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Novel clinical trial designs for the development of new antiretroviral agents.

ABSTRACT: The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-experienced patients - with 70-90% viral suppression rates in recent studies - has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy, and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or noninferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety, was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10-14-day study followed by institution of an optimized background regimen (OBR) in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response, and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent with a new OBR to those on a new OBR and placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population that necessitate careful consideration before initiating trials in them.

SUBMITTER: Mani N

PROVIDER: S-EPMC3343181 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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Novel clinical trial designs for the development of new antiretroviral agents.

Mani Nina N Murray Jeffrey J Gulick Roy M RM Josephson Filip F Miller Veronica V Miele Peter P Strobos Jur J Struble Kimberly K

AIDS (London, England) 20120501 8

The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-experienced patients - with 70-90% viral suppression rates in recent studies - has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy, and regulatory sciences (Foo ...[more]

PMID: 22301412

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Project description:Despite advances in pharmacotherapy, diabetic kidney disease (DKD) remains associated with a high burden of micro- and macrovascular complications often leading to premature mortality. New therapies are highly desirable to mitigate the burden of this disease. However, there are a number of barriers that hamper drug development in DKD. These include, amongst others, the lengthy and complex clinical trials required to prove drug efficacy and safety, inefficiencies in clinical trial conduct, and the high costs associated with these development programs. In this review a number of aspects are discussed, aiming to identify opportunities to transform and innovate drug development for DKD. Many clinical trials in DKD, as well as in other areas, face difficulties in timely and efficient enrolment of participants. To address this issue a network of sites should be created that are continuously recruiting individuals with DKD and collecting crucial information that can be used to understand prognosis and prognostic factors, and more importantly to serve as a pool of participants for recruitment to randomized trials. Second, the current clinical endpoints are late events in the progression of DKD. Endpoints based on lesser declines in estimated glomerular filtration rate (eGFR) or changes in albuminuria can shorten follow-up and/or lead to smaller and cheaper trials. Enrichment by enrolling clinical trial populations based on biomarker profiles is another approach that may facilitate clinical trial efficiency and conduct. Biomarkers can be used to individualize treatment by targeting populations more likely to respond leading to smaller and more efficient trials. Finally, using new trial design such as basket, umbrella or more broadly platform trials to assess a number of therapies simultaneously offers the potential to transform the drug development process in DKD. There are a number of opportunities to transform development approaches for new therapies for DKD. Platform trials along with appropriate biomarker-based enrichment strategies offer the possibility to foster drug development in a precision medicine era.

Dataset Information

Novel clinical trial designs for the development of new antiretroviral agents.

Publications

Novel clinical trial designs for the development of new antiretroviral agents.

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