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									                                  Clinical Trials Office
                                  (London and Leiden)



 Standard Operating Procedure (SOP) for
 the Set-up and Maintenance & Archiving
       of Trial Master Files (TMFs)
Scope
This SOP describes the essential documentation that is required by ICH GCP
guidelines to be filed in the Trial Master File (TMF) for all trials that fall under the EU
directive for clinical trials.

Abbreviations
CRF     Case report form
TMF     Trial master file


Introduction

All essential documents for the conduct of a clinical trial are filed in the Trial Master
Files (TMF).

Essential documents are those, which individually and collectively permit evaluation
of the conduct of a trial and the quality of the data produced.

Whilst demonstrating compliance with ICH GCP the filing of trial documents in an
orderly, timely manner also greatly assists the smooth running of the trial and any
future audit or inspection by the sponsor or regulatory authority.


Responsible Personnel
The trial coordinator (or other designated staff members) is responsible for setting-up
and maintaining the TMF.


Procedure
Set-up
The study TMF should be created as soon as possible during the set-up of the study.

ICH GCP (Section 8.2, 8.3 & 8.4) gives an extensive list of essential documents that
should be in place both in the Sponsor and Investigator file (appendix 2):

    Before the clinical phase of the trial commences
    During the clinical conduct of the trial
    After completion or termination of the trial.


            Standard Operating Procedure for Trial Master Files Version 1: 1st June 2006

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The TMF index (Appendix 1) should be printed off and filed in the TMF. This Index is
a template, which can be adapted to make it more trial specific. The file number,
which each section is located in should be updated when necessary.

Maintenance
As documents maybe amended during the trial it is important that amendment
chronologies are kept indicating the changes and the dates they are implemented.
Old documents must be retained in the TMF alongside the new amended version.

Any information or documents missing from the TMF must be recorded on a file note
and an explanation given. A file note must be placed in the TMF if any documents
are stored/ located elsewhere (e.g. Completed CRFs, Investigator brochure).

TMFs contain confidential information and should be locked away when not in use.
Access to the TMFs should be limited to authorised clinical trial personnel only.

Archiving
The TMF should be archived after the completion of the trial (timelines as applicable
to that trial).

ICH GCP Guidelines state that essential documents must be retained “until at least 2
years after the last approval of a marketing application in an ICH region”,
The GCP Commission Directive 2005/28/EC states that “the sponsor and the
investigator shall retain the essential documents relating to a clinical trial for at least
five years after its completion”.

Documents shall be retained for longer periods where required by other applicable
requirements or by agreement between the sponsor and the investigator. The main
requisite is that all documents are archived in a way that ensures that they are readily
available, upon request, to the competent authorities.


References
ICH Harmonised Tripartite Guideline for Good Clinical Practice (1996)- Section 8
GCP Commission Directive 2005/28/EC




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      Appendix 1
                                   [Add Trial Short Title]
                                   Trial Master File Index
                                                                                       GCP             File
Section         Title                              Contents                         Reference        Number
                                                                                  (If applicable)
                                 Contact details
  1       Study Personnel        CV’s Investigator & Co-investigators (if
                                                                                      8.2.10
                                 applicable)
          Trial Meetings         Meeting minutes                                      8.3.11
  2       /Visits                Monitoring/audit visit log/reports (if            8.2.20, 8.3.10,
                                 applicable)                                        8.4.4, 8.4.5
                                 Randomisation/Registration Log                       8.2.18
                                 Randomisation/registration procedure
          Randomisation /        Randomisation/registration form
  3
           Registration
                                 Unblinding procedures                                8.2.17
                                 Recruitment updates
                                 Ethics applications/amendments                        8.2.7
               Ethics            Ethics committee composition                          8.2.8
          Committees (EC)        Ethics Approval letter/s (all sites)                  8.2.7
  4        / Independent
                                 Interim/Annual Report/s                              8.3.19
           review boards
                (IRB)            Final report to document end of trial                 8.4.5
                                 All other correspondence with EC/IRB
                                 CTA applications                                      8.2.8
                                 CTA approval letter                                   8.2.8
                                 Amendment notification/s                              8.2.8
            Competent            Notification of Safety reports/updates               8.3.17
  5
          Authorities (CA)       Notification of study closure
                                 Interim/Annual Report/s                              8.3.19
                                 Inspection/audit documentation
                                 All other correspondence with CA
          Independent Data       Contact details
             Monitoring          Reports
  6
             Committee
               (IDMC)            Correspondence
                                 Copy of blank CRF                                     8.2.2
                                 Copy of all obsolete versions                         8.3.2
  7             CRF
                                 Correspondence of revisions the CRF
                                 Signed, dated & completed CRF’s                      8.3.14
                                 Normal ranges for laboratory/medical
                                                                                      8.2.11
                                 procedures.
            Laboratory &
  8                              Lab accreditation/validation                         8.2.12
              Samples
                                 Specific lab/sample instruction


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                                  All correspondence with Lab.


