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TREATMENT IND REG's CONDITIONS FOR "IMMEDIATELY LIFE-THREATENING" WILL BE DEFINED BY ANTICIPATED DEATH IN SIX MONTHS, FDA COM. YOUNG INDICATES

Executive Summary

FDA will stipulate a time frame in which an "immediately life-threatening" disease proposed for IND drug treatment will cause death, FDA Commissioner Young said April 29 in testimony to Chairman Weiss' (D-N.Y.) House Government Operations Subcommittee. Young testified that "although there is no specified time [in the proposal] within which death would occur, the time is expected to be reasonably short (e.g., within six months)." Young assured the subcommittee that the final reg, as reproposed by FDA, would add a timeframe to the immediately life-threatening definition. "The definition that I feel [is appropriate] and I believe you'll see coming forward [in the final reg] is the expectation that the patient will succumb to the illness within about a six-month period of time." The change in the "immediately life-threatening" criteria is one of several changes in the reg promised by FDA based on its initial review of comments on the proposal. In his testimony, Young noted four general areas of the proposal that will be revised in the final rule. By narrowing the immediately life-threatening criteria, FDA would be answering objections raised by the National Institutes of Health. National Institute for Allergy and Infectious Diseases' AIDS Treatment Branch Chief Maureen Myers, MD, for example, testified that her "concern about the proposed rule is that if drugs are made available under the treatment IND under very loose definitions," an inappropriate patient population might be treated with experimental drugs on an uncontrolled basis. As an example, Myers pointed out that the definitions in the proposed reg "would allow one to conclude that HIV infection, per se, in asymptomatic patients could be considered immediately life-threatening." Anyone who is infected with the AIDS virus, she said, "could conceivably . . . [be classified as having] an immediately life-threatening disease from the day they become infected." Those patients would then be eligible for treatment IND drug use and "our ability to conduct controlled clinical trials in those populations will be severely compromised," Myers said. Young commented that the addition of a six-month time frame to the definition of immediately life-threatening "would address . . . the concern raised by Dr. Myers." If the criteria includes anticipated death within six months, Young said, "the mere positivity [to the AIDS virus] would not put one in the category, as I interpret that definition, of immediately life-threatening." Young anticipates that INDs for immediately life-threatening diseases will comprise only 3-to-4% of all INDs issued by the agency. In addition to definitions, FDA acknowledged that the language in the regulation section of the Treatment IND proposal needs to be tightened up to assure that a sponsor must submit sufficient information to support an application for treatment status of a drug for immediately life-threatening conditions. Under the proposed rule, the Commissioner can deny a treatment IND for an immediately life-threatening disease if the drug "clearly does not provide a therapeutic benefit" or if the drug would "expose the patients to an unreasonable and significant additional risk of illness or injury." Testimony by NIH officals, ex-FDA commissioners and counsel, and doctors, indicate that the consensus reading of the rule is that the Commissioner would not be able to deny a treatment IND if there were insufficient information to show that there was not a therapeutic benefit or an additional safety risk. Young testified that the intent of the regulation is to require sufficient information to make the decision on treatment IND approvability. Young pointed to a number of passages in the preamble of the proposed rule as illustrative of that intent and assured the subcommittee that matching the final rule to the preamble language would be a top priority in revising the reg for final publication. "You saw me address [the requirement for sufficient evidence] and attempt to develop this in the preamble," Young said. The "key . . . area that I'm going to be focusing on . . . [in developing the final reg] is determining whether or not the preambular language satisfies . . . what we mean in the rule." FDA Center for Drugs and Biologics Acting Director Paul Parkman, MD, identified the proposed rule's language regarding rejection of treatment IND for immediately life-threatening illnesses as "the major issue in the Center [for Drugs and Biologics]." Weiss said that Center for Drugs and Biologics Deputy Director James Bilstad, MD, advised the subcommittee "of the fact that he did not know anyone in the Center for Drugs and Biologics who supports the new proposal's provisions regarding conditions where treatment INDs may be sold for diseases in life-threatening conditions." Top Ex-FDA Officials Ask For Better Definition of Substantial Evidence For Treatment INDs Weiss also identified Neuropharmacolgic Drugs Division Director Paul Leber, MD, and Office of Drug Research and Review Director Robert Temple, MD, as two FDA officials who perceived a disparity between the commissioner's intent and the language of the proposed reg. Weiss quoted Leber as saying: "I [am] concerned that the commissioner's intentions do not withstand . . . a literal interpretation of the . . . regulation. The language of regulations should be simple, clear and understandable. [The proposed regs] appear to have one meaning, while the preamble is read to imply another." A letter written by Temple to Parkman and introduced by Weiss into the hearing record states: "I realize that the commissioner believes the preamble does provide authority to require data to support use, even in life-threatening situations, and intends to implement the regulation that way if the final regulation is unchanged from the proposal . . . The basis for this interpretation in the preamble still seems weak to me and the words of the regulation itself pose all the problems." Written testimony from five former FDA commissioners (Charles Edwards, PharmD, Jere Goyan, MD, Arthur Hull Hayes, MD, Donald Kennedy, PhD, and Alexander Schmidt, MD) and four previous FDA general counsels (Nancy Buc, Richard Cooper, Peter Barton Hutt, and Richard Merrill) urged revision of the proposal to require "scientific evidence" for treatment INDs. While agreeing that evidence of effectiveness sufficient for NDA approval should not be required for treatment INDs for serious and life-threatening illnesses, the former FDAers said: "What we urge is a requirement of medical and scientific rationality -- a requirement