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Reducing Risk and Improving Efficacy of Clinical Trials: the Adaptive Design
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Reducing Risk and Improving Efficacy of Clinical Trials: the Adaptive Design

Surabhi Dangi-Garimella, PhD
However, adaptive designs present  an upfront cost. Says Bolognese, “To evaluate the use or material advantage of an adaptive design over traditional design creates upfront work—

more time in advance planning, increased use of resources (including recruiting statisticians and clinicians to help with the design), and increased expenditure.

All potential adaptations need to be predefined and the statistical performance characteristics of the adaptive design, if chosen, need to be documented. The goal is to more than offset this increased upfront cost with greater later cost savings.” Aptiv Solutions, a part of the ICON group that provides development solutions to the pharmaceutical and biopharmaceutical industry, recently announced a collaboration with Novartis, Janssen Pharmaceuticals, and Eli Lilly called the ADDPLAN DF Consortium. The goals are to develop statistical methods to design innovative dosefinding clinical trials with an emphasis on adaptive designs, and to develop software based on the data that emerge for the design, planning, and analysis of dose- finding trials.16

Drawbacks of the Adaptive Design

Although the adaptive trial design could bring about a substantive change in trial performance, there are some associated negatives. One is that the trial design cannot be easily adapted to a small scale, to evaluate less prevalent cancers, for instance. Additionally, conducting these trials is logistically difficult, especially in a scenario where multiple drugs are to be administered.17

In its industry guide for adaptive clinical trial design, the FDA introduced several concerns about the adaptive design, the most important being:

• design, analysis, or conduct flaws that can introduce bias and a Type I error (the false conclusion that the treatment is effective)

• despite control of Type I error, the adaptation process may provide positive study results that are difficult to interpret.18

The Regulatory Aspect

According to the guidelines suggested by the FDA and the European Monitoring Agency, trial sponsors that use adaptive designs in late-phase clinical trials should employ external, independent

Data Monitoring Committees (DMCs).19 Says Bolognese, “There could always be a perception of a potential for bias without a DMC external to the study sponsor. So regulatory agencies want that the sponsors be blinded to the results of interim analysis. Unblinded information is made available to the DMCs, who then make their recommendations.”

A DMCs typical function is conducting periodic review of interim study results to ensure patient safety, applying decision rules for adaptation, including early stoppage for futility or success, making recommendations for dose-regimen change, and/or sample size adjustment.19

Bolognese believes the regulatory agencies are very receptive to adaptive designs for early-phase trials, and are more cautious about late-stage adaptations, since phase 3 trials need a wellunderstood design and they need to be well controlled with defined statistical properties.

Collaborations to Promote Biomarker Implementation and the Adaptive Design

Several collaborative efforts have been initiated, within the Unites States as well as globally, to promote the integration of biomarkers into clinical trials. The Cancer Biomarkers Collaborative

(CBC) is a product of a partnership between the FDA, the National Cancer Institute, and the American Association for Cancer Research. More than 120 experts from various areas of cancer biomarker research constitute several different CBC committees.20 The Consortium draws input from national and international experts in academia, diagnostic and pharmaceutical industries, government agencies, regulatory bodies, and patient advocates, with the overall goal of improving cancer treatment.

The Foundation for the National Institutes of Health (NIH) launched the Biomarker Consortium in 2006; it is a publicprivate biomedical research partnership that includes the NIH, the FDA, CMS, and the Pharmaceutical Research and Manufacturers of America, to name a few members. The objective of this group is to identify, develop, and qualify potential high-impact biomarkers for diagnosis, predicting response, or improving clinical practice. The Consortium also aims to generate information that can aid with regulatory decision making and help the broad scientific community in general.21

Considering the potential risks and benefits associated with integrating biomarkers into phase 2 and 3 clinical oncology trials, experts from 3 global clinical trial organizations assembled a working committee to provide a new approach for achieving seamless integration of biomarkers into trials. The working group, which included members from the EORTC PathoBiology group, NCI, and the National Cancer Research Institute, also aimed at providing investigators with useful resources to assist in protocol development of biomarker-driven trials.14

Together, the panel identified the various challenges associated with biomarker integration into trial design (such as risks to patient safety, operational risks, and risks to biomarker development), and provided recommendations that could help surmount the challenges.14 The effort is under way: industry and the FDA are working together to economize the drug development process and to reduce the time-to-approval for new drug entities. The successful incorporation of biomarkers into mainstream trial design, by using means such as companion

diagnostic tests, could go a long way toward identifying the right population of patients for a particular drug candidate and also in evaluating patient response to a drug. This could help decide

the fate of a drug early on in a trial, instead of waiting to analyze outcomes at the end of phase 3, as is most commonly observed with the traditional study design.

