- ARE YOU READY ?

Joan Perou
November 2005

A systematic and independent examination of trial related
activities and documents to determine whether the
evaluated trial related activities were conducted and the
data were recorded analysed and accurately reported
according to the protocol, sponsor’s standard operating
procedures (SOPs) Good Clinical Practice , and the
applicable regulatory requirements

ICH 1.6
The act by a Competent Authority of conducting an official
review of documents, facilities, records, quality assurance
arrangements, and any other resources that are deemed by
the competent authority to be related to the clinical trial and
that may be located at the site of the trial at the sponsor’s
and/or contract research organisations’s facilities or at
other establishments which the competent authority sees fit
to inspect

EU Directive 2(l)
ICH 1.29
               EU Directive on GCP
           in Clinical Trials (2001/20/EC)

Verification of compliance (Article 15)

Member states shall appoint inspectors to verify compliance
  with GCP and GMP at any time before, during, after the trial

   trial sites
   manufacturing site of investigational product
   laboratories used for analyses
   sponsor premises
                The Role of the
           European Medicines Agency

   European Medicines Evaluation Agency (EMEA) based in
    London. Referred to as ‘The Agency’ in the Directive.

   The European Medicines Evaluation Agency changed its
    name in 2004 to become the European Medicines Agency

   ‘Inspections may be requested and coordinated by the
    European Medicines Agency’ (Directive 2005/28)
   The Medicines and Healthcare
products Regulatory Agency (MHRA)

   UK ‘Competent Authority’ (CA)
   Based in London
   Grants licences to conduct trials
   Monitors safety aspects of trials
   Provides enforcement - mandatory inspections started
    1 May 2004
        Types of Inspection

   Trial related

   Systems

   ‘For Cause’

   ‘Voluntary Inspection
    (finished April 2004)
          Inspection Preparation

   Refer to SOPs
   Appoint Inspection Co-ordinator
   Contact with the MHRA
   Respond to document requests from MHRA
   Training (including inspection training!)
   Ensure CVs, job descriptions are current
   Progress meetings with everyone involved
   Personal preparation
      Inspection Preparation

   Review and learn SOPs on documentation/process
   Document review - on selected trials
   File notes
   ‘Tidy up’ of files and filing area
   Clear and consistent labelling
   Security/access to documents
   Correct terminology - archive or storage area ?
   Archives
         Inspection Preparation

   Communication between PI, study team, sponsor
   Update training for investigator and study team -
    regulatory and study specific
   Check CVs and training records and update to include
    latest training
   Check Investigator Site Files – emails should be printed
    off and all documentation up to date and compliant with
    Essential Documents
   Check IMP - storage/temperature logs, accountability
   Check equipment - calibration and servicing
   Ensure copies of ICH and the Directive are available
                 GCP Inspection

Inspection Day

   Inspectors will work to Inspection Plan
   Appointed co-ordinator should be available to assist
    Inspectors throughout
   Facilities Check
   Pre-inspection meeting
   Interviews - according to Inspection Plan
   Process and document review
              GCP Inspection
Inspection Process

   Background information
   Interview technique
   Facilities information
   Documentation – records, files, patient notes
   Systems – processes and SOPs
   Equipment check – calibration and servicing
            GCP Inspection

Post- Inspection

   Close-out meeting
   Findings discussed
   Report issued
   Actions from report finalised
What are the Inspectors looking for ?

              Evidence of compliance and
           Total Quality Management Systems


   Data trail required
   Dates and version numbers of documents
   Evidence of distribution/receipt and document
    control systems
   Clear labelling/indices on files
   General tidiness, file notes if necessary but no
    yellow stickies !
What are the Inspectors looking for ?

              Evidence of compliance and
           Total Quality Management Systems

Standard Operating Procedures/processes should be:

   GCP Compliant
   Reflect current working practices
   Controlled, updated, managed
   Implemented only after training
What are the Inspectors looking for ?

                Evidence of compliance and
             Total Quality Management Systems

   Databases
   Archiving
   Contracts
   Training records/CVs
   SOPs for related departments
   Communication flow across departments
   Equipment
   Security
   Emergency out of hours procedures
        ICH E6 GCP Document

   1.0 Definitions
   2.0 Principles of ICH GCP

   3.0 Ethics Committees
   4.0 Investigator Responsibilities
   5.0 Sponsor Responsibilities

   6.0 Protocol/Amendments Format
   7.0 Investigator Brochure Format
   8.0 Essential Documents
    ICH - Essential Documents

 Essential Documents are those documents which
individually and collectively permit evaluation of the
conduct of the trial and the quality of the data produced.
These documents serve to demonstrate the compliance
of the investigator, sponsor, and monitor with the
standards of Good Clinical Practice and with all
applicable regulatory requirements.
           Files and Procedures

   Standard Operating Procedures (SOPS)
    (Provide overall guidance/policy)

   Department or clinical trial unit processes
    (Detail working procedures)

   Trial Master File
    (maintained by Sponsor)

    Investigator Centre File
    (maintained by Investigator/study team)
      ICH E6 GCP Document
Section 8.0 on Essential Documents

