Download Clinical Trials Design

Clinical Trials Design
Martha A. Feldman, RAC
Drug & Device Development Co., Inc.
P.O. Box 3515 Redmond, WA 98073-3515 USA
1-425-861-8262 FAX: 1-425-869-5854
[email protected]
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Clinical Trials Design
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Purposes of conducting clinical studies
Types of clinical studies
Ethical considerations
Regulatory requirements
Monitoring
Database management issues
Statistical considerations
Reports for submissions or papers
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Purposes of Clinical Studies
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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
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Types of Clinical Studies
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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”
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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
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Regulatory Considerations
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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
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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
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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
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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
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Post-marketing Study
• Surveillance or study
• Numbers to be negotiated
• Parameters determined as a result of Phase
3 study
• May involve labeling issues
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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
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Proof of Concept/Feasibility Study
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few patients (<5)
limited to one site
usually investigator-sponsored study
goal: prove concept, check instructions for
use; early safety and effectiveness
assessments
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Pilot Study
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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
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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
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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
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Monitoring
At least one a year on-site
Between visits: by telephone, e-mail,
FAX and courier services
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Prestudy Activities
• Investigator selection and qualification
• Site qualification:
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additional staff
sufficient number of subjects
laboratories, pharmacies
special needs
• Conduct Pre-study site visit
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Prestudy Site Visit
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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
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Routine, Interim Visit
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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
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“For Cause” Visit
• Possible reasons
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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
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Close-Out Visit
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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
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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.
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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
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Sponsor Reports - Submissions
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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)
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Investigator Reports
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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
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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
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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
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More References
• Center for Drug Evaluation and Research,
List of Guidance Documents (Jan 2003)
http://www.fda.gov/cder/guidance/guidlist.pdf
– Clinical Evaluation of (type of) drugs
– FDA Requirements for approval of drugs to treat
(disease or clinical condition)
– General considerations for the clinical evaluation of
drugs infants and children
– Study and evaluation of gender differences in the
clinical evaluation of drugs
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Even More References
– Clinical trial sponsors on the establishment and
operation of clinical trial data monitoring
committee
– ICH
• Safety
• Efficacy
• Quality
– Good Clinical Practices - January 1988
– ICH - E6: Good Clinical Practices
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