"PARALLEL TRACK" PROPOSAL FOR AIDS DRUGS WILL BE ADDRESSED BY FDA ADVISORY COMMITTEE WITHIN A MONTH; REPORT TO HHS DUE BY AUG. 21, MASON TELLS WAXMAN

An FDA advisory committee will be meeting in the next month to prepare a report for HHS Assistant Secretary for Health James Mason on unresolved issues with the proposed "parallel track" approach for expanding access to experimental AIDS drugs, Mason told Rep. Waxman's (D-Calif.) Energy & Commerce/Health Subcommittee July 20.

Noting that "a number of questions remain to be answered before we will be able to implement this initiative," Mason said he has asked FDA Commissioner Young "to have an FDA advisory committee help us resolve these issues. I have instructed him to have the committee obtain advice and suggestions from a wide variety of outside consultants including physicians conducting clinical trials, community-based physicians, persons who have AIDS or are infected with HIV, representatives from the pharmaceutical industry, and other interested parties as appropriate." The committee will meet "and submit an initial report on their progress to me no later than Aug. 21," Mason added.

The agency said it has not yet decided which advisory committee it will use to provide advice on the expanded access procedure. FDA Commissioner Young noted that National Institute of Allergy and Infectious Diseases Director Anthony Fauci, MD, who is credited with developing the proposal, and National Cancer Institute Director Samuel Broder, MD, will act as ex officio members of the committee.

Mason identified several issues that need to be addressed before implementation of the parallel track procedure, which would allow the release of certain promising experimental AIDS therapies after Phase I testing to those patients who cannot enter the efficacy trials and are unable to benefit from existing therapies. The unresolved questions, according to Mason, include:

"Procedures to identify and evaluate unexpected deaths or serious illness accompanying the use of the investigational agent";

"Management issues associated with the expanded availability protocol, including costs for associated medical care, drug administration, and monitoring laboratory procedures";

"Liability on the part of sponsoring drug companies or physicians who participate in the program";

"The process for establishing specific criteria for determining patient eligibility"; and

"Requirements for informed consent by the participating patients."

Mason was accompanied at the hearing by Young, Fauci, and Broder. The subcommittee also heard testimony from Pharmaceutical Manufacturers Association VP-Medical and Regulatory Affairs John Petricciani, MD, and representatives from the AIDS activist groups, Project Inform and ACT-UP. Both PMA and the AIDS activist groups emphasized the need for all affected parties to be involved in addressing potential problems with the parallel track procedure.

PMA identified several concerns industry has with the proposed procedure, including the potential effect on clinical trials and the drug development system. For example, the association questioned whether the procedure will result in a "problem in recruiting patients into the controlled clinical trial [that] will ultimately delay approval by FDA." The association also questioned whether patient populations would become saturated with experimental drugs, making participation in future clinicals difficult, and whether the procedure could result in a "decreased motivation on the part of FDA to expedite the approval of a new drug" (see box for list of PMA concerns).

Waxman's questions to witnesses also focused primarily on the possible effects on the clinical trial/drug development process. Fauci, in response to a question about whether the procedure would interfere with researchers' ability to gather efficacy data, told the congressman: "Expanded access is for people who cannot be on the protocol, so it isn't as if [patients have a choice]. If those guidelines are followed, in no way would an expanded access for those individuals who cannot be on the protocol interfere with the accrual of people who would qualify."

Asked the same question, Project Inform Codirector Martin Delaney maintained that the clinical trial system would not be compromised. Delaney asserted that clinical trial data might even be improved because AIDS patients desperate for therapy sometimes lie in order to meet eligibility criteria for clinical studies.

The intent of the hearing, Waxman said in his opening statement, "is to form a record of the proposal, its reach and its limits as well as the questions that remain unanswered."

The California Democrat characterized the "parallel track," or "expanded access," procedure as "an important proposal." Waxman declared that it "could change ground rules on research, clinical care, markets, and insurance. It could also provide access to drugs -- the good ones and the worthless ones -- long before data are available." If the proposal works, Waxman added, "it could revolutionize drug development. If it fails, it could cripple AIDS research for some time."

In addition to concerns about the clinical trial and drug development system, the subcommittee questioned whether manufacturers would participate if liability issues became a problem. Product liability was also raised by PMA in its testimony. Young suggested that legislative action might be necessary to reduce the risk of liability.

Drawing on the agency's experience with the Treatment IND process, Young noted that liability can be minimized by publishing protocols and data in scientific journals and information in consumer magazines, enhancing informed consent. FDA has also recommended that HCFA and third party payors reimburse for Treatment IND drugs since the agents have shown sufficient signs of effectiveness, "which provides a degree of shelter," Young said.