                                                                                       GCP               File
Section          Title                              Contents                         Reference         Number
                                                                                     (If applicable)

                                  Instructions for IMP handling                         8.2.14
                                  Drug ordering & shipping records                      8.2.15
                                  Drug accountability records                           8.2.23
            Investigational
  9        Medicinal Product      Documentation of IMP destruction                       8.4.2
                                  Sample IMP container label                            8.2.13
                                  Certificate of analysis of IMP                        8.2.16
                                  Final approved protocol (signed copy)                  8.2.2
                                  All previously approved versions                       8.2.2
               Protocol,
  10                              Protocol amendments                                    8.3.2
                                  Protocol peer review documentation
                                  Related correspondance
                                  Patient/Donor Information sheets                       8.2.3
                                  Patient/Donor Consent forms                            8.3.2
          Patients information
  11           & consent          All superseded versions of ICF & consent               8.3.3
                                  forms
                                  Sample GP letter
                                  All Study contracts/agreements                         8.2.6
                                  Financial agreements                                   8.2.4
             Agreements/
              Contracts           Insurance certificates/statements (if
  12                                                                                     8.2.5
                                  required)
                                  Related Correspondence
                                  Investigators brochure (IB) or Summary of
                                  product Characteristics                                8.2.1
            Investigators
  13          Brochure            Safety updates/Reports (appendages to
                                  the IB)                                                8.3.1

                                  Interim analysis reports                              8.3.19
                Reports
                                  Final Study Report                                     8.4.8
  14
                                  Blank SAE form                                         8.2.2
                                  SAE reporting procedure

                 SAE’s
                                  Reported SAEs                                        8.3.16
  15                              Annual safety report
                                  SUSAR reports – notification to PI’s, EC &         8.3.17, 8.3.18
                                  CA
                                     General trial file notes to document all
  16           File Notes                  deviations or omissions from
                                                 protocol/GCP etc.
                                  All trial correspondence (fax, phone log,
                                  letters, emails, newsletters) not
                General
                                  site/patient specific or specific to any              8.3.11
            Correspondence
                                  other MF section.


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        Appendix 2
        The following list of all essential documentation, which should be filed in the Trial
        Master File, is taken from ICH GCP section 8.2, 8.3 and 8.4.

        8.2 Before the Clinical Phase of the Trial Commences

        During this planning stage the following documents should be generated and should
        be on file before the trial formally starts



                                                                                                       Located in Files
                                                                                                             of
                   Title of Document                                     Purpose
                                                                                                       Investigator
                                                                                                                       Sponsor
                                                                                                       / Institution


                                                         To document that relevant and current
                                                         scientific information about the
8.2.1   INVESTIGATOR'S BROCHURE                                                                             X            X
                                                         investigational product has been
                                                         provided to the investigator

                                                         To document investigator and sponsor
        SIGNED PROTOCOL AND AMENDMENTS, IF
8.2.2                                                    agreement to the protocol/                         X            X
        ANY, AND SAMPLE CASE REPORT FORM (CRF)
                                                         amendment(s) and CRF

8.2.3   INFORMATION GIVEN TO TRIAL SUBJECT               .                                                   .            .

        - INFORMED CONSENT FORM (including
                                                         To document the informed consent                   X            X
        translations)

                                                         To document that subjects will be given
                                                         appropriate written information (content
        - ANY OTHER WRITTEN INFORMATION                                                                     X            X
                                                         and wording) to support their ability to
                                                         give fully informed consent

        - ADVERTISEMENT FOR SUBJECT                      To document that recruitment measures
                                                                                                            X             .
        RECRUITMENT (if used)                            are appropriate and not coercive

                                                         To document the financial agreement
8.2.4   FINANCIAL ASPECTS OF THE TRIAL                   between the investigator/ institution and          X            X
                                                         the sponsor for the trial

                                                         To document that compensation to
8.2.5   INSURANCE STATEMENT (where required)             subject(s) for trial-related injury will be        X            X
                                                         available

        SIGNED AGREEMENT BETWEEN INVOLVED
8.2.6                                                    To document agreements                              .            .
        PARTIES, e.g.:

