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

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 .

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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

ANNOTATIONS 12

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

FDA's final rule specifying its requirements for treatment use and sale of investigational new drugs was published 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 implications 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 "desperately ill patients before general marketing 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 administration 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 premature 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 considered 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 immediately 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 satisfactory alternative drug or other therapy available to treat that stage of the disease in the intended patient population...." Once again the supplementary information 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

A publication of The Hastings Center, 255 Elm Road, Briarcliff Manor, NY 10510 ? 1987

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therapies available. However... there should be flexibility in applying this concept so as best to serve desperately ill patients. For example, the mere fact that the disease in question has existing approved therapy does not mean that the approved treatments are satisfactory for all patients .... This criterion would be met, for example, if the ... patients . . . have failed on existing therapy, .. . could not tolerate the existing therapy, . . . or had other com- plicating diseases that made the existing therapy unacceptable ... "

3. "The drug is under investigation in a controlled clinical trial under an IND in effect for the trial or all clinical trials have been completed; and

4. "The sponsor of the controlled clinical trial is actively pursuing marketing approval of the investigational drug with due diligence. "

The third and fourth criteria are designed to respond to concerns expressed in response to the proposed regulations (March 19, 1987) that making investigational new drugs available for treatment use would be detrimental to the successful conduct of clinical trials. Concern was expressed that if patients could get access to investigational new drugs on treatment protocols, they would not participate in randomized clinical trials (RCTs). Why, for example, in the summer of 1986, would patients with AIDS have agreed to participate in the placebo-controlled trial of Azidothymi- dine (AZT) if they could have received the drug on a treatment protocol? Thus, FDA has incorporated in the final rule "a number of safeguards that are intended to ensure that the premarketing availability of drugs for treatment use does not create incentives for delay in the timely testing, development, and submission for marketing approval of promising therapies."

"In the case of a serious disease, a drug ordinarily may be made available for treatment use ... during Phase 111 investigations or after all clinical trials have been completed; however, in appropriate circumstances, a drug may be made available for treatment use during Phase II. In the case of an immediately life-threatening disease, a drug may be made available for treatment use during Phase II. In the case of an immediately life-threatening disease, a drug may be made available for treatment use..,. earlier than Phase ff, but ordinarily not earlier than Phase II" (? 312.34a).

Standards of Evidence

The regulations spell out conditions under which the FDA Commis-

sioner may deny a request for treatment use (? 312.34b). For a serious disease, a request may be denied "if there is insufficient evidence of safety or effectiveness to support such use." For an immediately life-threatening disease, a request may be denied "if the available scientific evidence, taken as a whole, fails to provide a reasonable basis for conclud- ing that the drug: May be effective for its intended use in its intended patient population, or would not expose the patients ... to an unreasonable and significant additional risk

.... ." Thus, FDA calls for stronger evidence

of safety and efficacy to support treatment use in patients with serious diseases than in those with immediately life-threatening diseases. Once again, the supplementary information makes it clear that FDA intends investigators and others to interpret these requirements intelligently and flexibly. In FDA's view, the final rule provides "a standard of medical and scientific rationality - a requirement for sufficient scientific evidence on the basis of which experts could" reach reasonable conclusions. While FDA prefers that such scientific evidence be derived from controlled clinical trials, it "is committed to reviewing and considering all available evidence, including results of domestic and foreign clinical trials, animal data, and, where pertinent, in vitro data. FDA will also consider clinical experience from outside a controlled trial, where the circumstances surrounding an experience provides sufficient indicia of scientific value."

"FDA expects that drugs for treatment use will be offered for indications that are the same as, or very similar to, those under study in a controlled clinical trial." Some of those comment- ing on the proposed regulations expressed concern that there are "some categories of drugs that the agency has previously authorized for distribution to treat patients that ... would not satisfy some or all of the technical criteria required for treatment use." Such drugs "include orphan drugs for non-serious diseases, 'compassionate' INDs, and INDs for drugs where marketing is not likely to be pursued, such as drugs intended to treat certain tropical diseases." FDA notes that this "final rule is not intended to restrict the premarketing availability of [such] categories of investigational drugs .. ." These are issues that are beyond the scope of this

rulemaking."

