Statistical Considerations on Subgroup Analysis in Clinical Trials

Abstract

The objective of subgroup analysis of a clinical trial is to investigate consistency or heterogeneity of the treatment effect across subgroups, defined based on background characteristics. As such, subgroup analysis plays an essential role in the interpretation of the clinical trial findings. Consistency of treatment effect across trial subgroups indicates that the average treatment effect is in general applicable regardless of the specific background characteristics. Substantial heterogeneity in treatment effect may be indicative that treatment benefit pertains only to a subset of the population. However, heterogeneity in the observed treatment effect across subgroups can arise due to chance as a result of partitioning the population into several subgroups. Furthermore, as it is known, clinical trials are generally not powered for detecting heterogeneity, thus statistical tests may miss detection of existing heterogeneity due to low power. In this article, we aim to: (i) outline the major issues underlying subgroup analysis in clinical trials and provide general statistical guidance for interpretation of its findings, (ii) provide statistical perspectives on the design and analysis of a clinical trial that aims for establishing efficacy in a targeted subgroup along with that of its overall population, and (iii) highlight some of the underlying assumptions and issues relevant to Bayesian subgroup analysis, subgroup considerations for noninferiority trials, personalized medicine, subgroup misclassification, and finally, subgroup analysis for safety assessment.

Key Words:

• Bayesian subgroup analysis
• Chance findings
• Enrichment
• Heterogeneity
• Personalized medicine
• Targeted and complementary subgroups

Acknowledgments

The authors thank Drs. Olga Marchenko and Lisa LaVange, the associate editors for this special issue of Statistics in Biopharmaceutical Research, for inviting us to submit our manuscript to this issue. The authors also thank Dr. José Pinheiro, the journal editor, and the two anonymous referees for their comments that helped improve the presentation of the materials. The authors are also thankful to Drs. Lisa LaVange, Edward Nevius, Gregory Campbell, and Robert O’Neill for their support and encouragement through the life of this project. The authors’ thanks also go to their former colleague and working group member Todd Sahlroot, who contributed greatly to this project prior to his retirement from the FDA in the Spring of 2013. Finally, the authors thank their statistical colleagues at the FDA who made several important comments on the original draft that helped them improve the presentation and the flow of the materials.

Additional information

Notes on contributors

Mohamed Alosh

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Kathleen Fritsch

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Mohammad Huque

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Kooros Mahjoob

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Gene Pennello

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Mark Rothmann

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Estelle Russek-Cohen

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Fraser Smith

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Stephen Wilson

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.

Lilly Yue

Mohamed Alosh (E-mail: [email protected]), Kathleen Fritsch (E-mail: [email protected]), Stephen Wilson (E-mail: [email protected]), Division of Biometrics III, OB, OTS, CDER; Mohammad Huque (E-mail: [email protected]), Office of Biostatistics, OTS, CDER; Fraser Smith (E-mail: [email protected]), Division of Biometrics IV, OB, OTS, CDER; Kooros Mahjoob (E-mail: [email protected]), Division of Biometrics I, OB, OTS, CDER; Gene Pennello (E-mail: [email protected]), Lilly Yue (E-mail: [email protected]), Division of Biostatistics, OSB, CDRH; Mark Rothmann (E-mail: [email protected]), Division of Biometrics II, OB, OTS, CDER; Estelle Russek-Cohen (E-mail: [email protected]), Division of Biostatistcs, OBE, CDER, Office of Biostatistics, Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993.