        - investigator/ institution and sponsor          .                                                  X            X

                                                                                                                          X
                                                                                                                       (where
        - investigator/ institution and CRO              .                                                  X
                                                                                                                       require
                                                                                                                         d)

        - sponsor and CRO                                .                                                  X            X

        - investigator/ institution and authority(ies)   .                                                  X            X

        DATED, DOCUMENTED APPROVAL/                      To document that the trial has been
        FAVOURABLE OPINION OF INSTITUTIONAL              subject to IRB/ IEC review and given
8.2.7                                                                                                       X            X
        REVIEW BOARD (IRB) / INDEPENDENT                 approval/ favourable opinion. To identify
        ETHICS COMMITTEE (IEC) OF THE                    the version number and date of the


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         FOLLOWING:                                       document(s).
         - protocol and any amendments
         - CRF (if applicable)
         - informed consent form(s)
         - any other written information to be provided
         to the subject(s)
         - advertisement for subject recruitment (if
         used)
         - subject compensation (if any)
         - any other documents given approval/
         favourable opinion

         INSTITUTIONAL REVIEW BOARD/                      To document that the IRB/ IEC is
8.2.8    INDEPENDENT ETHICS COMMITTEE                     constituted in agreement with GCP                 X            X
         COMPOSITION                                      (where required)

                                                          To document appropriate authorisation/
         REGULATORY AUTHORITY(IES)                        approval/ notification by the regulatory                       X
                                                                                                            X
         AUTHORISATION/ APPROVAL/ NOTIFICATION            authority(ies) has been obtained prior to                   (where
8.2.9                                                                                                    (where
         OF PROTOCOL                                      initiation of (where the trial in                           require
                                                                                                        required)
         (where required)                                 compliance with the applicable regulatory                     d)
                                                          requirement(s)

         CURRICULUM VITAE AND/ OR OTHER
                                                          To document qualifications and eligibility
         RELEVANT DOCUMENTS EVIDENCING
8.2.10                                                    to conduct trial and/ or provide medical          X            X
         QUALIFICATIONS OF INVESTIGATOR(S) AND
                                                          supervision of subjects
         SUB-INVESTIGATOR(S)

         NORMAL VALUE(S)/ RANGE(S) FOR MEDICAL/
         LABORATORY/ TECHNICAL PROCEDURE(S)               To document normal values and/ or
8.2.11                                                                                                      X            X
         AND/ OR TEST(S) INCLUDED IN THE                  ranges of the tests results
         PROTOCOL

         MEDICAL/ LABORATORY/ TECHNICAL
         PROCEDURES/ TESTS
         - certification or                               To document competence of facility to             X
8.2.12   - accreditation or                               perform required test(s), and support          (where          X
         - established quality control and/ or external   reliability of results                        required)
         quality assessment or
         - other validation

                                                          To document compliance with applicable
         SAMPLE OF LABEL(S) ATTACHED TO
8.2.13                                                    labelling regulations and appropriateness         .            X
         INVESTIGATIONAL PRODUCT CONTAINER(S)
                                                          of instructions provided to the subjects

         INSTRUCTIONS FOR HANDLING OF
                                                          To document instructions needed to
         INVESTIGATIONAL PRODUCT(S) AND TRIAL-
                                                          ensure proper storage, packaging,
8.2.14   RELATED MATERIALS                                                                                  X            X
                                                          dispensing and disposition of
         (if not included in protocol or Investigator's
                                                          investigational products and trial
         related materials Brochure)

                                                          To document shipment dates, batch
                                                          numbers and method of shipment of
         SHIPPING RECORDS FOR INVESTIGATIONAL             investigational product(s) and trial-
8.2.15                                                                                                      X            X
         PRODUCT(S) AND TRIAL-RELATED MATERIALS           related materials. Allows tracking of
                                                          product batch, review of shipping
                                                          conditions, and accountability

                                                          To document identity, purity, and
         CERTIFICATE(S) OF ANALYSIS OF
8.2.16                                                    strength of investigational product(s) to         .            X
         INVESTIGATIONAL PRODUCT(S) SHIPPED
                                                          be used in the trial

                                                          To document how, in case of an
                                                                                                             X
                                                          emergency, identity of blinded
         DECODING PROCEDURES FOR BLINDED                                                               (third party
8.2.17                                                    investigational product can be revealed                        X
         TRIALS                                                                                              if
                                                          without breaking the blind for the
                                                                                                       applicable)
                                                          remaining subjects' treatment

