STATEMENT BY

WILLIAM B. SCHULTZ

DEPUTY COMMISSIONER FOR POLICY

FOOD AND DRUG ADMINISTRATION

DEPARTMENT OF HEALTH AND HUMAN SERVICES

BEFORE THE

COMMITTEE ON LABOR AND HUMAN RESOURCES

UNITED STATES SENATE

FEBRUARY 22, 1996

INTRODUCTION

My name is William B. Schultz. I am the Deputy Commissioner for Policy at the Food and Drug Administration.

FDA SUPPORTS THE DISSEMINATION OF INFORMATION TO PHYSICIANS

FDA'S REGULATORY AUTHORITY

The legislative history of the Federal Food, Drug, and Cosmetic Act indicates that 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 in the FDA-approved labeling.

Generally, FDA does not prohibit the dissemination of information to health care professionals. Physicians access information about off label uses through compendia, journal articles, continuing medical education programs, symposia, and professional meetings. Physicians also have access to a number of databases 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 patient care. NLM currently offers free access to three databases relating to AIDS. FDA does not regulate a physician's access to any of these types of independent off label use information -- no matter how preliminary it may be. In addition, FDA does not prohibit a manufacturer from providing a physician information about off label uses if the physician requests that information. Recently, the Agency announced a proposed change to its policy with respect to the dissemination of reference texts (medical textbooks and compendia). Drug companies may distribute independent reference texts even if they contain certain information about off label uses of approved drugs, as long as the texts do not have a significant focus on an off label use of the manufacturer supporting dissemination of the text. FDA recognizes that all of these sources of information can be very important to good medical practice.

Although the FDC Act does not authorize FDA to regulate the practice of medicine, it specifically directs FDA to regulate the promotion of drugs and devices. Promotional materials are 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. Although submission of an article for publication in a journal is not promotional, the use of such an article to sell a drug or device is promotional.

Under current law, if a company wants to promote a use of a drug or device it can do so by submitting an efficacy supplement and getting that use onto the label. As I will explain later in my testimony, getting a use onto the label has benefits beyond being allowed to promote. For example, it ensures reimbursement from third party payors, it helps to get that use included in formularies, and it gives the medical community more complete information about the product. As I will further explain later in my testimony, the requirements for efficacy supplements are often significantly simpler than the requirements for applying for permission to market a product in the first place. Moreover, the Agency is considering a number of measures that will make the supplement process a more effective tool for getting additional uses on the label of drug and device products.

S. 1447

We recognize that the purpose of the bill is to enhance dissemination of information and not to facilitate or encourage promotion of off label uses. But we strongly believe that if the bill is enacted, that will be its effect. Drug and device manufacturers market their products principally by sending sales representatives, referred to as detail men and women, out to talk one on one with physicians who might prescribe their products. A detailer's job is to convince those physicians to use and prescribe their products. They do this by providing information that purports to describe the usefulness of their products in the patient population. Written materials such as journal articles that discuss favorable studies of these products are powerful tools in the hands of a detailer. If the bill is enacted, drug and device companies will be free to use these materials to promote off label uses.

Pursuant to the bill, after a company receives FDA approval of a drug or device for one use, it would be permitted to promote that product, through these other means, for other uses. The material that companies could distribute often would be very preliminary, based on poorly designed or wholly uncontrolled studies. Companies could promote the use of a product even when the evidence merely suggests or can be interpreted as suggesting that a product may work for a specific use. Effectiveness would not have to be demonstrated. Thus, if drug X is approved for cancer patients, and there is some preliminary data that suggests it is beneficial for patients with crippling arthritis, the drug's manufacturer would be permitted to promote the drug and encourage its use for arthritis on the basis of this preliminary or unsubstantiated data. This promotion would be permitted even though the data have not been reviewed by independent scientific FDA experts.

In addition, the clinical information that appears in the materials that the bill allows manufacturers to distribute has not been validated in any way. For example, neither peer reviewers nor textbook editors review the data underlying a study described in a journal article or textbook chapter. In fact, peer reviewers and editors do not even see that data.

FDA has serious concerns regarding the promotion of indications that have not been reviewed and approved by the Agency. Because promotional activities of drug companies and others are substantially motivated by profit and market expansion, the widespread promotion of prescription drugs and devices 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 and devices for off label uses could have a number of devastating consequences for the quality of medical care in this country.

PROBLEMS WITH PERMITTING PROMOTION OF OFF LABEL USES

Undercutting the Efficacy Standard

A fundamental precept of drug and device regulation in this country is that these products must be proven safe and effective before they can be sold. The requirement that these products must be proven effective, on the basis of 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. 108 Cong. Rec. S22044-46 (daily ed. October 3, 1962); S. Rep. No. 1744, 87th Cong., 2d Sess. Part 2 at 267, 271 (1962) ("On what logical basis can one possibly argue that the initial claim for a drug . . . should be supported by "substantial evidence" but that successive claims . . . should not be so supported?" 108 Cong. Rec. at S22045.)

