Both documents aim to provide guidance on the use of adaptive designs in clinical trials. The ICH E20 guideline is a draft version, and is currently under public consultation
Here's a side-by-side comparison of common topics and key differences:
Side-by-Side Comparison: ICH E20 Draft Guideline vs. FDA Guidance
| 1. Purpose and Scope |
ICH E20: Provides guidance on confirmatory clinical trials with an adaptive design within the context of its overall development program. Defines adaptive design as "a clinical trial design that allows for prospectively planned modifications to one or more aspects of the trial based on interim analysis of accumulating data from participants in the trial." Emphasizes "prospectively planned"
. Excludes unplanned modifications or changes based on external information, and routine operational monitoring . Focuses on principles for planning, conduct, analysis, and interpretation of trials to confirm efficacy and support benefit-risk assessment . While primarily for confirmatory trials, principles are relevant to all phases . |
FDA: Provides guidance to sponsors on the appropriate use of adaptive designs for clinical trials to provide evidence of effectiveness and safety of a drug or biologic
. Describes important principles for designing, conducting, and reporting results . Advises on information to submit for FDA evaluation, including Bayesian adaptive and complex trials relying on simulations . Primary focus is on adaptive designs for trials supporting drug effectiveness and safety, but concepts are useful for early-phase/exploratory trials and post-marketing commitments . Defines adaptive design as "a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial" .
| 2. Advantages and Challenges |
ICH E20:
Advantages: Provides flexibility against inaccurate assumptions
. Ethical advantages (e.g., early stopping for efficacy reduces exposure to inferior control) . Improved efficiency (e.g., increased power for a given expected sample size) . Improved understanding of treatment effects and decision-making (e.g., dose selection) . Challenges: Adds complexities and uncertainty to key principles
. Logistical difficulties in maintaining confidentiality . Risks to trial integrity . More complex and time-consuming planning and assessment . Conventional analysis methods may lead to increased Type I error and biased estimates . May provide less information about safety . Not beneficial in all settings (e.g., fast enrollment relative to endpoint assessment) . Requires clear and compelling justification weighing advantages against uncertainties .
FDA:
Advantages: Adjusts to information not available at trial start
. Statistical efficiency (greater power or smaller expected sample size/shorter duration) . Ethical considerations (e.g., early stopping for futility reduces patient exposure to ineffective treatment) . Improved understanding of drug effects (e.g., adaptive enrichment, adaptive dose selection) . Acceptability to stakeholders (e.g., sponsors willing to commit, patients willing to enroll in RAR trials) . Limitations: Requires specific analytical methods to avoid increasing erroneous conclusions and bias
. Methods may not be readily available for complex designs, requiring simulations . Efficiency gains in some respects may be offset by losses in others (e.g., increased maximum sample size, longer lead times) . Logistical challenges in trial conduct and integrity (e.g., limiting access to interim results, timely high-quality data) . Limited utility in certain settings (e.g., minimum safety sample size, long outcome ascertainment period) . Adaptive changes may lead to differing results before and after adaptation, challenging interpretability . |
| 3. Key Principles |
ICH E20:
Four key principles for confirmatory trials with adaptive designs: Adequacy Within the Development Program (proper design, conduct, analysis within overall program, limited complexity of adaptations at confirmatory stage)
. Adequacy of Trial Planning (pre-specification of adaptations, timing, rules, statistical methods, integrity approaches, documentation)
. Limiting the Chances of Erroneous Conclusions (controlling Type I error probability, understanding impact on safety and secondary endpoints, evaluating adequacy for trial objectives)
. Reliability of Estimation (reliable and unbiased treatment effect estimates, accurate measures of uncertainty, evaluation of bias and variability, reliability of interim estimates for adaptation decisions)
. Maintenance of Trial Integrity (limiting knowledge of unblinded data, use of independent IDMC, confidentiality agreements, minimizing inferred information from adaptations, documentation of processes)
. |
FDA:
Four key principles for trials providing substantial evidence of effectiveness: Controlling the Chance of Erroneous Conclusions (assessing probability of incorrect conclusions, addressing Type I error inflation due to multiple tests or adaptive features, use of simulations)
. Estimating Treatment Effects (reliable estimates for benefit-risk, addressing bias in estimates and confidence intervals, using adjusted methods when available)
. Trial Planning (complete pre-specification of design details, timing, type, statistical methods, adaptation algorithm; flexibility for deviations from anticipated algorithm with appropriate methods)
. Maintaining Trial Conduct and Integrity (limiting access to comparative interim results, use of independent personnel like DMC, planning to avoid issues from knowledge of accumulating data, documentation of access control)
. |
| 4. Types of Adaptations |
ICH E20:
Discusses Early Trial Stopping (efficacy or futility, group sequential designs, stopping boundaries, impact on safety/secondary endpoints)
. Sample Size Adaptation (based on nuisance parameters or interim treatment effect estimates, blinded vs unblinded, Type I error control, bias, maintaining integrity)
. Population Selection (targeted subpopulations, enrollment restriction, combining data, Type I error control, bias, scientific rationale)
. Treatment Selection (different doses/drugs, interim selection, combining data, Type I error control, bias)
. Adaptation to Participant Allocation (Response-adaptive randomization, covariate-adaptive, challenges with time trends, integrity)
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FDA:
Discusses Group Sequential Designs (interim analyses, stopping for efficacy/futility, Type I error control, binding vs non-binding rules, impact on safety/secondary endpoints, adjusted estimates)
. Adaptations to the Sample Size (based on nuisance parameters with/without treatment assignment, or comparative interim results, Type I error control, bias, trial integrity)
. Adaptations to the Patient Population (e.g., Adaptive Enrichment) (modifications based on comparative interim results, hypothesis tests in multiple populations, multiplicity, scientific rationale, diagnostic devices)
. Adaptations to Treatment Arm Selection (adding/terminating arms, dose-ranging, seamless designs, platform trials, Type I error control)
. Adaptations to Patient Allocation (covariate-adaptive and response-adaptive randomization, Type I error, predictability, short-term outcomes)
. Adaptations to Endpoint Selection (modification to primary endpoint choice, prespecified rules, multiplicity)
. Adaptations to Multiple Design Features (combining features, complexity, simulations often critical)
.
| 5. Special Topics and Considerations |
ICH E20:
Further Considerations on Data Monitoring (IDMC expertise, access to unblinded data, charter, independent statistical group, sponsor access)
. Planning, Conducting, and Reporting Simulation Studies (objectives, designs/analysis options, key operating characteristics, scenarios, implementation details, comprehensive report)
. Adaptive Designs Using Bayesian Methods (ICH E9 principles, informing adaptations, borrowing external information, prior distribution, false positive control, simulations, sensitivity analyses)
. Adaptive Designs in Time-to-Event Settings (number of events vs participants, follow-up time, independence assumption, Type I error control, longitudinal outcomes)
. Adaptive Designs in Exploratory Trials (relevance of principles, more adaptations, reliable decision-making, sponsor role in monitoring, safety)
. Operational Considerations (maintaining integrity, informed consent, randomization systems, drug supply, data quality/timeliness)
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FDA:
Simulations in Adaptive Design Planning (critical role, estimating operating characteristics, Type I error probability, nuisance parameters, number of iterations, precision, different random seeds)
. Bayesian Adaptive Designs (various uses, frequentist vs Bayesian inference, informative priors, simulations)
. Adaptations in Time-to-Event Settings (number of events vs subjects, follow-up, use of surrogate/intermediate outcomes)
. Adaptations Based on an Intermediate Endpoint (surrogate/intermediate endpoints, correlation with primary, Type I error inflation, safeguards)
. Secondary Endpoints (Type I error inflation, biased estimation, adjustment methods)
. Safety Considerations (adaptations on safety endpoints, sufficient safety information, minimum sample size/exposure, risk of escalating doses)
. Adaptive Design in Early-Phase Exploratory Trials (usefulness, less rigorous expectations, risk of erroneous conclusions)
. Unplanned Design Changes Based on Comparative Interim Results (discouraged without FDA discussion, difficulty in Type I error control)
