NHS R&D Forum Clinical Trial Workshop

1. NHS R&D Forum Clinical Trial Workshop

2. DH/ MRC Joint Project Peter Dukes Head – Infections & Immunity Section Responsibility - Research Governance / EU CTD

3. 2003 – Trialists Concerns • Impact Assessment • Feb 2003 - MHRA consultation on draft Regulations • May 2003 - MRC, CRUK, NCCHTA Impact Assessment • “Showstoppers” • Sponsorship • Single sponsor = industry model • Red tape • Extensive scope of the Directive • Complexity & duplication • Inappropriate prescription • Uncertainty • Law: Legal versus good practice requirements • Procedures • Risks of hiatus & mis-interpretation

4. UK progress on “showstoppers” Single Sponsor Model Your concerns • Industry model Status now • Sponsor may be a group • Joint responsibility • Allocated, separate responsibilities • International multicentre trials • Need better to understand how sponsorship works across several MSs

5. UK progress on “showstoppers” • Red tape • Status now • Extensive scope • Boundaries unclear • MHRA algorithm “with the lawyers” • Complexity & duplication • Trial no. = easy; authorisation = ? • Inappropriate prescription • MHRA (and EU draft GCP): law = principles of ICH GCP • GCP & pharmacovigilance: MHRA committed to risk based systems

6. UK progress on “showstoppers” • Uncertainty • Status now • Law versus guidelines • GMP finalised • GCP Directive still in draft • Recognises academic trials • Only the principles of ICH GCP will be law • Most EC guidelines finalised (= OK?) • Procedures • Transition arrangements – CTAs, DDXs rolled over • World didn’t end on 1 May 2005 • EMEA systems (developing OK?) • Risk of hiatus & mis-interpretation • MHRA contact point and FAQs • Joint DH/MRC Project outputs • Many organisations not up to speed

7. “Joint Project” aims • DH/MRC Joint Project to Codify Best Practice in Publicly-funded Trials • To support trialists, R&D managers & regulators • To enhance good practice • Current Website http://www.ncchta.org/eudirective/index.asp

8. Joint project work stream • Six (+ one) work streams • Systems – Peter Dukes • Quality partnerships – Marc Taylor • Sponsorship • Insurance & indemnity • Institutional trials portfolio management – Noreen Caine • Trial initiation to commencement – Barbara Farrell & Maxine Stead • Trial management & monitoring – Sarah Meredith • Trial supplies – Keith Preece • Pharmacovigilance – Simon Dyer &…

14. CLINICAL TRIALS AUTHORISATION

15. EU Clinical Trial Directive Overview • What is the Directive? • CTA Applications • Substantial Amendments • End of Trial • Summary

16. EU Clinical Trial Directive DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL 4 April 2001 on the approximation of the laws, regulations and administrative provisions of Member States relating to implementation of good clinical practice in the conduct of clinical trials

17. EU Clinical Trial Directive • Directive 2001/20/EC of the European Parliament and of the Council 04 April 2001 • Published in the Official Journal 01 May 2001 • Transposed in national legislation 01 May 2003 • Implemented 01 May 2004

18. What is the Directive ? The Directive • provides a definition of a clinical trial and for Investigational Medicinal Products • applies to all clinical trials of medicinal products • commercial and non commercial, • volunteers and patients • provides statutory basis for ethics committees • introduces timeframes • standardised documentation

19. What is the Directive ? The Directive (continued) • provides statutory basis for Good Clinical Practice • requires manufacture of Investigational Medicinal Products in compliance with Good Manufacturing Practice • provides statutory basis for inspections to verify compliance with GMP/GCP

20. What is the Directive ? The Directive (continued) • details responsibilities for sponsors and investigators in reporting of Adverse Drug Reactions/Adverse Drug Experiences • describes European clinical trial (EudraCT) and pharmacovigilance (EudraVigilance) databases

21. UK Regulations • A new Statutory Instrument was required to transpose the Directive into UK legislation • The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004 No. 1031) • Laid before Parliament 01 April 2004 • In force 01 May 2004

22. DDX,CTX/CTAs CTX, CTC, CTMP, DDX all replaced by CTA • CTCs, CTXs, DDXs and CTMPs approved before transitional arrangements ‘rolled over’ into CTAs • Healthy volunteer Phase 1 studies ongoing on 01 May 2004 required CTA • During the transition (April) applications made for either a CTX or a CTA

23. Clinical Trial What is a Clinical Trial? any investigation in human subjects, other than non-interventional trial intended • to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more IMP(s), • and/or to identify any adverse reactions to one or more IMP(s) • and/or to study absorption, distribution or metabolism and excretion of one or more IMP(s) with the object of ascertaining its (their) safety and/or efficacy

24. Medicine What is a Medicinal Product? • Any substance or combination of substances presented for treating or preventing disease in human beings. • Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or modifying, physiological functions in human beings. (substance – any matter irrespective of origin e.g. human, animal, vegetable or chemical)

25. Investigational Medicinal Product What is an Investigational Medicinal Product? a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but • used or assembled (formulated or packaged) in a way different from the authorised form • used for an unauthorised indication • used to gain further information about the authorised form

26. CTA Application • requirements for the submission to the Competent Authority are laid out in the Commission guidance note (ENTR/CT 1) • requirements not identical across all Member States • Attachment 1 to Guidance lists requirements

27. EudraCT • European Clinical Trials database https://eudract1.emea.eu.int/eudract/mainPage.do • Application forms • Copies of the Directive and Guidance notes • Data confidential to Regulatory bodies in MS, EMEA and Commission to share trial data throughout EU

