OP0229PHASE\u2005II CLINICAL TRIALS SYSTEMATICALLY OVERESTIMATE TREATMENT EFFECTS OF SUBSEQUENT PHASE III TRIALS IN RHEUMATOID ARTHRITIS

Abstract

Background Phase 3 (P3) clinical trials are the mainstay of drug development in all areas of medicine, including rheumatology, allowing to determine safety and efficacy of new drugs on their way to approval. Historically, efficacy results of P3 trials have often been disappointing with respect to the expectations set by phase 2 (P2) trials. It is unclear whether these observations are reflection of a true bias or merely a play of chance. Objectives To systematically compare efficacy results of P2 versus P3 trials in RA and investigate potential determinants of efficacy differences. Methods We performed a systematic review of disease modifying anti-rheumatic drugs (DMARDs) tested in P2 trials in rheumatoid arthritis (RA) over the last 20 years for which also P3 trials exist. We searched Medline, EMBASE, and the Cochrane Library to identify all randomized controlled double-blind trials investigating biological (b) and targeted synthetic DMARDs in RA. The criteria for inclusion in the analyses were defined as follows: (i) treatment arms in P2 and P3 used the same treatment regimen; (ii) the same RA population was studied (DMARD naïve; conventional DMARD insufficient responders (IR); bDMARD IR). The treatment regimen was regarded the same when a DMARD was used at the same dose, interval and route in P2 and P3. Multilevel mixed model logistic regression was used to determine a summary estimate for comparison of P2 versus P3 results on the outcomes of American College of Rheumatology (ACR)20, ACR50, and ACR70 responses (in separate models). Results are expressed as Odds Ratio (OR) and 95% confidence intervals (95% CI). Possible determinants of systematic overestimation were explored using the same statistical technique, investigating study and baseline characteristics of the individual trials and study arms, respectively. Results In total 1290 abstracts were screened of which 133 were regarded as potentially relevant, with 44 trials (19 agents, 48 regimens, 17476 patients) finally included in the analysis. Summary estimates revealed that outcomes of P2 trials were systematically overestimating the subsequent P3 results for ACR20 (OR: 1.40; 95% CI: 1.15-1.57; p≤0.001), ACR50 (OR: 1.36; 95% CI: 1.21-1.54; p≤0.001) and ACR70 (OR: 1.39; 95% CI: 1.02-1.90; p=0.037). Exploration of determinants of this systematic bias revealed that inclusion criteria for minimum number of required swollen (IC-SJC) and tender joints (IC-TJC) as well as the joint count used for inclusion (28 vs. 66/68 joint count) were significant determinants of P2/P3 efficacy differences. Figure 2 shows scatter plots of efficacy differences (shown as OR), revealing that higher IC-SJC and IC-TJC, as well as using the 66-JC instead of the 28-JC for study inclusion lead to a significantly lower chance of efficacy overestimation. Conclusion Our results reveal that Phase 2 clinical trials overestimate the treatment effects when compared with subsequent Phase 3 trials in RA. The identification of this systematic bias towards overestimation of efficacy by Phase 2 studies has implications for considerations of clinical investigators, sponsors, and regulatory agencies during the development and licencing process of new compounds, as well as potential ethical implications. Acknowledgement We want to thank Dr. Eva Chwala for her assitance with the literature search and Bruno Bierbaumer, MSc for his important contribution to the database infrastructure. Disclosure of Interests Andreas Kerschbaumer Speakers bureau: Bristol-Myers-Squibb, Celgene, Pfizer, Harald Herkner: None declared, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, GlaxoSmithKline, ILTOO, Janssen, Medimmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Daniel Aletaha Grant/research support from: AbbVie, Bristol-Myers Squibb, and MSD, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medac, Merck, MSD, Pfizer Inc, Roche, and UCB