OVERVIEW OF DIRECTIVE 2001/20 Paul Derbyshire Background & History CONDUCT OF TRIALS III/3976/88 (July 1991) ICH/135/95 (January 1997) 2001/20 75/318 Q,S,E Testing Part 4B: GCP 91/507 MEDICINAL PRODUCTS 65/65 Extended Codified 2001/83 75/319 CPMP GMP & PhV 91/356 GMP GCP Directive Conduct of clinical trial: No legal text on application of GCP/GMP No harmonisation between MS 2003/94 GMP 2 Aims of Directive 2001/20 Protect trial subjects Persons incapable of giving legal consent Minors & incapacitated adults Pharmacovigilance procedures monitor ADRs EUDRACT & Eudravigilance databases Improve quality of clinical research Providing a legal basis for GCP/GMP Reduce duplication in paperwork Harmonises ethics committee & competent authority requirements & procedures EUDRACT database Produce credible & reliable data GMP/GCP verification by inspection 3
Directive 2001/20 of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Implementation in 25 Member States will not be Harmonized Must follow National Law & not the Directive 4 Definition 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 is likewise considered a medicinal product. 5 Definition Clinical Trial Any investigation in human subjects 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 ADME of one or more IMP(s) with the object of ascertaining its (their) safety and/or efficacy. 6
Definition Clinical Trial Includes: All phase I IV trials: Diagnostic, Prophylactic, Therapeutic, Safety, Efficacy, Pharmacokinetic, Pharmacodynamic, Bioequivalence, Dose response, Pharmacogenomic, Pharmacoeconomic etc. Patients or healthy volunteers. Commercial or non-commercial. Excludes Non-Interventional Trials 7 Definition Non-Interventional Trial A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. Assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data. 8 Non-Interventional Study Use of licensed product within the SmPC Administration not decided by trial protocol Decision to use licensed product is clearly separate from decision to include patient in the trial No additional interventions or tests applied Data collection and analysis epidemiology Collection and analysis of data on a licensed medicinal product used within the approved SmPC during routine clinical practice 9
Definition 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, or when used for an unauthorised indication, or when used to gain further information about the authorised form. 10 Investigational Medicinal Product Test substance New active substance Licensed substance used or assembled differently Use of a licensed product for an unauthorised indication Use of a licensed product to gain further information on the product Reference substance: Placebo Active comparator 11 Investigational Medicinal Product Chemical entities Biotechnology products Cell therapy products Gene therapy products Plasma derived products Other extractive products Immunological products (vaccines, allergens, immune sera) Herbal medicinal products Radiopharmaceutical products Homeopathic products 12
Article 1- Scope: Applies to commercial & non-commercial trials Article 2 Definitions: New term non-interventional trial Article 3 Protection of subjects Subject/legal representative prior interview before consent Subject contact point? 13 Article 4 Minors Risk threshold & degree of distress defined & constantly monitored Protocol endorsed by EC with paediatric expertise/advice Article 5 Incapacitated adults Life-threatening or debilitating condition Risk threshold & degree of distress defined & constantly monitored Protocol endorsed by EC with relevant expertise/advice Benefit outweighs risk or no risk at all 14 Article 6 Ethics Committee Suitability of supporting staff Investigator payments Strict timelines single request for supplementary information Article 7 Single opinion Single EC opinion per MS 15
Article 9 Commencement of a trial Obtain a Clinical Trial Authorisation Implicit authorisation tell & wait Written authorisation Part A products & special characteristics Gene, somatic & xenogenic cell therapy & GMO Timelines amend request once during evaluation 16 Article 10 Conduct of a clinical trial Significant amendments EC opinion 35 days End of trial notification 90 days Early termination or halt 15 days Article 11 Exchange of information European clinical trial database EUDRACT Accessible only to MSs, EMEA & Commission 17 Article 13 Manufacture & Import of IMP Manufacturers/import authorisation Each MS has own timeline & procedure - < 90 days Qualified Person to ensure each batch: Manufactured in compliance with Directive 91/356 (Directive 2003/94) & Annex 13 - GMP Product Specification File & CTA Imported IMP manufactured & checked to equivalent GMP standard, PSF & CTA Imported licensed comparator: Certified manufacture to equivalent GMP or Undergone all relevant analyses, tests or checks to confirm quality in accordance with CTA Maintain a register of certified released batches 18
Article 15 Inspection verification Member States to appoint inspectors Results recognised by all Member States Inspection reports available to MSs, EMEA & Ethics Committee. Article 17 Notification of serious adverse reactions SUSARs Fatal or life-threatening 7 days Follow-up within 8 days Other SUSARs 15 days Annual report of all suspected serious ADRs Eurdravigilance clinical trial module database 19 Legal Responsibility Article 2 - Sponsor An individual, company, institution or organisation which takes responsibility for the initiation, management and/or financing of a trial. Article 19 The sponsor or legal representative must be established in the Community 20 Clinical Trial Oversight EUDRACT & Eudravigilance CA Authorisation Monitoring Declaration EC CT Declare date of Commencement Opinion BEFORE Amendments Pharmacovigilance Monitoring DURING End of trial Early termination Temporary halt Declaration AFTER GMP & GCP Inspection Verification 21
Areas Covered by 2001/20 Clinical Trial Authorisation Pharmacovigilance Ethics Approval GCP & GMP Inspections GMP of IMP Directive 2003/94 Annex 13 Directive 2001/20 GCP Directive EUDRACT & Eudravigilance Qualified Person Manufacturing & Importation Authorisation 22 Additional Directives & Guidance GCP requirements: New Directive on Principles of GCP 2005? Draft guidance on principles of GCP July 2002 Draft guidance on Trial Master File June 2002 Draft document on Manufacture/Importation Authorisation Holder requirements April 2001 GCP Inspections Draft guidance on qualification of inspectors June 2002 Draft guidance on inspection procedures June 2002 23 Additional Directives & Guidance GMP requirements: Volume 4, Annex 13 July 2003 Directive 2003/94 30 April 2004 Draft document on Manufacture/Import Authorisation application content July 2002 Final guidance documents April 2003 (Notice to Sponsors): EUDRACT database Clinical Trial Authorisation (incl. amendments & end of trial declaration) Ethics Committee Opinion Pharmacovigilance reporting Collection, verification & presentation of AEs/ARs Eudravigilance database 24
Major Implications Sponsor or legal representative must be established in the EEA EU manufacture/import sites must have an authorisation All IMPs must comply with GMP & be released by a QP All Phase I IV trials are included CTA required in all EU member states 25 Member States End of easy countries for commencement of clinical studies NL, DE, BE, UK (Phase I healthy volunteer studies) etc. Max. 60 day authorisation procedure with one amendment only Preparation and planning will need to be optimal Protocols will have to be developed to a final concept No back & forward between sponsor & EC One opportunity for response Amendment 35 day procedure Sponsor will need to comply with strict safety reporting timelines Increased level of compliance Monitoring through GCP & GMP inspections & EUDRACT 25 Impact on Clinical Research Organisations Established Pharma: Greater resources & infrastructure to adapt May place early phase studies outside EU Small Medium Sized Pharma: Most affected 10 to 25% increase costs Resources & infrastructure will be lacking QP release Investigator-driven studies less attractive Those dealing with cell or gene therapy products could face delays (180 days) Publicly-Funded Research: Requirement for a single sponsor Vastly increased costs due to additional resources & infrastructure 100 to 400% 26