The addition of the "efficacy standard" revolutionalized drug development and approval, not only in the United States, but worldwide, as well. Essentially, a manufacturer cannot just say that a product works for a particular disease or condition, it must prove that the product works for that disease or condition. The only way manufacturers can prove efficacy is by submitting data from well-controlled clinical trials for evaluation by independent experts at FDA. Anecdotal reports and poorly controlled observations do not suffice because those kinds of reports may be wrong or may not be an adequate basis for conclusion. We know this because we have had experience with this type of information. Many drugs approved before 1962 turned out not to work when, after 1962, they had to be (and were) studied. Even when such 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.

The solid foundation that is laid down by the efficacy standard is one of the main reasons that there is a strong sense of confidence in the drug products that are on the U.S. market today. Because the standard requires well-controlled clinical trials, once FDA has made a determination of effectiveness, there can be a high degree of confidence that the drug will work. Thus, when a manufacturer claims that a product is safe and effective for a particular disease or condition, doctors can be confident that the product is in fact safe and effective for that disease or condition. Patients, in turn, can have confidence in the quality of the products they are receiving.

Eliminating the need for well-controlled studies would be a major setback for 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 effective for their intended uses, it is far less likely that we would know that these drugs will work to decrease mortality in heart attack patients, to delay or prevent breast cancer recurrence, or to treat chronic hepatitis B and C. In the absence of the efficacy requirement, the market will be filled with drugs that manufacturers claim work and that physicians use because of a belief that they work, but for which there is relatively little evidence.

Disincentive to Conduct Studies

Under the approach taken in the bill, we might never learn whether interferon alpha actually works to treat hepatitis B -- yet the manufacturer could promote its use. This is precisely the scenario that Congress sought to prevent when it added the effectiveness requirement to the definition of a new drug. A group of Senators, lead by Senator Kefauver, argued that unless the effectiveness requirement was added to the definition of drugs, "the expectation would be that the initial claim would tend to be quite limited, which of course, would expedite approval of the new drug application. Thereafter, 'the sky would be the limit' and extreme claims of any kind could be made," subject only to FDA's enforcement authority. 108 Cong. Rec. at S22046.

Because the incentive to conduct research on uses of drugs and devices will decrease, the end result will be that the dissemination of off label information pursuant to this bill will actually reduce the amount of information that health care providers receive about drugs and devices.

Safety Issues

For example, the drugs encainide and flecainide were approved for life-threatening and symptomatic arrhythmias, which are abnormal rhythms of the heart. In the late 1980's, physicians began to prescribe these two 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.) This off label use, which was supported by published peer-reviewed journal articles, was intended to prevent the well-documented increased mortality of heart attack victims who have a high level of VPCs by suppressing those VPCs. The use was logical and became so widespread that the National Institutes of Health decided to study the effectiveness of encainide and flecainide in 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 -- that is the death rate among those receiving the drug was more than twice the rate of those receiving a placebo. If these unapproved uses 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 a class of drugs called calcium channel blockers (CCBs). These drugs are effective for patients suffering from angina, which is chest pain caused by insufficient oxygen to the heart muscle. CCBs have no established role in patients who have had a heart attack but have no symptoms. These patients do, however, benefit from another class of drugs, beta-blockers, which are known to reduce mortality by 25-30% after heart attacks. Nevertheless, CCBs are widely used in this patient population and there are publications that could be interpreted as supporting this use. 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 of no known 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.

Yet another example of a case where the distribution of published articles on off label use could have resulted in very serious harm to the public involves the fentanyl transdermal system (Duragesic). Approved for use in chronic pain in patients requiring opioids, the fentanyl patch was not approved for acute post-operative pain because of concern that it would cause respiratory depression (a serious condition in which less air reaches the lungs) in those patients not used to the effect of opioids. A number of publications prior to the time of approval, however, described the drug as safe and effective for post-operative pain. After approval, reports to FDA and the literature documented life-threatening respiratory depression in post-operative patients given the patches. Extensive promotion of this off label use could have been disastrous.

There are many other claims that could be promoted through peer-reviewed journal articles describing off label uses that could be detrimental to a large number of patients if they were heavily promoted. FDA fears that problems illustrated by these examples would be multiplied if manufacturers were given free rein to promote unapproved uses.

Unbalanced View

The current law governing promotion requires balance. Changing the law to allow the distribution of journal articles and other similar materials that discuss off label uses will allow drug detail men and women to provide materials that describe favorable study results of their product for a particular use, but without providing copies of materials that go the other way.