. Design Changes Based on Information From a Source External to the Trial (acceptable, do not affect validity, challenging to ensure solely external)
. |
| 6. Documentation |
ICH E20:
Prior to conducting: Rationale (clinical and statistical), description of adaptations (aspects, timing, rule, estimands), statistical analysis methods (interim, primary/secondary, sensitivity), implementation details (who does what, committee roles), steps to maintain confidentiality/integrity (information transfer, access control, records), operating characteristics (simulation report if critical)
. Core elements in protocol, other details in separate documents (e.g., IDMC charter), details of adaptation rule may be restricted . After completion (marketing application): All prospective plans, information on how design was implemented (actual timing, conduct variations, interim results, adaptation decisions, deviations), compliance with data access/integrity processes, IDMC deliberations records, appropriate reporting of results
. |
FDA:
Prior to conducting: Rationale, detailed description of adaptation plan (number/timing of analyses, modifications, rule), roles of bodies (DMC/adaptation committee), prespecification of statistical methods (interim/final, software, code), evaluation/discussion of operating characteristics (Type I error, power, sample size, bias, coverage - analytical or simulation)
. Detailed simulation report if primary technique (trial description, examples, parameter configurations, iterations, results, code, summary) . Comprehensive data access plan (who performs, who has access, control, decisions, dissemination, compliance evaluation, meeting minutes) . Can be in protocol or separate documents . Evaluating and Reporting a Completed Trial: All prospective plans, committee charters, supporting documentation, compliance with planned rule and data access, deliberation records, interim analysis results, appropriate reporting in package insert (design, adjusted estimates/cautions)
. |
| 7. Regulatory Interactions |
ICH E20:
States that the draft guideline is currently under public consultation and does not yet confirm full regulatory acceptance or supersede current regional guidance
. The final guideline will indicate key adaptive design principles and approaches for which discussion at the planning stage is particularly critical . Specific feedback is sought on principles and their impact on industry-regulatory interactions to inform finalization . Sponsors should discuss potential implications of adaptations on trial conduct with regulators at the planning stage . Documentation prior to trial initiation should align with national and regional regulatory requirements .
FDA:
Encourages sponsors to explore design options and discuss them with FDA at regulatory meetings (e.g., End-of-Phase-2, Type C)
. Increased complexity of adaptive trials may warrant earlier and more extensive interactions . FDA's role shifts from safety focus in early development to more extensive evaluation of design and analysis in later phases to ensure reliable results . SPAs for complex adaptive designs only if extensive prior discussion with FDA . FDA review considers whether design and analysis satisfy key principles (Type I error control, reliable estimation, integrity, prespecification) . FDA generally not involved in prospectively planned adaptive decision-making; this is sponsor's responsibility, often via a committee (e.g., DMC) . Meeting minutes of closed sessions and comparative interim results generally kept confidential until trial conclusion, except for safety risks . All important documentation should be submitted to FDA during design stage for feedback prior to initiation . |
| 8. Definition of Adaptive Design |
ICH E20:
"a clinical trial design that allows for prospectively planned modifications to one or more aspects of the trial based on interim analysis of accumulating data from participants in the trial."
|
FDA:
"a clinical trial design that allows for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial."
| 9. Definition of Interim Analysis |
ICH E20:
Not explicitly defined as broadly as FDA. Focuses on "sequential analyses of accumulating unblinded data with anticipated rules for stopping"
.
FDA:
"any examination of data obtained from subjects in a trial while that trial is ongoing and is not restricted to cases in which there are formal between-group comparisons." Includes baseline, safety, PK/PD, biomarker, or efficacy data
. Broader than ICH E9 definition .
| 10. "Prospectively Planned" |
ICH E20:
Means "the potential trial adaptations are pre-specified in the clinical trial protocol prior to initiation of the trial."
