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Adaptive Clinical Trials – When Timing is EverythingPresentation by Esther ChoCourse PHA 661 American Pharmaceutical IndustryProfessor Donald Orloski – Fall 2013

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Presentation Outline

I. What is Adaptive Clinical Trial Design? Definition Traditional vs. Adaptive Seamless Design

II. Case Study: Simponi

III. Trends

IV. References

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What is Adaptive Clinical Trial Design?

Adaptive randomization design

Group sequential design

Sample size re-estimation design

Drop-the-loser design

Adaptive dose-finding design

Adaptive treatment-switching design

Hypothesis-adaptive design

Adaptive seamless phase II/III design

Multi-adaptive design

FDA: “a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim) from subjects in the study” [1]

The purpose is to make clinical trials more flexible, efficient and fast…without undermining its validity and integrity. [2]

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Traditional vs. Adaptive Accept/reject null hypothesis in

a well-defined population (no modification without amendments)

Not more than two or three study arms

Standard Phase I-IV phases with clearly separated Phase II and III and allows for little learning

Standard statistical methods

Pre-specified modifications are allowed based on interim analysis

Many treatment arms

Allow early detection and early stop if warranted (sometimes referred to as Phase II/III combined)

Different set of risks and decision points than conventional/ Bayesian statistical methods

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Adaptive Trial Design: Seamless

“Combines two trials into one single trial with longer duration, and which in a single trial addresses objectives that are normally achieved through separate trials”

No waiting between the two phases and lengthy decision process

Reduce cost by earlier elimination of not useful treatment arms

[3]

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Case Study: PURSUIT-SC trial program

Adaptive seamless design

71% of the 1,065 patients initially involved in the study were streamed through to the Phase 3 dose-confirming stage [5]

Phase II/III: 6 Weeks, Four Treatment Arms

Safety profile/maintenance study: 54 weeks

Clinical Response, remission and healing observed, improved QOL [6]

FDA approved Simponi in May 2013 Janssen Biotech, Inc. – Horsham,

Penn. (Johnson & Johnson) This injection treats adults with

moderate to severe ulcerative colitis. Chronic disease that affects about

620,000 Americans Causes inflammation and ulcers in the

inner lining of the large intestine and is one of two main forms of chronic inflammatory bowel disease [4]

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Trends According to Thomson Reuters, compound annual growth rate over last 10

yrs = 19% (38% over last 2 years). Mostly phase I, II or I/II cancer trials, no predominant indication for phase II/III or III adaptive trials [7]

In a study conducted by Tufts, one global top 20 drug development company reports saving more than $70 million each year through various adaptive techniques. [8]

PhRMA letter to FDA includes this design type as part of the alternative approval pathways to expedite development of much needed new antibiotics. [9]

Logistical considerations including flexible sample sizes, informed consent modifications, sufficient interaction with regulatory authorities and trial integrity issues must be factored in. [10]

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References1. Guidance for Industry: Adaptive design clinical trials for drugs and biologics. U.S. Food and Drug Administration Web site.

http://www.fda.gov/downloads/Drugs/.../Guidances/ucm201790.pdf. Published February 2010. Accessed October 27, 2013.2. Mahajan R, Gupta K. Adaptive design clinical trials: methodology, challenges and prospect. Indian J Pharmacol. 2010 August,

42(4): 201-207. doi: 10.4103/0253-7613.68417.3. Sietsema W, Ulker A, et al. An introduction to adaptive clinical trial designs. Regulatory Rapporteur.

http://www.topra.org/sites/default/files/regrapart/1/3225/focus1.pdf. Published October 2010. Accessed October 27, 2013.4. US Food & Drug Administration. FDA approves Simponi to treat ulcerative colitis.

http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm352383.htm. Published May 2013. Accessed October 27, 2013.

5. PURSUIT boosts adaptive clinical trial profile. Aptiv Solutions Web site. http://www.aptivsolutions.com/blog/2013/10/pursuit-boosts-adaptive-clinical-trial-profile/. Published 2013. Accessed October 27, 2013.

6. A special meeting review edition: Highlights in Crohn’s disease and Ulcerative Colitis. Digestive Disease Week 2012. A Phase II/III Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety and Efficacy of Subcutaneous Golimumab Induction Therapy in Patients with Moderately to Severely Active Ulcerative Colitis: PURSUIT-SC; May 19-22, 2012; San Diego, CA. http://www.gastroenterologyandhepatology.net/files/2013/02/gh0812_sup51.pdf. Gastroenterology & Hepatology. Published 2012. Accessed November 4, 2013.

7. Gauging adaptive designs in clinical trials. Thomson Reuters Web site. http://lsconnect.thomsonreuters.com/gauging-adaptive-design-in-clinical-trials/. Published 2013. Accessed November 2, 2013.

8. R&D senior leadership brief: The adoption and impact of adaptive trial designs. Tufts University Web site. http://csdd.beehivemedia.com/files/TuftsCSDDBrief1final_new.pdf. Published 2013. Accessed October 27, 2013.

9. Pharmaceutical Research and Manufacturers of America. Letter to Division of Dockets Management Food and Drug Administration. http://phrma.org/sites/default/files/pdf/phrmacommentsonalternativeapprovalpathwayfda-2012-n-1248final.pdf. Published 2013. Accessed October 27, 2013.

10. Chokekijchai S. Talk presented at: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Advanced Workshop Review on Drug Development in Clinical Trials; February 2-6, 2009; Bangkok, Thailand. http://www.ich.org/fileadmin/Public_Web_Site/Training/GCG_-_Endorsed_Training_Events/Advanced_workshop__Rev_of_Drug_Dev_in_CT/Day_4/7-Adaptive_design.pdf. Accessed October 27, 2013.