Abstract
The pharma industry is gradually coming to realize that the classically
structured clinical trial does not offer enough flexibility to make use of
continuously emerging knowledge that is generated as the trial progresses.
This report is a comprehensive assessment of the benefits, challenges, and
accumulated industry experience with regard to adaptive clinical trials.
It includes:
- A critique of the structural, conceptual, and ethical issues inherent in
the traditional clinical trial.
- An in-depth review, based on actual case studies (e.g., Napo, Genaera,
Pfizer, Lilly, Millennium, and various academic institutions) of the use of
adaptive and Bayesian approaches in Phases I, II, and III
- An assessment of various hybrid and seamless designs in which the line
between trial stages is blurred
- Evolving regulatory positions of FDA, EMEA, and ICH on adaptive designs;
industry response and initiatives
- A review of specialized software vendors (e.g., Cytel, Tourtellotte,
Pharsight, CTriSoft) and their applications that have emerged to support
adaptive designs.
- A CHI Insight Pharma survey of the views and experiences of individuals
involved with adaptive designs
- Three future scenarios for the integration of adaptive designs in clinical
trials by 2015: (1) United States Leads the Way, (2) Globally Integrated
Midphase Revamping, and (3) the Late Phoenix Scenario
- Roundtable interviews with senior executives in industry and consulting
who bring decades of combined experience in adaptive and Bayesian clinical
trial designs
Unacceptable levels of attrition in the clinical stage of development are
driving profound changes in the architecture, design, and analysis of clinical
trials. The majority of respondents to our survey said that reduction in
patient numbers, less exposure to study drug, and drops in overall trial
duration were key points in favor of adaptive designs; however, a majority
also had specific concerns with adaptive trials\concerns that involved
methodological, logistical, and regulatory uncertainties:
Methodological: Will adaptive and/or "seamless" designs lead the
sponsor to erroneous conclusions if used in Phase II and (in particular) in
pivotal trials?
Logistical: Can such trials be fully kept under control without major
organizational change/expansion and/or increased dependency on outside
statistical and monitoring advice?
Regulatory: Will regulatory authorities (FDA, EMEA) accept adaptive
designs and- more importantly- will they accept the trial sponsor' s
interpretation of the results of such trials?
Adaptive Clinical Trials: Innovations in Trial Design, Management, and
Analysis examines the key challenges involved in adaptive trials, such as:
- Staff training requirements
- EDC to enable near-real-time capture, validation, and analysis of
trial-emergent data
- Working with Data Monitoring Committees (DMC)
- Ways in which adaptive modifications \ e.g., dropping and replacing a
dosage arm \ can have ripple effects on a project' s critical path
- The challenges of prognosis, analysis and interpretation
Adaptive trials are emerging as a solution to lengthening development
timelines, runaway costs, and overall lack of predictivity in the drug
development process. Drug companies, regulators, and academic investigators
have shown a willingness to explore adaptive and Bayesian options as part of a
general revamping of the drug development process. We predict that increasing
guidance and endorsement from regulatory bodies will lead the industry to
fully embrace adaptive trials by 2015.
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