Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology

Abstract

Phase 3 trials are the mainstay of drug development across medicine but have often not met expectations set by preceding phase 2 studies. A systematic meta-analysis evaluated all randomized controlled, double-blind trials investigating targeted disease-modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis. Primary outcomes of American College of Rheumatology (ACR) 20 responses were compared by mixed-model logistic regression, including exploration of potential determinants of efficacy overestimation. In rheumatoid arthritis, phase 2 trial outcomes systematically overestimated subsequent phase 3 results (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.39, 95% confidence interval: 1.25–1.57, P < 0.001). Data for psoriatic arthritis trials were similar, but not statistically significant (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.35, 95% confidence interval: 0.94–1.94, P = 0.09). Differences in inclusion criteria largely explained the observed differences in efficacy findings. Our findings have implications for all stakeholders in new therapeutic development and testing, as well as potential ethical implications.

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Fig. 1
Fig. 2: Descriptive comparison of ACR response rates of phase 2 and phase 3 studies.
Fig. 3: Mixed-model analysis for comparison of phase 2 versus phase 3 clinical effects in rheumatoid arthritis.
Fig. 4: Results of psoriatic arthritis trials confirm data obtained in rheumatoid arthritis.
Fig. 5: Exploratory analysis of efficacy bias between phase 2 and phase 3 clinical trials in rheumatoid arthritis.

Data availability

Due to the nature of this analysis, the data that support the findings of this study were published previously. Primary outcomes used for the analyses of this study are shown in the Supplementary Information. All references for the trials included for analyses are also listed in the Supplementary Information.

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Acknowledgements

The authors thank B. Bierbaumer for his assistance in building the underlying database for this project.

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Contributions

A.K. contributed to development of hypothesis, statistical methods, study screening and selection, data extraction, manuscript preparation and creation of tables and graphs. J.S.S. contributed to development of hypothesis, study selection and manuscript preparation. H.H. contributed to development of hypothesis, statistical methods and manuscript preparation. T.S. contributed to data extraction, manuscript preparation and creation of tables. E.C. contributed to literature search, preparation of the manuscript and creation of tables. D.A. contributed to development of hypothesis, statistical methods, study selection and manuscript preparation.

Corresponding author

Correspondence to Daniel Aletaha.

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Competing interests

A.K. has received consulting or lecture fees from Bristol-Myers Squibb, Celgene, Eli-Lilly, Merck Sharp and Dohme and Pfizer and non-financial support from Gilead; J.S.S. received grants to his institution from Abbvie, AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer and Roche and provided expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, Glaxo, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB; H.H. has no financial relationship to disclose and is Co-ordinating Editor of the Cochrane EC Group; T.S. has no financial relationship to disclose; E.C. has no financial relationship to disclose; D.A. has received grants from AbbVie, Novartis, Roche and SoBi, consulting and lecture fees from Abbvie, Amgen, Celgene, Gilead, Galapagos, Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sandoz and Sanofi/Genzyme.

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Extended data

Extended Data Fig. 1 Detailed exploratory analysis of efficacy bias between phase 2 and phase 3 clinical trials in rheumatoid arthritis.

Heatmaps visualizing the association of the evaluated variables and the study phase (interaction) with the different American College of Rheumatology (ACR) responses (ACR20/50/70) uncorrected (left) and corrected for multiple testing using Bonferroni correction (right). The color code expresses the size of the p-values for interaction term between the respective determinant and study phase, testing the H0: OR = 1; the underlying estimates (beta) and degrees of freedom for the respective analyses are shown in the table in blue and red font color, respectively.

Extended Data Fig. 2 Scatterplot showing number of swollen joints required for study inclusion over time.

Circle colors represent phase 2 (blue) or phase 3 (red) trials, respectively.

Extended Data Fig. 3 Scatterplot showing number of tender joints required for study inclusion over time.

Circle colors represent phase 2 (blue) or phase 3 (red) trials, respectively.

Extended Data Fig. 4 Boxplot showing joint counts used for study inclusion (28/66 joint count) over time.

Box colors represent phase 2 (blue) or phase 3 (red) trials, respectively.

Extended Data Fig. 5 Funnel plots showing plotting the standard error (y-axis) against the odds ratios for ACR responses (x-axis).

Each dot represents a study arm selected for comparison. Study arms of phase 2 studies are shown in blue, phase 3 studies are shown in red.

Supplementary Information

Supplementary Information

Supplementary Tables 1–7, Supplementary References and Study Protocol.

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Kerschbaumer, A., Smolen, J.S., Herkner, H. et al. Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology. Nat Med 26, 974–980 (2020). https://doi.org/10.1038/s41591-020-0833-4

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