1st Global QA Conference &21st SQA Annual Meeting

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Phase I Clinical Study Audits

“A Deeper Scrutiny”

Cheryl J. Priest, R.N.

24 February 2005

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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