audit and inspection in clinical trial

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Audit and Inspection in Clinical Trial

• Dr. Ranjeet Prasad
• (MBA,CCRP,BDS)

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OBJECTIVE

• 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

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OBJECTIVE (Conti)

• AUDIT PROCEDURES RULE
• PREPRATION FOR AUDIT
• MULTIPLE CHOICE QUESTION

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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
  sops, GCP, and Applicable regulatory
  requirements.
• (ICH-GCP Sec. 1.6)

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Purpose 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

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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

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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

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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, For Clinical Trial Use
  Only to protect blinding where applicable
• Drug Product Accountability
• Control Quantity

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What to audit (Cont)

• IRB/EC
• Responsibilities
• Composition, functions and operations
• Procedures
• Records
• Investigators and sub-investigators
• Qualifications and agreements
• Essential documents

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What 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)

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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

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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)

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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

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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

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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

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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

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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

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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

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What 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)

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Steps in FDA Inspection Process
Site Location
FDA Office

1. Select Site
2. Contact Site
3. Schedule Site

7. Present Findings 8. Depart (483)
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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.

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Difference 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.
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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

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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

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Types 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
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Routine 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

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For-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.

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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)

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What Gets Audited

• 5 Categories
• Regulatory and protocol compliance
• Subject Records
• Investigational Product
• Adverse events, SAEs or complications
• Documentation

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How 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
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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

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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

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Audit Procedures

• Pre Audit Procedure
• During Audit Procedure
• After Audit Procedure

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Pre-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

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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 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

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Pre-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

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Pre-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

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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

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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

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Audit 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

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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

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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

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Dos

• 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.

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Dos (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.

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Dos (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

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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

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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.

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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

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Multiple 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

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Multiple 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

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Multiple 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

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Multiple 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

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Multiple 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

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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
• 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

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Multiple 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

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Multiple 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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