1. 1st Global QA Conference & 21st SQA Annual Meeting Falcon Consulting Group, LLC 1 Phase I Clinical Study Audits “A Deeper Scrutiny” Cheryl J. Priest, R.N. 24 February 2005

2. Falcon Consulting Group, LLC 2 Phase 1 Clinical Study Audit

3. Falcon Consulting Group, LLC 3 Phase 1 Clinical Study Audit

4. Falcon Consulting Group, LLC 4 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

5. Falcon Consulting Group, LLC 5 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

6. Falcon Consulting Group, LLC 6 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

7. Falcon Consulting Group, LLC 7 What Confronts the Auditor? Sometimes complex safety assessments Potential expedited monitoring and data transmittal Unique Investigational Products and dosing Precise “systems” for biological samples

8. Falcon Consulting Group, LLC 8 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?

9. Falcon Consulting Group, LLC 9 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

10. Falcon Consulting Group, LLC 10 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

11. Falcon Consulting Group, LLC 11 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

12. Falcon Consulting Group, LLC 12 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

13. Falcon Consulting Group, LLC 13 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

14. Falcon Consulting Group, LLC 14 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

15. Falcon Consulting Group, LLC 15 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

16. Falcon Consulting Group, LLC 16 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

17. Falcon Consulting Group, LLC 17 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

18. Falcon Consulting Group, LLC 18 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

19. Falcon Consulting Group, LLC 19 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

20. Falcon Consulting Group, LLC 20 Phase I Clinical Study Audits

21. Falcon Consulting Group, LLC 21 Phase I Clinical Study Audits

22. Falcon Consulting Group, LLC 22 Phase I Clinical Study Audits

23. Falcon Consulting Group, LLC 23 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.institutewww.institute of clinical research. org