Clinical Trials Design

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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 [phone]
• mfeldman_at_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 lt 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 lt 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 (lt5)
• 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 gt 1 year) and use of IVD (may take lt
  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
• Investigators 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/c
  der/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