Study Development and Design Suzanne Adams RN MPH Director, Clinical Operations Jefferson Clinical Research Institute

Study Design: Learning Objectives Participants will be able to: 1. Describe types /characteristics of clinical research studies 2. Identify the 4 phases of clinical trial 3. Demonstrate understanding of study design factors

Study Design: Types and Characteristics Observational Registry Interventional Prospective Retrospective Cross-sectional Cohort Randomized Controlled (RCCT) Quasi-Experimental (no randomization) Crossover/Stratified Blinding / Double Blind Single Site or Multi-Center RCC with Enrolling Sites Adaptive/Pragmatic Design Patient-Centered/Patient Reported Outcomes Comparative Effectiveness Big Data, Computational Analyses

Study Design: Industry vs. Academic Sponsor Industry clinical research processes can be long and expensive. Investment over $1 billion (15.2 m phase I / $41.7 m phase II / $115.2 m in phase III years for a compound or device to advance from benchtop to bedside Subjects may be assigned to take one or a combination of:  Investigational drugs  Approved drugs  Placebo* (*Standard Care) Sponsor manages registering and reporting / Clinicaltrials.gov, IND to FDA Academic Research Intramural funding / Support for pilot studies – informing larger grant development Resources and sharing Value of Academic Capital NIH Clinical and Translational Science Awards Requirements for Reporting Results - Clinicaltrials.gov

Study Design: Drug Development Phases

Study Design: Phase I and II Phase I Test investigational drug for the first time in humans Small number of healthy volunteers Evaluate safety - Determine safe dosage range - Identify adverse effects. NOTE: Due to toxicity of the agent, cancer trials may do Phase I studies on subjects with advanced disease who have not responded to SOC treatment Phase II Investigational drug given to a larger number of people People have a particular disease or condition Determine effectiveness - Further evaluate safety IIa Pilot clinical trials may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy IIb Well controlled trials representing the most rigorous demonstration of efficacy Sometimes referred to as pivotal trials

Clinical Trial Design: Phase III and IV Phase III Several hundred to several thousand people Participants have the appropriate disease or condition Additional testing for safety, effectiveness, side effects, comparative effectiveness IIIa Trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) Also conducted in special groups or under special conditions dictated by the nature of the medicine and disease. Provide information for package insert and labeling IIIb Clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine's approval and launch. These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g., quality of life, marketing) Phase IV After a drug is available by prescription, FDA requires reporting of additional information to assess longer-term risks, benefits and use Post-marketing Surveillance or Pharmacovigilance

Study Design: Elements Research Question based on Scientific Background and Rationale Hypothesis / Null Hypothesis Objectives / Endpoints selected to support the study's hypotheses Sample Size / Power sample calculation Validity – Internal, External, Construct Data Collection and Analyses– Descriptive, Correlation, Inferential Intervention Design and Risk Evaluation Randomization to avoid Selection Bias or Probability sampling Blinding to avoid Observation Bias

Industry vs. Federal Grants vs. Investigator-Initiated CONSIDERATIONS Funding Source (Commercial, Federal, Foundation) Duration of Study Size and Scope Conflicting or Competing Studies Specific Aims/Exploratory Aims Endpoints and Outcomes Investigator Role/Expectations FDA Interactions for IND/IDE / Exemption “Waiver” Contract Research Organizations Trial Networks DSMB/DSMP Enrollment Goals and Timelines/Milestones Data Quality Monitoring

Study Design: Elements of Operational Analysis Tools for Pre-Screening and Screening Equipment: Acquisition and Care (Maintenance) Coordinator Training Standard of Care Overlap Subject Injury Language Investigational Product/Device Control Management/Cooperation/Resources needed for required labs or tests Safety Assessments Subject Retention Clean Data / Data Query Resolution Analysis Responsibilities

Clinical Research: Non-Clinical Site Fees : Median non-clinical U.S. site fee/subject increased from $4,000 to $6,500. “Non-clinical site fees” include visit, start-up, IRB, pharmacy, administrative and other fees, except charges for procedures and tests with CPT codes, or scale assessments.

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