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Research and Reporting Methods |

Genomic Alteration–Driven Clinical Trial Designs in OncologyGenomic Alteration–Driven Clinical Trial Designs in Oncology

Richard Simon, DSc
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 24 May 2016.


From the National Cancer Institute, Rockville, Maryland.

Disclosures: None disclosed. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2413.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

Requests for Single Reprints: Richard Simon, DSc, Associate Director, Division of Cancer Treatment & Diagnosis, Biometric Research Program, National Cancer Institute, 9609 Medical Center Drive, Rockville, MD 20892-9735; e-mail, rsimon@nih.gov.

Author Contributions: Conception and design: R. Simon.

Analysis and interpretation of the data: R. Simon.

Drafting of the article: R. Simon.

Critical revision of the article for important intellectual content: R. Simon.

Final approval of the article: R. Simon.

Statistical expertise: R. Simon.


Ann Intern Med. 2016;165(4):270-278. doi:10.7326/M15-2413
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The established molecular heterogeneity of human cancers necessitates the development of new paradigms to serve as a reliable basis for precision medicine. The assumptions underlying some of the conventional approaches to clinical trial design and analysis are no longer appropriate because of the molecular heterogeneity of tumors of a given primary site. This article reviews some clinical trial designs that have been actively applied in the codevelopment of therapeutics and predictive biomarkers to inform their use in oncology. These include the enrichment design, the basket design, and the umbrella design. Oncology leads most other therapeutic areas in development of personalized or precision medicine. Personalized or precision medicine is practiced daily in oncology on the basis of tumor genomics and may evolve in other therapeutic areas as it has in oncology, rather than according to inherited polymorphisms as so often imagined. Consequently, some of the clinical trial designs described here may serve as a possible blueprint for therapeutic development in fields other than oncology.

Figures

Grahic Jump Location
Figure 1.

Traditional 2-stage design for a single-group phase 2 clinical trial.

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Grahic Jump Location
Figure 3.

Randomized basket design.

Color denotes primary site/histologic type of tumor, and shape represents genomic mutation type. See Figure 2 for legend.

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Grahic Jump Location
Figure 4.

Phase 3 enrichment design.

Color denotes primary site/histologic type of tumor, and shape represents genomic mutation type. See Figure 2 for legend.

Grahic Jump Location
Grahic Jump Location
Figure 5.

Phase 3 umbrella design.

Color denotes primary site/histologic type of tumor, and shape represents genomic mutation type. See Figure 2 for legend.

Grahic Jump Location

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