Novel clinical trial designs for the development of new antiretroviral agents

Abstract

We thank Dunn et al.[1] for their comments on our article. The article [2] reports an expert discussion on antiretroviral drug development at a time when the great majority of patients, including most who have experienced virological failure once or more, have licensed treatment options that if, adhered to, will help achieve durable virological suppression. As discussed in the article, traditional large-scale comparative trials like those pivotal for the licensure of raltegravir or etravirine are therefore difficult to conduct. There remains, however, a small group of patients for whom a likely suppressive treatment regimen may not be available, and for whom new agents that are efficacious against viral strains with multiple resistances to existing drugs would be of value. Due to the relative scarcity of patients without remaining treatment options, and to the recognized risk of aggravating drug resistance with incompletely suppressive regimens, drug development in this population is a challenge. As a first point of response to the comment by Dunn et al. [1], we note that the proposed study design discussed at the meeting principally addresses a population that would not be recommended for study in traditional 24–96 week placebo controlled trials according to present European or US regulatory and clinical guidance [3,4]. Dunn et al. [1] question whether the efficacy assessment in the proposed study adds value, over and above that obtained in phase 1/2 dose ranging monotherapy studies. In this context, we note that investigational agents that might be studied according to the proposed design are most likely to be new agents of existing drug classes. Thus, the primary efficacy objective of the randomized phase would be to assess in-vivo antiviral potency against a range of viruses with different genotypic resistance mutation patterns relevant to the drug class, and possibly conferring cross resistance to the new agent. Traditional monotherapy dose-ranging studies are generally performed in treatment-naive patients, and this information would not be obtained in such studies. If ‘functional’ monotherapy (add-on) studies in drug-class experienced patients failing their present regimen were performed in phase 1/2, these might be designed as smaller, pilot-type studies of a similar design as the randomized phase of the proposed pivotal study. Dunn et al. [1] rightly note that the proposed study would not provide randomized evidence of the durability of response. In this context, an assumption of the rationale for the proposed design is that, if an antiretroviral drug showed reasonable short-term potency against a certain viral resistance strain, available experience indicates that it would be highly likely to contribute to the long-term durability of response to a combination regimen, provided that the other agents had different mechanisms of action and did not select for similar drug resistance mutations. The second, nonrandomized phase of the proposed study would provide observational data on the durability of response, to be analyzed in relation to estimated optimized background therapy activity. Furthermore, it would provide information on emerging resistance mutations to the new agent in case of failure. As was discussed at the meeting, in order to generate randomized comparative data on the contribution of the new agent to the durability of response, the agent could be investigated in traditional, reasonably sized studies, which would likely have a noninferiority design. The meeting deliberations, which were prompted by the present treatment landscape, noted that such studies would most readily be conducted in treatment naive or lightly treatment experienced patients. Also, in such studies, rates of emerging drug resistance in case of viral failure would provide valuable information on the barrier to resistance of the agent. Finally, Dunn et al. [1] pose valid questions concerning the lack of randomized evidence on safety with the proposed study design. Neither the meeting nor our report systematically covered the issue of what supporting safety data would be required to bring a drug to market in the context of pivotal trials of the kind proposed. The size of the safety database, as well as the trials in which this may be generated, may differ depending on the range of treatment populations that are targeted in the drug development program. This will need to be further defined by regulatory agencies, if the proposed path is followed. Acknowledgements Conflicts of interest There are no conflicts of interest.