                                                                                                                         X
                                                          To document method for randomisation
8.2.18   MASTER RANDOMISATION LIST                                                                          X          (third
                                                          of trial population
                                                                                                                      party if

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                                                                                                                         applicab
                                                                                                                           le)

                                                             To document that the site is suitable for
8.2.19   PRE-TRIAL MONITORING REPORT                                                                            .           X
                                                             the trial (may be combined with 8.2.20)

                                                             To document that trial procedures were
                                                             reviewed with the investigator and the
8.2.20   TRIAL INITIATION MONITORING REPORT                                                                    X            X
                                                             investigator's trial staff ( may be
                                                             combined with 8.2.19)




         8.3 During the Clinical Conduct of the Trial

         In addition to having on file the above documents, the following should be added to the
         files during the trial as evidence that all new relevant information is documented as it
         becomes available

                                                                                                          Located in Files of
                       Title of Document                                     Purpose
                                                                                                         Investigator/
                                                                                                                         Sponsor
                                                                                                          Institution

                                                              To document that investigator is
                                                              informed in a timely manner of
8.3.1    INVESTIGATOR'S BROCHURE UPDATES                                                                      X             X
                                                              relevant information as it becomes
                                                              available

         ANY REVISION TO:
         - protocol/ amendment(s) and CRF
                                                              To document revisions of these trial
         - informed consent form
8.3.2                                                         related documents that take effect              X             X
         - any other written information provided to
                                                              during trial
         subjects
         - advertisement for subject recruitment (if used)

         DATED, DOCUMENTED APPROVAL/ FAVOURABLE
         OPINION OF INSTITUTIONAL REVIEW BOARD
         (IRB)/ INDEPENDENT ETHICS COMMITTEE (IEC)
         OF THE FOLLOWING:
                                                              To document that the amendment(s)
         - protocol amendment(s)
                                                              and/ or revision(s) have been subject
         - revision(s) of
                                                              to IRB/ IEC review and were given
8.3.3    - informed consent form                                                                              X             X
                                                              approval/ favourable opinion. To
         - any other written information to be provided
                                                              identify the version number and date
         to the subject
                                                              of the document(s)
         - advertisement for subject recruitment (if used)
         - any other documents given approval/
         favourable opinion
         - continuing review of trial (where required)

         REGULATORY AUTHORITY(IES)                                                                                          X
         AUTHORISATIONS/ APPROVALS/                           To document compliance with                                 (where
8.3.4                                                                                                         X
         NOTIFICATIONS WHERE REQUIRED FOR:                    applicable regulatory requirements                         required
         - protocol amendment(s) and other documents                                                                        )

         CURRICULUM VITAE FOR NEW
8.3.5    INVESTIGATOR(S) AND/ OR SUB-                         (see 8.2.10)                                    X             X
         INVESTIGATOR(S)

         UPDATES TO NORMAL VALUE(S)/ RANGE(S)
                                                              To document normal values and
         FOR MEDICAL/ LABORATORY/ TECHNICAL
8.3.6                                                         ranges that are revised during the              X             X
         PROCEDURE(S)/ TEST(S) INCLUDED IN THE
                                                              trial (see 8.2.11)
         PROTOCOL

         UPDATES OF MEDICAL/ LABORATORY/
         TECHNICAL PROCEDURES/ TESTS
         - certification or                                   To document that tests remain                               (where
8.3.7    - accreditation or                                   adequate throughout the trial period            X          required
         - established quality control and/ or external       (see 8.2.12)                                                  )X
         quality assessment or
         - other validation (where required)

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         DOCUMENTATION OF INVESTIGATIONAL
8.3.8    PRODUCT(S) AND TRIAL-RELATED MATERIALS         (see 8.2.15)                                  X           X
         SHIPMENT

         CERTIFICATE(S) OF ANALYSIS FOR NEW
8.3.9                                                   (see 8.2.16)                                   .          X
         BATCHES OF INVESTIGATIONAL PRODUCTS

                                                        To document site visits by, and
8.3.10   MONITORING VISIT REPORTS                                                                      .          X
                                                        findings of, the monitor

         RELEVANT COMMUNICATIONS OTHER THAN             To document any agreements or
         SITE VISITS                                    significant discussions regarding trial
8.3.11   - letters                                      administration, protocol violations,          X           X
         - meeting notes                                trial conduct, adverse event (AE)
         - notes of telephone calls                     reporting

                                                        To document that consent is obtained
                                                        in X accordance with GCP and
                                                        protocol and dated prior to
8.3.12   SIGNED INFORMED CONSENT FORMS                                                                X            .
                                                        participation of each subject in trial.
                                                        Also to document direct access
                                                        permission (see 8.2.3)

