Audit and Inspection in Clinical Trial

Dr. Ranjeet Prasad (MBA,CCRP,BDS)



What is 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 sop¶s, GCP, and Applicable regulatory requirements.

(ICH-GCP Sec. 1.6)

Purpose of Audit
‡ The purpose of a sponsor¶s audit is to evaluate the trial conduct and compliance with:‡ Quality Systems and SOPs ‡ Protocol ‡ Good clinical practices & other applicable regulatory requirements

‡ Auditors are independent of the clinical trial/ data collection system(s) ‡ Sponsor or CRO or Site

What to audit
‡ Organization and personnel 
Responsibilities and functions - Ensure clear responsibilities exist so as to minimize ambiguity between:‡ Investigator and sub-investigator ‡ Sponsors and contractors ‡ Contractors/suppliers (CROs, Labs, IRBs) ± audit suppliers!

‡ Qualification, training and adequacy of staff ‡ List of monitors ‡ List of all investigators

What to audit (Cont«)
‡ Quality management systems 
        Management responsibilities Procedures and their adequacy Training Documentation control Change control Deviations and non conformities management QC, QA Internal Monitoring Program Internal Auditing Program

What to audit (Cont«)
Investigational drug
‡ Manufacturing, packaging, labeling and coding of the investigational product (including placebo and active comparator where applicable) in accordance with applicable GMP standards ‡ Labeling requirements, ³For Clinical Trial Use Only´ to protect blinding where applicable ‡ Drug Product Accountability ‡ Control Quantity

What to audit (Cont«)
± ± ± ± Responsibilities Composition, functions and operations Procedures Records

‡ Investigators and sub-investigators
± Qualifications and agreements

‡ Essential documents

What to audit (Cont«) Essential documents:
± Investigator¶s brochure

‡ Has all current info been provided to the investigator?
± Signed protocol and amendments ‡ How are changes and deviations to the protocol handled? ± Advertisements for subject recruitment ± Informed consent forms ‡ Approved by IRB/IEC? ‡ All been signed off according to requirements? ± Financial aspects of the trial ‡ Approved by IRB/IEC? ± Insurance statement (where required)

What to audit (Cont«)

Essential Document :
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Subject Databank Subject screening log Subject identification code list Subject Enrollment log Case report forms Documentation of CRF corrections Serious adverse events reporting Signature sheet Signed agreements between parties IRB/IEC approval/favorable opinion IRB/IEC composition

What to audit (Cont«)
Essential Document : ‡ Regulatory authorities authorization/approval/ notification of the protocol ‡ Normal value(s)/ranges for medical/laboratory tests ‡ Certifications or accreditation of labs (or other means that establishes competency of lab)

What to audit (Cont«)
Essential Document : ‡ At the clinical site:- investigational product and trial related materials 

Instructions for handling Shipping records Certificates of analysis of product shipped Accountability at the trial site

‡ Decoding procedures for blinded trials ‡ Master randomization list and method

What to audit (Cont«)
Essential Document : ‡ Records of retained body fluids/tissue samples (if any) ‡ Monitoring visit reports
‡ Pre trial ‡ During trial ‡ Post trial

‡ Final report by investigatory ‡ Clinical study report ‡ Archiving

What to audit (Cont«)
Bio-analytical Laboratories :
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Documentation control including archiving Qualification of instruments Qualifications and Training of staff Bio-analytical method validation Receipt and storage of samples Handling of reagents and solution Testing conducted as outlined in protocol CFR 11 compliance

What to audit (Cont«)
Computerized systems (used to create, modify, maintain, archive, retrieve or transmit data):
‡ ‡ ‡ ‡ Identify software and hardware used, when and where? Check security of the system (individual Login, secure passwords) Check traceability Check audit trail capabilities where applicable:‡ Who made the changes? ‡ When and ‡ Why, Certification of changes by appropriate authorities

‡ ‡

Check validation status where applicable Check record retention capabilities

What to audit (Cont«)
Computerized systems (used to create, modify, maintain, archive, retrieve or transmit data) :

‡ Adequate procedures that need to be in place:‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ System setup/installation Data collection and handling System maintenance Data backup, recovery and contingency plans Security Change control Alternative recording methods Personnel training

What to audit (Cont«)
Statistical component: ‡ Check statistical procedures and methods used are according to protocol ‡ Check statistical package used has been validated ‡ Review statistical analysis and results ‡ Check integrity of data and timely locking of database

