1. Adaptive ClinicalTrials –WhenTiming is Everything
Presentation by Esther Cho
Course PHA 661 American Pharmaceutical Industry
Professor Donald Orloski – Fall 2013
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2. 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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3. What is Adaptive
ClinicalTrial 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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4. 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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5. AdaptiveTrial Design: Seamless
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 “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]

6. 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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7. 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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8. References
1. 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.
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