UK Implementation of the EU Clinical Trial Directive 2001/20/EC:

UK Implementation of the EU Clinical Trial Directive 2001/20/EC: GCP Aspects. Dr. Colin Wilsher, FRQA. BARQA GCP Committee Chairman; & Pfizer Worldwide Development Quality Assurance. GIQAR, Roma, October 2005 Version 09 Sept 05 1 UK Statutory Instrument 1031/2004, transposed the European Union Directive 2001/20/EC into UK law and was effective from 1 st May 2004. Version 09 Sept 05 2 1

MHRA own Summary of SI 1031/2004 Pharmacology studies in healthy human volunteers (Phase 1 studies) require authorisation from the MHRA where previously they only needed a favourable opinion of an ethics committee; Investigational medicinal products (IMPs) must be manufactured to good manufacturing practice (GMP) standards and the manufacturer must have a manufacturing licence; Each trial must have an identified sponsor who takes responsibility for its initiation, management and conduct. To establish our ethics committee system on a statutory basis (Regulations 5 to 10, and Schedule 2); Version 09 Sept 05 3 MHRA own Summary of SI 1031/2004 (cont) To require all clinical trials to be conducted in accordance with the principles of good clinical practice (GCP) (Regulations 28 to 31, and Schedules 1 and 5); To provide additional protection for minors and physically or mentally incapacitated adults who are candidates for clinical trials (Regulations 14 to16 and Parts 3 & 5 of Schedule 1 for incapacitated adults and Regulation 15 and Part 4 of Schedule 1 for minors ); Version 09 Sept 05 4 2

MHRA own Summary of SI 1031/2004 (cont) To require sponsors to provide trial medicines free of charge to patients if they are not covered by a prescription charge (Regulation 28); To provide for inspection by the MHRA for GCP and GMP to help ensure those standards are maintained (Regulations 47 to 52, Parts 2 & 3 of Schedule7,and Schedule 9; and To provide for enforcement of these new provisions (Regulations 47 to 52 and Schedule 9). Version 09 Sept 05 5 So what are the differences between the EU Clinical Trial Directive (2001/20/EC) and the UK Statutory Instrument (1031/2004)? Version 09 Sept 05 6 3

Good clinical practice and protection of clinical trial subjects Section 28. (1) No person shall (a) conduct a clinical trial; or (b) perform the functions of the sponsor of a clinical trial (whether that person is the sponsor or is acting under arrangements made with that sponsor), otherwise than in accordance with the conditions and principles of good clinical practice. Version 09 Sept 05 7 New legal definition of adult in the UK. Section 2. adult means a person who has attained the age of 16 years Version 09 Sept 05 8 4

Nurses & Pharmacists can become Investigators and Chief Investigators. investigator means, in relation to a clinical trial, the authorised health professional responsible for the conduct of that trial at a trial site, and if the trial is conducted by a team of authorised health professionals at a trial site, the investigator is the leader responsible for that team chief investigator means (a) in relation to a clinical trial conducted at a single trial site, the investigator for that site, or (b) in relation to a clinical trial conducted at more than one trial site, the authorised health care professional, whether or not he is an investigator at any particular site, who takes primary responsibility for the conduct of the trial; authorised health professional means (a) a doctor, (b) a dentist, (c) a nurse, or (d) a pharmacist; Version 09 Sept 05 9 Definition of Electronic Signature electronic signature means data in electronic form which are attached to or logically associated with other electronic data and which serve as a method of authentication; Version 09 Sept 05 10 5

Sponsor. Definition of sponsor changed from ICH and EU CTDir (wording changed with regard to individual, company, institution or organisation ) sponsor means, in relation to a clinical trial, the person who takes responsibility for the initiation, management and financing (or arranging the financing) of that trial. 3(11) A person who is a sponsor of a clinical trial in accordance with this regulation must (a) be established in the European Community, or (b) have a legal representative who is so established. Version 09 Sept 05 11 Urgent safety measures Reporting 3 days from date of urgent safety measures. In contrast fatal & life threatening SUSARs only require notification 7 day after sponsor is first aware. There could be several days before a sponsor is aware of action taken independently by the investigator. 30. (1) The sponsor and investigator may take appropriate urgent safety measures in order to protect the subjects of a clinical trial against any immediate hazard to their health or safety. (2) If measures are taken pursuant to paragraph (1), the sponsor shall immediately, and in any event no later than 3 days from the date the measures are taken, give written notice to the licensing authority and the relevant ethics committee of the measures taken and the circumstances giving rise to those measures. Version 09 Sept 05 12 6

