The meeting, chaired by Roy Gulick of Cornell University, was convened to focus on clinical trial design issues for HIV-infected individuals who have limited antiretroviral therapeutic options. Heidi Jolson, the FDA's outgoing Director of the Division of Antiviral Drug Products, noted that the FDA's interest was in registrational rather than treatment strategy trials and that for the purpose of the meeting, the "highly treatment experienced (HTE) population" would refer to individuals who lacked or had lost response to two or more HAART regimens and who had experience with one or more members of each class of drugs.
Martin Schechter of the Canadian Clinical Trials Network gave an overview of trial design options in adults. He noted that as individuals moved from treatment naive to salvage, population heterogeneity increased, but that heterogeneity only matters if the variables are strongly prognostic. He questioned whether blinding in salvage trials introduced more bias than it prevented, as it could wipe out the adherence advantage of an arm with lower pill burden. He rued the fact that factorial designs are woefully underutilized in the medical arena.
Carlton Hogan of the Coalition for Salvage Therapy (CST) gave the patients' perspective. The CST was uncomfortable with intensification designs that simply add one new agent to an already failing regimen ("virtual monotherapy") and he stressed that it was vitally important that the FDA proactively offer clear, unambiguous guidance related to the use of more than one investigational agent. The CST advocated strongly that background therapy be optimized individually based on genotypic and phenotypic resistance testing (optimized background regimen [OBR]) and recommended a modified factorial design on top of OBR. With three new agents (A, B, C) this would be:
Such a design would improve chances of virologic control in each arm, reduce development of resistance to new agents as well as OBR drugs, allow the effects of individual agents to be discerned, and may be attractive to potential participants. However, there is no true control arm; it may be difficult to ascribe adverse events to one particular agent with certainty and, if certain combinations fail to achieve virologic control, study participants would be exposed to toxicity without commensurate benefit.
Dr. Jolson pointed out that in 1999 the FDA had written to sponsors indicating that more than one investigational agent could be used and that the Agency was extremely supportive of factorial designs. The FDA had concerns about intensification trials in salvage populations.
There was general support among the advisory panel for a modified factorial design in HTE individuals. It was felt that it would be unethical to enroll "deep salvage" individuals in trials -- they should be granted expanded or compassionate access to new agents.
Michael Marco presented TAG's position.
Daniel Vittecoq of the European Agency for the Evaluation of Medicinal Products (EMEA) summarized the new approach adopted by the EMEA to the registration of new antiretroviral drugs with particularly promising resistance or pharmacokinetic profiles for use in HTE individuals.
Phase II studies would establish the drug dosage in treatment-naive persons or HIV-negative volunteers. Phase III trials in HTE individuals should be superiority designs -- either substitution or intensification trials. There would be a 2-4 week assessment of efficacy and a 12-16 week assessment of durability and safety. Primary endpoints would be the proportion of participants achieving "undetectable" viral loads and >0.5 log10 difference between arms.
Jim Rooney of the Intercompany Collaboration (ICC) gave the agency's perspective. He noted some of the difficulties of trials involving more than one agent: isolating the benefit of a single agent, the limited availability of new agents, and unexpected interactions and toxicities. He suggested that placebos should not be used often in the salvage setting as they would greatly increase the pill burden, (thereby decreasing adherence), and advocated using change in viral load as an endpoint. He suggested a trial design with short-term monotherapy followed by longer-term combination therapy:
Stage 1 would provide evidence of antiviral activity, allow for resistance monitoring and provide short-term safety and tolerability data.
In the discussion that followed, members of the panel suggested that trial designs include an early escape mechanism for non-responders. Endpoints suggested include decrease in viral load, increase in CD4 count, proportion with plasma viral load below detectability and the slope of plasma viral load decline during the first few weeks on monotherapy or initial intensification of a failing regimen. Community members stressed the need for a system for monitoring the safety and toxicity of agents post-registration.
Victor DeGruttola of the Harvard School of Public Health further addressed the issue of the modified factorial design. Although it does not have the full efficiency of the true factorial design, it allows comparison of several agents (A vs. B, B vs. C, and A vs. C). Some of the ability to discern all of the interactions among agents is lost, but it provides the best power to look at interactions between drugs.
Michael Saag of the University of Alabama at Birmingham suggested that study participants be stratified prior to randomization according to the number of treatment options available based on resistance testing. Those with 3 or more options would be randomized to receive:
Those with less than three options would be randomized to receive:
Dr. DeGruttola presented on the choice of endpoints for salvage studies. He questioned whether study withdrawal should be counted as failure or as censored, noting that each analysis is likely biased. He recommended doing both analyses as well as more sophisticated analyses.
Dr. Gulick presented data on the low response rate in HTE individuals. He noted that predictors of response include adherence, baseline plasma viral load, baseline CD4 count, resistance profile, number of active drugs, and drug plasma levels.
In the discussion that followed, it was suggested that baseline plasma viral load should be the plasma viral load off therapy. Endpoints should include: change in plasma viral load (0.4-0.5 log10 reduction in plasma viral load over 8 weeks); resistance; viral fitness; toxicity; adherence and quality of life. The proportion of study participants with undetectable plasma viral load or plasma viral load reduction of 0.4-0.5 log10 over 8 weeks should be correlated with clinical outcome. Predictors of success on therapy should be studied.
Finally, the role of shorter-term trials (e.g., 16 weeks) in assessing the safety and efficacy of new antiretrovirals in HTE individuals was discussed. Some clinicians suggested that "deep salvage" individuals need urgent access to new agents and so shorter-term registrational trials in HTE individuals may be needed. The community members present were unanimous in expressing concern about approving agents with fewer than 24-weeks of data for conditional approval and fewer than 48-weeks for full approval. They noted that there is great need for adequate safety data, especially Phase IV post-registration, and that industry had not demonstrated a willingness to do systematic long-term safety monitoring. Before the FDA grants approval based on shorter-term trials, sponsors should demonstrate that they are committed to looking at long-term toxicities -- and systems (cohort studies, databases, etc.) should be set up to monitor drug adverse events. Because FDA approval permits off-label use of drugs, earlier approval may be dangerous. Compassionate or expanded use programs should be set up as soon as the investigational agents go into larger Phase III trials so that "deep salvage" individuals who need these agents to construct a viable regimen may have access to them.
In conclusion, Dr. Jolson said that safety data beyond 8 weeks is needed and encouraged sponsors to follow up study participants from early trials for as long as possible.
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