of some scientific evidence on the basis of which an expert could rationally conclude that the drug may be effective in the intended patient population." The ex-FDAers suggested that "such positive evidence could be obtained in a variety of ways, including from clinical trials outside the United States, from animal data, and, perhaps in some circumstances, from in vitro data." It could also be obtained, the testimony states, "from clinical experience where the circumstances surrounding the experience provide sufficient indicia that it has scientific value." Young acknowledged the criteria suggested by the former officials and said he would "take the comments under consideration." FDA General Counsel Thomas Scarlett maintained that the proposed reg, as written, would allow the agency to require the necessary information to make a judgement about a treatment IND request. Under "the preamble . . . coupled with the illogic of supporting a negative determination based on no information at all, the agency would, as the preamble says, require information that would allow it to reach a . . . conclusion both about the therapeutic promise of the drug and [safety of] the drug before the treatment IND [was allowed]," Scarlett asserted. Weiss asked Scarlett if FDA could put that language into the final rule. Scarlett responded, "We certainly will consider doing that and it's one of the things that's emerged out of this drug ruling." Deputy Commissioner Norris added that the agency "never intended . . . to shift the burden [of providing] evidence to the agency -- that remains with the sponsor of the drug." Weiss was skeptical on political grounds that FDA's inclination to change the regulatory language would be accomplished in the final reg. A series of FDA and Office of Management and Budget (OMB) memos indicated, Weiss suggested, that FDA recommendations to maintain discretion to reject treatment IND applications for insufficient evidence had been overridden by OMB. Weiss noted that an "OMB document received by the subcommittee reveals that OMB wants to remove requirements [for safety and efficacy for drugs for life-threatening illnesses], claiming that unlike FDA, it believes that 'it is not a federal responsibility to second guess the licensed medical practitioner . . . that this patient will benefit from use of this drug.'" Weiss also referred to several documents which indicated, he said, that in the final stages of negotiation for the proposed rule, FDA objected to the deletion of safety and efficacy requirements for life-threatening treatment INDs. Weiss commented that even if FDA's intent is to restore safety and efficacy requirements to the final reg, "you're going to be subject to the same overriding from people who have not heard any of this testimony . . . and who are not experts in [this] field; they will make the final judgement." Young acknowledged that OMB would have to sign off on the final reg but promised to "focus on these comments" and bring them "forward to [OMB]." Young also said the agency, in preparing the final reg, would focus on misuderstandings as to when in the clinical study time frame treatment INDs could be instituted. The Commissioner said that "the agency would expect, as a general rule, drugs for immediately life-threatening diseases to be made available, at the earliest, near the end of Phase II and more likely into Phase III." Drugs for serious diseases, Young said, would generally be made available "well after Phase III clinical trials are underway, more towards the middle of Phase III." Young indicated that some comments to the agency have interpreted the rule as allowing treatment INDs around the Phase I stage of investigations. Young said the agency would only allow a treatment IND at that stage in extraordinary situations. Such a situation might occur, he said, "if there was a drug like penicillin that [was] brought forward for AIDS, where you know . . . that a person is anticipated to die without treatment." PROBABLE CHANGES TO IND TREATMENT AND SALE PROPOSAL, IDENTIFIED BY FDA COM. YOUNG DURING TESTIMONY TO REP. WEISS The following has been excerpted from Com. Young's prepared testimony for the April 29 hearing before Chairman Weiss' Government Operations Subcommittee. Minor paragraphing and graphic changes were made by "The Pink Sheet." There is some uneasiness concerning whether the actual language of the reproposed regulation would adequately meet its stated purpose of making available only truly promising drugs, or whether a number of fraudulent products would also meet the regulatory standards. I can assure you the final rule will contain sufficient safeguards against such products. The focus here is on the degree to which the therapeutic benefit and safety of the drug needs to be established. Moreover, some have questioned whether the rule requires that enough data be presented for the Commissioner to reach his or her judgment. While the preamble addresses this point, the rule, according to its critics, implies that a negative be proven. There is a second major concern heard from both the orphan drug and clinical research communities as to whether broadening distribution of investigational drugs under treatment IND's would undercut the ability to pursue valid controlled clinical trials. As I mentioned earlier, due diligent pursuit of controlled clinical trials is required by the rule, and we will make certain the final rule will include whatever safeguards are required to ensure the integrity of clinical trials. A third category of concerns focuses on the ethical issues involved, specifically those involving informed consent and review by local institutional review boards (IRB's). For example, the reproposal suggested that FDA would look favorably upon requests to waive local IRB review for treatment IND's. This may well be another area where we need to focus more attention in the final rule. We also need to be absolutely sure that adequate informed consent is obtained in each instance. We have also heard a large number of concerns regarding the sale of investigational new drugs under treatment IND's. There was widespread fear among some, for example, as to whether FDA would be able to enforce the "manifestly unfair" standard effectively, and even a number of industry representatives questioned our ability in this regard. Moreover, given current rules governing reimbursement of investigational new drugs by third parties, a number of concerns were raised as to whether a broadened treatment IND program would impose excessive costs on desperately ill patients. We recognize this is a sensitive issue. However, as stated before, these drugs may not be made widely available if the sponsor is unable to charge for the drug.
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