MRCDH Joint Project: Implementing UK Medicines for Human Use Clinical Trials Regulations Trial Manag

1
MRC/DH Joint Project Implementing UK Medicines
for Human Use (Clinical Trials) Regulations
Trial Management Monitoringwww.ct-toolkit
.ac.ukPlanning a New Trial GCP (Management and
Monitoring)Trial Scenarios
2
Thanks to

• Working Group
• Noreen Caine
• Barbara Farrell
• Martin Landray
• Sarah Meredith
• Cathy McDowell
• Yolanda Moraes
• Jane Robertson
• Maxine Stead

• Expert Panel
• Peter Brocklehurst
• Marion Campbell
• Rory Collins
• Janet Darbyshire
• Stephen Evans
• Ian Oulsnam
• Peter Sandercock
• Tony Soteriou
• Tom Walley
• Simon Wessely

3
Good Clinical Practice

• Definition
• "a standard for the design, conduct,
  performance, monitoring, auditing, recording,
  analyses, and reporting of clinical trials that
  provides assurance that the data and reported
  results are credible and accurate, and that the
  rights, integrity, and confidentiality of trial
  subjects are protected.
• (ICH GCP)

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 . . . Awaiting
  revision of Regulations and Specific Modalities
  for non-commercial trials

5
Relevant principles of GCP

• Conducted in compliance with the protocol
• Each individual involved in trial should be
  qualified by education, training and experience
  to perform his/her tasks
• Informed consent of trial subject obtained before
  participation in trial
• Information recorded, handled and stored to allow
  accurate reporting, interpretation and
  verification
• Records that could identify participants
  protected to respect privacy and confidentiality
  in accordance with Data Protection Act
• Systems with procedures that assure the quality
  of every aspect of the trial shall be implemented

6
Range of non-commercial trials

• Stage first in man studies
• pragmatic comparisons of routine treatments
• Sites single centre
• international multi-centre
• Funding slush funds
• MRC or HTA

7
Risk assessment

• Assessment of trial-specific hazards and ways to
  minimise chances of harm
• Rights of participants
• consent process - vulnerability of study
  population
• privacy - systems for data protection
  anonymisation
• Safety of participants
• hazards of intervention - inherent danger,
  clinical experience
• hazards of assessment
• Reliability of results - robustness of trial
  design
• power, completeness of follow-up
• inaccuracy, bias or fraud - eligibility criteria,
  randomisation process, objectivity of outcome
  assessment

8
Trial Management Systems

• Project management
• Contracts
• Insurance/indemnity
• Quality assurance
• Monitoring
• Training
• Pharmacovigilance
• Endpoint assessment

• Computer systems
• Data management
• IMP management
• Statistical analysis
• Writing of reports and publications
• Regulatory submissions
• Archiving

9
Trial Management Documentation

• Write it down, file it and know where to find it!
• Document management system
• Protocol
• Generic standard operating procedures
• Trial-specific SOPs
• Trial Master File
• Essential documents
• See MRC GCP or ICH GCP for details

10
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

11
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

12
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 RD
  director
• Trial scenarios reflecting broad range of trials
• Individual assessment of appropriate monitoring
• Group discussion of areas of disagreement
• Attempt to achieve consensus
• Use results to expand and illustrate workstream
  advice

13
General conclusions

• Oversight - always necessary, but structures will
  vary
• TSC as well as a management group for large,
  multi-centre trials
• DMC independent of investigators sponsor if
  safety issues
• Personnel - ensure all understand protocol
  responsibilities
• investigator meetings or at sites visits
• Confirmation of participant existence - highly
  desirable
• signed consent form, medical record,
  investigation report or ONS
• Consent procedures vital - training of all
  involved
• copy of signed form to coordinating centre (if
  patient agrees)
• check at site by RD staff or on site monitoring
  visit (if done)
• Eligibility - importance will vary according to
  trial
• Randomisation - essential assignment cannot be
  predicted
• Trial supplies - storage and check on what
  patient received
• Data accuracy - needs will vary according to
  trial
• identify key items and develop checks (central or
  SDV)

14
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

15
Workshop scenarios

• Trial of prescribing strategies in managing sore
  throat
• Trial of aspirin and heparin in acute ischaemic
  stroke
• Trial of early versus late feeding of growth
  restricted babies born prematurely after abnormal
  antenatal Dopplers