DHHS Eagle graphic
ASL Header
Mission Nav Button Division Nav Button Grants Nav Button Testimony Nav Button Other Links Nav Button ASL Home Nav Button
US Capitol Building
Search
HHS Home
Contact Us
dot graphic Testimony bar

This is an archive page. The links are no longer being updated.

Testimony on Supplemental Indications for Approved Prescription Drugs by Michael Friedman
Deputy Commissioner for Operations
Food and Drug Administration
U.S. Department of Health and Human Services

Before the House Committee on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental Relations
September 12, 1996


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 Al) )roving 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 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. An NDA 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.

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)A, 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 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. S22044-46 (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 fall 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.

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 to 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 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 symposia, and professional meetings. Physicians also have access to a number of 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 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 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 it,,v 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?

In a 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.

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.

  • As health 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 its contraindications, adverse effects, and other important information about the manufacturer's product.

  • 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 a new 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 concerns 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 an( have several ideas for additional 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' 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.

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 Unlabeled Uses:
  • 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 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 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.e., 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 reflects 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 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:

    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 infect on 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, 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 PDLFFA, 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 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 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 timeframe. 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 trial i requiring demonstration of actual clinical benefit, such as improved survival or quality of life. Companies more quickly can demonstrate tumor regression than increased survival, i line Clinical benefit is established in post-approval studies. This accelerated approval mechanism is available for new product applications 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 acute 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).

Pediatric Labeling

We already are demonstrating how relatively limited ( Sir a 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 in(i 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 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 indications.

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 been minimal. The ODA's most powerful incentive Is it s marketing exclusivity clause. Once an orphan drug is approved, exclusivity gives sponsors 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.

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 patient; 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 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 there 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 drug with known value. Widespread promotion of this use would make the problem even.

It is 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 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-rate 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 C.

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 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 leave 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 medic


Privacy Notice (www.hhs.gov/Privacy.html) | FOIA (www.hhs.gov/foia/) | What's New (www.hhs.gov/about/index.html#topiclist) | FAQs (answers.hhs.gov) | Reading Room (www.hhs.gov/read/) | Site Info (www.hhs.gov/SiteMap.html)