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Classic and Novel Designs Used in Regulatory Approvals

1.5 credits


Full course description

The Georgia Clinical & Translational Science Alliance- Georgia CTSA and Southern California Clinical and Translational Science Institute -SC-CTSI have collaborated to provide free, high quality educational programs for clinical research professionals at novice to expert levels of experience. At the completion of each course or program, participants earn contact hours recognized by a certificate and/or badge.


This course presents an in-depth review of the principles and application of statistics in randomized controlled trials, including basic terminologies, and fundamentals of research design and analysis.


  1. Classical Design Issues
    • Phases of Drug Development
    • Control Groups
    • Controlling for Bias
    • Multi-Regional Clinical Trials
    • Controlling for Multiplicity
  2. Phases of Drug Development: Phase I
    • Safety and Dosing
    • First-in-Human (FIH) Studies
    • Typically in healthy volunteers except in oncology trials
    • Single Ascending Doses (SAD), Multiple Ascending Doses (MAD)
    • For Oncology, 3+3 Design is used most commonly in Phase I
  3. Phases of Drug Development: Phase II:
    • Provide preliminary evidence of a drug's clinical efficacy, considered exploratory trials
    • Design of Phase II Trials Goal:to find the optimal dosage, more flexibility in numerical values of Type I & II errors.
    • Decision-Making in Phase II: Internal decisions, e.g., whether to move to Phase III
      • Example:Type I Error - A decision to launch a phase 3 program with an ineffective drug.
      • Example: Type II Error - An incorrect decision that a treatment has insufficient efficacy to move onto Phase III.
    • Adaptive Dose-Finding – Bias & Random Error
  4. Phases of Drug Development: Phase II:
    • Confirmatory trials designed to provide definitive evidence of efficacy and safety.
    • Increased scrutiny from regulatory agencies.
      • Incorrect conclusions from exploratory (Phase I & II) trials put the Sponsor at risk.
      • Incorrect conclusions from confirmatory (Phase III) trial put the consumer at risk.
  5. Type I and Type II Error
  6. Bias and random error
    • Bias: a systematic tendency to incorrectly over/underestimate true treatment effectExample: placing more ill patients into the clinical trials in the experimental arm.
    • Random error: the difference between estimate and true effect (simply over/underestimating randomly)
    • Avoiding Bias
      • Randomization- to avoid conscious/unconscious tendency to allocate sicker patients to a specific group.
      • Blinding
        • Patient/Single-Blind; Investigator/Double-Blind; Sponsor/Triple-Blind
        • Blinding sponsor avoids "operational bias" which is making changes to protocol or how the drug is given during the trial to improve/influence the consequences of drugs.
  7. Minimizing Random Error
    • Bigger sample size is primary approach
    • Enroll more homogenous patient population and better training for collecting endpoints.
  8. Single-Arm Trials
    • Typically used in oncology trials
    • Problematic: You do not know how the patient would have reacted without the drug (trial lacks a control)
  9. Placebo Controls and Active Controls
    • Gold Standard for demonstrating efficacy and safety
    • Biggest Problem: not ethnical to withhold medication for sick patients and evaluation of comparative efficacy
    • Superiority v. Non-Inferiority with Active Controls
  10. Types of Endpoints:
    • Continuous Variables
    • Ordinal Variables
    • Dichotomous/Binary Variables - Risk difference, relative risks, and odds ratio
    • Survival or Time-To-Event
    • Composite Endpoint (combination of various endpoint)
  11. Analysis of Confirmatory Trials
    • Intention-to-Treat Principle - Include and follow all randomized subjects, and include all measurements in the analysis.
    • Handling missing data - Tends to introduce bias
    • Intercurrent events and estimands
      • New revision to ICH E9 on Statistical Principles
      • Example: rescue therapy, discontinuation due to adverse event
  12. Controlling for Multiplicity
    • Multiple tests lead to multiple opportunities for a Type I error
    • New FDA Guidance Document on multiple endpoints
    • Statistical adjustment required for confirmatory trials to Control Experiment-Wise Error Rate
  13. Interim Analyses
    • Phase III Trials are monitored by an External Data Monitoring Committee (DMC) to protect patient safety
  14. Multiregional Clinical Trials
    • Many Phase III trials for registrational purposes are conducted in multiple regions/countries.
    • ICH Guidance Document (E17) on multiregional trials
    • Concerned with Extrinsic (diet, healthcare) or Intrinsic factor (DNA/genes)
    • Examples of Regional Inconsistencies- Merit HR Study, Plato Study.
  15. Novel Designs
    • Adaptive Designs
    • Platform and Umbrella Designs
    • Program Decision-Making Approach
    • Designs for Special Populations
  16. Adaptive Design
    • Rationale for Adaptive Phase 2 and 3 Trials
      • Substantial uncertainty exists
      • Adaptive clinical trials are designed to take advantage of accumulating information and modify aspects of the study based on pre-determined decision criteria without undermining validity and integrity of the trial to increase success of trials
    • Characteristics of Adaptive Design
      • Clarity of goals
      • Frequent review of data & potential modification of trial
      • Adaptive by "design"
      • Extensive use of simulation
    • Types of Adaptive Designs
      • Traditional: changing study eligibility criteria, stopping early for the sake of efficacy, blinded sample size re-estimation, increasing population sizes
      • Newer: Doses dropping or stopping for futility, adaptive randomization, unblinded sample sizes (to make significant statistical difference), endpoint selection, seamless phases, platform trials, basket trials
    • Conditions that Favor or Do Not Favor Adaptive Design
      • Favor: Fast turnaround of data, slow enrollment relative to primary outcome measure, availability of biomarkers that are predictive of final outcome, broad dose range to study
      • Do not favor: Fast enrollment relative to readout of primary outcome measure, complex drug packaging, and heterogeneous study features over time
    • What Do Adaptive Designs Buy Us? - Increases efficiency and increases accuracy
    • What Do Adaptive Designs Cost Us? - Require greater set-up time, simulations &, operations
    • The Adaption Process
    • Simulation-Guided Trial Design - To find operating characteristics and decision criteria
    • Longitudinal Modeling
    • Operational Considerations - Randomization/IVRS capability evaluation
    • Program Decision-Making Approach
      • Design of entire clinical program including sample sizes for phase II and phase III studies; to maximize drug's expected net present value (eNPV)
    • Platform and Umbrella Designs
      • Platform trial: investigate multiple drugs for same disease
      • Basket trial: investigate one drug for multiple ailments
  17. Other Innovative Designs
    • Pediatric Studies – Bayesian borrowing info from adult population
    • Small Populations/Orphan Drugs – relaxed type/error rate requirement, historical controls
    • Biomarker-Based Designs – Simultaneously determine efficacy in biomarker-sensitive population and in broader population at the same time


