DIA Conference Talk USA, The EU Directive - Germany
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Managing, Inspecting & Conducting Clinical Trials After the EU Directive. Germany as a Case Study . For DIA colleagues, Feb 22, 2005

Managing, Inspecting & Conducting Clinical Trials After the EU Directive. Germany as a Case Study . For DIA colleagues, Feb 22, 2005

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DIA Conference Talk USA, The EU Directive - Germany Presentation Transcript

  • 1. Managing, Inspecting, and Conducting Clinical Trials after the EU Directive Dr. Diana A. Taylor, MSc Establishing Competitive Advantage in Today’s Pharmaceutical and Biothech Industries: The Integration of Project Management, Financing, and Outsourcing Porcesses The Drug Information Association Philadelphia, USA, February 22 nd 2005
  • 2. Contents
    • The German Drug Law and Regulations: How was the EU Directive Implemented into National Law
    • Project Management: Implementing German Drug Law and Requirements into Company Processes
    • A Case Study: Practical Experience with the German Authorities
  • 3. The German Drug Law
    • A rznei m ittel g esetz, AMG
    • 6th August 2004
    • GCP-Rechtsverordnung
    • 14th August 2004
    • 3. Bekanntmachung
    • 30 August 2004
    • www.bfarm.de
    • B undesinstitut f ür Ar znei m ittel
  • 4. The German Drug Law, AMG
    • The Investigator & the Sponsor - R & R
    • The Role of the Ethics Committees
    • The Duties of the Competent Authority
    • The Inspections in Germany
  • 5. The Investigator & the Sponsor
    • § 40 (1) German Drug Law
    • The Investigator and the Sponsor have to comply with the requirements for Good Clinical Practice when conducting clinical trials according to Article 1 Paragraph 3 of the Directive 2001/20/EC of the European Parliament and the Council of 4th April 2001...
  • 6. The Investigator defined
      • § 4 (25) Prüfer ist in der Regel ein für die Durchführung der klinischen Prüfung bei Menschen in einer Prüfstelle verantwortlicher Arzt
      • oder in begründeten Ausnahmefällen eine andere Person, deren Beruf auf Grund seiner wissenschaftlichen Anforderungen und der seine Ausübung voraussetzenden Erfahrungen in der Patientenbetreuung für die Durchführung von Forschungen am Menschen qualifiziert.
  • 7. The Investigator defined
      • § 4 (25) Investigator is usually a medical doctor responsible for the conduct of a clinical investigation in humans in an investigational site,
      • or in case of a justified exception , another person, whose profession qualifies him/her for the conduct of research in humans on the basis of its scientific requirements and who has experience in patient care through the execution of the profession.
  • 8. The Investigator as Manager
    • §40 (1.5)
    • a clinical investigation may only be responsibly conducted ... by an adequately qualified investigator
    • and the director of the clinical investigation is an investigator, a principal investigator or a co-ordinating investigator with proven experience of at least 2 years in clinical investigations with drugs.
    • Not a medical doctor
  • 9. Investigator or Doctor?
    • §40 (1.9)
    • a clinical investigation may only be conducted
    • für die medizinische Versorgung der betroffenen Person ein Arzt ... verantwortlich ist
    • if for the medical care of the concerned person ... a medical doctor is responsible
  • 10. Investigator - Sponsor transfer of duties
    • Anzeigepflicht des Prüfers nach § 67 des AMG bei der zuständigen Behörde
    • Abschnitt 4. 12 (3)
    • Der Prüfer kann dem Sponsor die Durchführung der Anzeigen bei der zuständigen Behörde übertragen und hat dies zu dokumentieren.
    • The investigator may transfer his duties towards the CA to the sponser and must document this.
  • 11. Drug Safety in Clinical trials
    • §13 Duties of the Sponsor
    • To document in detail all AE reported by the investigators
    • To submitt, on request, to the National CA and to the CA of other MS, and to all investigators:
      • SUSARs within 15 days
      • Death within 7 days + 8 days
      • Issues requiring new benefit/risk assessment within 15 days
  • 12. Clear ways - uncertain means
    • §40 (1.7)
    • E ach investigator must be informed by a scientist responsible for the pharmacological-toxicological tests about their results and foreseeable risks regarding the clinical investigation
    • personally or in writing
    • consultation or Investigator’s Brochure
  • 13. National nuances - international compliance?
    • one site - many investigators - principle investigator
    • many sites - Sponsor appoints Leiter der klinischen Prüfung - co-ordinating investigator
    • according to ICH E6, not to EU Directive
      • investigator
      • principle investigator
      • co-ordinating investigator
  • 14. Sponsors, Representatives & Logistics
    • § 40 (1.1)
    • a clinical investigation may only be conducted if
    • ... ein Sponsor oder ein Vertreter des Sponsors vorhanden ist, der seinen Sitz in einem Mitgliedstaat der EU ... hat .