NEW Principles of GCP. (Changes / differences from ICH in Red) SCHEDULE 1 PART 2 CONDITIONS AND PRINCIPLES WHICH APPLY TO ALL CLINICAL TRIALS Principles based on International Conference on Harmonisation GCP Guideline(a) 1. Clinical trials shall be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with good clinical practice and the requirements of these Regulations. 2. Before the trial is initiated, foreseeable risks and inconveniences have been weighed against the anticipated benefit for the individual trial subject and other present and future patients. A trial should be initiated and continued only if the anticipated benefits justify the risks. 3. The rights, safety, and well-being of the trial subjects are the most important considerations and shall prevail over interests of science and society. Version 09 Sept 05 13 4. The available non-clinical and clinical information on an investigational medicinal product shall be adequate to support the NEW Principles of GCP. (Changes / differences from ICH in Red) cont. 5. Clinical trials shall be scientifically sound, and described in a clear, detailed protocol. 6. A trial shall be conducted in compliance with the protocol that has a favourable opinion from an ethics committee. 7. The medical care given to, and medical decisions made on behalf of, subjects shall always be the responsibility of an appropriately qualified doctor or, when appropriate, of a qualified dentist. 8. Each individual involved in conducting a trial shall be qualified by education, training, and experience to perform his or her respective task(s). 9. Subject to the other provisions of this Schedule relating to consent, freely given informed consent shall be obtained from every subject prior to clinical trial participation. Version 09 Sept 05 14 10. All clinical trial information shall be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and 7

NEW Principles of GCP. (Changes / differences from ICH in Red) cont. 11. The confidentiality of records that could identify subjects shall be protected, respecting the privacy and confidentiality rules in accordance with the requirements of the Data Protection Act 1998 and the law relating to confidentiality. 12. Investigational medicinal products used in the trial shall be (a) manufactured or imported, and handled and stored, in accordance with the principles and guidelines of good manufacturing practice, and (b) used in accordance with the approved protocol. 13. Systems with procedures that assure the quality of every aspect of the trial shall be implemented. Version 09 Sept 05 15 NEW Principles of GCP. (Changes / differences from ICH in Red) cont. Conditions based on Article 3 of the Directive 14. A trial shall be initiated only if an ethics committee and the licensing authority comes to the conclusion that the anticipated therapeutic and public health benefits justify the risks and may be continued only if compliance with this requirement is permanently monitored. 15. The rights of each subject to physical and mental integrity, to privacy and to the protection of the data concerning him in accordance with the Data Protection Act 1998 are safeguarded. 16. Provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor which may arise in relation to the clinical trial. Version 09 Sept 05 16 8

Ethics Committee (EC) ONE Application for ethics committee opinion 14. (1) An application for an ethics committee opinion in relation to a clinical trial shall be made by the chief investigator for that trial. (2) A chief investigator for a trial shall make an application for an ethics committee opinion in relation to that trial to one ethics committee only, regardless of the number of trial sites at which the trial is to be conducted. New UKECA United Kingdom Ethics Committees Authority formed. Version 09 Sept 05 17 Workings of Ethics Committee (differences from the Directive in red) Includes contract between sponsor & site. (h) if the subjects are to include persons incapable of giving informed consent, whether the research is justified having regard to the conditions and principles specified in Part 5 of Schedule 1; (l) the terms of any agreement between the sponsor and the owner or occupier of the trial site which are relevant to the arrangements referred to in sub-paragraph (k); and Version 09 Sept 05 18 9

Workings of Ethics Committee (Cont.) The UK may have taken a provision from the EU guidance note on submissions to EC [ENTR/F2/BL D (2003) April 2003 & ENTR/CT2 revision 1 April 2004] and put it into the UK Law:- 6.1.2.8. Financial arrangements. This includes information on financial transactions, and compensation to subjects and investigator/site. It might be the responsibility of either the Ethics Committee or the competent authority to review the arrangements for rewarding or compensating investigator(s) / sites and trial subjects as well as the relevant aspects of any agreement between the sponsor and the site according to national provisions. Version 09 Sept 05 19 Most importantly UK SI 1031 has given powers for GCP Inspections. Version 09 Sept 05 20 10

MHRA Inspection Findings Most frequent non-compliances from the Statutory Programme Version 09 Sept 05 21 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 Version 09 Sept 05 22 11

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 Version 09 Sept 05 23 UK MHRA GCP Inspection Findings Investigational Medicinal Product Missing documentation: shipping records, accountability, dosing records Emergency codes not supplied prior to study start Ethical approval Lack of approval for study advertising Version 09 Sept 05 24 12

UK MHRA GCP Inspection Findings Informed Consent Missing elements Inconsistencies with protocol, not updated with protocol amendments Poor version control Incorrect form used Unclear process Version 09 Sept 05 25 UK MHRA GCP Inspection Findings Subject safety and confidentiality Lack of involvement of PI Unclear procedures (and testing of procedures) for out of hours emergency contacts Subjects not provided with emergency contact details Subject details sent into Sponsor company Ineligible subjects entered into studies Version 09 Sept 05 26 13

UK MHRA GCP Inspection Findings Miscellaneous Findings Lack of documentation of validation of computer systems Uncontrolled database unlock/re-lock Lack of GCP training Lack of documented calibration of equipment Unidentified or unexpected laboratory samples analysed for a range of tests - this may be outside the protocol and therefore without consent. Version 09 Sept 05 27 Any Questions? Version 09 Sept 05 28 14