However, the FDA commissioner explained, "in this earlier [release of drugs under] parallel track, I don't believe that's as institutionalized yet, and it's possible that congressional action that would deal with some actions that would clarify the responsibility of individuals in partaking of experimental drugs might help the manufacturer be more willing to take the risk, because we're not talking about a few people, but tens of thousands of individuals that may be using experimental drugs."

Bristol-Myers' DDI, which has been cited by both FDA and NIAID as a candidate for release under the parallel track system, is apparently not going to be handled under the procedure. Mason told the subcommittee that the drug would not be released under the system, but would be made available under a Treatment IND (see related story, p. 19).

Mason has been acting as an intermediary between FDA and NIAID in developing the expanded access/parallel track program. Fauci had first proposed the idea of early release of promising agents to patients not able to qualify for clinical trials at a June AIDS conference ("The Pink Sheet" June 26, "In Brief"). Fauci met with Young and Mason on July 13 to discuss a NIAID draft proposal for how such a program could be implemented and FDA subsequently prepared a document of its own describing the proposed program.

The two agencies' proposals are almost identical. Major aspects of the program include:

Promising agents could be made available at the time they are in or are entering efficacy studies if adequate safety is demonstrated in Phase I studies. "Priority will be granted to agents showing encouraging signs of efficacy," FDA said. NIAID's proposal adds that an "indication of efficacy would not be a requirement."

The intent of expanded access is not to provide research data, but "meaningful data may be collected regarding experience with the drug and could contribute to a fuller understanding of these experimental therapeutic interventions and how they can be most effectively utilized," FDA said.

Candidates for expanded access will be considered on a case-by-case basis. "Decisions regarding the appropriateness of expanded access would rely on a number of factors including Phase I trial results, the endpoints being evaluated, the type of drug in question, as well as the supply of the drug," NIAID said. FDA also included as a factor the "availability of satisfactory alternative therapies."

"The sponsor of a drug under expanded access will be responsible for ensuring that clinical trials are ongoing and that the expanded access had no detrimental impact on the controlled clinical study. Any indication that this was occurring would result in discontinuation of the program. The sponsor should submit a plan for monitoring and evaluating the potential for slowing conduct of controlled clinical trials at the time a trial for expanded access is requested," FDA said. NIAID concurred with discontinuing a study if the parallel track approach had a "detrimental effect" on the controlled study.

Patient eligibility criteria would be determined prior to implementation of the program and physicians would have to document that their patients meet the criteria.

An outside committee, such as NIAID's AIDS Research Advisory Committee, could be responsible for reviewing candidate drugs and making recommendations to FDA. The commmittee would also monitor agents that are available to assure the appropriateness of continued availability.

Informed consent is essential. Patients must adequately be informed of the potential risks involved with experimental drugs with limited clinical data.

PMA CONCERNS WITH PARALLEL TRACK PROPOSAL

In testimony to Rep. Waxman's Energy and Commerce Health Subcommittee, PMA cited the following as "industry's most significant concerns" with FDA/NIAID's proposal for expanded access to experimental AIDS drugs.

1. What impact will wider availability of experimental drugs in much less controlled conditions have on understanding safety issues of the drug? Will some manufacturers decide to discontinue studying a drug because of false-positive adverse events in the parallel track?

2. Will there be a problem in recruiting patients into the "controlled" clinical trial and will that ultimately delay approval by FDA?

3. Will the parallel track system result in patient populations that are saturated with experimental drugs, therefore making it increasingly difficult to conduct studies of newer and potentially more effective drugs as they come to the point of clinical testing?

4. Will the parallel track system result in a decreased motivation on the part of FDA to expedite the approval of a new drug due to its availability in the proposed parallel track?

5. Can the parallel track system be designed so that the data generated do not hinder FDA approval but instead are useful in the NDA filing? Will data on safety be so confusing that they will delay or compromise approval when reviewed by FDA?

6. Will unrecognized adverse events in the parallel track system result in product liability issues after marketing?

7. Who will decide which drugs and which patient populations are candidates for parallel track? For example, will it be limited to situations in only AIDS, only cancer, only other life-threatening illnesses, patients with earlier stages of disease? What will the decision-making process be and what role will industry play?

8. How will the parallel track system be integrated into multi-drug therapy studies, which will be required to make significant progress in this disease, as was the case for TB and leukemia?

9. How will the FDA deal with black market copies of drugs that are being developed on fast tracks, including the parallel track?

10. Since less than one-third of drugs that enter Phase II are eventually approved for marketing, diversion of resources to large-scale development at this early stage before clinical safety and efficacy are well established will take resources otherwise available for developing additional promising new drugs.