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Integrating Data From Randomized Controlled Trials and Observational Studies to Assess Survival in Rare Diseases

A. Torbicki, M. Bacchi, M. Delcroix, HW. Farber, HA. Ghofrani, B. Hennessy, P. Jansa, S. Mehta, L. Perchenet, T. Pulido, D. Rosenberg, LJ. Rubin, BKS. Sastry, G. Simonneau, O. Sitbon, R. Souza, LJ. Wei, R. Channick, R. Benza,

. 2019 ; 12 (5) : e005095. [pub] -

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20023958

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.

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$a Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.
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$a Bacchi, Marisa $u Biostatistics, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (M.B., B.H.).
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$a Delcroix, Marion $u Department of Pneumology, University Hospitals Leuven, Belgium (M.D.).
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$a Farber, Harrison W $u Pulmonary Center, Boston University School of Medicine, MA (H.W.F.).
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$a Ghofrani, Hossein-Ardeschir $u University of Giessen and Marburg Lung Center, Germany, member of the German Center of Lung Research, and Department of Medicine, Imperial College London, United Kingdom (H.-A.G.).
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$a Hennessy, Brian $u Biostatistics, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (M.B., B.H.).
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$a Jansa, Pavel $u Clinicial Department of Cardiology and Angiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic (P.J.).
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$a Mehta, Sanjay $u Canada Respirology Division, London Health Sciences Centre, ON (S.M.).
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$a Perchenet, Loïc $u Global Medical Affairs, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (L.P.).
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$a Pulido, Tomas $u Cardiopulmonary Department, Ignacio Chávez National Heart Institute, Mexico City, Mexico (T.P.).
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$a Rosenberg, Daniel $u Epidemiology & Observational Studies, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (D.R.).
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$a Rubin, Lewis J $u Division of Pulmonary and Critical Care Medicine, University of California, San Diego Medical School (L.J.R.).
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$a Souza, Rogério $u INCOR Heart Institute, University of Sao Paulo, Brazil (R.S.).
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