References

1. Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst. 2012;104(8):568-569.

2. Guidance for industry: adaptive design clinical trials for drugs and biologics. FDA website. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf. Published February 2010. Accessed March 27, 2013.

3. What is adaptive design? Berry Consultants website. http://www.berryconsultants.com/adaptive-designs/. Accessed May 13, 2014.

4. Ha K, Wexler J. Adaptive clinical trials not an industry fad but new drug development benchmark – experts. INC Research Insight website. http://www.incresearch.com/news/InTheNews/
Adaptive-Clinical-Trials-Biopharm-Insight.pdf. Accessed May 13, 2014.

5. Berry Consultants website. http://www.berryconsultants.com/. Accessed May 13, 2014.

6. Cytel website. http://www.cytel.com/. Accessed May 21, 2014.

7. Chustecka Z. Enzalutamide first-line in prostate cancer: trial stopped. Medscape. http://www.medscape.com/viewarticle/812955. Published October 22, 2013. Accessed May 14, 2014.

8. Levitan D. Ibrutinib CLL trial stopped early. cancerNetwork website. http://www.cancernetwork.com/hematologic-malignancies/ibrutinibcll-trial-stopped-early. Published January 22, 2014.
Accessed May 14, 2014.

9. Droppert P. J&J prostate cancer trial shouldn’t have been stopped early. Xconomy website. http://www.xconomy.com/national/2012/06/03/jj-prostate-cancer-trial-shouldnthave-been-stopped-early/. Accessed May 13, 2014.

10. Biomarkers Definitions Working Group. Biomarkers and surrogate end points: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.

11. Groves E, Hill J, Ung C. Integration of Molecular Biomarkers into Clinical Development. http://www.quintiles.com/library/white-papers/integration-of-molecular-biomarkers-into-clinical-development/. Published March 29, 2010. Accessed May 14, 2014.

12. Wason J, Marshall A, Dunn J, Stein RC, Stallard N. Adaptive designs for clinical trials assessing biomarker-guided treatment strategies. Br J Cancer. 2014;110:1950-1957.

13. Caffrey, MK. Mutations that drive lung cancer also driving frontiers of treatment. Am Manag Care 2014;20(7):SP214-SP215.

14. Hall JA, Salgado R, Lively T, Sweep F, Schuh A. A risk-management approach for effective integration of biomarkers in clinical trials: perspectives of an NCI, NCRI, and EORTC working group. Lancet Oncol. 2014;15(4):e184-e193.

15. Hunting, B. Taming the monster–the economic benefits of adaptive trials. Aptiv Solutions website. http://www.aptivsolutions.com/blog/adaptive-trials/2012/03/taming-the-monsterthe-economic-benefits-of-adaptive-trials/. Published March 29, 2012. Accessed May 16, 2014.

16. Novartis, Janssen Pharmaceuticals, Eli Lilly and Aptiv Solutions form a consortium to develop technologies for design and execution of adaptive dose finding trials [press release]. Reston, VA: Aptiv Solutions; February 18, 2014. http://www.aptivsolutions.com/press-release/2014/02/novartis-janssen-pharmaceuticals-eli-lilly-andaptiv-solutions-form-a-consortium-to-developtechnologies-for-design-and-execution-of-adaptive-dose-finding-trials/.

17. Rollins G. A new paradigm for companion diagnostics in cancer: will new clinical trial methods speed drug, biomarker use? Clinical Laboratory News. 2013;39(1):1-4. http://www.aacc.
org/publications/cln/2013/january/Pages/Paradigm.aspx. Accessed May 19, 2014.

18. Guidance for industry: adaptive design clinical trials for drugs and biologics. FDA website. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf. Published February 2010. Accessed March 27, 2013.

19. Data Monitoring Committee (DMC) membership. Cytel website. http://www.cytel.com/strategic-consulting/dmc-membership. Accessed May 21, 2014.

20. AACR-FDA-NCI Cancer Biomarkers Collaborative. AACR website. http://www.aacr.org/home/scientists/working-groups--task-forces/aacr-fda-nci-cancer-biomarkers-collaborative.
aspx. Accessed May 16, 2014.

21. The Biomarkers Consortium website. http://www.biomarkersconsortium.org/whatwedo.php.Accessed May 16, 2014.
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