Tipologie di Audit e loro caratteristiche

Riunione sottogruppo GCP-GIQAR

21 Marzo 2006

Francesca Bucchi

Clinical Study Documents Clinical Study Documents e.g. Protocol, Clinical Study e.g. Protocol, Clinical Study Reports, IB, RegulatoryReports, IB, RegulatorySubmissions Submissions

ORIENTATED TOWARDS

Investigator sitesInvestigator sites

Internal FacilitiesInternal FacilitiesClinical Pharmacology UnitsClinical Pharmacology UnitsArchiveArchive

System AuditsSystem AuditsEgEg, Pharmacovigilance,, Pharmacovigilance,

Study ManagementStudy Management

CROsCROs/Labs/Other /Labs/Other facilitiesfacilitiesE.g. Quintiles, IVRSE.g. Quintiles, IVRS

Clinical Study Clinical Study DatabasesDatabases

Scope of Sponsor Audit ActivityScope of Sponsor Audit Activity

Computer Systems Computer Systems ValidationValidation

Investigational Product Investigational Product Distribution Sites Distribution Sites Joint audit programme with Joint audit programme with GMP QA GMP QA

G lo b a l C Q A

IB /C S P */C S R /H L D s/o th er d o cu m en ts- firs t h um an d os ing - p ivo ta l p hase II/III - B io eq u iva len ce - 10% o f o thers* inc lud in g In form ed C onsent & C R F

W hat is A u d ited?

In vestig a to r S ites- reg u la to ry su bm iss io n

s ta tus- p rio rity o f the p ro jec t in

R & D p ortfo lio- p ivo ta l s ta tus o f s tud y

A straZ en eca F ac ilitiesC lin ica l P harm aco log y U n it,A rch ive , M arke tin g C om p an ies , e tc

S ystem A u d itsA dverse E ven t R ep ortin gIn fo rm ed C on sent P ro cess e tc

C R O s/L ab s/o th er fac ilitiesC ovance , Q u in tiles e tc

D atab ases- p ivo ta l p hase II/III - b io eq u iva len ce- 10% o f o th ers

P ro jec t aud ito rs S ystem s/C R O /Lab g roup

PROCEDURES1 - Preparing for the Audit

2 - Conducting the Audit

3 - Reporting the Audit

15 working days

Draft Report Issued

15 working days

Responses Provided

Responses Reviewed/Accepted

Final Report Issued

Reporting of an Audit

CRITICAL OBSERVATIONS:

Deficiencies or lack of compliance with Company Standards, GCP or current regulatory requirements or expectations that provide an immediate and significant risk to products, patient safety or data integrity and/or which may have major impact on acceptability of the product and/or data from a regulatory authority standpoint.

SIGNIFICANT OBSERVATIONS:

Deficiencies or lack of compliance with Company Standards, GCP or current regulatory requirements or expectations that provide a potentially significant risk to products, patient safety or data integrity or could potentially result in significant observations from a regulatory authority.

·

*

PROCEDURAL RECOMMENDATIONS:

Procedural observations pertain to lack of documented procedure.

They describe issues that may require amendments to be made to

SOPs or a procedure to be put in place to avoid a recurrence.

Reporting of an Audit (cont’d)

Responsibilities• Lead Auditor:

Will facilitate organising, conducting and reporting of the audit. He/she will lead the audit activities and will prepare the audit report

• PSA (Project Specific Auditor)

In line with Line Management is responsible for:

- Development of the audit programme

- Being the focal point of contact with the clinical teams for audits

- Ensuring that auditors conducting audits are aware of project related audit issues

Responsibilities (cont’d)

• Process Owner:

He/she is responsible for Harmonisation of all operational activities of the process, including its development and improvement

SYSTEMS AUDITS

What are Global Systems What are Global Systems Audits?Audits?

A systems audit is a review of the organisation, procedures and documentation related to a selected system, or an examination of a process or group of processes that result in an end product.

Why a “systems” approachWhy a “systems” approach ??

• All work is process driven and the systems approach focuses on auditing the process

• It can act as key fact finding tool for process improvement

• It can provide an evaluation of interfaces within Sponsor, and between Sponsor and preferred providers

• It can assess of cross-functional consistency in a global organisation

Some of the key areas for which a systems approach would be adopted include:

• Process Management and Training

• Trial Management

• Monitoring

• Data Management

• Safety Management

• Investigational Product (IP) Management

• Archiving of Essential Documents

• Computerised systems

How are they performed?How are they performed?

Systems audits may consist of visit-based audits covering a number of locations or desk-based from the CQA offices.