28. Application Form 12 Pages Checkbox/Text Annex 1 A. Trial ID B. Sponsor ID C. Applicant ID D. Information on IMP E. Information on Placebo F. Site responsible for IMP release G. Information on Trial H. Population of Trial subjects I. Proposed sites/labs ( I4 - shared Sponsorship) J. Information on REC K. Checklist L. Signature

29. Accompanying data Core Information: • receipt of confirmation of EUDRACT number • covering letter • application form • xml file on disc • protocol with all current amendments • SmPC (for products with marketing authorisation in the Community)

30. Accompanying data Core Information/continued: • investigator’s brochure • investigational medicinal product dossier • simplified IPMD for known products • list of CAs to which application has been submitted and details of decisions • copy of EC opinion when available

31. Accompanying data UK Specific Information: Protocol related • summary of protocol • outline of all active trials with same IMP

32. Accompanying data IMP related • copy of manufacturer’s authorisation or QP declaration of GMP equivalent to EU GMP • copy of importer authorisation (if relevant) • viral safety studies • samples of labels in national language • applicable authorisations to cover trials or product with special characteristics (if available) • TSE certificate • declaration of GMP status of active biological substance

33. Phase 1 (HVT) Ph 1/2/3 patient trial, product unknown Ph 1/2/3 patient trial, product known Ph 1/2/3 patient trial, cross referral Phase 4 Additional protocol 610 2700 2250 140 140 100 Fees Fee

34. Assessment Process • Application validated • Acknowledgement letter • MHRA has 30 days from receipt of valid application • Approval or ‘Grounds for Non Acceptance’ (GNA) letter • Sponsor has 14 days to address GNA issues raised • MHRA response by day 60 (from original receipt) Approval or Rejection letter Parallel process and same timelines as for Ethics Committee opinion

35. Amendments • Amendments to the protocol and/or supporting data are subdivided into substantial and non-substantial • Only substantial amendments need to be approved by the CA and/or EC • Attachment 5 to Guidance lists criteria • Needs updated xml file if changes to the original are being made

36. Substantial Amendments Form Annex 2 4 Pages A. Trial, Amendment ID B. Sponsor ID C. Applicant ID D. Type of Amendment E. Reasons for Amendment (one or two sentences) F. Brief Description of changes G. List of docs appended H. I. Signature

37. Additional investigator site Protocol changes Changes to the IMP dossier 1 section 2 sections 3 sections Annual service fee nil nil 100 200 300 200 Fees Fee

38. End of Trial • Article 10 (c) of the Directive and regulation 27 of the UK Statutory Instrument • Sponsor has legal requirement to notify the Competent Authority of the End of the Trial within 90 days of completion • Summary of clinical trial report within 1 year Sponsor continues to be liable for Annual Service Fee until ‘End of Trial’ form received by MHRA

39. End of Trial Form Annex 3 2 pages Trial ID Applicant ID End of Trial declaration date premature or temporary (+ reasons) Signature

40. Summary • Single application form for all medicinal clinical trials and amendments • Same data as required for ethics application and same timelines • Where possible checkboxes used to simplify form filling • ‘How to do a CTA application’ is on the MHRA website

41. Joint Project on clinical trials: quality partnerships Marc Taylor, Department of Health marc.taylor@doh.gsi.gov.uk www.ncchta.org/eudirective/ MRC/DH joint project

42. Why did this work matter? • £3.5 billion pharmaceutical R&D in UK • 2,500 pre-licensing industry trials in 2001/02 • UK tradition of collaborative publicly funded clinical trials • 1,100 NHS trials registered with Current Controlled Trials • UK Clinical Research Collaboration • NHS research networks in mental health, children diabetes, Alzheimer’s, stroke • Risk-based, proportionate regulation MRC/DH joint project

45. Sponsorship & other responsibilities • Collaborative partnerships and sponsorship • Responsibilities under the UK Regulations • Can a person be a group? • More about groups as sponsors • What are the sponsorship responsibilities? • What about investigators? • What’s new,what isn’t: insurance and indemnity MRC/DH joint project

46. EMEA MHRA Ethics committees Manufacturers or importers sponsors Chief investigators Trial suppliers Qualified persons investigators Those performing sponsor’s functions Figure 1 Roles under the UK Regulations MRC/DH joint project

47. Sponsor can be a person or group • Directive defines sponsor as individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a clinical trial. • Does not have to be the funding organisation. • Can be a single sponsor, like a pharmaceutical company. • A group can take on roles and responsibilities of sponsorship. • Parties to group could agree in writing to allocate these roles and responsibilities to particular persons and organisations. • Each then responsible for roles and responsibilities it takes on. MRC/DH joint project

48. When the sponsor is a group • Investigator could take on some sponsorship responsibilities. • Sponsors could delegate responsibilities for which they remain ultimately responsible. • Sponsor (or group) should define, establish and allocate all trial-related duties and functions. • Protocol should include a scheme of allocation and delegation. • UK Regulations enable a group requesting a CTA to allocate responsibilities of sponsorship in three sets: Pharmacovigilance Authorisation GCP & conduct MRC/DH joint project

49. Group sponsor MRC/DH joint project

50. Sponsorship responsibilities: authorisation Make arrangements to... • Request a Clinical Trial Authorisation • Arrange undertakings about inspection • Notify MHRA and ethics committee of • substantial amendments to the CTA • substantial amendments to the protocol • the end of the trial MRC/DH joint project