1st global qa conference & 21st sqa annual meeting falcon consulting group, llc 1 phase i...
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1st Global QA Conference &21st SQA Annual Meeting
Falcon Consulting Group, LLC1
Phase I Clinical Study Audits
“A Deeper Scrutiny”
Cheryl J. Priest, R.N.
24 February 2005
Falcon Consulting Group, LLC2
Phase 1 Clinical Study Audit
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Phase 1 Clinical Study Audit
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What is a Phase 1 Clinical Study? Initial introduction of a new drug in humans
Closely monitored and controlled
Healthy volunteers or patients (20-80)
Increasing doses and associated side effects
Drug metabolism, pharmacokinetics, mechanism of action
Assessment of Safety
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What Confronts the Auditor? Phase III Pivotal Studies are CQA
priorities:
– 70% of companies audit all Phase III trials
– 90% perform pre-inspection audits
– Phase I Audits?
No GCP Quality Standards specific to
Phase I
Customized Phase I Audit Plans
Different Phase I subject populations
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What Confronts the Auditor? Broad subject screening and recruitment
or
very specific patient recruitment
Special Informed Consent processes
Diverse site personnel and roles
Focused assessment of Unit facilities
Controlled environment and workflow
Unique and varied study documentation
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What Confronts the Auditor?
Sometimes complex safety assessments
Potential expedited monitoring and data
transmittal
Unique Investigational Products and
dosing
Precise “systems” for biological samples
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Phase I Audit Plan Customized GCP Audit Strategy
Audit details specifically related to:
– Study design and complexity
– Study population
– Type of dosing and sampling
– Type of Investigational Product
– Facility/environmental controls
Who should audit?
When should you audit?
What should you audit?
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Phase I Subject Diversity
Healthy volunteers
– Auditing of data more simple
– Safety events easier to define and verify
Complex subjects – e.g. Cancer, HIV
– Effectiveness of audit impacted by auditor
therapeutic expertise
– Safety events potentially “hidden” by disease
and may be subtle to auditor review
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Phase I Subject Recruitment
Large scale “preliminary” screening and
recruitment efforts needs auditor
attention:
– Systems
– Documentation
Specifically selected diseased population
with rigid entry criteria forces auditor to:
– Verify entry criteria
– Confirm protection of “vulnerable” population
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Phase I Informed Consent
Subject protection and ethics
Auditor verification:– Clearly stated study intent– No ambiguity or suggestion of individual benefit – Adequacy particularly for patient “vulnerable” subjects
Auditor specific and focused review:– Informed consent administration and “work flow”– Informed consent documentation
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Phase I Site Staff and Delegation
Auditor attention to:
– Numerous and diverse roles
– Qualifications and therapeutic expertise
– Staff Training – specifically on Unit SOPs
– Demonstrated knowledge of protocol and written standards
– Appropriateness of responsibilities
– Investigator oversight
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Phase I Site Facilities Auditor observations for specific studies:
– Academic or typical Phase I Unit?
– Logistics and subject segregation
– Security and environmental controls
– Storage – Investigational Product and samples
– Food preparation and diet management
– Subject privacy and confidentiality
– Emergency equipment and transport
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Phase I Documents and Data
Electronic source and/or study data (validated?)
Screening and recruitment forms or database
Worksheets and flow charts
Essential and regulatory Investigator documents
Outpatient or inpatient hospital records, other “source”?
Investigational Product accountability records
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Phase I Subject Safety Auditor confirmation for specific studies:
– Adequate medical oversight of dosing procedures
– Adequate medical assessment of subject safety
Auditor intense review to ensure adequacy of safety
reporting:
– Complex source data for diseased subjects may be challenging
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Phase I Monitoring
Auditor evaluation of:
– Monitor qualifications and relevant therapeutic
experience
– Monitor “real time” observation of dosing (as
applicable)
– Documentation of monitoring activities and
findings
– Frequency and adequacy of monitoring
performance
– Data integrity
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Phase I Investigational Products Auditors must concentrate on:
– Any special handling of Investigational Product (e.g. radio-labeled
studies)
– Special Investigational Product preparation
– Sophisticated dosing schemes and regimens
– Accountability procedures and documentation
– Qualifications/appropriateness of “handlers” of investigational product
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Phase I Samples
Auditor close observations and critical
review:
– “Systems” for sample collection and processing
– Study-specific workflow and precise timing
– Verification of appropriate sample identification
– Adequacy of sample storage and controls
– Transmittal to analytical laboratory
– Standards and procedures for sample handling
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Phase I Unit Quality System
Is there one?
Auditor needs to note:
– Applicable written standards for the Unit?
– SOPs for conduct of specific types of studies?
– Emergency procedures and training
– Systems integrity and testing
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Phase I Clinical Study Audits
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Phase I Clinical Study Audits
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Phase I Clinical Study Audits
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References
H. Gertzen, “ Clinical Quality Assurance Benchmarking”,
Applied Clinical Trials, June, 2004.
M. Agrawal, E. Emanuel, “ Ethics of Phase I Oncology
Studies”, JAMA, June, 2003.
www.fda.gov
www.institute of clinical research. org