FDA's New Rule on Treatment Use and Sale of Investigational New Drugs

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  • FDA's New Rule on Treatment Use and Sale of Investigational New DrugsAuthor(s): Robert J. LevineSource: IRB: Ethics and Human Research, Vol. 9, No. 4 (Jul. - Aug., 1987), pp. 1-4Published by: The Hastings CenterStable URL: http://www.jstor.org/stable/3563542 .Accessed: 12/06/2014 13:04

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    July/August 1987

    Volume 9 Number 4 July/August 1987

    FDA's New Rule on Treatment Use and Sale of Investigational New Drugs by Robert J. Levine 1 Deception and the Placebo Effect in Biomedical Research by R. J. Connelly 5

    Can a Court Order Participation in Research? by Angela R. Holder 8

    Is Post-Marketing Drug Follow-Up Research or Advertising? by Gary B. Weiss and Wiliam J. Winslade 10

    LETTERS 11


    FDA's New Rule on Treatment Use and Sale of Investigational New Drugs by Robert J. Levine

    FDA's final rule specifying its require- ments for treatment use and sale of investigational new drugs was pub- lished on May 22, 1987, and became effective one month later.1 This article surveys some of the highlights of this rule and explores some of its implica- tions for institutional review boards (IRBs) and others responsible for protecting the rights and welfare of human research subjects.

    On balance this is a good rule. Interpreted intelligently and flexibly, as FDA intends, it should accomplish its intended purpose, which is "to facilitate the availability of promising new drugs to desperately ill patients" without disrupting the orderly conduct of new drug development. Some features of

    Robert J. Levine is Professor of Medicine and Lecturer in Pharmacology, Yale University School of Medicine.

    this rule, however, present problems, some of them formidable, to IRBs, physicians, investigators, and patients.

    Treatment Use

    The primary purpose of treatment use, the only one mentioned in FDA's summary of the new rule, is to provide therapy in the form of "promising investigational new drugs" for "desper- ately ill patients before general market- ing begins." A secondary objective is stated in ?312.34; namely, "to obtain additional data on the drug's safety and effectiveness." As we interpret and apply the new rule it is important to keep in mind its primary purpose. We should not create unwarranted bureau- cratic obstacles to the timely adminis- tration of these drugs to patients "for whom no comparable or satisfactory alternative... therapy is available."

    FDA specifies four criteria for permit- ting treatment use of an investigational new drug (?312.34b).

    1. "The drug is intended to treat a serious or immediately life-threatening disease...." "Immediately life- threatening" is defined as "a stage of a disease in which there is reasonable likelihood that death will occur within a matter of months or in which pre- mature death is likely without early treatment." Further elaboration of FDA's meaning may be found in the "supplementary information" published with the final rule (p. 19467). "This does not mean that a clinician would have to make a [precise] prognosis... but only to provide a general yardstick for decision-making purposes ....FDA will apply a common sense interpretation of the term so that death within more than a year would not normally be consid- ered immediately life-threatening... ."

    "The phrase 'or in which premature death is likely without early treatment' is intended to describe those fatal illnesses where [while] death... may not be imminent...immediate treatment is necessary to prevent premature death. For example, an anti-retroviral drug might be found [which may] delay progression from the asymptomatic state to AIDS-Related Complex (ARC) and then [to] AIDS. Although this progression would ordinarily take more than 12 months...this circumstance would be interpreted as fitting the definition of immediately life- threatening."

    The term "serious" is not defined. In the supplementary information, FDA again recommends sensible judgments: "....the stage of a disease is important in determining whether it is imme- diately life-threatening, serious, or not serious .... For diseases such as multiple sclerosis... the regulation would not be applicable to those stages" of the disease that are not considered serious. "FDA will seek to define the intended patient population and, [when] medically appropriate...will limit treatment use to particular stages of a disease or to patients with a particular set of symptoms."

    2. "There is no comparable or satis- factory alternative drug or other therapy available to treat that stage of the disease in the intended patient population...." Once again the supplementary informa- tion explains what FDA means by "comparable or satisfactory": "...absence of alternative therapy should be prerequisite to granting a treatment IND, because one of the major principles underlying [this] policy is that these drugs would be necessary to fill an existing gap in the medical

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  • July/August 1987

    must be greater still in medical practice where charges are not limited to recovery of legitimate costs as they are in the new regulations. Moreover, it is the industrial sponsor, and perhaps the pharmacy, not the practitioner, who will recover these costs.

    The most important consideration is this: No unnecessary bureaucractic obstacle should be placed between promising new drugs that have met the standards of "medical and scientific rationality" prescribed by FDA and desperately ill patients for whom there are no comparable or satisfactory alternatives.

    The professionals who will make these drugs available to such patients are medical practitioners who want first and foremost to treat patients. Unlike clinical investigators, they have no personal commitment to contribute either to generalizable knowledge or to the development of data to support an application for a permit to market a new drug. Many of them are likely to see the requirement to draft a protocol and then to wait weeks or months for its review and approval by an IRB as an important disincentive to their seeking drugs for treatment use. In this respect, the requirement for IRB review may defeat the new rule's purpose of "facil- itating the availability" of these drugs.