IND Requirement

All treatment use of investigational new drugs must be in compliance with

FDA's IND regulations (? 312.24c). This means, among other things, that investigators must comply with FDA regulations calling for informed consent and IRB review. While there can be no quarrel about the necessity for informed consent, the uniform requirement for IRB review is, in my view, questionable.

In the proposed regulations, FDA stated its willingness to waive the requirements for IRB review for treatment protocols. FDA explained that such waivers would often be appropriate "because there would be adequate guarantees of subject protection through the informed consent process." In the final rule, however, FDA "has removed the presumption of IRB review waiver ...." FDA offers these reasons for this decision: "IRBs are well placed to determine the adequacy of informed consent. Knowledgeable about the reputation and competence of local practitioners whose work they oversee, these IRBs may also be better able to provide greater insight into the potential benefits than can be gained by review by a distant IRB or by FDA. Also the need for review may be greater when practitioners are permitted to charge for investigational drugs."

In evaluating the requirement for IRB review and the reasons supplied by FDA for this requirement, keep in mind that the primary purpose of the new rule is to make promising new drugs available for desperately ill patients. This set of activities is much more closely akin to medical practice than to clinical investigation. This perspective is reflected in FDA's consistent reference to the recipients of these drugs as "patients" rather than as "subjects," the term used in FDA's informed consent and IRB regulations. Furthermore, FDA considers the provision of investigational drugs to patients as being "in addition to the normal clinical trial process necessary to gain marketing approval."

Yes, IRBs are well placed to determine the adequacy of informed consent. But for good reasons elaborated elsewhere,2 they do not review plans for informed consent to medical practice. Whether an IRB should consider the competence of investigators as a criterion for approval of protocols is a topic of considerable controversy; 3, pp. 25-27 in my view, the IRB usually defers to other agents and agencies who are held responsible for such determinations - e.g., hospital and departmental staff committees and industrial sponsors (? 312.1a). If the need for review is greater when practitioners are permitted to charge for drugs, then the need



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 industrial sponsors to request such waivers when they seem appropriate and FDA to be liberal in granting them. When there is doubt about particular protocols, 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 commercialization 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 presumption 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 distribution 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 recovery 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 investigational 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 anything 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 "experimental."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 reimbursement 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 economic burden on some industrial sponsors 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 objective is to increase the efficiency of the drug approval process.9 In this way safe and effective drugs could more promptly be made available commercially 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 Policy for Protection of Human Subjects calls upon the IRB to be "particularly cognizant of the special problems of research involving vulnerable populations, such as chil- dren, prisoners, pregnant women, men- tally disturbed persons, or economically or educationally disadvantaged persons" (emphasis supplied).

Before I discuss specific problems, recall that introduction into federal regulations of the requirement for equitable selection of subjects was based on a perception in the mid-1970s that participation in a clinical trial was a burden from which vulnerable persons were to be protected. In recent years, however, it has become increas- ingly apparent that many persons consider such participation beneficial.3,pp.192-193 Clearly, some desperately ill patients will consider access to these promising new drugs beneficial even in the context of a clinical trial.

In order to illustrate some of the problems the new cost recovery policy will present, let us imagine that it is time to begin to recruit patients for participation in a placebo-controlled randomized clinical trial (RCT) designed to evaluate a new drug, EX-1987. Prelim- inary data suggest that this drug is effective in preventing the progression of AIDS Related Complex (ARC) to AIDS. There is no commercially available "comparable or satisfactory alternative." Let us listen in on a conversa-

tion between an imaginary physician and a sophisticated patient with ARC.

Physician: "EX- 1987 seems to be your best hope to fight off the development of lethal complications. At this point the only way to get even a 50% chance of receiving the drug is to volunteer to participate in the RCT."

Patient: "Yes, but after enrollment for the RCT has been completed, the drug will be eligible for treatment use status. Why not wait for that?"

Physician: "Although it might be eligible, we cannot be certain. It might turn out, as it did in the case of AZT in 1986, that there is simply not enough to go around."

