Pulmonary hypertension trials: how can we do better?

Abstract

Conducting clinical trials on pulmonary hypertension in the US and Western Europe has become increasingly difficult and costly because of many challenges. These include a limited patient population that makes recruitment difficult. Recruiting internationally has helped, but can add variability. The choice of end points is important but ideal end points that reflect pathogenesis of the disease are not available. The 6-min walk distance has been used in most trials to date, but recent trials have used an ‘event-driven’ design, in which combined outcomes are used to reflect progression of the disease. This design has advantages but requires many hundreds of patients and may take up to several years. Thus, there is still a role for functional or hemodynamic end points to enable testing of more new agents. Assuring the safety and scientific integrity of clinical trials without excessive regulation will also help facilitate the evaluation of additional therapies for this devastating disease.

Keywords:

• clinical trials
• clinical trial design
• clinical trial end points
• clinical trial recruitment
• pulmonary hypertension

Financial & competing interests disclosure

NS Hill received research grants from Actelion, Bayer, Gilead, Reata and United Therapeutics and is a consultant for Actelion, Bayer and Gilead. IR Preston received research grants from and is a consultant for Actelion, Bayer, Gilead and United Therapeutics. K Roberts received research grants from Actelion, Bayer, Gilead and United Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Recruitment into pulmonary arterial hypertension (PAH) trials is challenging because it is an orphan disease and large event-driven trials take up many of the eligible patients.

• Simplifying trial design and avoiding stringent enrollment criteria (such as for age or 6-min walk distance) can help.

• Using international recruitment also helps, but avoid centers that are inexperienced with clinical trials or PAH care.

• The 6-min walk distance end point is simple to perform, inexpensive and has been used to obtain approval for most of our currently available drugs.

• However, the 6-min walk distance is affected by many factors besides the severity of PAH and improvements have not correlated well with survival.

• The event-driven design has been used in several trials recently and has shown significant slowing of disease progression sustained over a couple of years.

• Unfortunately, survival has not been an achievable end point because of the number of patients and length of time needed.

• We need newer end points that better reflect the effect of drugs on disease progression, ideally in shorter periods of time than the event-drive trials.

• Such end points could still be quality of life or functional outcomes, but newer imaging approaches are also promising.

• Measures to ease the regulatory burden and reduce the paperwork load on IRBs, investigators and coordinators would also facilitate the conduct and reduce cost of clinical trials.