The audits may be conducted as a combination of documentation review, questionnaires and/or Interview

Audit ProcedureAudit ProcedurePreparation• Assign Audit Team• Identify Audit Sponsor (global/local)• Define scope of the audit• Define audit references and standards• Develop audit plan & tools (e.g. audit method

questionnaires, checklists, agenda)• Identify audit sample• Notification – early enough to ensure that personnel

involved are available• Request for documentation

Audit ProcedureAudit Procedure (cont’d)Conducting the Audit• Audit may involve visits to one or more Sponsor sites or

may be conducted via telephone discussions and review of documents only

• Duration – between 2 and 4 days per site• Balance between discussions, review of documents and

review of facilities• Discussions – encouraging staff to explain their daily

work, understanding the issue & root cause• Focus is not on the individual• Review of documents – e.g. procedures, training

records, CVs, job descriptions, documents related to the system audited

• Review of facilities – e.g. archive

Audit ProcedureAudit Procedure (cont’d)

Reporting and Follow-up

• Initial feedback at the end of the audit

• Draft audit report issued to Audit Sponsor for responding

• Final report includes responses and actions

• Audit Sponsor responsible for follow-up audit findings

Investigator Site Audits

ABC HOSPITAL

Why Investigator Sites?Why Investigator Sites?

• Obligation to ensure that studies are conducted to the relevant national and international laws

• Obligation to ensure that studies are conducted to GCP

• Assurance that the company and investigator sites would stand up to a regulatory inspection

• Which studies?– regulatory submission status– priority of the project in R&D portfolio– pivotal status of study

• Which centres?– 1 - 15%

Investigator Site AuditsInvestigator Site Audits

Investigator Site AuditsInvestigator Site Audits• Selection of investigator sites is based on:

RecruitmentSite workloadSite with new investigator, monitoring staff or

using new systemsCoordinating investigator sitesRequests from study teams/compliance concerns

(“For cause”)

How are they performed?

• Examination of 3 basic aspects– Nature of the investigator’s conduct of the

study– The interaction between the monitor and the

investigator– Patient source data that supports entries on the

CRF• In 2 steps

– At monitor’s office – At study site

Investigator Site AuditsInvestigator Site Audits

What happens at the investigator site?

OPENING MEETING

• Introductions

• Objectives

• Audit procedure

• Investigator interview

• Role of staffINVESTIGATOR FILE AUDIT

SOURCE DATA VERIFICATION

DRUG STORAGE/DISPENSING ACCOUNTABILITY

EXIT MEETING

• Verbal feedback - key audit observations

• Clarify any outstanding issues

• Auditor notes investigator’s comments

• Thank site staff

TOUR OF STUDY RELATED FACILITIES / EQUIPMENT

DOCUMENT AUDITS

Scope of Document AuditsScope of Document AuditsThe document audits refer but are not limited to:- High Level Documents (HLDs) (integrated summary

of data across studies for a particular section of a regulatory submission)

- Investigator’s Brochures (IBs)- Clinical Study Protocols (CSPs)- Clinical Study Reports (CSRs) The quality of the document is assessed for

internal consistency and against appropriate source documents, further to GCP and applicable regulatory requirements

How are they performed?

• Review against relevant clinical SOPs, guidelines, templates, etc.

• Check for completeness and logic

• A review of the text for accuracy and consistency

• A review against the source

DATABASE AUDITS

SCOPESCOPE

• It is limited to the information in the clinical study database and the supporting documentation for the process from database set up to clean file

• The audit of one database is divided into blocks and may be staged over time

PROCEDUREPROCEDURE

• Audit Structure

It will be conducted in 3 blocks:

1) To verify presence and approval of a selection of DM documentation for the study

2) To verify data with clean data status from data entry site

3) To verify data that have completed central validation and to verify selected DM documentation

PROCEDUREPROCEDURE

• Electronic Data Capture

For studies using Web Based Data Capture the procedure will be adjusted by omitting the verification of clean data from blocks 2 and 3

Audit of Clinical Research Organisations and Clinical

Laboratories

This audit covers but is not limited to:

• Clinical Research Organisations (CROs)

• Academic Research Organisations

• Site Management Organisations

• Collaborative Research Groups

• Clinical Laboratories (Labs)

• Other external provides of services such as IVRS, e-clinical technologies, etc.

• Clinical Pharmacology Units (CPUs)

SCOPE OF THE AUDIT

It may be one of 3 types:

• Initial assessment audit of capabilities before work is transferred to the CRO/Lab

• Follow-up of assessment of ongoing activities

• For-cause audit where specific problems have been highlighted