Study Development and Design Suzanne Adams RN MPH

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

Study Design: Industry vs. Academic The Industry clinical research process 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 • 10 -15 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* 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

Likelihood of Approval by Phase and Disease Group Nature, 2009

Study Design: Types and Characteristics • Observational • Registry • Interventional • • Prospective Retrospective Cross-sectional Cohort • • RCCT Randomization Crossover/Stratified Blinding / Double Blind • Single Site or Multi-Center • RCC with Enrolling Sites • • • Adaptive Design Patient-Centered Patient Reported Outcomes Comparative Effectiveness Big Data Analyses

Clinical Trial 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

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

Assessing Feasibility Internal Financial Estimates and Projections • Cost to Institution • Potential for / Level of Success • Data Management / EDC Use vs. • AE / SAE Reporting Requirements • Scientifically Sound - Subject Safety • Training and Education Needs Site Feasibility Questionnaires – Level of Specificity • Experience • Access • Capabilities • Past Performance • Audit Record

Feasibility: Assessment of Subjects, Staff, and Stuff Subjects • Number / Availability of Subjects • Access to Subject Population • Subject Burden Staff • Sufficient Research Staff • Skill Set/ Experience of Research Staff • Research Staff Burden • Investigator Training and Experience • Investigator Effort and Availability • Investigator Engagement Resources • Equipment • Facilities (Lab etc. , ) • Accommodations

Budgeting and Financial Feasibility • Staff Effort • IRB/IEC fees (including continuing review and amendments) • Study start-up administrative costs • SAE reporting • Monitoring plan • Long-term document storage • Study maintenance fees • Subject reimbursement • Organizational overhead • Translation services • Pharmacy charges

Protocol Evaluation and Assessment • Objectives that address specific questions or a hypothesis statement • Scientific background and study rationale providing the basis for the trial • Trial design consistent with study goals and depicted in a study schema • Subject selection and enrollment using specific inclusion and exclusion criteria • Procedure and events schedule: treatment plan, visits, clinical procedures, laboratory tests, questionnaires, other measures • Management of AEs, expected AEs, and actions to be taken or stopping rules • Statistical considerations/ rationale for study design, sample size, and analysis plan • Methods for quality control and quality assurance • Methods for human subjects protection and safety

Operational Analysis • Tools for Pre-Screening and Screening • Equipment: Acquisition, Care, and Feeding • 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

Feasibility: Assessment of Start up Time and Effort Individual Project Metrics General Performance Metrics • CDA Turnaround • Number of Studies coming in • Regulatory Document Submission • Time in Pipeline • IRB packet–Development, Submission, Approval • Meeting Enrollment Goals • Contract Review and Execution • Account establishment • Time to first subject enrolled • Meeting Enrollment Goals • Data Quality Report • Meeting Endpoints • Account Balances/Residuals • Balance/Flow to support personnel • Overall Site Performance

Information and Resources • FDA and CFR • IRB Guidance • Investigator Drug/Device Brochure • CORE Lab/Operations Manual • JCRI Standard Operating Procedures • JCRI Business Operations (Grants and Contracts) • RACE Federal Grant Management • TJU/H Websites

Questions and Comments Thank You !