for 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.

(Slide 10)
　Prescription drug advertising and promotional labeling, which includes all written, printed or graphic material disseminated by a drug manufacturer about its product, is regulated according to the following standards: promotion may not be false, lacking in fair balance, or misleading in any particular; a manufacturer may only recommend or suggest the drug for those uses contained in the FDA-approved product labeling; and, in order to claim clinical effects not contained in the approved labeling, substantial evidence (as demonstrated by more than one adequate and well-controlled study) must be demonstrated.

(Slide 11)
　Furthermore, all prescription drug advertising and promotional labeling must meet the test of ‘fair balance’ dictated by a regulation found in another section of the C.F.R. An advertisement does not meet this test if it: “fails to present a fair balance between side effects and contraindications, and ’effectiveness’ presented in similar scope, depth or detail.” [21 C.F.R. 202.1] A manufacturer cannot mention the positive effects of a product without also mentioning the negative effects with equal prominence.

　For off-label uses, not only is the effectiveness of the drug product in question, but also the safety of the product for that use is not determined. Therefore, it is often not possible for a physician or health care decision-maker to properly judge the benefit-risk ratio of the prescribing decision in the absence of adequate and well-controlled investigations. Because of publication bias, physicians have access to more positive information about off-label uses than to negative information. And until a new use is approved and included in a product’s approved labeling, FDA is prevented by federal trade secret laws from disseminating any negative information we may have in our files even though positive information may be published and readily available in the literature.

(Slide 12, 13)
　Therefore, claims for off-label uses generally are deemed violative and an enforcement action is taken by FDA when these claims come to our attention. Some examples of the most commonly discovered off-label claims are listed below:
　An implication that a study has broader applicability than it does, such as suggestions that the drug is effective in the elderly or in pediatrics when those subpopulations were not studied specifically.
　Recommendations for dosage and durations of therapy beyond what was studied.
　An implication that a drug prevents disease progression−especially mortality or irreversible morbidity−when the studies’ endpoints represented symptom control only.
　Comparative claims of equivalence, maintenance of effect, or similar effectiveness when the studies were designed to find a difference−and no difference was found. Comparative claims of superiority or clinical advantage when no head-to-head study was done.
　Recommendation for dosages outside those found in labeling.

(Slide 14)
　Comparative claims must be backed by substantial evidence as demonstrated by adequate and well-controlled studies. Standards for such studies include the need for the comparison to be fair. For example, a study that uses a maximum dose of the study drug compared to a marginally effective dose of the comparator is not a fair comparison. Furthermore, the effects compared must be based on direct comparisons, that is, the studies compare the products head-to-head. Meta-analyses, assumptions, or expert opinion cannot substantiate comparative claims.

(Slide 15)
　Studies to substantiate a comparative claim must have the ability to detect a difference. This usually requires a placebo arm. In the situation where the results show no difference between the two active agents, without a placebo arm it is often not possible to know whether either drug was effective in the study and whether the trial had the capability to detect a difference if there were one. The need for a placebo arm in comparative studies is especially important for many treatments that often do not distinguish themselves from placebo in controlled trials. This includes antidepressants, antihistamines, GI motility agents, drugs used for asthma prophylaxis, angina treatments, antihypertensives, and drugs for congestive heart failure.

(Slide 16)
　Once a drug is on the market, of course, physicians may prescribe as they judge pertinent. Once a drug is approved for marketing, FDA does not regulate how, and for what uses, physicians may prescribe that drug. In order to appropriately use drug products, physicians depend on reliable scientific data and information on off-label-uses of approved products.
　Physicians access information about off-label uses through compendia, reference publications, journal articles, continuing medical education programs, symposia, and professional meetings. FDA does not regulate a physician’s access to any of these types of independent off-label use information sources. In addition, FDA does not prohibit a manufacturer from providing a physician information about off-label uses if the physician requests that information. It only regulates that information that is disseminated by or on behalf of medical product sponsors that is used to sell a drug. Because such promotional activities of drug companies are substantially motivated by profit and market expansion, the widespread promotion of prescription drugs for uses that have not been determined to be safe and effective could be detrimental to the health and safety of the public. Permitting companies to promote drugs for off -abel uses could have a number of devastating consequences for the quality of medical care since not all off-label uses are safe and effective.