    FDA states that it is willing to waive the requirement for IRB review when such waivers would serve the "best interest" of patients or subjects. All things considered, in most instances such waivers would be more likely to serve the interests of these patients than would IRB review. Thus, I urge indus- trial sponsors to request such waivers when they seem appropriate and FDA to be liberal in granting them. When there is doubt about particular proto- cols, or when it seems that IRB review might serve some useful purpose in some institutions "expedited review procedures" (? 56.110) should be man- dated. Those responsible for expedited review should be charged to determine whether full IRB review is warranted for particular protocols.

    Charging for New Drugs

    The new rules also define conditions in which drug manufacturers may charge for investigational new drugs. The purpose of these provisions is "to provide sufficient incentives for drug manufacturers to make [such] drugs available to patients before general marketing begins, but under sufficient safeguards so as to prevent commer- cialization of the product as well as to ensure the integrity of clinical trials."

    Charges for drugs made available for treatment use are permitted "provided (i) There is adequate enrollment in the ongoing clinical investigations under the authorized IND; (ii) Charging does not constitute commercial marketing of a new drug...; (iii) The drug is not being commercially promoted or adver- tised; and (iv) The sponsor of the drug is actively pursuing marketing approval with due diligence" (? 312.7d.2). Author- ization for these charges may be accomplished by notifying the FDA "in writing in advance of commencing any such charges .... Authorization for charging goes into effect automatically 30 days after receipt by FDA of the information amendment, unless the sponsor is notified to the contrary."

    These provisions reflect FDA's basic premise that treatment use is intended to provide therapy for desperately ill patients and that drug manufacturers should not be expected to subsidize such therapy. With regard to charging for drugs dispensed in the course of conducting clinical trials, the presump- tions are different in important respects. FDA considers the expense of the drugs in this context a "normal cost of doing business," a burden that the industrial sponsor is expected to assume. "Under the final rule, [such charges] would normally not be allowed." According to FDA Commissioner Frank Young, there is "a presumption against charging during a clinical trial, and that presump- tion can be overcome only upon a showing of economic necessity."4 Authorization for such charges requires "prior written approval of FDA. In requesting such approval, the sponsor shall provide a full written explanation of why charging is necessary in order for the sponsor to undertake or con- tinue the clinical trial, e.g., why distri- bution of the drug to test subjects should not be considered part of the normal cost of doing business" (? 312.7d.1).

    Whether for treatment use or for clinical trial use, investigational drugs may not be "commercialized"; the sponsors may not charge "a price larger than that necessary to recover costs of manufacture, research, development, and handling of the investigational drug" (? 312.7d.3).

    These changes in Food and Drug Administration policy are not as radical as they may seem at first. Since 1980 FDA regulations have authorized recov- ery of costs for investigational medical devices. The language proscribing "commercialization" in the new rule for drugs is substantially the same as that found in the medical device regulations (? 812.7b).

    Problems from Cost Recovery

    Who will pay the charges for inves- tigational new drugs authorized by the new rules? Insurance companies pay for most therapies for most Americans. However, third-party payers generally have been disinclined to finance any- thing for which they are not strictly required to pay. One justification for refusing to pay for certain therapies has been that they are "research" or "exper- imental."5-7 This is how third-party payers have responded to such innova- tions as heart and liver transplants. Now that we have a class of remedies already labeled "investigational" by the federal government, at least some insurance companies will undoubtedly refuse to cover them. Some commentators have protested that this is unfair because promising new drugs, in some cases life- saving therapies, will be available only to those who can afford to pay for them.1, p. 19474

    FDA, while acknowledging the impor- tance of this concern, suggests that the problem may not be as large as some fear, in response to a request for com- ments on the proposed regulations, some manufacturers indicated that they prob- ably will not charge, regardless of the sale provision. "One pharmaceutical firm commented on its willingness as a sponsor to assist patients in finding possible third party reimbursement through such sources as health insurance carriers, government grants, and philan- thropic foundations." FDA points out that "the subject of third party reimburse- ment is outside the agency's jurisdiction and expertise . . . ." FDA further calls attention to the fact "that in some instances, without the authority to recover costs, no one would have access to these new drugs ... ." That is, since it would impose too much of an eco- nomic burden on some industrial spon- sors to provide drugs for treatment use without charging, they would choose instead to provide no drugs at all for treatment use.

    To say that important therapies, in some cases life-saving, will be made available only to those who can pur- chase them is not to say anything new. FDA's new policies only add to the list of such therapies. This problem was studied in detail by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. In its report, issued in 1983, it concluded: "Equitable access to health care requires that all citizens be able to secure an adequate level of health care without excessive burdens." 8, p 4 It is vitally important that those responsible for health care policy


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    in the United States begin the task of defining just what is "an adequate level of health care." It remains to be seen whether this will include promising investigational new drugs for patients with serious or life-threatening dis- orders. Meanwhile, it seems inappropri- ate to criticize FDA for a type of unfairness that it did not create and that it is powerless to resolve. In its way, FDA is doing what it can to make promising new drugs available to some, albeit not all, desperately ill people who would not otherwise have access to them. The only other thing that FDA could do to facilitate pursuit of this laudable objec- tive is to increase the efficiency of the drug approval process.9 In this way safe and effective drugs could more promptly be made available commer- cially and unquestionably eligible for third-party payment.

    Equitable Selection of Subjects

    As IRBs review proposals to conduct clinical trials of new drugs for which cost recovery is authorized, they will be presented with some difficult problems in determining that selection of subjects is equitable. FDA reminds them that the proposed Federal...


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