I would like to illustrate with an example. Human growth hormone currently is indicated for use only in children who are short because they lack sufficient growth hormone and children who are short because of kidney problems. Its use in children who are short, but have no growth hormone deficiency or underlying kidney problem, is an off label use of uncertain value and safety. We identified four journal articles that discuss this off label use -- two more or less supported the off label use and two did not. If a physician receives information about this off label use from a detail person, it is possible that he or she will receive only the two favorable articles. On the other hand, if the physician were conducting his or her own research into the subject, he or she would likely locate both the pro and con articles. Given the approximately $20,000 per year price tag of human growth hormone, the pain a child must endure because of multiple drug injections each week, and the potential adverse effects that growth hormone may cause (such as diabetes and possibly tumor growth), it is important that physicians see all pieces of the scientific puzzle until the answer is clear.

By using this example, I am not targeting a specific drug or drug company. I am merely trying to illustrate what the bill would permit and why FDA has serious concerns.

What makes this situation even more troubling is that when we have evidence that a particular use is unsafe or ineffective, federal confidentiality laws frequently prohibit FDA from disseminating that information. Thus, there are off label uses about which positive studies appear in the literature and negative data are contained in our files. However, depending on its source, FDA may be unable to use that information to ensure that the medical community has all of the available facts on which to base treatment decisions.

Even under current law, physicians have access to positive articles about off label uses and FDA may be unable to counter those positive articles with any negative information that might be in our files. However, under current law, company detail men and women cannot use those articles to promote potentially dangerous off label uses.

The Bill's Requirements Are Not Substitutes for FDA Review

The purpose of the "peer review" process, for example, is to determine if an article is worthy of publication. At its best, peer review can ensure that the reader is provided with enough detail and clarity to make a general judgment about the strengths and weaknesses of the study. However, there are no generally accepted standards for what constitutes "peer review." Essentially, anyone can establish a "peer review" journal; the rigor of the review varies considerably.

Regardless of the rigor, there are severe limitations inherent in the peer review process that make it inappropriate to rely solely on a peer-reviewed journal article for efficacy determinations. For example, peer reviewers almost never receive the study protocol. They cannot tell what the initial hypothesis was or whether the final analysis represents the planned analysis or an analysis crafted with the results in hand. Peer reviewers do not have access to the underlying data. The peer reviewers must rely on the data and facts as they are presented by the author. FDA, on the other hand, does have access to the data and can verify the critical statistical outcomes and the conclusions of a study. Moreover, peer reviewers do not necessarily have the time or the expertise in all aspects of the subject matter to adequately review the information. In fact, a survey reveals that a peer reviewer spends on average less than three hours reviewing a prospective article. The peer review process cannot guarantee the correctness or authenticity of the article, nor can it detect fraudulent or flawed research.

The data and information supporting off label uses that appear in reference textbook chapters, which could highlight off label uses of particular drugs or devices, CME materials, and materials related to third party coverage and reimbursement are even less likely to be validated than that in peer-reviewed journals. In fact, we have no reason to believe that such data have been reviewed or validated at all. Textbook editors do not review the data underlying information about off label uses that appear in those books. The recognition of suggested uses in texts or treatment guidelines for purposes of third-party reimbursement serve different societal purposes. The decision to include such uses is not based on the standards used by FDA to substantiate safety and efficacy. FDA has serious concerns about a provision that allows companies to use these types of unproven/unvalidated information for promotional purposes.

There are many instances when uncontrolled studies have supported a use and subsequent well-controlled studies have failed to show effectiveness. Moreover, the literature is laden with studies that report preliminary findings -- e.g., studies that involve a small number of patients and case reports or are not properly controlled. Although the studies or reports may be scientifically accurate, they are not sufficient to show safety and efficacy. Thus, companies should not be allowed to use these less rigorous studies to promote off label uses of approved products.

GETTING SUPPORTED OFF LABEL USES ON THE LABEL

There are several good reasons for drug companies to submit these "efficacy supplements":

• 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 continue to grow in size and number, a sponsor's ability to get their 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, contraindications, adverse effects, and other important information about the manufacturer's product.

• 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.

• And, of course, the manufacturer can promote the use, whether through the use of journal articles or other means.

We have been working on ideas for encouraging and expediting efficacy supplements for unapproved uses and for otherwise addressing industry concerns. We are doing a number of things and have several ideas for additional progress in this area. Let me summarize them for you:

Expediting Review of Efficacy Supplements

We should, however, be able to exceed the PDUFA targets. I believe we should try to reduce the 6-12 month timeframes. To do so, we will need to give supplements a greater priority than they have had in the past, and we are committed to that.

Fewer Data Are Needed Than Commonly Believed

Pediatric Labeling

Seek Out the Most Appropriate Off Label Uses

The best way to get information to physicians about the best uses of the drug and device armamentarium, Madam Chairman, is to have it in the product's labeling. Our collective goal ought to be to get this done.

CONCLUSION

I would be happy to answer any questions.

Recent Testimonies

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