　The scope of off-label drug use, however, is not easy to determine. At the request of Dr. Robert Temple, who supervises the activities of the Division of Drug Marketing, Advertising and Communications, I designed an analysis of marketing data to determine what proportion of the most frequently used drugs in 1995 were prescribed for diagnoses that did not correspond to the indications in the FDA-approved labeling. An estimate of the proportion of prescribing that represented such off-label use was made. The analysis did not include an estimate of off-label use as defined by patient subpopulations, dosage, duration of use, or other elements of drug labeling. Only the diagnoses associated with drug use were examined for their correspondence to labeled indications.

(Slide 17)
　The associated diagnoses for 43 drug products (that were not available as generic products in 1995) plus 21 generic drugs were analyzed using labeling as printed in the 1995 Physician’s Desk Reference. These 64 drugs represented those drugs most frequently mentioned by office-based physicians in the U.S. in 1995. The data base used was the 1995 National Disease and Therapeutic Index, IMS America. Diagnoses that represented different indications than appeared in product labeling, no matter how implausible or irrational, were included in our definition of off-label use.

(Slide 18)
　To summarize the results of this analysis, for the 43 branded drug products most prescribed by office-based physicians in 1995 combined, 4.7% of their use was for off-label diagnoses. For the 21 generic drugs combined, 2.0% of use was for off-label diagnoses. It is obvious that, at least for the most widely prescribed drugs in the U.S., most drugs do not have large-volume off-label uses when looking at indication alone.

(Slide 19)
　Of the 64 drug products analyzed, only 7 products were associated with off-label uses that represented more than 10% of their respective total use in 1995. These products were:

　Klonopin (clonazepam)80.5%
　Unasyn (ampicillin, sulbactam) 29.2%
　Seldane (terfenadine)20.9%
　Claritin (loratadine)17.2%
　Daypro (oxaprozin)14.0%
　Bactrim DS (trimethoprim, sulfamethoxazole)13.5%
　Relafen (nabumetone)13.0%

　In each of these cases, the off-label use was, in various ways, peculiar:
　Klonopin, a benzodiazepine, was developed for the U.S. market as an anti-epileptic drug but is plainly being used for a variety of typical benzodiazepine uses which explains its very high proportion of off-label use.
　Unasyn is an ampicilllin/beta-lactamase inhibitor combination; its off-label use was almost completely for conditions treatable by ampicillin alone, i.e., pneumonia and septicemia. Therefore, even though use of the combination in these settings is off-label, it is consistent with use of a component of the drug product.
　Daypro and Relafen are NSAIDs labeled only for arthritis, not for acute painful syndromes, probably because of their long half lives. They are, however, effective in pain of shorter duration, too, and are being used in this manner.
　The two non-sedating antihistamines, Seldane and Claritin, were used for dermatologic conditions, off-label but plausible uses.
　The off-label use for Bactrim DS is principally for sinusitis, another off-label, but plausible use.

(Slide 20)
　There were other interesting, albeit small-volume, off-label uses detected for drugs that still had patent life and for which an incentive to do substantiate the effectiveness of the use existed and for which labeling supplements should be encouraged. These included:
　ACE Inhibitors for chronic renal disease (Capoten alone is labeled for diabetic neuropathy)
　Procardia XL for Raynaud’s Disease
　Dilantin for trigeminal neuralgia
　Paxil, Prozac and Zoloft for migraine and for pre-menstrual syndrome
　Prozac for obesity
　Prilosec for gastric ulcer
　Zantac for urticaria

(Slide 21)
　I am aware of only a few published studies that measured off-label use of drugs in the U.S. Only one of the studies estimated off-label use on a national level as does the analysis I just described. That study was done by the U.S. General Accounting Office. It surveyed a randomized sample of oncologists and found that 33% of drug administrations for cancer treatment were for off-label uses. This finding is in accordance with all suspicions that drugs to treat cancer have the highest levels of off -label use.