    • ... a sponsor or a representative of the sponsor is available with a residence in one of the MS of the EU
  • 15. The changed role of the Ethics Committee
    • From adviser to authority under the law
      • Legal responsibility +
      • Legal accountability in place? -
  • 16. Functions of the Ethics Committee
    • Single Opinion - Single Ethics Committee in each Member State
    • Local Ethics Committees – National regulations
      • Beginning of the Clinical Trial
      • Amendment of the Protocol
      • End of Clinical Trial
  • 17. National nuances with the Ethics Committees in D
    • §40 (1.2)
    • The Central Ethics Committee - responsibility of each Federal State
    • no explicit positive vote from the Ethics Committee - no clinical study, even if the CA gives permission
    • vote from Ethic Committee is to be monitored by the sponsor
    • (max 60 days)
    • The local Ethics Committees
      • responsible for the local clinical study site and its staff
      • supplies the central Ethics Committee with an opinion within 30 days (no monitoring by the sponsor)
  • 18. Documents for the Ethics Committee
    • Member State specific
    • Protocol related
    • Investigational medicinal product related
    • Facilities & staff related
    • Finance related
    • Subject related ... The Patient
  • 19. Patient Information: real time with the doctor
    • §40 (2)
    • Die betroffene Person ist durch einen Prüfer, der Arzt ist, ... aufzuklären; ihr ist eine allgemein verständliche Aufklärungsunterlage auszuhändigen.
    • Persönliches Gespräch - “Gelegenheit zu einem Beratungsgespräch mit einem Prüfer ...”
    • The concerned person must be enlightened by an investigator who is a medical doctor ; she/he must be given a generally understandable enlightening materials
    • Personal conversation - “occasion for a personal consultation with an investigator ...”
  • 20. On the presumed will of the minor
    • §40 (4)
    • Consent of minors
    • the explicit wish of the minor is to be considered
  • 21. Group benefit
    • §41 (2.1)
    • the clinical study must be for the benefit of a minor, suffering a disease
    • or
    • §41 (2.2 a)
    • the clinical study must be of direct benefit for the group of patients, who suffer the same disease
  • 22. Protecting the child patient: New demands - New institutions
      • §42 (1) The Ethics Committee must provide an external expert opinion when giving an opinion on a clinical trial with children
      • The BfArM will install a commission for medicines for children and adolescents
  • 23. Procedures & Timelines with the Ethics Committee
    • §42 - procedures at the Ethics Committee - positive opinion is compulsory - single opinion from a single MS
    • Application by the Sponsor with the Ethics Committee of
    • the Investigator
    • the Principal Investigator
    • the Co-ordinating Investigator
  • 24. Procedures & Timelines with the Ethics Committee
    • Application – within 10 days confirmation of receipt 14 days deadline for formal deficiencies
    • * subsequently explicit opinion within 60 days
    • * 1x request for additional informationen – clock stop
    • Single centre studies (10 + 14 days)
    • * subsequently explicit opinion within 30 days
    • Single centre Phase I studies from a drug development project known to the EC – within 14 days
    • IMP for gene therapy, somatic cells, and IMP containing genetically modified organisms (10 + 14 days) subsequently 60 + 30 + 90 days
    • Xenogenic cell therapy - œ
    • Sponsor must monitor deadlines – remind, demand & warn
  • 25. Procedures & Timelines with the Ethics Committee
    • Substantial amendment - 20 days explicit
      • somatic cells, IMP containing genetically modified organisms, and IMP for gene therapy - 35 days
      • xenogenic cells - œ
      • Additional investigational site - 30 days from the central EC, implicit
  • 26. Procedures & Timelines with the Competent Authorities
    • Application - within 10 days confirmation of receipt 14 days deadline for formal deficiencies
    • * subsequently within 30 days opinion implicit
    • * 1x objection - Sponsor has 90 days to respond
    • * subsequently 15 days explicit
    • Single centre Phase I studies from a drug development project known to the CA – within 14 days
    • IMP for gene therapy, somatic cells, and IMP containing genetically modified organisms (10 + 14 days) subsequently 60 + 30 + 90 days explicit
    • xenogenic cells - œ explicit
    • Amendments - 20 days implicit
      • somatic cells, IMP for gene therapy, and IMP containing genetically modified organisms - 35 days
      • xenogenic cells - œ
  • 27. National nuances with the Competent Authority in Germany
    • Is the BfArM satisfied ?
    • Implicit authorisation
    • Sequential application or in parallel with the Ethics Committee
    • Flexible interpretation of time-lines, e.g.
