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Specific Aspects and Significance of Subgroup Assessment in Confirmatory Clinical Trials

https://doi.org/10.30895/1991-2919-2021-11-2-81-93

Abstract

 Patient subgroup analysis plays an important role in interpretation of confirmatory clinical trial results and is mandatory in most cases. The purpose of subgroup analysis is to assess the consistency (heterogeneity) of the treatment effect in subgroups of patients identified based on such characteristics as demographics, stage and severity of the underlying disease, presence of a certain genetic mutation, etc. However, existing methodological issues (the problem of multiple comparisons, detection of differences between subgroups by chance alone, etc.) make it difficult to carry out the analysis and often lead to controversial conclusions. The aim of  the study was to analyse and summarise foreign regulatory approaches to subgroup analysis in confirmatory clinical trials, and to elaborate science-based requirements for subgroup analysis and interpretation of the results by clinical trial sponsors and experts when assessing the risk-benefit ratio of medicinal products for the purpose of their authorisation in Russia and the  Eurasian Economic Union. This paper discusses the objectives of subgroup  analysis and statistical approaches to its performance, provides relevant examples of such analysis from regulatory practice. It describes approaches to interpretation of subgroup analysis depending on the presence/absence of evidence supporting the primary hypothesis of the study, the nature of the experimental medicinal product’s heterogeneous effects in the  subgroups, and selection of the subgroups. The paper highlights areas of concern in subgroup analysis, potential controversies in interpretation of the  obtained results, and regulatory expectations. The recommendations  presented in the paper can be used by experts in the assessment of the risk-benefit ratio, as well as by medicine developers in the preparation of clinical trial protocols and reports. 

About the Authors

O. I. Basova
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation

Olga I. Basova 

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation 



I. V. Lysikova
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation

Irina V. Lysikova, Cand. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation 



O. Yu. Ivanova
Scientific Centre for Expert Evaluation of Medicinal Products
Russian Federation

Olga Yu. Ivanova 

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation 



References

1. Alosh М, Fritsch К, Huque M, Mahjoob K, Pennello G, Rothmann M, et al. Statistical considerations on subgroup analysis in clinical trials. Stat Biopharm Res. 2015;7(4):286–303. https://doi.org/10.1080/19466315.2015.1077726

2. Dane A, Spencer A, Rosenkranz G, Lipkovich I, Parke T, PSI/EFSPI Working Group on Subgroup Analysis. Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis. Pharm Stat.2019;18(2):126–39. https://doi.org/10.1002/pst.1919

3. Millen BA, Dmitrienko A, Ruberg S, Shen L. A statistical framework for decision making in confirmatory multipopulation tailoring clinical trials. Drug Inf J. 2012;46(6):647–56. https://doi.org/10.1177/0092861512454116

4. Jones HE, Ohlssen DI, Neuenschwander B, Racine A, Branson M. Bayesian models for subgroup analysis in clinical trials. Clin Trials. 2011;8(2):129–43. https://doi.org/10.1177/1740774510396933

5. Simon R. Bayesian subset analysis: application to studying treatment-by-gender interactions. Stat Med. 2002;21(19):2909–16. https://doi.org/10.1002/sim.1295

6. Kahan BC, Jairath V, Doré CJ, Morris TP. The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials. 2014;15:139. https://doi.org/10.1186/1745-6215-15-139

7. Ting N. Statistical interactions in a clinical trial. Ther Innov Regul Sci. 2018;52(1):14–21. https://doi.org/10.1177/2168479017716491

8. Dmitrienko A, Millen B, Lipkovich I. Multiplicity considerations in subgroup analysis. Stat Med. 2017;36(28):4446–54. https://doi.org/10.1002/sim.7416

9. Mahaffey KW, Wojdyla DM, Carroll K, Becker RC, Storey RF, Angiolillo DJ, et al. Ticagrelor compared with clopidogrel by geographic region in the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2011;124(5):544–54. https://doi.org/10.1161/circulationaha.111.047498

10. Schneider L. A resurrection of aducanumab for Alzheimer’s disease. Lancet Neurol. 2020;19(2):111–2. https://doi.org/10.1016/s1474-4422(19)30480-6

11. Carroll J. In a stunning turnaround, Biogen says that aducanumab does work for Alzheimer’s — but data mining incites controversy and questions. Endpointsnews. 2019. October 22. https://endpts.com/ina-stunning-turnaround-biogen-says-that-aducanumab-does-workfor-alzheimers-and-theyre-prepping-a-pitch-to-the-fda/

12. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, et al. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961–72. https://doi.org/10.1056/nejmoa0804626

13. Pocock SJ, Stone GW. The primary outcome fails — what next? N Engl J Med. 2016;375(9):861–70. https://doi.org/10.1056/nejmra1510064

14. Stone GW, Sabik JF, Serruys PW, Simonton CA, Généreux P, Puskas J, et al. Everolimus-eluting stents or bypass surgery for left main coronary artery disease. N Engl J Med. 2016;375(23):2223–35. https://doi.org/10.1056/nejmoa1610227

15. Fornell D. EXCEL trial authors say european surgery society claims of bad science are groundless. DAIC. 2020. January 2. https://www.dicardiology.com/content/excel-trial-authors-say- european-surgerysociety-claims-bad-science-are-groundless

16. O’Riordan M. Former EXCEL investigator alleges trial manipulation, prompting vehement denials. TCTMD. 2019. October 7. https://www.tctmd.com/news/former-excel-investigator-allegestrial-manipulation-prompting-vehement-denials


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For citations:


Basova O.I., Lysikova I.V., Ivanova O.Yu. Specific Aspects and Significance of Subgroup Assessment in Confirmatory Clinical Trials. The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2021;11(2):81-93. (In Russ.) https://doi.org/10.30895/1991-2919-2021-11-2-81-93

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ISSN 3034-3062 (Print)
ISSN 3034-3453 (Online)