FDA:
Means "that the adaptation is planned and details specified before any comparative analyses of accumulating trial data are conducted. In nearly all situations, potential adaptive design modifications should be planned and described in the clinical trial protocol (and in a separate statistical analysis plan) prior to initiation of the trial."
Key Differences and Nuances:
Stage of Guidance: The most significant difference is that ICH E20 is a draft guideline currently under public consultation
, while the FDA guidance is a finalized document from November 2019 . ICH E20 explicitly states it does not supersede current regional guidance until finalized . Emphasis on "Confirmatory Trials": Both documents primarily focus on adaptive designs in confirmatory clinical trials. However, ICH E20 consistently uses the phrase "confirmatory clinical trials" throughout its document, defining its scope around them
. The FDA guidance states its "primary focus...is on adaptive designs for clinical trials intended to support the effectiveness and safety of drugs," but also acknowledges the usefulness of concepts for early-phase/exploratory trials and post-marketing commitments . Definition of Interim Analysis: The FDA guidance provides a broader definition of "interim analysis" compared to the ICH E9 definition, stating it's "any examination of data obtained from subjects in a trial while that trial is ongoing and is not restricted to cases in which there are formal between-group comparisons"
. ICH E20 uses the term more in the context of "sequential analyses of accumulating unblinded data with anticipated rules for stopping" . Handling Unplanned Changes: The FDA guidance explicitly addresses "Unplanned Design Changes Based on Comparative Interim Results," strongly discouraging them without prior FDA discussion due to the difficulty in controlling Type I error
. It also discusses "Design Changes Based on Information From a Source External to the Trial," which are generally considered acceptable as they don't affect statistical inference validity, but notes the challenge in ensuring the decision was entirely based on external information . ICH E20 directly states its scope "does not include trials with unplanned modifications to the design" or "design changes based entirely on emerging information from a source external to the trial" . While both recognize the issue, the FDA guidance delves more into how these situations might be handled if they arise. Level of Detail on Specific Adaptations: Both documents cover similar types of adaptations (early stopping, sample size, population, treatment arm, patient allocation). However, ICH E20 includes a dedicated section on "Adaptive Designs in Time-to-Event Settings"
and "Adaptive Designs Using Bayesian Methods" as full sections within its "Special Topics and Considerations," suggesting a more structured and perhaps deeper dive into these areas. The FDA also covers these, but they are subsections . Trial Integrity and Confidentiality: Both documents strongly emphasize maintaining trial integrity and limiting access to unblinded interim results to independent parties (e.g., IDMC)
. However, ICH E20 suggests that details of the adaptation rule "could be reserved for a specific document rather than the protocol, such as a confidential appendix to the IDMC charter" , and that sponsor personnel, investigators, and participants could be shielded from knowledge of specific adaptive changes . The FDA also mentions that the protocol could outline only the general approach with details reserved for documents like the DMC charter . Documentation: Both guidances provide extensive lists of documentation requirements before and after conducting an adaptive trial. ICH E20's section 6.1 and 6.2 provide a comprehensive outline of what should be documented, including explicit links between clinical and statistical assumptions and simulation results
. The FDA also requires detailed simulation reports and data access plans . Context of Development Program: ICH E20 places a strong emphasis on the "Adequacy Within the Development Program"
, suggesting that increasing the number and complexity of adaptations at the confirmatory stage should generally be limited and not replace a sequence of multiple trials or a proper dose-ranging trial . This principle is woven into the justification of adaptive designs. The FDA also touches upon this by noting that adaptive designs are useful for early-phase exploratory trials .
In summary, while both the ICH E20 draft guidelines and the FDA guidance share a common understanding of adaptive designs and their core principles, the ICH E20 document, being a newer draft, appears to offer a more structured and perhaps slightly more detailed approach to certain advanced topics and their implications within the overall drug development program. The FDA guidance provides a solid foundation of principles that aligns with many aspects of the ICH E20 draft, particularly regarding the need for robust statistical methods, trial integrity, and comprehensive documentation.
