Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations

Abstract

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Conflict of interest statement

Disclosures

The views expressed in this article are those of the authors, some of whom were, or currently are, employees of pharmaceutical, consulting, or contract research companies and may have financial conflicts of interest related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who attended the IMMPACT meeting and were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by ACTTION. ACTTION has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, philanthropy, and other sources. Preparation of background literature reviews and the article was supported by ACTTION. No funding from any other source was received for the meeting, nor for the literature reviews and article preparation. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred.

SMS has received in the past 36 months a research grant from the Richard W. and Mae Stone Goode Foundation. RHD has received in the past 5 years research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, AstraZeneca, Biogen, Biohaven, Boston Scientific, Braeburn, Celgene, Centrexion, Chromocell, Clexio, Concert, Coronado, Daiichi Sankyo, Decibel, Dong-A, Editas, Eli Lilly, Eupraxia, Glenmark, Grace, Hope, Hydra, Immune, Johnson & Johnson, Lotus Clinical Research, Mainstay, Medavante, Merck, Neumentum, Neurana, NeuroBo, Novaremed, Novartis, NSGene, Olatec, Periphagen, Pfizer, Phosphagenics, Quark, Reckitt Benckiser, Regenacy (also equity), Relmada, Sanifit, Scilex, Semnur, Sollis, Spinifex, Syntrix, Teva, Thar, Theranexus, Trevena, Vertex, and Vizuri. In the past 36 months DCT has received research grants and contracts from US Food and Drug Administration and US National Institutes of Health, and compensation for consulting on clinical trial and patient preferences from AccelRx, Eli Lilly, Flexion, GlaxoSmithKline, and Pfizer. MPM has been supported in the past 36 months by research grants from NIH, FDA, NYSTEM, SMA Foundation, Cure SMA, Friedreich’s Ataxia Reseach Alliance, Muscular Dystrophy Association, ALS Association, and PTC Therapeutics, has received compensation for consulting from Neuropore Therapies, Inc. and Voyager Therapeutics, and has served on Data and Safety Monitoring Boards (DSMBs) for NIH, Novartis Pharmaceuticals Corporation, AstraZeneca, Eli Lilly and Company, aTyr Pharma, Inc., Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Cynapsus Therapeutics, Voyager Therapeutics, and Prilenia Therapeutics Development, Ltd. CE does not have any financial conflicts of interest specifically related to the issues discussed in this article. JTF has received research grants and contracts from US Food and Drug Administration, and National Institutes of Health, and consulting fees from Analgesic Solutions, Aptinyx, Biogen, Campbell Alliance, Daiichi Sankyo, DepoMed, Evadera, Jansen, Lilly, Novartis, Vertex, and Pfizer; DSMB services from NIH-NIA and Cara Therapeutics. MCR reports participation in scientific advisory boards with compensation for Site One Therapeutics, and with CODA Biotherapeutics. ZB was a salaried employee of Alexion Pharmaceuticals at the time of the meeting. LBB was a salaried employee of the U.S. Food and Drug Administration at the time of the meeting, and in the past 36 months, she has received compensation for consulting on clinical trial outcomes from Aclaris, Afyx, Alnylam, Bellerophon, Biogen, Brickell, Jazz, Leo, Plethora, Scynexis, Therapeutics MD, and Zynerba. LG does not have any financial conflicts of interest specifically related to the issues discussed in this article. SSE reports service on data monitoring committees for AstraZeneca, Merck, BMS, GeneOne, and Marinus; consulting for Johnson & Johnson, Shionogi, Biomarin, Alkermes, InsMed, Innovative Science Solutions, AbbVie, PTCBio, and Amgen; and an invited lecture for Sanofi. SRE reports compensation from Takeda / Millennium, Pfizer, Roche, Novartis, Achaogen, Huntington's Study Group, ACTTION, Genentech, Amgen, GSK, American Statistical Association, FDA, Osaka University, Nationa Cerebral and Cardiovascular Center of Japan, NIH, Society for Clinical Trials, Statistical Communications in Infectious Diseases (DeGruyter), AstraZeneca, Teva, Austrian Breast & Colorectal Cancer Study Group (ABCSG)/Breast International Group (BIG) and the Alliance Foundation Trials (AFT), Zeiss, Dexcom, American Society for Microbiology, Taylor and Francis, Claret Medical, Vir, Arrevus, Five Prime, Shire, Alexion, Gilead, Spark, Clinical Trials Transformation Initiative, Nuvelution, Tracon, Deming Conference, Antimicrobial Resistance and Stewardship Conference, World Antimicrobial Congress, WAVE, Advantagene, Braeburn, Cardinal Health, Lipocine, and Microbiotix, and grants from NIAID/NIH outside the submitted work. SI was a salaried employee of Eli Lilly and Company at the time of this meeting. MPJ has received in the past 36 months research grants from US the US National Institutes of Health, the Department of Education, the Administration of Community Living, the Patient-Centered Outcomes Institute, and National Multiple Sclerosis Society, the International Association for the Study of Pain, and the Washington State Spinal Injury Consortium, and compensation for consulting from Goalistics. RJ is a salaried employee of Pfizer and holds Pfizer stock. CK does not have any financial conflicts of interest specifically related to the issues discussed in this article. NPK is an employee of Analgesic Solutions, a research and consulting firm with numerous clients in the pharmaceutical and medical device industry. JPK was a salaried employee of Acadia Pharmaceuticals at the time of the meeting. EAK was a salaried employee of Collegium with stock at the time of the meeting. DL is a salaried employee of Scilex Pharmaceuticals, formerly known as Semnur Pharmaceuticals. JDM has had advisory board or consulting agreements with the following entities over the past decade as follows: advisory board for Clexio Biosciences, Esteve Pharmaceuticals, Flexion Therapeutics, Quark Pharmaceuticals, Quartet Medicine, Collegium Pharmaceutical, Biogen, Novartis, Aptinyx, Nektar, Allergan, Grünenthal, Eli Lilly and Company, Depomed, Janssen Pharmaceuticals, Teva, KemPharm, Abbott Laboratories, Plasma Surgical, Chromocell, Convergence Pharmaceuticals, Inspirion, Pfizer, Daiichi Sankyo, and Trevena; has served as a consultant to Trigemina, Editas Medicine, and Plasma Surgical; and has served on data safety monitoring boards for Novartis and Allergan. PJM has received research grants, consulting fees, and speaker fees from Abbvie, Amgen, Boehringer Ingelheim, BristolMyersSquibb, Celgene, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, SUN Pharma, and UCB. KVP has received in the past 36 months research grants and contracts from the US Food and Drug Administration and US National Institutes of Health. SNR has received research grants from US National Institutes of Health and Medtronic Inc., and has served as a consultant for Aptinyx, Allergan, Grunenthal, and Insys Therpaeutics. IS was a salaried employee of Gruenenthal Gmbh at the time of the meeting. LT is an employee of Pfizer and holds Pfizer stock. JT was a salaried employee of NeurogesX, Inc. at the time of the meeting and is a partner and managing director of the Aquila Consulting Group LLC. ADW in the past 36 months has received an investigator initiated grant from Collegium Pharmaceuticals, and has consulted for Pfizer and Analgesic Solutions. HDW was a salaried employee of the University of Washington at the time of the meeting, is currently a salaried employee of the pharmaceutical company Boehringer Ingelheim, and within the past 36 months was previously a salaried employee of a scientific consulting firm Evidera.

Figures

Figure 1

Interpretation of confidence intervals

Figure 2

Continuous distribution function (CDF) example