What is Inspection
‡ ³The act by a regulatory of conducting and 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/or CRO¶s facilities, Other establishments deemed appropriate by the regulatory authority´

(ICH-GCP Sec 1.29)

Steps in FDA Inspection Process

FDA Office 1. Select Site 2. Contact Site 3. Schedule Site 9. Write Report (EIR) 10. Classify Inspection

Site Location 4. Arrive (482) 5. Review Records 6. Interview Staff 7. Present Findings 8. Depart (483)

FDA Form ± 483 (Notice of Observation)
‡ A summary report of inspectional observations. ‡ It is a list of objectionable conditions or practices observed during the inspection, prepared by the FDA investigator and presented to the auditee at the conclusion of an inspection.

Difference between Audit and Inspection
Inspectors are employed of the company who work for a active clinical quality assurance (CQA) function (i.e. Sponsor/CRO) To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements.

Inspector are employed by government, through the agency of the regulatory or competent Authority (i.e. FDA/DCGI) To ensure that trial related obligations and acceptability of resultant clinical data is in support of a new drug approval.

Who is responsible for Audit and Inspection
‡ The following entities have rights to conduct the Audit/Inspection at site based on regulation
‡ ‡ ‡ ‡ ‡ FDA/CDSCO OHRP: ( Department of health and Human Services) The Sponsor of the clinical trial CRO/ Cooperative Groups/Grant-Funded Research IRBs and Institutions

Reason to Audit and Inspection
‡ In connection with a clinical study, An Audit/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

Types of studies Audit/Inspection
To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. This is referred as ³ROUTINE AUDIT´ ³Study-oriented Audit´

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 ³FOR-CAUSE AUDIT´ ³Investigator ± oriented Audit´

Routine Audit/Inspection
‡ FDA: 
      To evaluate data supporting a new drug or device application To verify site data and conduct To verify how the study was monitored To evaluate quality of research ongoing at the institution. To Justify placing a grant Continuous Funding To Verify data

‡ Sponsor: ‡ In-house (CRO): ‡ Cooperative Groups/Grant Funded Research:

For-Cause Audit/Inspection
‡ Done by FDA / Sponsor/In-house (CRO)/ IRB ‡ Cause:
1. 2. 3. 4. 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 ethnicity/race location.

When is Study Audited
‡ At anytime during the study ‡ After the study is completed prior to regulatory approval for the product ‡ At any time after regulatory approval (15 years) if a safety concern with the product (rare)

What Gets Audited
5 Categories :
1. 2. 3. 4. 5. Regulatory and protocol compliance Subject Records Investigational Product Adverse events, SAEs or complications Documentation

How Auditor select the sites
Study oriented audits 
Patient Enrollment: Highest
enrolling sites

Investigator oriented audits
It generally occur when the drug regulatory authority has cause to suspect particular research¶s conduct i.e. ³For-cause Audit 

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 Trial Importance: Pivotal studies.

Audit Procedure-rule
3 to 5 minutes rule : 
To provide documents requested by Inspector  If not available be truthful  Beyond five minutes inspector may assume that it has been fabricated

Documentation thumb rule: 
If not documented means not done  If documented does not mean that it is done

Tips on Document Requests
‡ Do not provide or copy these information for FDA/Auditor: 
Financial data (salary information, budgets) ‡ (except financial disclosure of clinical investigators)  Personnel data (performance appraisals) ‡ (except qualifications [job descriptions] and training records)

‡ Remember 3-5 minute rule

Audit Procedures
‡ Pre Audit Procedure ‡ During Audit Procedure ‡ After Audit Procedure

Pre-Audit preparation
1) CRC Preparation: 
Notify all staff involved in study about the audit with date, time & 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

Pre-Audit preparation Cont«.
1) CRC Preparation (Continue): 
Assemble all study documents in one place, they should be complete and well organized  Assure accessible photocopier, provide a backup if necessary (to provide document when requested by them)  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

Pre-Audit preparation Cont«..
2) 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 preparation
3) Auditor¶s Preparation: 
Auditor should have 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

Audit Procedure (During) 
Auditors present their credentials (photo ID) & a Notice of Inspections (Form 482) 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

Audit Procedure (During) cont«.
‡ Auditor¶ s common observations for study:
1. Protocol Non-adherence 2. Inadequate & inaccurate records 3. Failure to report adverse events 4. Failure to report concomitant therapy 5. Inadequate drug accountability 6. IRB/IEC problems 7. Informed Consent issues