   8.2 Lists all those documents that must be on file
    prior to start of study

   8.3 Lists all those documents which may require
    updating during the course of the study

   8.4 Lists all those documents which need to be added
    to the other two sections at the end of the study to
    complete the Trial Master File prior to archiving.
       The Centre Investigator File

Sample list (see ICH 8.0 for complete list)

   Investigator Brochure (current version)
   Final Protocol + amendments (all signed and dated)
   Ethics Committee documentation
   Study correspondence
   Original signed consent form(s) for each patient
   CV of Investigator and study team
   Delegation log/signature record
   Serious adverse event reports (copies)
   Laboratory normal ranges/methods
    The Centre Investigator File

Sample only - see ICH 8.0 for complete list

   Patient Enrolment Log
   Training certificates for study team
   Calibration certificates for study equipment
   Randomisation codes
   Monitoring visit log
   Subject screening log
   Drug receipt/dispensing documentation
              Centre Delegation Log

   Ensure the staff delegation log is up to date:
   Should list names of staff delegated to each procedure
   Should reflect the current situation
   Should be signed by the investigator, and updated when
    appropriate throughout trial.
   Copy available in Trial Master File (sponsor) and Investigator
    Site File
   If new staff are recruited the list should be updated, but old
    versions must not be destroyed.
            Investigator Brochure

   Mandatory requirement for trials using unlicensed
   The most recent version should be held on file at centre
   A log on file should track previous versions if removed
   Safety update letters should be filed together with
    Investigator Brochures.
   Updated versions of the Investigator Brochures should
    include the safety updates.
   Investigator Brochures should be updated at least

   Any change to the protocol is an amendment
   All ‘substantial’ amendments must be sent to ethics
    committees and the MHRA
   There must be a letter of favourable opinion from the ethics
    committee (within 35 days) before the amendment can be
    implemented .
   The MHRA will not review all amendments but the ethics
    committee will given an opinion.
   It is important that all amendments are tracked so that their
    status is known.
      Inspectors will check the following
             have been obtained:

   Clinical Trial Authorisation from Competent Authority
   Favourable opinion from a Recognised ethics committee
   Opinion on suitability of local investigator and facilities from local
    ethics committee
   Permission from NHS Trust for trial to take place within that Trust
    (R & D approval)
   Eudract number from the Eudract database for all trials which
    commenced after 1st May 2004
        Grading Definitions



          Inspection Findings

   Absence of investigator from trial related
    duties/monitoring visits - heavy delegation
   Inappropriate delegation of duties.
   Dating of consent form by inappropriate person
   Inadequate training records/CVS
   Insufficient certificates/calibration of equipment.
   Temperature logs not kept for investigational product
          Inspection Feedback
MHRA requested:

   Index of SOPs
   Organigrams
   Summary of responsibility of departments involved in
    clinical trials
   Overview of Trust arrangements for trials
   Protocols, consent forms and patient information sheets
    for those trials selected

   MHRA selected names from organigrams
   Trust had no influence on trials selected
   MHRA not interested in investigator status
        Inspection Feedback
MHRA priorities (according to Bristol)
 Non-commercial trials
 Paediatric studies
 Investigators conducting numerous trials
 Greatest number of patients at risk
 Anything that would jeopardise patient safety
 Trust systems and procedures
 Evidence of training - certificates reviewed
 Procedures in place to terminate study in event of
  emergency situations
        Inspection Feedback
Lessons Learned
 Trust systems and processes must incorporate SOPs for
  clinical research
 Archiving of records must be sufficient to ‘reconstruct’
  trial if required by MHRA
 Disaster recovery plan must be in place in case of
 All staff must be trained - this should include basic
  training for those not directly involved in research, I.e.
  I.T. staff and medical records staff
 Formulate an action plan for what you feel is not
  ‘perfect’ and set a time frame for action - prepare this
  prior to the Inspection
            EU Directive On GCP
        in Clinical Trials (2001/20/EC)
Article 1

   Good clinical practice is a set of internationally recognised
   ethical and scientific quality requirements which must be
   observed for designing, conducting, recording and
   reporting clinical trials that involve the participation of
   human subject.
    Compliance with this good practice provides assurance
   that the rights, safety and well-being of trial subjects are
   protected, and that the results of the clinical trials are
                   ‘Due Diligence’

     Regulation 51 Medicines for Human Use
        (Clinical Trials) Regulations 2004

A person does not commit an offence under these Regulations if
   he took all reasonable precautions and exercised all due
   diligence to avoid the commission of that offence.

Where evidence is adduced which is sufficient to raise an issue
  with respect to that defence, the court or jury shall assume
  that the defence is satisfied unless the prosecution proves
  beyond reasonable doubt that it is not
                  Key Messages

   Document everything - ‘if it isn’t in writing it is a rumour!’
   Ensure you have a verifiable ‘data trail’ for each trial
   Identify all trial documents with appropriate reference
    numbers, dates and version numbers
   Work to clearly defined written processes
   Know your own role/responsibility and competencies
   Ensure you are properly trained (with training records)
   Ensure all safety reporting is done on time
   Pay extra attention to the consent procedure and

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