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
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Prospective
Retrospective
Cross-sectional
Cohort
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RCCT
Randomization
Crossover/Stratified
Blinding / Double Blind
• Single Site or Multi-Center
• RCC with Enrolling Sites
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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”
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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 !