Audit Procedure (During) cont«.
‡ Closing meeting (exit interview):
At site visit completion, Auditor conducts ³exit interview´ with all responsible site personnel to:  Review findings  Clarify misunderstandings  Describe any deviations from current regulations  Suggest corrective action, if appropriate

Audit Procedure (During) cont«.
‡ Auditor (FDA) may issue a Form FDA 483 (Notice of Observation) to the Investigator. This form will detail the findings from the audit that may constitute compliance violation

After Audit Procedure
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:

‡ Inspector should present a Form FDA 482 ³Notice of Inspection.´ ‡ Have all subject records organized and available. Give the inspected only those records specifically requested. ‡ Make scrupulous notes of comments/concerns/ deficiencies pointed out by the inspected ‡ Question entries in the inspector¶s notes regarding adverse findings.

Do¶s (Cont«)
‡ Clarify or attempt to resolve issues as they are made known. (remember 3-5 rule) ‡ If the questions seems vague, ask for clarification before answering. Make sure the inspection understands your response. ‡ Be courteous, professional and available.

Do¶s (Cont«)
‡ 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 of the outcome as soon as possible ‡ Answer- Politely, co-operate, understanding them factfully, without speculation or guess work

Do Not
‡ Do not give more information than asked for. ‡ Do not offer to change data unless it can be verified with the sponsor and supported by source documents. ‡ Do not discuss other studies. ‡ Do not discuss financial arrangement between you and sponsor

Do Not (cont )
‡ ‡ ‡ ‡ ‡ Do not hide information or volunteer information Do not sign affidavits. Do not allow pictures Do not leave the inspector alone Do not initial/sign any errors.

Key to Success
‡ Compliance is Organizational responsibility & mandatory act ‡ Compliance is not a individual responsibility ‡ Integrity as a culture ‡ Document properly what you do ‡ Do not document what you do not do ‡ Do it right at for the first time, at right time, in right manner

Multiple choice questions
1) Audit is:
a) b) c) d) Systemic examination of trial Independent examination of trial Both of above None of above

2) Purpose of audit : trial conduct and compliance with
a) b) c) d) GCP and regulatory authorities Protocol and Sponsor SOP Quality System All of the above

Multiple choice questions
3) Manufacturing, packaging, labeling and coding of the investigational product must be compliance with
a) b) c) d) GCP GMP Both of the above None of the above

4) What documents not to be show during audit/inspection
a) b) c) d) Certifications or accreditation of labs Normal value(s)/ranges for medical/laboratory tests Monitor and CRC appraisal letter All of the above

Multiple choice questions
5) What to be audited from following
a) b) c) d) e) a) b) c) d) e) Decoding procedures for blinded trials Financial disclosure of Investigator Salary structure of CRC and CRA Both (a) & (b) Both (a) & (c) Sponsor Regulatory authority CRO Pharmaceutical Industries All of the above

6) Inspection is done by:

Multiple choice questions
7) A summary report of inspectional observations is done on:
a) b) c) d) Form 482 Form 483 Form 1571 Form 1572

8) Inspectors are employed by Sponsor/CRO for the purpose of:
a) b) c) d) Audit Inspection Both of the above None of the above

Multiple choice questions
9) ³Notice of Inspection´ is to be report on:
a) b) c) d) Form 482 Form 483 Form 1571 Form 1572

10) Inspectors are employed by government/Regulatory authority for the purpose of:
a) b) c) d) Audit Inspection Both of the above None of the above

Multiple choice questions
11) If the site is out of compliance and the sponsors want to either verify the problem or be reassured that no problem exists, referred as: a) For cause audit b) For cause inspection c) Routine audit d) Routine inspection 12) Sponsor want to ensure that a site is complying with Protocol, SOP, GCP and applicable regulatory requirements, Procedure referred as: a) For cause audit b) For cause inspection c) Routine audit d) Routine inspection

Multiple choice questions
13) ³For Cause Audit´ is:
a) b) c) d) ³Investigator ± oriented Audit´ ³Study-oriented Audit´ None of the above All of the above

14) When is Study Audited:
a) b) c) d) e) At anytime during the study After the study is completed prior to regulatory approval for the product At any time after regulatory approval None of the above All of the above

Multiple choice questions
15) During audit, auditor must be present :
a) b) c) d) Photo ID and Form 483 Photo ID Form 482 Photo ID and Form 482

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