Clinical trial designs in PAH: shifting from functional measurements to long-term clinical outcomes.
Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature that leads to right ventricular dysfunction, right ventricular failure, and premature death. There are a number of medications already on the market, representing different therapeutic classes and possessing multiple mechanisms of action. Three new agents were approved by the US Food and Drug Administration in 2013, and others are currently in development. Recent advancements in PAH have resulted in increased survival and improved quality of life; however, no therapy provides a cure. Experts in the field are now utilizing clinical trial designs and end points that better reflect the disease progression among patients with this chronic disease. Although randomized placebo-controlled monotherapy trials are considered the strongest design, ethical and practical considerations have led to an increasing number of randomized trials designed to compare a PAH-specific treatment with placebo as an add-on to standard therapy. As many patients who enroll in clinical trials are already being treated for their condition, it may be unethical to withdraw or delay lifesaving therapies. The most widely used primary end point for PAH trials, change in 6-minute walk distance (6MWD) from baseline, has substantial limitations. Although it is generally reproducible, inexpensive, and relatively easy to conduct, the 6MWD is not designed to assess disease progression. Recent data have shown that 6MWD has inconsistent correlation with key indicators of disease progression such as hospitalization due to PAH, worsening right-sided heart failure, and death. The Task Force on End Points and Clinical Trial Design that met at the 4th World Symposium on Pulmonary Hypertension (WSPH) in 2008 in Dana Point, California, questioned the clinical relevance of the 6MWD as a primary end point and recommended the use of a composite end point--time to clinical worsening (TTCW)--in phase 3 or pivotal trials. TTCW may include time from randomization to PAH-related hospitalization, need for interventional procedures (ie, lung transplantation or balloon atrial septostomy), and mortality. More recently, at the 5th WSPH, held in 2013 in Nice, France, experts reiterated these recommendations. They further noted that, as clinical trials increasingly allow background therapies and are longer in duration, it may be more meaningful to use primary end points that measure "clinical worsening" rather than 6MWD. This paradigm shift will not only lead to a clearer demonstration of efficacy and safety as new agents come on the market, but will provide important information on long-term benefits (ie, the effects of drugs on clinical deterioration) that can assist payers as they strive to make value-based formulary decisions and provide cost-effective high-quality care.
Sean M
SM
Studer
Robert J
RJ
Gilkin
D002986:Clinical Trials as Topic / Q000379:methods*; D017281:Cost of Illness; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D005080:Exercise Test; D006801:Humans; D006976:Hypertension, Pulmonary / Q000191:economics / Q000628:therapy*; D017410:Practice Guidelines as Topic