Patient: "Well, to be on the safe side then, I'll sign up for the RCT. Then if the drug becomes available for treatment use, I'll exercise my right to withdraw without prejudice and then we can go ahead and get me the drug on the treatment protocol."

Physician: "You certainly have the right to do that. But if many patients do that the validity of the RCT will be destroyed. We will never know whether EX-1987 is truly safe and effective."

Patient: "That is not my problem. Besides, I understand that cost recovery for EX- 1987 will amount to about $8000 per year. I can afford it but most patients with ARC cannot. There will be plenty of patients left who cannot afford to do anything but stay in the RCT. Just between you and me, Doc, if those sponsors and investigators were smart, they would recruit only those who, unlike me, are unable to buy their way out of the RCT when EX-1987 becomes available for treatment use."

Physician: "Given that the drug is so expensive, it is conceivable that the industrial sponsor might petition FDA to permit cost recovery for the drug from participants in the RCT."

Patient: "That's bizarre! Do you mean to tell me that the sponsors could persuade the IRB that there is a valid null hypothesis, that there is no evidence that EX-1987 is better or worse than placebo, and then persuade FDA that treatment with it is worth $8000 a year? I cannot believe that.

"Besides, how could they maintain the double-blind? Do you mean that they would also charge patients in the placebo group $8000 a year?"

Physician: "You have a point there. It seems to me that cost recovery would make more sense when new drugs are compared with the best available standard therapy. In this case, though, since there is no standard therapy, perhaps they will have to consider historical controls."

Perhaps they will. In this imaginary

conversation I have only suggested some of the difficult problems for the conduct of clinical trials that I anticipate from the new cost recovery policy. For further discussion of these and related problems the reader is referred to several recent publications.1'5-7

If interpreted intelligently and flexibly as FDA intends, the final rule is likely to accomplish its primary purpose, to facilitate the availability of promising new drugs to desperately ill patients, without serious disruption of the orderly conduct of drug development. Since a uniform requirement for IRB review and approval of treatment protocols is likely to defeat the rule's purpose, FDA should liberally grant waivers of this requirement; in questionable cases FDA should require expedited review for purposes of determining whether full IRB review is necessary for particular protocols in some institutions.

Authorization of cost recovery for investigational new drugs will be prob- lematic because in at least some cases these therapies will be available only to those who can afford to pay for them without the aid of insurance. Cost recovery may also present formidable obstacles to the ethical conduct of scientifically sound randomized clinical trials. These concerns notwithstanding, FDA's authorization of cost recovery for investigational new drugs is likely to accomplish more good than harm.

REFERENCES 'Food and Drug Administration: Investigational

New Drug, Antibiotic, and Biological Drug Product Regulations; Treatment Use and Sale; Final Rule. Federal Register 52 (No. 99): 19466- 19477, May 22, 1987.

2Levine, R.J.: Informed consent in research and practice: Similarities and differences. Acrhives of Internal Medicine 143: 1229-1231, 1983.

3Levine, R.J.: Ethics and Regulation of Clinical Research. Urban & Schwarzenberg, Baltimore, Second edition, 1986.

4Young, FE.: Cover letter for the Final Rule (1). June 5, 1987.

5Lind, S.E.: Can patients be asked to pay for experimental treatment? Clinical Research 32: 393-398, 1984.

6Lind, S.E.: Dilemmas in paying for clinical research: The view from the IRB. IRB: A Review of Human Subjects Research 9 (No. 2): 1-5, March/April, 1987.

7Chalmers, T.C.; van Den Noort, S.; Lockshin, M.D.; Waksman, B.H.: Summary of a Workshop on the role of third-party payors in clinical trials of new agents. New Engl J. Med. 309:1334-1336, 1983.

8The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Securing Access to Health Care: The Ethical Implications of Differences in the Availability of Health Services. U.S. Govt. Printing Office, Stock No. 040-000-0472-6, Washington, 1983.

9Commission on the Federal Drug Approval Process: Final Report. U.S. Govt. Printing Office No. 98-901-0, Washington, October, 1982.



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