      • Phase I studies from a drug development project known to the CA - within 14 days
  • 28. Duties of the Competent Authority - the Inspections
    • adequate number of inspectors
    • sufficient resources for inspections also on request by EMEA
    • inspectors are adequately qualified and trained
    • declaration of interest about any financial ties to inspected parties
    • suitable means of identification of inspectors
  • 29. Inspections after AMG
    • § 64 AMG – supervision
    • §25 AMG – during application for marketing authorisation
    • §15 GCP-V
      • Inspections are conducted on behalf of the EU and are recognised by the other Member States
      • Inspections are registered in the EudraCT database
  • 30. Contents
    • The German Drug Law and Regulations: How was the EU Directive Implemented into National Law
    • Project Management: Implementing German Drug Law and Regulations into Company Processes
    • A Case Study: Practical Experience with the German Authorities
  • 31. Project Management ... Company Processes
    • SOP Handbook
    • specific roles and responsibilities
    • skills, competencies & CVs
    • relevant qualifications
    • appraisal system
    • continuous education & training
  • 32. Implementing German Drug Law into company processes
    • A rznei m ittel g esetz, AMG
    • 6th August 2004
    • GCP-Rechtsverordnung
    • 14th August 2004
    • 3. Bekanntmachung
    • 30 August 2004
    • www.bfarm.de
    • B undesinstitut f ür Ar znei m ittel
  • 33. The EudraCT number
    • Appoint and train a single or a number of Users for the EudraCT database
    • Appoint a team responsible for a clinical trial
    • Release a synopsis for a clinical trial specifying all the information needed for the EudraCT number and also all the MS involved – at least 6 months before the planned application with the competent EC & CA
    • Co-ordination between the MS invoved – with which CA will the sponsor apply for the EudraCT number
    • Obtain the application forms from the EudraCT database
  • 34. The Application forms
    • Ensure the application form for the EC and the CA are identical
    • §7 of the GCP-V describes in detail which documents are to be attached to each application
    • Submitt the application both in electronic and in paper format (4 copies); each local EC receives one copy as well (ensure documentation of receipt)
    • Ensure that the documents in each set are identical and complete
    • Monitor the updates of documents with the EC and CA in each MS and between MS
  • 35. Approval Amendment End
    • After approval, ensure complete communication to all involved parties – sponsor, CA, EC & CA in MS involved
    • Substantial amendments – definitions – application form – communication
    • Other amendments – definitions – documentation for inspection – communication
    • End of clinical trial form (90 days) – definition: last visit last patient or data base lock / Termination or Suspension (15 days) – inform CA, EC and CA of MS involved
    • If an EudraCT number was received but no clinical trial was initiated: after EU directive – end of trial form, after GCP-V in Germany – no mention – not clarified yet
    • Submitt a summary of the clinical tgrial report within 1 year after end of trial – internal process management – medical writing
  • 36. Inspections in Germany
    • An inspection may take place before the start of a clinical trial – during the application procedure, during the conduct of a trial and after the end of a trial
      • Ensure that all documents at all sites involved are complete and available (ICH E6 on GCP)
      • Ensure that requirements concerning sponsor, CRO, investigation sites and relevant staff are met
      • Decide on archiving of the documents at the sponsor – centralised (at Regulatory Affairs or at Clinical Development) or decentralised (at Regulatora Affairs and at Clinical Development and at Drug Safety etc)
  • 37. Training & Education
    • Assess available SOPs and adjust to new regulations appropriately
    • Compile a new Handbook of SOPs
    • Train relevant staff on new SOPs
    • Document training sessions … and outcomes!
  • 38. Contents
    • The German Drug Law and Regulations: How was the EU Directive Implemented into National Law
    • Project Management: Implementing German Drug Law and Regulations into Company Processes
    • A Case Study: Practical Experience with the German Authorities
  • 39. A case study experience
    • Single centre, bioavailability, asthma, drug for inhalation, CRO (after GCP-V 30 days)
      • July 2004 – beginn of project
      • Application on 8th October 2004
        • Confirmation of receipt on 21st October (>10 days)
        • Meeting of the EC on 4th November
        • Request for further information: dated 5th November, received 8th November
        • Reply to request on 11th November
        • Positive vote on XXXXXX
  • 40. Request for further information
    • Confirmation by each investigator on received information on toxicological-pharmacological properties of the IMP
    • Explicit mentioning of
      • Insurance sum
      • Insurance conditions
    • Laboratory safety tests:
      • Blood clotting
      • TSH
  • 41. Documents with the application form
    • Information for the investigator: IB or SPC – document from the Co-ordinating investigator on successful information about toxicological-pharmacological properties of the IMP plus confirmation letter on the subject from each investigator
    • Justification for sex distribution of subjects
    • Compassionate use programme (after end of trial)
    • Agreement between sponsor and investigation site (use FDA forms)
  • 42. Tipps and advice
    • When cross-reference to documents – supply copies of referenced documents at that place in the file
    • No legal regulation for the EC
      • Academic EC
      • EC under the Federal Commissions of Medical Professionals
    • Formal check by the CA formalistic – new staff
    • No differentiation between formal check and content
      • Mainly labeling and IMP dossier
        • Use additional documents for information on labeling
        • 3. Bekanntmachung (draft) will regulate information for uniform IMP dossier – no EU document yet available
  • 43. Thank you Dr. Diana A. Taylor, MSc