Clinical Trials Design

Clinical Trials Design
By:Martha A. Feldman, RAC
Drug & Device Development Co., Inc.

Purposes of conducting clinical studies
Types of clinical studies
Ethical considerations
Regulatory requirements
Monitoring
Database management issues
Statistical considerations
Reports for submissions or papers

Purposes of Clinical Studies
Further scientific knowledge
Prove concept
Evaluation of product features, capabilities
Obtain initial safety data
Substantiate claim/indication for use
Establish degree of efficacy or effectiveness
Compare with competitor product; marketing evaluation

Types of Clinical Studies
Prospective or retrospective
Blinded/masked or open label
Randomized or not
Active control or placebo
Normal subjects or patients
Actual or surrogate clinical endpoints
Statistically significant or “anecdotal”

Ethical Considerations
Human Subject Review: IRB, Declaration of Helsinki
Informed consent, community consent, waiver of consent
Use of placebos versus positive control
Use of normal subjects
Use of investigational material in addition to standard care
Vulnerable populations

Regulatory Considerations
Drug/Therapeutic Biologic Studies

Overall investigation Plan
Phase 1 - Normal subjects: usually < 50 subjects, at one facility, safety parameters
Phase 2 - Patients: about 50 - 100 subjects; at two sites; may do some dose-range assessment; safety and some initial efficacy
Phase 3 - Patients: few hundred to several thousand; multiple sites; main support study
Phase 4 - Patients (post-marketing): varies


Phase 1 Clinical Study
Normal subjects; occasionally use patients
See if/how pharmacokinetics data from animal studies extrapolates to human data
Document pharmacodynamic effects
Usually open label with ascending doses; establish dose-range
Build safety profile: monitor adverse effects

Phase 2 Clinical Study
Patients or people with clinical condition
Confirm dose range is similar in such people; if not, re-define range
Blinding, randomization, controls used
Strict entry criteria
Initial efficacy determination

Phase 3 Clinical Study
Few hundred to few thousand patients
Multiple sites
Blinding, randomization, controls, prospective
May have slightly broader entry criteria - age, severity of disease,
Continue developing safety and efficacy profiles

Post-marketing Study
Surveillance or study
Numbers to be negotiated
Parameters determined as a result of Phase 3 study
May involve labeling issues

Device Clinical Studies
“It Depends”
Steps in Investigation Plan
Proof of concept/Feasibility: < 5 subjects or patients; one site, safety and some effectiveness
Pilot study: 20-50 subjects; “test drive” protocol, case report forms, initial effectiveness and safety; two sites
Pivotal study: 50 - 500 subjects; multiple sites; main supporting study for claims

Proof of Concept/Feasibility Study
few patients (<5)
limited to one site
usually investigator-sponsored study
goal: prove concept, check instructions for use; early safety and effectiveness assessments


Pilot Study
More rigorous protocol
May be up to 50, but usually around 20 subjects
One or two sites
Company-sponsored study
“Test drive” protocol, comparison of use at two sites, safety and some effectiveness data; finalize training plan
Adjust final protocol for pivotal trial

Pivotal Study
The main study to support the submission
Subject number could be from around 100 to several hundred
Multicenter study; each site should enroll sufficient subjects for separate analyses
Should demonstrate device is independent of inventors


IVD Studies
May be done in two parts: collection of samples (may take > 1 year) and use of IVD (may take < 1month); separate protocols
Collection of samples may involve dozens of sites; testing phase may be at minimum of three sites
Study size may range for 100 (for some monitoring studies) to several thousand (for screening indication)
May enrich samples with stored, known, positive samples: special IRB and consent issues

Monitoring
At least one a year on-site
Between visits: by telephone, e-mail, FAX and courier services

Prestudy Activities
Investigator selection and qualification
Site qualification:
additional staff
sufficient number of subjects
laboratories, pharmacies
special needs
Conduct Pre-study site visit

Prestudy Site Visit
Meet investigator, coordinators, other staff
Review protocol, case report forms
Emphasize consent procedure, requirements
Review adverse event procedures
Review investigator documentation
Review Regulatory Notebook
Visit, as needed, labs, pharmacy, etc.
“Build” study team

Routine, Interim Visit
Review regulatory notebook
Verify consent procedures followed
Ensure study eligibility criteria met
Compare data entries on CRFs and source data
Check investigational product accountability
Check for unreported adverse events
Resolve queries

“For Cause” Visit
Possible reasons
too little/too much enrollment
much greater number adverse events
badly completed case report forms
new coordinator/investigator needing training
results “too good”
Monitor has concerns about investigator or coordinator compliance with regulations

Close-Out Visit
Regulatory Notebook is complete
Supplies accountability checks out
All queries resolved
No unreported, unresolved adverse events
All patient follow-up completed
Investigator’s report done
Files prepared for FDA inspections and for storage

Database Management Issues
Programming for the case report entries
Developing a data entry plan; data entry verification plan
Generating queries for the monitors to have coordinators resolve
Entering amended data; database clean-up
Data editing plan
Closing database; data validation plan; send to statistician
Developing tables for the reports, submissions, etc.

Statistical Considerations
Developing hypotheses
Calculating sample size requirements
Developing plan for interim analysis, if needed, and for final analysis (including sub-analyses)
Determining how interim analysis results impact sample size
Perform analysis and data evaluation
Write statistical report

Sponsor Reports - Submissions
Adverse event reports
Use of investigational product without consent
IRB withdrawal of approval
Annual reports
Updating submissions with each advance in the investigational plan (e.g., study completion or termination)

Investigator Reports
Withdrawal of IRB approval
Use of product without consent
Adverse events - to sponsor and IRB
Study status reports; study close-out report
For device studies: malfunction, repair or replacement

Other Reports
Publications, posters, presentations
can review manuscript for proprietary information
cannot stop the publication of negative results
off-label use: company may not promote it, but can distribute articles written by health care practitioners
References

Code of Federal Regulations, Title 21
Part 50 - Informed Consent
Part 56 Institutional Review Boards
Part 312 - Investigational New Drug, antibiotic, Biotechnology-Derived Product regulations
Part 812 - Investigational New Device regulations
FDA Guidance Document on Good Clinical Practices, January 1988
ICH Guidance Document E6 - Good Clinical Practices
More References

Clinical Trials Design.ppt