Efficacy measures for clinical trials: A review series

The last two decades have witnessed considerable expansion in cystic fibrosis (CF) treatment options and associated improvements in patient outcomes. Whereas in the early 1990s limited therapeutic options included systemic antibiotics, inhaled bronchodilators, and pancreatic enzymes, the commercial development of inhaled dornase alfa began a parade of randomized controlled trials of medications to mitigate the respiratory complications of cystic fibrosis that continues to this day. Today, many more treatment options targeting the sequelae of CF lung disease are available, including multiple aerosolized antibiotics, hypertonic saline, and chronic macrolides, and more recently, CFTR modulators addressing the problem closer to the basic defect, with many more medications in the development pipeline (https://www.cff.org/Our-Research/Drug-DevelopmentPipeline/) (date accessed 05/31/2016). Addition of these medications to the CF treatment regimen has been associated with a continued increase in the projected survival of our patients as well as a growing adult population. At the same time, our understanding of the natural history of CF lung disease has led us to begin intervening much earlier, with newborn screening for CF allowing management of very young children with few symptoms and apparently ‘normal’ lung function. We should anticipate that disease-modifying medications that treat the basic CF defect will have their greatest potential for long term impact when introduced as early as possible, preventing the development of the complications of CF. As we investigate newer and hopefully more effective CF therapies, we must recognize that available study subjects are not the same as those engaged in those earlier trials: today's subjects tend to be older and prescribed more medications. Tomorrow's study designs may need to evolve to account for what is essentially a “healthier” population, and defining appropriate clinical endpoints is of paramount interest to facilitate the development of newer, more effective medications. Whereas improvements in lung function in a compromised population were able to satisfy regulatory scrutiny in past years, it may well be that other efficacy endpoints will be better-suited for current and future studies. This will require characterization of both clinically relevant (i.e. that satisfy the regulatory requirement of improvement in the way a patient feels, functions or survives) and reasonably sensitive efficacy endpoints. We have commissioned a series of reviews addressing three areas of efficacy endpoints that may prove useful in future clinical studies. In this current issue is the first of the series, addressing physiologic measures, with particular discussion of our current challenges using change in lung function (e.g., FEV1) as a measure of efficacy [1]. In subsequent issues there will be reviews of biomarker and of imaging measures, and how those might serve as meaningful surrogates for treatment-associated benefit in future trials. These reviews are written from the perspectives of clinicians and biostatisticians, with the intent of providing clarity as to the current state of clinical investigation in CF. In addition, we have invited commentary from the regulatory agencies (the first appears in this issue) [2]. We hope these reviews generate considerable conversation from investigators, clinicians, regulatory agencies, patients and families, as we are all working together for the same purpose – to improve the health and survival of our patients that we serve.