gcp audit and inspection - are you ready

1. GCP AUDIT AND INSPECTION - ARE YOU READY ? Joan Perou November 2005

3. Inspection The act by a Competent Authority of conducting an official review of documents, facilities, records, quality assurance arrangements, and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at the site of the trial at the sponsor�s and/or contract research organisations�s facilities or at other establishments which the competent authority sees fit to inspect EU Directive 2(l) ICH 1.29

4. EU Directive on GCP in Clinical Trials (2001/20/EC) Verification of compliance (Article 15) Member states shall appoint inspectors to verify compliance with GCP and GMP at any time before, during, after the trial at: trial sites manufacturing site of investigational product laboratories used for analyses sponsor premises

5. The Role of the European Medicines Agency European Medicines Evaluation Agency (EMEA) based in London. Referred to as �The Agency� in the Directive. The European Medicines Evaluation Agency changed its name in 2004 to become the European Medicines Agency �Inspections may be requested and coordinated by the European Medicines Agency� (Directive 2005/28) In Directive 2001/20 The EMEA is referred to sometimes by its full name and sometimes as the Agency. In Directive 2005/28 the European Medicines Agency is referred to. They are the same organisation. They changed their name in 2004 from the European Medicines Evaluation Agency to the European Medicines Agency. The are a European organisation, coincidentally based in London. They are responsible for co-ordinating inspections within Member States.In Directive 2001/20 The EMEA is referred to sometimes by its full name and sometimes as the Agency. In Directive 2005/28 the European Medicines Agency is referred to. They are the same organisation. They changed their name in 2004 from the European Medicines Evaluation Agency to the European Medicines Agency. The are a European organisation, coincidentally based in London. They are responsible for co-ordinating inspections within Member States.

6. The Medicines and Healthcare products Regulatory Agency (MHRA) UK �Competent Authority� (CA) Based in London Grants licences to conduct trials Monitors safety aspects of trials Provides enforcement - mandatory inspections started 1 May 2004 The Medicines and Healthcare Products Regulatory Agency are the U.K. competent authority responsible. They are based in London Give licences to conduct clinical trials, the CTAs Monitor safety aspects of trials Inspect predominately U.K. studies but will also inspect centres that are part of a multi-centre study if requested to do so by the EMAThe Medicines and Healthcare Products Regulatory Agency are the U.K. competent authority responsible. They are based in London Give licences to conduct clinical trials, the CTAs Monitor safety aspects of trials Inspect predominately U.K. studies but will also inspect centres that are part of a multi-centre study if requested to do so by the EMA

7. Types of Inspection Trial related Systems �For Cause� �Voluntary Inspection (finished April 2004) What types of inspection: Trial related where the inspectors will mainly review trial data and will track the audit trail � from the very start of the study right along the path of the trial. Inspectors will check the dates, example the date of the final protocol, when the protocol was given approval through the various agencies. The dates the supplies were sent to the centre, the dates the patients were entered etc. Dates, version numbers are all expected to be consistent. A systems inspection is where processes and procedures are checked to make sure that for instance proper Standard Operating Procedures are in place to allow consistent working practices in compliance with GCP For cause is where there is an inspection scheduled for a reason. The Inspectors arrive because they believe there are issues of non-GCP compliance that they need to investigate further. The voluntary inspection programme in the U.K. finished in April 2004. Under the voluntary scheme pharma companies, contract research organisations and trial sites were able to volunteer to host an inspection to enable them to ascertain their own strengths and weaknesses prior to the mandatory inspections taking place. This scheme finished on 30 April when the mandatory inspections startedWhat types of inspection: Trial related where the inspectors will mainly review trial data and will track the audit trail � from the very start of the study right along the path of the trial. Inspectors will check the dates, example the date of the final protocol, when the protocol was given approval through the various agencies. The dates the supplies were sent to the centre, the dates the patients were entered etc. Dates, version numbers are all expected to be consistent. A systems inspection is where processes and procedures are checked to make sure that for instance proper Standard Operating Procedures are in place to allow consistent working practices in compliance with GCP For cause is where there is an inspection scheduled for a reason. The Inspectors arrive because they believe there are issues of non-GCP compliance that they need to investigate further. The voluntary inspection programme in the U.K. finished in April 2004. Under the voluntary scheme pharma companies, contract research organisations and trial sites were able to volunteer to host an inspection to enable them to ascertain their own strengths and weaknesses prior to the mandatory inspections taking place. This scheme finished on 30 April when the mandatory inspections started

8. Inspection Preparation Refer to SOPs Appoint Inspection Co-ordinator Contact with the MHRA Respond to document requests from MHRA Training (including inspection training!) Ensure CVs, job descriptions are current Progress meetings with everyone involved Personal preparation

9. Inspection Preparation Documentation Review and learn SOPs on documentation/process Document review - on selected trials File notes �Tidy up� of files and filing area Clear and consistent labelling Security/access to documents Correct terminology - archive or storage area ? Archives

10. Inspection Preparation Centre Communication between PI, study team, sponsor Update training for investigator and study team - regulatory and study specific Check CVs and training records and update to include latest training Check Investigator Site Files � emails should be printed off and all documentation up to date and compliant with Essential Documents Check IMP - storage/temperature logs, accountability Check equipment - calibration and servicing Ensure copies of ICH and the Directive are available

11. GCP Inspection Inspection Day Inspectors will work to Inspection Plan Appointed co-ordinator should be available to assist Inspectors throughout Facilities Check Pre-inspection meeting Interviews - according to Inspection Plan Process and document review

12. Inspection Process Background information Interview technique Facilities information Documentation � records, files, patient notes Systems � processes and SOPs Equipment check � calibration and servicing

13. Post- Inspection Close-out meeting Findings discussed Report issued Actions from report finalised

14. What are the Inspectors looking for ? Evidence of compliance and Total Quality Management Systems Documents: Data trail required Dates and version numbers of documents Evidence of distribution/receipt and document control systems Clear labelling/indices on files General tidiness, file notes if necessary but no yellow stickies !

