Managing Monitoring R&D Forum Annual Meeting 10 May 2005

1. Managing MonitoringR&D Forum Annual Meeting10 May 2005 Sarah Meredith MRC Clinical Trials Unit and UKCRC Barbara Farrell UK Trial Managers Network

2. Outline • Monitoring and good clinical practice (GCP) • Methods of monitoring • Selection of proportionate methods • Practical exercise Based on • MRC/DH Joint Project: Implementing UK Medicines for Human Use (Clinical Trials) Regulations • See Clinical Trials Toolkit: www.ct-toolkit.ac.uk

3. Purpose of study monitoring To ensure that: • The rights and well-being of trial participants are protected • The reported trial data are accurate, complete, and verifiable from source documents • The conduct of the trial is in compliance with the currently approved protocol/amendments, with GCP, and with the applicable regulatory requirements.

4. Good Clinical Practice Legislation: incorporates principles of ICH GCP Guidelines based on those principles • ICH Guideline for GCP primarily intended for clinical trials leading to submission of data to medicinal product regulatory authorities • MRC Guideline for GCP primarily intended for trials of effectiveness of established therapies • Commission Directive on GCP (published 8.5.05) Applies to all trials of medicines in EU Guidance on “specific modalities” of GCP in non-commercial trials awaited

5. Relevant principles of GCP in Commission Directive • Each individual involved in trial should be qualified by education, training and experience to perform his/her tasks • Necessary procedures to secure the quality of every aspect of the trial shall be complied with • Conducted in accordance with Helsinki Declaration (1996) • Protocol shall provide inclusion and exclusion criteria, monitoring and publication policy • Investigator/sponsor shall consider all relevant guidance • Information recorded, handled and stored to allow accurate reporting, interpretation and verification and confidentiality of subjects’ records

6. Range of trials • Stage: ‘first in man’ studies pragmatic comparison of routine treatments • Sites: single centre international multi-centre • Intervention: education toxic substance or hazardous procedure • Sponsor: trust, university, industry, public funder, European organisation

7. Proportionate trial management unimportant • Commercial v. non-commercial • Medicinal product v. other interventions • Systems should depend on risks to patients and trial: • intervention - type, status, danger and clinical experience • vulnerability of the population • sites - number, distance, team experience • trial design - eligibility, outcomes, data collection methods • For trials of medicinal products • licensed v. unlicensed • whether or not the data are to be used for marketing authorisation or to extend indications

8. Trial Management Documentation • Write it down, file it and know where to find it! • Document management systems • Protocol • Generic standard operating procedures • Trial-specific SOPs • Trial Master File • Essential documents - documents with enable the conduct of the trial and quality of the data to be evaluated • See MRC GCP or ICH GCP for details • “Content in accordance with specificities of the phase of clinical trial” • Commission guidance awaited

9. Monitoring procedures “fit for purpose“ • Types of monitoring • oversight - e.g. TMG, TSC, DMC • ‘good housekeeping’ – e.g. protocol compliance, data consistency • central monitoring – e.g. look for outlier sites, ONS to confirm pt existence/outcome • on-site monitoring • Procedures should be determined by • risk assessment • trial design • number/experience of sites • Coordination of monitoring to avoid duplication • Coordinating centre / Sponsor / Care organisation

10. ICH GCP on-site monitoring not required “The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size and endpoints of the trial. In general there is a need for on-site monitoring, before, during and after the trial; however …central monitoring in conjunction with procedures such as investigators’ training and meetings and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.” ICH GCP 5.18.3

11. Monitoring assessment by Expert Panel Aim: to develop advice on the use of different approaches to monitoring in individual trials • Expert Panel • mainly experienced trialists • plus MHRA inspector, major funder and R&D director • Trial scenarios reflecting broad range of trials • Individual assessment of appropriate monitoring • Group discussion of areas of disagreement • attempt to achieve consensus

12. Example 1 - Pilot RCT of streptokinase, aspirin & heparin in acute MI (ISIS) Design: 2x2x2 factorial placebo-controlled trial Population: 600 patients with suspected acute MI Sites: 8 hospitals (7 in UK 1 in Australia) Entry criteria: Dr diagnosed suspected MI <24hrs of onset Randomisation: 24 hr central telephone service Interventions: 6 groups - IV streptokinase or placebo (1 hr) - IV heparin or placebo (48 hrs) - oral aspirin or placebo (28 day) Supplies: Treatment packs held in ER Outcomes: SAEs in hospital + deaths < 1 yr Data: Paper CRFs. Data entry at coordinating centre Experience: Very experienced coordinating centre Variable experience at sites

13. What are the main hazards? • Potentially hazardous interventions and little clinical experience of streptokinase • Vulnerable population, some of which may not be capable of giving informed consent • Complex design and double blind trial, therefore it is particularly important to ensure that the patients receive the allocated treatment

14. Monitoring 1 - Before recruitment Oversight • A trial steering committee • An independent DMC is essential • A trial management group Before the start of recruitment: Minimum • Investigators meeting - trial procedures and consent • Written assurance from each investigator that setup was complete • Investigator questionnaire to check appropriate training and skills Optimal • Most also considered a site visit to review setup and trial supply arrangements desirable, particularly for inexperienced sites

15. Without site visiting Annual investigator meetings Verification of pt existance Collect signed consent form at coordinating centre Collect ECG/lab results Flagging if poss Collect signed consent at coordinating centre (patient consent required) Review of eligibilty prior to randomisation ECG/blood test results Collect death certificates, discharge summaries and lab reports With site visiting Annual site visits (or as required) Patient existence from clinic records Check consent forms in patient’s clinical records Check eligibility against clinic records Check completeness and accuracy of AE reports against clinic records in a sample Monitoring 2 - During recruitment

16. Monitoring 3 - End of trial • Drug reconciliation by return of unused treatment packs to coordinating centre or record of destruction • Written confirmation from each site regarding archiving

17. Example 2: 1o care RCT of prescribing strategies for a self-limiting illness Interventions:1. No prescription; 2. Immediate prescription 3. Prescription to be filled if no improvement Outcome:patient-assessed symptom duration Randomisation:sealed envelopes in GP surgeries - most vulnerable aspect • Oversight: Trial management group; no DMC • Essential to ensure randomisation not compromised • Pre-trial meeting/site visit to train all staff involved • During trial site visits to check where envelopes kept & patients allocated in order of presentation • Patient treatment corresponded to allocated treatment • Patient existence & consent check • possible centrally but efficient to do during site visits

18. Every trial needs: • Systems and procedures appropriate to its design and risks to assure the quality of trial • Documentation of: • Risk assessment • Trial management systems • Procedures for monitoring • Clarity about which partner is doing what