Introduction

1. Impact of the Clinical Trials Directive and Subsequent UK Clinical Trials Statutory Instrument on the Clinical Chemistry/Bioanalytical Laboratory

2. Introduction • So what are these “New Laws” • Requirements of the New Laws • Impact upon laboratories • GCLP as a possible solution • UK GCP Inspections so far

3. The “New Law” • ICH GCP • EU Clinical Trials Directive • EU Member states Introduce Laws • UK Statutory Instrument covering Clinical Trials • Imminent “EU Good Clinical Practice Directive”

4. GCP Guidelines ICH Good Clinical Practice Guidelines (ICH, International Conference on Harmonisation) An International ethical and scientific quality standard. Standard for designing, conducting, recording and reporting trials. Effective 1997 ICH is not a Regulatory or Receiving Authority

5. GCP Regulations EU Clinical Trials (CT) Directive Directive number 2001/20EC Members States to Publish laws covering GCP by 1st May 2003 To implement these laws by 1st May 2004 Also requires member states to establish an Inspection programme to monitor compliance

6. GCP Regulations UK MCA The Medicines for Human Use (Clinical Trials) Regulation 2004 Statutory Instrument 1031 UK Law covering GCP 100 plus page document Covers ALL clinical research using IMPs Adopting ICH GCP Guidelines Effective 1st May 2004

7. UK position and possible developments • Inspection team to conduct audits every 2-3 years. • GCP and Pharmcovigilance inspection teams up and running • Routine Inspections now on-going • GCP Inspection team up to 8 people and growing

8. Requirements of these “Laws” • When it comes to the Laboratory requirements they are consistent. • In terms of conduct of a trial ICH GCP is the stated standard or more accurately the “Principles” to be followed. • So what does ICH GCP say?

9. What does ICH GCP say about laboratories • 2.13 “Systems with procedures that assure the quality of every aspect of the trial should be implemented” • 8.2.12 Essential Documents: “Medical/Laboratory/Technical procedures/Tests • -certification or accreditation or established quality control and /or external quality assessment or other validation (where required) • 8.3.7. Any updates of the above.

10. GCP Requirements for Labs OK, so you need a little imagination! However the principle is that: Documented systems should be in place to assure the quality of the work of the laboratory. Laboratories should have established QC and QA procedures to ensure the validity of the results produced.

11. GCP Regulations EU Good Clinical Practice Directive Directive for comment issued July 2004 Comments due to be received by September 2004.

12. Impact Upon Laboratories • Only impacts on laboratories which undertake the analysis of samples from a “clinical trial”. • So what is a clinical trial? • Under the law a clinical trial is one which involves and IMP (Investigational Medicinal Product)

13. Labs working on Clinical Trials • If your lab does analyse samples from clinical trials then you are subject to the law and inspection for compliance with its requirements. • From previous slides you are now aware of these requirements !!!!!

14. How will THEY know • As part of the implementation of GCP the “Competent Authorities” have established a database of all trials across Europe. • As a Sponsor of a Clinical Trial you must obtain a Clinical Trial Number. (EUDRACT Number)

15. EUDRACT Issue of “Clinical Trial Number” as part of Regulatory Approval. Required to identify any facilities, including laboratories employed during a trial, in the EUDRACT application. System up and running

16. Accreditation • My lab has accreditation so am alright! • Well no your not. • Most accreditation will cover the science part but not the compliance areas. • GCP Inspector have particular requirements which CAP and the accreditation schemes do not.

17. I am a GLP Lab • So what, different Regulations and different requirements with different Inspectorate. • At present in the UK the fact that you may be part of the GLP monitoring program does not have any legal benefit when it come to GCP.

18. Difference between GLP and GCP in the lab • Different laws • Different roles and responsibilities • Different reporting mechanisms • Claim of compliance • Standards in conduct (science) however is the same

19. What are some of the differences • Regulations • Approval • Plans • Conduct • Reporting • Quality Assurance

20. Why do we need GCLP • To assist laboratories understand the regulatory requirements • To define a quality standard for laboratories undertaking the analysis of samples from clinical trials which meets the regulatory requirements.

21. The objectives of GCLP • The scientific standards are no different to GLP. • Protocol and reporting procedures can be different between GLP and GCP. • GCLP is GLP with the Toxicology bits removed and the clinical parts added.

22. The scope of GCLP • The principles identified within the document should be interpreted and applied to any laboratory that undertake the analysis of samples generated during the conduct of a clinical trial. • GCLP is not the same as proficiency testing schemes.

23. Content of GCLP Principles • Organisation and Personnel • Facilities • Equipment materials and reagents • Standard Operating Procedures (SOP) • Planning, Conduct and Reporting • Quality Control and Quality Audit • Retention of study records and reports.

24. MHRA GCP Inspections Statutory GCP Inspections from 1st May 2004, 19 to date: • 6 Pharmaceutical companies • 5 Investigator sites • 3 Phase I Units • 2 Niche Providers • 1 Laboratory • 1 non-commercial organisation • 1 CRO

25. MHRA GCP Systems Inspections Project management Contracting/Sub-contracting Quality Assurance Monitoring Training Pharmacovigilance Computer systems Data management Statistical Analysis Report writing Regulatory submissions Archiving Medical Advisors Laboratory Investigational medicinal product management Essential documents for selected clinical trial plus visits to selected investigational sites

26. MHRA Inspection Findings Most frequent non-compliances from the Statutory Programme

27. UK MHRA GCP Inspection Findings Contracts, agreements and insurance • Contracts not in place • Responsibilities not clearly defined • Unclear ownership of documents and data • Lack of consistency between protocol and contract • Insurance includes exemptions which may not cover certain patient populations

28. UK MHRA GCP Inspection Findings Quality Systems • Lack of essential SOPs • SOPs not updated • SOPs do not reflect current practice or current legislation • Insufficient time between SOP issues and becoming effective, which leads to training issues • Lack of QA activity, no involvement in vendor selection • Meetings and decisions not documented

29. UK MHRA GCP Inspection Findings Miscellaneous Findings • Lack of validation of computer systems • Uncontrolled database unlock • Lack of GCP training • Lack of calibration of equipment • Unidentified or unexpected laboratory samples analysed for a range of tests - this may be outside the protocol and therefore without consent.

30. Summary • If your Lab is involved in the analysis of samples from a clinical trial then there will be an impact. • You will need to know what the requirements of GCP in the lab are. • System you operate will need to comply with the Law • Staff will need to know the law and its requirements.