Feldman 20 February 2003 1

Clinical Trials Design

Martha A. Feldman, RACDrug & Device Development Co., Inc.

P.O. Box 3515 Redmond, WA 98073-3515 USA

1-425-861-8262 FAX: 1-425-869-5854

mfeldman@druganddevice.com

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Clinical Trials Design

• 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

• 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

• 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

• 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

• 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: – additional staff – sufficient number of subjects– laboratories, pharmacies – special needs

• Conduct Pre-study site visit

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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

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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

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“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

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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

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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

• 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

• 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