PARALLEL TRACK AIDS DRUG DISTRIBUTION CAN BE OKAYED BY NIAID; NIH INSTITUTE WILL REVIEW EXPANDED ACCESS PROPOSALS AND FORWARD RECOMMENDATIONS TO FDA

The National Institute for Allergy & Infectious Diseases will have a lead role in the review of parallel track drug applications. Under the Public Health Service's proposed parallel track policy, published in the May 21 Federal Register, applications for distribution of drugs under the expanded access program will be reviewed by the institute before being forwarded to FDA. The policy provides that unless a sponsor desires otherwise, "FDA would refer all parallel track proposals to the AIDS Research Advisory Committee (ARAC)," a panel of experts chartered by NIAID. The committee will make a recommendation to NIAID and, "after review, the Director of NIAID will forward a recommendation, through the Director of NIH, to the Commissioner of FDA." Requests to be presented to the ARAC committee, the proposal notes, "will...in all cases...be screened and scheduled by NIAID Committee Management Staff." Sponsors may, if they wish, submit their applications directly to FDA. The policy for allowing early distribution of investigational agents applies only to therapies to treat AIDS and HIV-related diseases. PHS, however, is specifically requesting comments on whether the policy "should be extended beyond AIDS-related therapies to those therapies for other life-threatening diseases." The agency is accepting comments on the proposed policy through July 20. The proposal was drafted as a policy statement instead of a reg as a shortcut to avoid some regulatory procedures. The document sets out the criteria to be used in reviewing a parallel track application, criteria for patient and physician eligibility, monitoring controls, and reasons for terminating a protocol. The reasons for putting a parallel track protocol on clinical hold are also outlined in an accompanying FDA reg published in a same day Federal Register notice. Under the proposal, investigational drugs could be made available to certain AIDS/HIV patients through studies without concurrent control groups at the same time or after the initiation of controlled Phase II studies. To be eligible to receive a drug under the expanded access program the patient must: 1) have "clinically significant HIV-related illness" or be at "imminent health risk due to HIV-related immunodeficiency"; 2) be unable to participate in the clinical trial; and 3) be unable to take standard treatment (i.e., the standard treatment is contraindicated, cannot be tolerated, or is no longer effective for the person). Approval criteria for a parallel track application generally follow the requirements outlined by HHS earlier this year ("The Pink Sheet" Feb. 26, T&G-4). A study can include an uncontrolled, parallel component if the application shows, "promising evidence of efficacy," "evidence that the drug is reasonably safe", sufficient data to recommend a starting dose, preliminary pharmacokinetic data and dose-response data, "lack of a satisfactory alternative therapy," a description of the patient population, with priorities for treatment established if the drug will be in short supply, sufficient amounts of the drug for both the controlled trials and expanded access program, approval of Phase II protocols, a plan for monitoring the impact on controlled trials, and information describing educational efforts that will be undertaken to ensure that participating physicians have sufficient knowledge about the risks and benefits of the therapy. The proposal institutes several safeguards to ensure that the expanded access program is not having a detrimental effect on the conduct of controlled clinical trials. Adverse effects on the conduct of clinicals are one of the reasons for putting an expanded access study under clinical hold, and the policy statement specifies that sponsors must establish a Data and Safety Monitoring Board, or its equivalent, to monitor the uncontrolled and controlled clinical trials for, among other things, enrollment problems in the controlled trials. FDA's clinical hold reg establishes fairly broad criteria for placing a parallel track study on hold. In addition to the standard criteria for placing a study on hold, the proposal allows the agency to halt a parallel track study if "there is reasonable evidence" that the uncontrolled part of the study "is impeding enrollment in, or otherwise interfering with the conduct or completion of, a study that is designed to be an adequate and well-controlled investigation of the same or another investigational drug." The reg explains that the agency "would look to whether enrollment is proceeding at the expected rate and whether an adequate number of enrolled patients are completing the trial." When an "unexpectedly slow rate of enrollment or an unusually high drop-out rate that is not attributable to adverse drug experience occurred and there was an ongoing open, nonconcurrently controlled study of the drug, this would ordinarily be considered reasonable evidence that the open, nonconcurrently controlled study is interfering in the conduct or completion of the adequate and well-controlled trial," FDA said. To facilitate the monitoring of controlled clinical trials, the agency "would generally require that a protocol for a controlled clinical trial of a drug for which an open, nonconcurrently controlled study of the drug is also proposed, contain estimated times for full enrollment, estimated drop-out rates, and an expected date of completion of the trial." Other reasons for clinical hold include studies showing lack of efficacy of the drug; availability of another drug with "a better potential benefit/risk balance"; insufficient quantities of the drug for both controlled clinicals and the expanded access protocol; approval of the drug for the same patient population; a sponsor not actively pursuing marketing approval; or if "the commissioner determines that it would not be in the public interest for the study to be conducted or continued." PHS has previously said that cost recover would be unlikely for parallel track studies ("The Pink Sheet" March 19, p. 9). The proposal, however, leaves the question open, noting that existing IND regs provide for recovery of costs "in the unusual circumstance in which the trial could not otherwise continue." The proposed policy states that "sponsors should specify the extent of economic support they would be willing to provide to pursue the expanded access of the investigational agent through the parallel track." The parallel track policy also calls for establishment of a "national human subjects protections review panel" that will provide patient protections, such as ensuring informed consent, that are traditionally handled by IRBs. The policy proposes to waive requirements for local IRB review in lieu of the national committee. Under the proposal, the ARAC would establish an ad hoc subcommittee to carry out the duties of the panel until a permanent body is established. IRB review would still be required for the controlled clinical trials of the investigational therapy.