1. When and how often are audits conducted?

CTSU sites are audited every 18 to 36 months, sometimes as often as every 12 months. The first audit is due within 36 months of the first patient accrual. Affiliate pharmacy operations are audited at least once during a 6-year period.

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2. How are audit sites selected?

CTSU may select sites that have open accrual to a study, closed a study, or have withdrawn their membership from the Cooperative Group. Selection of terminated sites for audit is at the discretion of the CTSU. The CTSU uses the Clinical Trials Monitoring Branch Audit Information System (CTMB-AIS) and communicates with the Cooperative Group Audit Coordinators to identify sites for audit based on patient enrollment. CTSU, also, works with the Cooperative Group Statistical Centers to select CTSU cases and specific data items that will be audited. For case selection for all audits, the CTSU requires a sampling stratification for 10 percent of Group cases, 10 percent of endorsed cases (where applicable) and 10 percent of non-endorsed cases (where applicable). These guidelines were outlined by the CTMB. In any of the 10 percent calculations, it is permissible to round either up or down in determining the number of cases. Selected non-endorsed cases must be cases enrolled via the CTSU at least 90 days prior to the scheduled audit date.

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3. Will there be an additional audit for protocols accessed through the CTSU?

The CTSU works with the Cooperative Group Audit Coordinators to coordinate audit visits. The coordinating process for auditing CTSU enrollments includes the selection of sites, scheduling sites, scheduling auditors and protocol cases, identifying data points, reporting requirements, and providing followup information. Once the 10% of non-endorsed cases has been delineated, if less than three CTSU patients enrolled in non-endorsed studies at an individual site are selected for an audit, CTSU coordinators will ask Cooperative Group auditors to audit CTSU cases per the Cooperative Group Mechanism. If more than four CTSU patients at an individual site enrolled in non-endorsed studies are selected for audit, CTSU auditors would augment/facilitate the Cooperative Group Audit team for the CTSU cases.

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4. Who may observe audits?

As determined by the NCI, representatives from CTEP or their designee and representatives from other Federal regulatory agencies may attend on-site audits as observers. The Clinical Trials Monitoring Branch notifies the Cooperative Group or CTSU of the audits where observers will attend.

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5. When are audit sites notified of an upcoming audit and the patients that are selected for the audit?

The Cooperative Group sends letters to sites at least 8 weeks in advance of the audit date. The letter describes the audit visit and indicates if CTSU will be participating in the audit. The patient list for audit selection is supplied to the site approximately 2 to 4 weeks in advance of the scheduled audit.

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6. Which types of patients are eligible for audit?

All patients are eligible for an audit, but most cases will be likely be chosen from patients accrued since the previous audit. Multi-modality, IND, complex protocols, and high accruing protocols are the types of studies that are emphasized.

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7. Will any patient cases be selected for a limited review?

The patient list for audit selection is supplied to the site approximately 2 to 4 weeks in advance of the scheduled audit. One or more unannounced CTSU patient case(s) may be selected for limited review on the day of the audit. A limited review of a patient case is defined as the review of at least the informed consent and eligibility criteria, on study, initial treatment, first response, and overall review of the data quality (missing documentation, data inaccuracies, etc.).

Limited reviews may also be conducted on unannounced patient cases, but they are not counted towards the number required for audit.

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8. How is the audit conducted?

CTSU Audit Coordinators work with the Cooperative Group Statistical Center sponsoring the protocol to provide copies of data forms submitted to the CTSU to verify against the primary medical record and other source documents.

Both CTSU and Cooperative Group auditors use audit worksheets when auditing CTSU cases.

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9. What does the site need to do to prepare for the audit?

The site prepares for the audit by gathering all source documentation pertaining to the selected cases. For each selected case, sites should make the following records should be available:

Informed consent documents Protocol flow sheets Hospital charts Physician and research notes Outpatient and clinic records Correspondence X-rays Scans Other pertinent studies

To expedite the review, the site must flag all key documents (on-study forms, lab reports, scans and imaging studies, consent forms, etc.).

For the selected protocols, the following documents should be provided:

IRB approvals, re-approvals, and amendment approvals Annual reports submitted to the IRB Current version of the protocols, including any amendments and informed consents in use at the site

All records regarding the disposition of investigational drugs, specifically copies of drug orders, return receipts, transfer forms, and the NCI Drug Accountability Records, must be available. The Pharmacy should be alerted that the auditors will conduct an on-site inspection of investigational agent storage facilities, procedures, and records.

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10. What are on-site audit procedures?

