Title: audit and inspection in clinical trial
1Audit and Inspection in Clinical Trial
- Dr. Ranjeet Prasad
- (MBA,CCRP,BDS)
2OBJECTIVE
- WHAT IS AUDIT
- PURPOSE OF AUDIT
- WHAT IS INSPECTION
- DIFFERENCES BETWEEN AUDIT AND INSPECTION
- WHO IS RESPONSIBLE FOR AUDIT AND INSPECTION
- TYPES OF AUDIT AND INSPECTION
- REASON FOR AUDIT AND INSPECTION
- WHEN AND WHAT GET AUDITED
3 OBJECTIVE (Conti)
- AUDIT PROCEDURES RULE
- PREPRATION FOR AUDIT
- MULTIPLE CHOICE QUESTION
4What 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
sops, GCP, and Applicable regulatory
requirements. - (ICH-GCP Sec. 1.6)
5Purpose of Audit
- The purpose of a sponsors 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
6What 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
-
7What 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
8What 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, For Clinical Trial Use
Only to protect blinding where applicable - Drug Product Accountability
- Control Quantity
9What to audit (Cont)
- IRB/EC
- Responsibilities
- Composition, functions and operations
- Procedures
- Records
- Investigators and sub-investigators
- Qualifications and agreements
- Essential documents
10What to audit (Cont)
- Essential documents
- Investigators 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)
11What 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
12What 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)
13What 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
14What 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
15What 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
16What 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
17What 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
18What 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
19What is Inspection
- The 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,
- Sponsors and/or CROs facilities,
- Other establishments deemed appropriate by the
regulatory - authority
-
- (ICH-GCP Sec 1.29)
20Steps in FDA Inspection Process
Site Location
FDA Office
- Select Site
- Contact Site
- Schedule Site
7. Present Findings 8. Depart (483)
21FDA 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.
22Difference between Audit and Inspection
AUDIT INSPECTION
Inspectors are employed of the company who work for a active clinical quality assurance (CQA) function (i.e. Sponsor/CRO) Inspector are employed by government, through the agency of the regulatory or competent Authority (i.e. FDA/DCGI)
To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. To ensure that trial related obligations and acceptability of resultant clinical data is in support of a new drug approval.
23Who 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
24Reason 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
25Types of studies Audit/Inspection
Routine For-Cause
To ensure that a site is complying with Protocol, SOP, GCP and Applicable regulatory requirements. This is referred as ROUTINE 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 FOR-CAUSE AUDIT
Study-oriented Audit Investigator oriented Audit
26Routine Audit/Inspection
- 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. - Cooperative Groups/Grant Funded Research
- To Justify placing a grant
- Continuous Funding
- To Verify data
27For-Cause Audit/Inspection
- Done by FDA / Sponsor/In-house (CRO)/ IRB
- Cause
- 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.
28When 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)
29What Gets Audited
- 5 Categories
- Regulatory and protocol compliance
- Subject Records
- Investigational Product
- Adverse events, SAEs or complications
- Documentation
30How Auditor select the sites
Study oriented audits Investigator 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 Trial Importance Pivotal studies. It generally occur when the drug regulatory authority has cause to suspect particular researchs conduct i.e. For-cause Audit
31Audit 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
32Tips 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
33Audit Procedures
- Pre Audit Procedure
- During Audit Procedure
- After Audit Procedure
34Pre-Audit preparation
- 1) CRC Preparation
- Notify all staff involved in study about the
audit with date, time duration of the audit. - Ensure the Investigators 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
35Pre-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 CRAs 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
36Pre-Audit preparation Cont..
- 2) CRAs 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
37Pre-Audit preparation
- 3) Auditors 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
38Audit 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
39Audit 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
40Audit Procedure (During) cont.
- 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
41Audit 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
42After 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
43Dos
- Inspector should present a Form FDA 482 Notice
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 inspectors notes
regarding adverse findings.
44Dos (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.
45Dos (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
46Do 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
47Do 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.
48Key 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
49Multiple choice questions
- 1) Audit is
- Systemic examination of trial
- Independent examination of trial
- Both of above
- None of above
- 2) Purpose of audit trial conduct and
compliance with - GCP and regulatory authorities
- Protocol and Sponsor SOP
- Quality System
- All of the above
50Multiple choice questions
- 3) Manufacturing, packaging, labeling and coding
of the investigational product must be compliance
with - GCP
- GMP
- Both of the above
- None of the above
- 4) What documents not to be show during
audit/inspection - Certifications or accreditation of labs
- Normal value(s)/ranges for medical/laboratory
tests - Monitor and CRC appraisal letter
- All of the above
51Multiple choice questions
- 5) What to be audited from following
- Decoding procedures for blinded trials
- Financial disclosure of Investigator
- Salary structure of CRC and CRA
- Both (a) (b)
- Both (a) (c)
- 6) Inspection is done by
- Sponsor
- Regulatory authority
- CRO
- Pharmaceutical Industries
- All of the above
52Multiple choice questions
- 7) A summary report of inspectional observations
is done on - Form 482
- Form 483
- Form 1571
- Form 1572
-
- 8) Inspectors are employed by Sponsor/CRO for the
purpose of - Audit
- Inspection
- Both of the above
- None of the above
53Multiple choice questions
- 9) Notice of Inspection is to be report on
- Form 482
- Form 483
- Form 1571
- Form 1572
-
- 10) Inspectors are employed by government/Regulato
ry authority for the purpose of - Audit
- Inspection
- Both of the above
- None of the above
54Multiple 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 - For cause audit
- For cause inspection
- Routine audit
- Routine inspection
- 12) Sponsor want to ensure that a site is
complying with Protocol, SOP, GCP and applicable
regulatory requirements, Procedure referred as - For cause audit
- For cause inspection
- Routine audit
- Routine inspection
55Multiple choice questions
- 13) For Cause Audit is
- Investigator oriented Audit
- Study-oriented Audit
- None of the above
- All of the above
- 14) 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
- None of the above
- All of the above
56Multiple choice questions
- 15) During audit, auditor must be present
- Photo ID and Form 483
- Photo ID
- Form 482
- Photo ID and Form 482
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