Community Support for FDA's New HIV Clinical Trial Proposal

February 18, 2011

Debra Birnkrant,MD                                                                             
Director, Division of Antiviral Products
Center for Drug Evaluation and Research
Food and Drug Administration

Re: New HIV Trials Design Guidance

Dear Dr. Birnkrant:

            We are writing to express our strong support for the FD's new two-part hybrid proposal for HIV trial design for treatment-experienced patients.  Initially, short term durability would be assessed from one to two weeks on a case by case basis, depending on the resistance profile of each drug.  This would be followed by a 24 week assessment period with an optimized background regimen where dose responses, safety, longer-term durability and resistance would be evaluated.

            We support this ingenious new design because we are very concerned about the future of ethical trial design for HIV treatment experienced patients as well as feasible HIV drug development in the era of highly active antiretroviral therapy (HAART).  The HIV community is very fortunate to have a large antiviral armamentarium of anti-HIV drugs of various classes.  Nevertheless, there are a significant number of treatment experienced patients who are resistant to all currently marketed antiretroviral (ARV) therapies. 

            Demonstrating the superiority traditionally required by the agency to prove effectiveness is now virtually impossible without conducting trials in treatment experienced patients whose virus is not fully suppresses or subjecting patients to TORO type designs that are essentially placebo controlled trials.  Both options are absolutely unacceptable to the HIV affected community at this juncture. We firmly believe these approaches are unethical, outmoded and require a paradigm shift.

            A number of recent NDAs have demonstrated that it is almost impossible to evaluate the contribution of an investigational agent in the presence of a fully suppressive background regimen of three or more HAART drugs.  As a result, vicriviroc, a once daily CCR5 inhibitor and apricitabine, a cytidine analogue with activity against M184V resistant mutations have recently failed to demonstrate the efficacy necessary for FDA approval even though both drugs would certainly have been a valuable addition for treatment experienced patients.  Moreover, their failure to obtain agency approval will undoubtedly have a chilling effect on the willingness of sponsors to develop new ARV drugs in the future. 

            We believe that this new two-part hybrid design for treatment experienced patients will enable sponsors to demonstrate the contribution of their new drugs without administering sub-optimal long-term regimens or subjecting the very vulnerable treatment experienced patients not lucky enough to be in the new drug arms to functional monotherapy trials that will surely confer resistance to the new drugs that may be a patient's only chance for survival. 

This new paradigm will also demonstrate safety and efficacy pursuant to the spirit of agency%u2019s Accelerated Approval (AA) regulations which permits earlier approval of drugs that treat serious and life-threatening diseases with an unmet medical need based on a surrogate endpoint.  Clinical trial data since 1997 have consistently shown that failure to achieve a virologic response within two weeks is predictive of long-term effectiveness of an investigational agent.  Clinical benefit is also a well-settled result of full viral suppression.  Since the AA regulations were promulgated in 1992, virologic response has been the basis for the accelerated approval of approximately 20 new drugs.  Every one of these drugs also received full FDA approval based on 48 weeks of confirmatory safety and durability data thereafter.

The new two-part hybrid proposal would still allow the agency to comply with the letter of the AA regulations by granting accelerated approval at 24 weeks and full approval at 48 weeks, but we wonder if the AA regulations are now anachronistic.  We believe that it is appropriate for the agency to grant full approval at 24 weeks in conjunction with requiring mandatory 48 week post-marketing studies because HIV RNA is a now considered a validated endpoint.  Short and longer-term safety and durability data will be required by the agency pursuant to the spirit of the AA regulations with either scenario.

            The undersigned HIV community based organizations urge the agency to approve and implement this new two-part hybrid design.  We are relying on the FDA to exercise the judgment necessary to address the HIV drug development issues we now face.  We firmly believe that this new paradigm will ensure ethical expedited trial design with life-saving new drugs for treatment experienced patients limited or no available options by providing a reasonable and prudent pathway in which to develop new ARV drugs in the HAART era. 

            Thank you and the members of your Division for your tireless efforts on behalf of people with HIV/AIDS.  We very much appreciate your consistent willingness to listen to and interact with the HIV affected community.  We look forward to continuing this successful partnership in the future.

Very truly yours,