A quiet, well-lit workroom should be provided for the audit team. The Principal Investigator or designee and his/her research staff should be available throughout the audit to answer any questions and help the auditors locate necessary information in the source documents. Audit team members will sign the site-monitoring log and use the source documents to verify specific data related to the clinical research trial. The Regulatory Binder and all source documents must be available to the auditor. An appointment with the Pharmacist will be scheduled if a pharmacy audit is planned or if a site close-out visit is scheduled.

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• IRB Review (IRB documentation and informed consent review)
• Pharmacy review (accountability of investigational agents and pharmacy operations)
• Individual Patient Case Records

12. What will the auditor do?

The auditor will:
	Verify that informed consent for the patient is signed, dated, and on file.
	Verify that the appropriate version of the consent is signed.
	Verify that the patient met the eligibility criteria.
	Verify that the data collected (as provided by the Cooperative Group sponsoring the trial) is in compliance with the protocol and is consistent with source documentation. The auditor will identify inconsistencies, determine accuracy of endpoint, and compliance to adverse event reporting.
In addition, the auditor will confirm that the following regulatory documents are on file:
	IRB approval letters
	IRB letters of annual approval
	IRB approved consent forms in compliant with required elements per CRF (Code of Federal Regulations)
	Copy of IRB assurance
	FDA 1572 Form and Curriculum Vitae for each investigator listed on the 1572 form
	Site registration approval letters and e-mails
	Laboratory certification when applicable (CLIA and or/CAP)
	Safety reports and memos with appropriate IRB correspondence
	Additional documents as required

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13. When are CTSU Independent Clinical Research Sites (CICRS) audited?

CICRS are audited 18 months after their first enrollment. The CTSU Audit Coordinators will send the pre-audit letter, list of cases selected, and other audit-related information using the same timeframes listed above. The audit process, including scheduling and reporting mechanisms, is also followed as outlined above.

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14. What ratings are used to communicate findings?

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15. How is the rating 'unacceptable' defined?

An inclusive and precise definition of what constitutes an unacceptable finding is difficult to construct. Rather than developing an inclusive quantitative definition, the Clinical Trials Monitoring Branch (CTMB) uses a set of terms or examples of major and lesser deficiencies, a system for assessing each component of an audit, and a standard audit report format using the CTMB-AIS. The CTSU uses the same procedure.

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16. What is a major deficiency?

Major deficiency is defined as a variance from protocol-specified procedures where research integrity of data accuracy have potentially been compromised. The following are examples of major deficiencies:

Protocol was never approved by IRB IRB reapproval has expired Informed consent document is lacking the elements required by the Code of Federal Regulations Patient did not meet all eligibility criteria specified in the protocol Pre-entry and entry clinical or laboratory assessments that are missed or obtained outside the protocol specifications Errors discovered that potentially affect patient stratification Patient's signed consent form is missing Consent form was not current IRB approved version at the time of patient registration Reportable adverse event was not reported to IRB Toxicity that would require filling an Expedited Adverse Event Report (AER) was not reported Grades, types, or dates/duration of serious toxicities were inaccurately recorded Incorrect agent/treatment used Concomitant medication was administered that is prohibited by the protocol Dose deviations (error outside the range of +/- 10%) Receipt, use, and disposition of supplied investigational agents cannot be reconciled NCI Drug Accountability Forms (DARFs) are not maintained Tumor measurements/evaluation of status or diseases not performed according to protocol parameters Errors were made in reporting endpoints as specified in the protocol Documentation is missing Numerous transcription errors were made without reasonable explanation Data submission is delinquent

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17. What is a lesser deficiency?

A lesser deficiency is generally deemed to not have a significant impact on the outcome or interpretation of the study and is not described as a major deficiency. However, at the discretion of the audit team, an excess of lesser deficiencies may be treated as a major deficiency in determining the final rating of a component.

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18. How will site staff learn about audit results?

An exit interview will be held with the Principal Investigator and his/her research staff at the conclusion of the audit to summarize findings, discuss site performance standards, and present recommendations from the audit team. This interview provides the opportunity for education, dialogue, immediate feedback, and clarification.

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19. Who receives a copy of the audit report?

Copies of the final audit report are sent to the Cooperative Group sponsoring the protocol and to the Principal Investigator at the site. A copy of this audit report will be forwarded to CTMB.

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20. If the site is found to have deficiencies, what are next steps?

If the site is found to have deficiencies in any of the three categories (Regulatory Compliance, Pharmacy Accountability, and/or Individual Patient Case Records), the institution is required to submit a written response and/or corrective action plan to the CTSU. A copy of this written response will be forwarded to CTMB.

Any component designated as "unacceptable" will have a mandatory re-audit.

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