Bridging Study versus Prespecified Regions Nested in Global Trials

Abstract

Ethnic sensitivity to drug treatment has received worldwide attention since the development of the ICH E-5 guidance. The concept of a bridging study was first introduced in the 1990s. The informativeness of statistical inference from small bridging clinical trials with a study size as small as 40 patients is often questionable. In addition, statistical metrics for evaluating the consistency of region-specific treatment effects to global treatment effects have been controversial. Since 1998, the evolution of the approaches to ethnic sensitivity of a drug effect has ranged from criteria to accept foreign clinical data to partnership in harmonization for global drug development.

We consider and compare an indirect method and a direct method to evaluate the treatment effect in a bridging study by borrowing the strength of effect observed in the foreign trial. When a multiregional clinical trial is the drug development approach, we consider a prospectively planned evaluation of global treatment effect without sacrificing the opportunity to also evaluate a prespecified region-specific treatment effect that has a reasonable number of patients and under the same common protocol.

We discuss the similarities and the differences between the bridging study problem and the noninferiority study problem. Concerns with extrapolating the results of the study to other regions are raised in regard to the bridging approach that prompts consideration of streamlining clinical trials. When the intrinsic versus extrinsic factors may not be well understood, one approach to addressing heterogeneity issues is a two-stage adaptive test that not only builds in an additional region-specific treatment effect hypothesis, but also addresses potential ethnic sensitivity to overall multiregional treatment effects. The two-stage adaptive test provides flexibility to assess variance using the blinded data at the late stage of the trial, and thus has the potential to withdraw the region-specific hypothesis due to large variability in the clinical endpoint, eliminating an uninformative region-specific effect assessment.

Keywords

Nested region Noninferiority Pharmacogenomics Subgroup Two-stage adaptive test

Get full access to this article

View all access options for this article.

References

International Conference on Harmonization. Ethnic Factors in the Acceptability of Foreign Clinical Data (ICH E-5). CPMP/ICH/289/95. London: European Agency for the Evaluation of Medicinal Products; 1998.

Chern

. Acceptability of foreign clinical data among Asian countries. Presented at the PhRMA workshop Challenges and Opportunities: Multi-Regional Clinical Trials, Bethesda, Maryland, October 29–30, 2007.

Wang

O'Neill

Hung

HMJ

. Approaches to evaluation of treatment effect in randomized clinical trials with genomic subset. Pharm Stat. 2007;6:227–244.

Hsiao

Chern

Chen

Lin

. Algorithm for evaluation of bridging studies in Taiwan. Drug Inf J. 2003;37:123(s)–128(s).

Hsiao

Wang

Hsu

Liu

. An overview of bridging evaluations in Taiwan. Int Chinese Stat Assoc Bull. 2005;(January):29–36.

Inglefinger

Mosteller

Thibodeau

Ware

. Biostatistics in Clinical Medicine, 2nd ed. New York: Macmillan; 1987.

Hasselblad

Kong

. Statistical methods for comparison to placebo in active-control trials. Drug Inf J. 2001;35:435–449.

Wang

Hung

HMJ

Tsong

Utility and pitfalls of some statistical methods in active-controlled clinical trials. Control Clin Trials. 2002;23:15–28.

Snapinn

. Alternatives for discounting in the analysis of noninferiority trials. J Biopharm Stat. 2004;14:263–273.

10.

US Food and Drug Administration. Critical Path opportunities list. March 2006. Available at: http://www.fda.gov/oc/initiatives/criticalpath/.

11.

International Conference on Harmonization. Guideline E-5. Ethnic factors in the acceptability of foreign clinical data: questions and answers. CPMP/ICH/5746/03. 2006. Available at: http://www.ich.org/cache/compo/276–254-1.html.

12.

Wang

. Genomic biomarker derived therapeutic effect in pharmacogenomics clinical trials: a biostatistics view of personalized medicine. Taiwan Clin Trials. 2006;4:57–66.

13.

Wedel

DeMets

Deedwaria

Challenges of subgroup analyses in multinational clinical trials: experiences from the MERIT-HF trial. Am Heart J. 2001;142(3):502–511.

14.

Paez

Janne

Lee

EGFR mutations in lung cancer, correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500.

15.

Fukuoka

Yano

Glaccone

Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003;21:2297–2246.

16.

Wang

. Biomarker as a classifier in pharmacogenomics clinical trials: a tribute to 30th anniversary of Pharmaceutical Statistician Institute (PSI). Pharm Stat. 2007;6:283–296.

17.

Hsiao

Liu

. A two-stage design for bridging studies. J Biopharm Stat. 2005;15(1): 75–83.