Steve Snapinn, PhD, is Vice President of Global Biostatistical Science at Amgen for the past 14 years. This department provides biostatisticaland statistical programming support to all phases of Amgen’s drug development programs. Prior to Amgen, for 20 years, Steve was Senior Director of Biostatistics at Merck.Dr. Snapinn has a Ph.D. from the University of North Carolina at Chapel Hill in 1973.He is former editor of Statistics in Biopharmaceutical Research and is a fellow of the American Statistical Association. He has approximately 100 publications in the statistical and medical

Learner Level: Beginner


This symposium is designed for Clinical Research Assistant/Associates or Clinical Research Coordinators in academia, clinics, hospitals, industry, or CRO with 1- 2 years of clinical research experience.Individuals may be new to clinical research with limited knowledge of clinical trial conduct, good clinical practices, regulations and common terminology associated with clinical research.

Contact Hours:

Emory Nursing Professional Development Center (ENPDC) is accredited as a provider of nursing continuing professional development by the American Credentialing Center’s Commission on Accreditation. Attendees to this CNE activity will be awarded 1.5 contact hours by ENPDC. No conflict of interest has been found with the speaker for this CNE activity nor with the members of the planning committee.

Need Help with Registration? Please contact us at or 404-727-9208.

Program Information: This is the third course in a five (5)-course program. To complete the entire program and earn a badge CLICK HERE.



Learner Disclosures:

Accreditation Status: Emory Nursing Professional Development Center (ENPDC) is accredited as a provider of nursing continuing professional development by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation.

Financial Relationships: ENPDC has evaluated everyone who has the ability to control content of this activity (planning committee members, subject matter experts, presenters) and found that no relevant financial relationships exist.

Awarding Contact Hours: To obtain contact hours participants must:

·       Review the entire activity

·       Pass the quiz

·       Complete the evaluation at the end

Certificates will be distributed at the end of the evaluation.


Enduring Materials Dates:


·       Start Date: 4/22/2024

·       Expiration Date: 4/22/2027

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