　Another study was conducted in inpatients at a large pediatric teaching hospital where only 7% of drugs were for off-label indications. A third study found that 22.6% of women who delivered a baby at one hospital received at least one drug for an off-label indication during the prenatal period.

(Slide 22)
　As was mentioned previously, the FDA Modernization Act of 1997 has had a substantial impact on FDA’s regulatory activities. At least 2 sections of this Act were designed by Congress to increase the flow of off-label information from drug manufacturers to physicians and other medical decision-makers.

(Slide 23)
　Section 114 addresses the use of economic information in drug advertising and promotional labeling. It directs FDA to regulate such economic information according to the evidentiary standard of ‘competent and reliable scientific evidence’ when that information is directed toward managed care decision makers for drug purchasing and formulary development. Congress intended that FDA interpret this standard according to the precedent set by the Federal Trade Commission since this is the standard they use when reviewing evidence to support claims of effect for non-prescription drugs and almost all other marketed products. It is important to note that Congress clearly intended that FDA apply this standard only to economic information that is directly related to an approved indication.
　Economic information containing claims of drug effects not related to an approved indication would continue to be regulated according to the established evidentiary standards I discussed earlier. The challenge in the interpretation of this new law will be to determine which drug effects are directly related to approved indications.

(Slide 24)
　Section 401 addresses the dissemination of information on off-label uses of drugs. This section of the statute does not become effective until November of 1998. It will allow drug or device manufacturers to disseminate reprints or reference publications that include reports of scientifically sound clinical investigations about off-label uses of drugs or devices.

(Slide 25)
　In order to do this, the manufacturer must either certify that the studies are or will be completed and a supplemental application has been or will be submitted; or apply for an exemption for the supplemental application requirement. Congress directed FDA to promulgate regulations to clarify the requirements of the statute.

(Slide 26)
　In conclusion, widespread promotion of unapproved uses raises significant safety concerns. We know of a number of instances where physicians have used drugs for off-label uses that have resulted in disastrous consequences. For example, the drugs encainide and flecainide were approved for life-threatening and symptomatic arrhythmia. In the late 1980s, physicians began to prescribe these two drugs for heart attack victims who were experiencing ventricular premature complexes, a type of symptomatic or minimally symptomatic arrhythmia. This off-label use, which was supported by journal articles, was intended to prevent the well-documented increased mortality of heart attack victims by suppressing the arrhythmia. Ultimately, a National Institutes of Health study of the effectiveness of encainide and flecainide demonstrated that the risk of death was not decreased but was more than doubled in the patients receiving encainide and flecainide. If this unapproved use had been heavily promoted by drug companies, it is estimated that thousands more unnecessary deaths would have occurred.

　Another example relates to the widespread off-label use of calcium channel blockers. These drugs are effective for patients suffering from angina. They have no established role in patients who have had a heart attack but have no symptoms. These patients do, however, benefit from beta-blockers, which are known to reduce mortality after heart attacks. Nevertheless, calcium channel blockers are widely used in this patient population in lieu of beta blockers. It is certain that many lives are lost each year because a drug of no known benefit is being used for an unapproved use in place of a drug with known value.
　FDA is highly aware of the need care givers have for unbiased information about the best uses of drugs. However, unvetted information from a commercial source is of questionable value to physicians. FDA believes the best way to get information to physicians about the uses of drugs is to have that information on the product’s label.

(Slide 27)
　The U.S. will be seeing more off-label clinical and economic information disseminated by manufacturers as a result of the FDA Modernization Act of 1997. Plans are in place for FDA evaluation of the impact of these new laws on the submission of labeling supplements for off-label uses and on the risk of this information dissemination to public health.

(Slide 28)
　Striking the proper balance between the need to regulate the promotion of unapproved uses for drugs and devices and the need for reliable scientific data and information on unapproved uses of approved products has long been and will continue to be a difficult and controversial challenge for the agency.