Audits & Inspections
in
Clinical Research
What is an Audit
A systematic and independent examination of trial related activities and documents to
determine whether the evaluated trial related activities were conducted and the data were
recorded, analyzed and accurately reported according to the:
- Protocol
- Sponsor’s SOP
- GCP
- Applicable regulatory requirement
What is an Inspection
,
The act by a regulatory authority, of conducting an official review of
documents, facilities, records, and any other resources that are deemed by
the authority to be related to the clinical trial and that may be located at the:
- Site of the Trial
- Sponsor’s and CRO’s facilities
- Other establishments deemed appropriate by the regulatory authority.
Who can Audit a Clinical Trial
The following entities have rights to conduct the Audit/Inspection at site based on regulation
- FDA
- DHHS (Department of Health and Human Services)
- IRBs and Institutions
What triggers an
Audit/Inspection
In connection with a clinical study, an inspection may be undertaken if there
are:
- Concerns about its safety, data or ethics
- Monitor standards of clinical research
- When there is suspicion of fraud or scientific misconduct
- When there is serious quality systems breakdown
What all can be
audited/inspected
- Site
- Investigators and Study Team
- IRB/IEC
- Sponsor
- CRO, if involved
- Laboratories
- Pharmacy (e.g. Investigational Drug Services)
- Devices
Why sites are audited:
Routine (Study oriented inspection)
- To ensure that a site is complying with Protocol, SOP, GCP, and applicable regulatory
requirements.
- This is referred as ‘’Routine Audit’’.
For-Cause (Investigator-oriented Inspection)
- If the site is out of compliance and the sponsors want to either verify the problem or be
reassured that no problem exists. This is referred as “For-Cause Audit”.
Routine Audit:
FDA: - To evaluate data supporting a new drug or device application.
Sponsor:
- To verify site data and conduct
- To verify how the study was monitored
In-house (CRO) - To evaluate quality of research ongoing at the institution
For Cause Audit:
FDA/Sponsor /In-house (CRO)/IRB:
- Allegation / Suspicion of non-compliance
- Safety or efficacy data is inconsistent with other study sites
- PI conducting research outside area of specialty
- Accrual is abnormally high for geographical or location.
When can a site be audited:
- At anytime during the study
- After the study is completed prior to regulatory approval
- At anytime after regulatory approval.
On what basis the sites are
selected for an Audit:
Study oriented audits:
- Patient Enrollment: Highest enrolling sites
- Patient Retention: Large number of screen failures, unusually high patient drop-out rates
- Adverse Events: Large number of severe adverse events at only one or two sites
Investigator oriented audits:
- Generally occur when the drug regulatory authority has cause to suspect particular
researcher’s conduct i.e. For-cause audit
Pre-Audit Procedures:
CRC Preparation:
- Notify all staff involved in the study about the audit with date, time and duration of the audit.
- Ensure the Investigator’s attendance during the Audit
- Reservation/Arrangement for quiet, comfortable place to work and to assemble the necessary
documents for Auditor.
- Defined SOP/Agenda should be present and properly reviewed by all staff involved in trial
before audit about interaction of auditor with site, from his welcome to exit.
- Assemble all study documents in one place, they should be complete and well organized.
- Assure accessible photocopier, proved a backup if necessary (to provide a document when
requested by them)
Pre-Audit Procedures:
Confirm/Verify about the CRA’s presence during the Audit and
Review all the essential documents or any other problem which is found during this review so
that the situation may be able to be remedied before audit.
CRA’s preparation:
- Review and verification of every essential document should be complete and properly placed.
- Ensure resolution of unresolved queries before audit
- Notify confirmation of audit agenda to site for conduct of audit at selected site
Pre-Audit Procedures
Auditor’s Preparation:
- Auditor should have an Audit plan/Agenda.
- Auditor may also prepare working documents for use during audit, sometimes it becomes
necessary to generate audit-specific working
- Notify conduct of audit to CRA and Site
What happens during Audit:
- Auditors present their credentials (Photo ID) and a Notice of Inspections Form to the Clinical
Investigator
- Conduct Introductory Meeting
- Auditor will start auditing by reviewing specific data related to trial study and regulatory
requirements.
- they will document all their findings
- Auditor also interview site staff directly involved in trial activities and process.
What happens during Audit:
Auditor’s common observations for study:
- Protocol non-adherence
- Inadequate and inaccurate records
- Failure to report adverse events
- Failure to report concomitant therapy
- Inadequate drug accountability
- IRB/IEC problems
- Informed Consent Issues
What happens during Audit :
Closing Meeting (Exit Interview)
- At site visit completion, Auditor conducts “exit interview” with all responsible site personnel to:
- Review findings
- Clarify misunderstandings
- Describe any deviations from current regulations
- Suggest corrective action, if appropriate
- Auditor (FDA) may issue a Form 483 (Notice of Observation) to the Investigator. This form will detail the
findings from the audit that may constitute compliance violation.
What happens after Audit:
After the Audit is complete, the Auditor prepares an:
- Audit certificate: A declaration of confirmation by the auditor that an audit has taken place.
- Audit report / Establishment Inspection Report (EIR): A written evaluation by the Sponsor’s auditor of the results of the
audit.
- EIR Classification:
Classification & Type of Letter
- NAI (No Action indicated): Notice of no significant deviations
- VAI (Voluntary Action Indicated): informational
- OAI (Official Action Indicated): Warning
What gets Audited:
1. Regulatory and protocol compliance
2. Subject Records
3. Investigational Product
4. Adverse events, SAEs or complications
5. Documentation
Some Do’s:
Inspector should present a Form FDA 482 “Notice of Inspection”.
- Have all subject records organized and available. Give the inspector only those records
specifically requested.
- Make notes of comments/concerns/deficiencies pointed out by the inspector
- Question entries in the inspector’s notes regarding adverse findings.
- Clarify or attempt to resolve issues as they are made known.
- If the questions seems vague, ask for clarification before answering. Make sure the inspector
understands your response.
- Be courteous, professional and available.
Some Do’s:
- Object to requests for unreasonable information (e.g. Financial records and Home addresses of
subjects). In this case, The Investigator may ask for a written request from the FDA.
- Let the sponsor know the outcome as soon as possible.
- Answer – politely, co-operate, understanding them factfully, without speculation or guess
work.
But Don’t even think of…
- Giving more information than asked for.
- Offering to change data unless it can be verified with the sponsor and supported by source
documents.
- Discussing other studies.
- Discussing financial arrangement between you and sponsor
- Hiding information or volunteer information
- Signing affidavits
- Allowing pictures
- Leaving the inspector alone
- Putting initials/signing any errors.
Thank You