15. What are the Inspectors looking for ? Evidence of compliance and Total Quality Management Systems Standard Operating Procedures/processes should be: GCP Compliant Reflect current working practices Controlled, updated, managed Implemented only after training

16. What are the Inspectors looking for ? Evidence of compliance and Total Quality Management Systems Databases Archiving Contracts Training records/CVs SOPs for related departments Communication flow across departments Equipment Security Emergency out of hours procedures

17. ICH E6 GCP Document 1.0 Definitions 2.0 Principles of ICH GCP 3.0 Ethics Committees 4.0 Investigator Responsibilities 5.0 Sponsor Responsibilities 6.0 Protocol/Amendments Format 7.0 Investigator Brochure Format 8.0 Essential Documents

18. Essential Documents are those documents which individually and collectively permit evaluation of the conduct of the trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.

19. Files and Procedures Standard Operating Procedures (SOPS) (Provide overall guidance/policy) Department or clinical trial unit processes (Detail working procedures) Trial Master File (maintained by Sponsor) Investigator Centre File (maintained by Investigator/study team)

20. ICH E6 GCP DocumentSection 8.0 on Essential Documents 8.2 Lists all those documents that must be on file prior to start of study 8.3 Lists all those documents which may require updating during the course of the study 8.4 Lists all those documents which need to be added to the other two sections at the end of the study to complete the Trial Master File prior to archiving.

21. The Centre Investigator File Sample list (see ICH 8.0 for complete list) Investigator Brochure (current version) Final Protocol + amendments (all signed and dated) Ethics Committee documentation Study correspondence Original signed consent form(s) for each patient CV of Investigator and study team Delegation log/signature record Serious adverse event reports (copies) Laboratory normal ranges/methods

22. Sample only - see ICH 8.0 for complete list Patient Enrolment Log Training certificates for study team Calibration certificates for study equipment Randomisation codes Monitoring visit log Subject screening log Drug receipt/dispensing documentation

23. Ensure the staff delegation log is up to date: Should list names of staff delegated to each procedure Should reflect the current situation Should be signed by the investigator, and updated when appropriate throughout trial. Copy available in Trial Master File (sponsor) and Investigator Site File If new staff are recruited the list should be updated, but old versions must not be destroyed.

24. Investigator Brochure Mandatory requirement for trials using unlicensed products. The most recent version should be held on file at centre A log on file should track previous versions if removed Safety update letters should be filed together with Investigator Brochures. Updated versions of the Investigator Brochures should include the safety updates. Investigator Brochures should be updated at least annually.

25. Amendments Any change to the protocol is an amendment All �substantial� amendments must be sent to ethics committees and the MHRA There must be a letter of favourable opinion from the ethics committee (within 35 days) before the amendment can be implemented . The MHRA will not review all amendments but the ethics committee will given an opinion. It is important that all amendments are tracked so that their status is known.

26. Inspectors will check the following have been obtained: Clinical Trial Authorisation from Competent Authority Favourable opinion from a Recognised ethics committee Opinion on suitability of local investigator and facilities from local ethics committee Permission from NHS Trust for trial to take place within that Trust (R & D approval) Eudract number from the Eudract database for all trials which commenced after 1st May 2004

27. CRITICAL MAJOR OTHER

28. Inspection Findings Centre: Absence of investigator from trial related duties/monitoring visits - heavy delegation Inappropriate delegation of duties. Dating of consent form by inappropriate person Inadequate training records/CVS Insufficient certificates/calibration of equipment. Temperature logs not kept for investigational product

29. Inspection Feedback MHRA requested: Index of SOPs Organigrams Summary of responsibility of departments involved in clinical trials Overview of Trust arrangements for trials Protocols, consent forms and patient information sheets for those trials selected MHRA selected names from organigrams Trust had no influence on trials selected MHRA not interested in investigator status

30. Inspection Feedback MHRA priorities (according to Bristol) Non-commercial trials Paediatric studies Investigators conducting numerous trials Greatest number of patients at risk Anything that would jeopardise patient safety Trust systems and procedures Evidence of training - certificates reviewed Procedures in place to terminate study in event of emergency situations

31. Inspection Feedback Lessons Learned Trust systems and processes must incorporate SOPs for clinical research Archiving of records must be sufficient to �reconstruct� trial if required by MHRA Disaster recovery plan must be in place in case of emergency All staff must be trained - this should include basic training for those not directly involved in research, I.e. I.T. staff and medical records staff Formulate an action plan for what you feel is not �perfect� and set a time frame for action - prepare this prior to the Inspection

32. EU Directive On GCP in Clinical Trials (2001/20/EC) Article 1 Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording and reporting clinical trials that involve the participation of human subject. Compliance with this good practice provides assurance that the rights, safety and well-being of trial subjects are protected, and that the results of the clinical trials are credible.

33. A person does not commit an offence under these Regulations if he took all reasonable precautions and exercised all due diligence to avoid the commission of that offence. Where evidence is adduced which is sufficient to raise an issue with respect to that defence, the court or jury shall assume that the defence is satisfied unless the prosecution proves beyond reasonable doubt that it is not

34. Key Messages Document everything - �if it isn�t in writing it is a rumour!� Ensure you have a verifiable �data trail� for each trial Identify all trial documents with appropriate reference numbers, dates and version numbers Work to clearly defined written processes Know your own role/responsibility and competencies Ensure you are properly trained (with training records) Ensure all safety reporting is done on time Pay extra attention to the consent procedure and documentation