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IND TREATMENT USE "SUFFICIENT EVIDENCE" STANDARD FOR EFFICACY DATA URGED BY PMA IN COMMENTS TO FDA: ASSN. OBJECTS TO PRECEDENT TO PROVE A NEGATIVE

Executive Summary

PMA is pushing a "sufficient evidence" standard for efficacy data to support approval of a treatment IND. The association submitted comments on the IND Treatment and Sale proposals on May 4 containing a redrafted regulation incorporating the tighter efficacy standard. PMA urged the stipulation that treatment use will be permitted if "the potential benefits outweigh the potential risks of the drug in the treatment of patients; and . . . there is sufficient evidence of the drug's safety and effectiveness to justify its intended treatment use." As proposed by FDA, the reg does not call for an efficacy determination. Treatment use would be permitted where: the drug is intended to treat an immediately life-threatening or otherwise serious disease; there is no satisfactory alternative drug or other therapy to treat the disease; the drug is under investigation in a controlled clinical trial under an IND; and the sponsor of the trial is pursuing marketing approval of the investigational drug with "due diligence." The efficacy standard urged by PMA has a similar intent but is more restrictive than the efficacy language suggested by previous FDA top officials (commissioners and chief counsels) during testimony at Chairman Weiss' (D-N.Y.) April 29 House Government Operations Subcommittee hearing on the IND regs. At the Weiss hearing, ex-FDA Chief Counsel Richard Cooper urged that a standard of "scientific evidence" be written into the treatment IND regs to build in a requirement for medical and scientific rationality to FDA's decision-making process for approving a treatment IND ("The Pink Sheet" May 4, p. 8). The March 19 reproposal does not ensure that adequate efficacy evidence will be available to the agency prior to initiation of a treatment IND, PMA maintained. Except for a finding that the drug would expose patients to an unreasonable risk, the FDA commissioner may deny treatment use only if the drug clearly does not provide a therapeutic benefit. "Since it is virtually impossible to prove a negative," PMA asserted, "the commissioner will have taken on an unprecedented and unwise burden if the reproposal is finalized." PMA urged that FDA delay implementation of the IND regs and hold an open public hearing on the subject. "There should be a full and open discussion of [the] essential public health issues by all interested and affected parties. The public hearing approach used by the agency in the past to address important regulatory issues is one that should be considered," PMA said. The public hearing approach has de facto been an effective way to table major FDA and HHS policy efforts in the past. FDA has been pressing to publish treatment and sale rules in conjunction with the IND Rewrite, which becomes effective in mid-June. PMA alluded to the dichotomy between the preamble and regulatory language in the March 19 proposal. The association said that intentions expressed in the preamble of the reproposal are not carried through in the regs themselves. In suggesting the rule might expose patients to drugs for which there is insufficient evidence of safety and efficacy, PMA asserted that "the reproposal, contrary to what is contemplated in the preamble, would not require that sufficient evidence be available to the commissioner." PMA also expressed the concern that the reproposal would present a drain on FDA resources and would contibute to a slowdown in the agency's NDA approval process. "In dealing with the immediate requirement to monitor and control these treatment pharmaceuticals, the agency would diminish its ability to proceed with timely approval of the treatment use drugs as well as other drugs under review," the association maintained. PMA asserted that a drug sponsor's ability to conduct clinical trials in order to gain NDA approval could also be "jeopardized or unduly delayed" under the reproposal. Patients who are eligible for controlled trials "will naturally be extremely reluctant to enter into and complete randomized controlled clinical trials in which they may receive comparative treatment or placebo," the association stated. "Rather, patients would seek treatment under treatment protocols." Had the proposed rules been in effect during the past several years, they could have hindered the development of a treatment for AIDS, according to PMA. "Widespread use of miscellaneous unproven experimental products too early in the developmental process could have blocked or markedly delayed the development of zidovudine [Burroughs Wellcome's AZT]," the association said. PMA's argument about the effect of the treatment proposal on the AZT development mirrors testimony by one of FDA's advisory comittee chairmen at the April 29 House hearings ("The Pink Sheet" May 4, p. 5). In addition to taxing FDA resources, PMA continued, the regulation would also cause a "considerable diversion of the sponsor's resources," including "production facilities, manpower involved in distribution of and accounting for the drug, data collection and processing, and in some cases competition for a limited supply of drug between treatment protocol use and controlled clinical trials." The sale provision of the reproposal may make sponsors or investigators less apt to pursue NDA approval since "development costs could be recouped, and even profits made, from those sales," PMA said. A "further compelling public reason" for prohibiting sale, according to PMA, is the need to protect patients from being sold products of "questionable" effectiveness. "If a regulatory program were adopted in this country under which experimental compounds could be sold to patients early in the development process, commercialization of unproven remedies would be encouraged," PMA said. FDA involvement in the pricing of investigational new drugs might also present problems, the association maintained. "It would be counterprodutive, and a misuse of the agency's resources, to seek to develop a resource within FDA regarding pricing matters. We note that FDA has neither the competence nor the legal authority to regulate the price of pharmaceuticals," PMA stated. Noting that "compassionate" drug treatment procedures have evolved at the agency over the years, PMA said that "we believe that that procedure has matured to the point that it should become a formal part of FDA procedures and regulations, and that, so established, it would meet the laudable intent of the March 19 proposal." The reproposal should specify how some existing compassionate treatment programs will be continued, PMA stated. In some cases a sponsor is treating a limited number of patients where no alternative therapy is available and the sponsor, with FDA's approval, does not intend to seek NDA approval. "Such treatment INDs should be permitted to continue or to be initiated but are not covered in the reproposal," the association suggested. The association also urged FDA to require that medical practitioners who have obtained treatment INDs report safety information to the supplier in addition to FDA. The confidentiality of the sponsor's data could be "compromised" under the reproposal in that FDA "will expect" practitioners to be supplied with an investigator's brochure containing pre-clinical and clinical data, PMA said. "It may be sufficient to provide only a portion of the information in the investigator's brochure which may be relevant to the proposed treatment use rather than providing all available information," the comments suggested. In any case, PMA maintained, supplying drug to a practitioner under the practitioner's treatment use IND "should not automatically mandate the sponsor of a clinical investigational IND to supply the investigator brochure or any other such information to the licensed practitioner when the latter sponsors his own treatment use IND."
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