                                                        To document the existence of the
                                                        subject and X substantiate integrity
                                                        of trial data collected. To include
8.3.13   SOURCE DOCUMENTS                                                                             X            .
                                                        original documents related to the
                                                        trial, to medical treatment, and
                                                        history of subject

                                                        To document that the investigator or
                                                                                                                   X
         SIGNED, DATED AND COMPLETED CASE               authorised member of the                       X
8.3.14                                                                                                         (original
         REPORT FORMS (CRF)                             investigator's staff confirms the           (copy)
                                                                                                                   )
                                                        observations recorded

                                                        To document all changes/ additions                         X
                                                                                                       X
8.3.15   DOCUMENTATION OF CRF CORRECTIONS               or corrections made to CRF after                       (original
                                                                                                    (copy)
                                                        initial data were recorded                                 )

                                                        Notification by originating
         NOTIFICATION BY ORIGINATING
                                                        investigator to sponsor of serious
8.3.16   INVESTIGATOR TO SPONSOR OF SERIOUS                                                           X           X
                                                        adverse events and related reports in
         ADVERSE EVENTS AND RELATED REPORTS
                                                        accordance with 4.11

                                                        Notification by sponsor and/ or
         NOTIFICATION BY SPONSOR AND/ OR                investigator, where applicable, to
         INVESTIGATOR, WHERE APPLICABLE, TO             regulatory authorities and IRB(s)/
                                                                                                       X
         REGULATORY AUTHORITY(IES) AND IRB(S)/          IEC(s) of unexpected serious adverse
8.3.17                                                                                              (where        X
         IEC(S) OF UNEXPECTED SERIOUS ADVERSE           drug reactions in accordance with
                                                                                                   required)
         DRUG REACTIONS AND OF OTHER SAFETY             5.17 and 4.11.1 and of other safety
         INFORMATION                                    information in accordance with 5.16.2
                                                        and 4.11.2

                                                        Notification by sponsor to
         NOTIFICATION BY SPONSOR TO
8.3.18                                                  investigators of safety information in        X           X
         INVESTIGATORS OF SAFETY INFORMATION
                                                        accordance with 5.16.2

                                                        Interim or annual reports provided to                     X
         INTERIM OR ANNUAL REPORTS TO IRB/ IEC          IRB/ IEC in accordance with 4.10 and                    (where
8.3.19                                                                                                X
         AND AUTHORITY(IES)                             to authority(ies) in accordance with                   required
                                                        5.17.3                                                    )

                                                                                                                  X
                                                        To document identification of subjects                  (where
8.3.20   SUBJECT SCREENING LOG                                                                        X
                                                        who entered pre-trial screening                        required
                                                                                                                  )

                                                        To document that investigator/
                                                        institution keepsa confidential list of
8.3.21   SUBJECT IDENTIFICATION CODE LIST                                                             X            .
                                                        names of all subjects allocated to trial
                                                        numbers on enrolling in the trial.


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                                                             Allows investigator/ institution to
                                                             reveal identity of any subject

                                                             To document chronological
 8.3.22    SUBJECT ENROLLMENT LOG                            enrollment of subjects by trial                  X                .
                                                             number

                                                             To document that investigational
           INVESTIGATIONAL PRODUCTS
 8.3.23                                                      product(s) have been used according              X                X
           ACCOUNTABILITY AT THE SITE
                                                             to the protocol

                                                             To document signatures and initials of
 8.3.24    SIGNATURE SHEET                                   all persons authorised to make                   X                X
                                                             entries and/ or corrections on CRFs

                                                             To document location and
           RECORD OF RETAINED BODY FLUIDS/ TISSUE
 8.3.25                                                      identification of retained samples if            X                X
           SAMPLES (IF ANY)
                                                             assays need to be repeated




            8.4 After Completion or Termination of the Trial

            After completion or termination of the trial, all of the documents identified in sections 8.2
            and 8.3 should be in the file together with the following

                                                                                                        Located in Files of
                      Title of Document                                  Purpose
                                                                                                        Investigator
                                                                                                        / Institution
                                                                                                                        Sponsor


                                                        To document that the investigational
                                                        product(s) have been used according to
                                                        the protocol. To document the final
          INVESTIGATIONAL PRODUCT(S)
8.4.1                                                   accounting of investigational product(s)             X            X
          ACCOUNTABILITY AT SITE
                                                        received at the site, dispensed to subjects,
                                                        returned by the subjects, and returned to
                                                        sponsor

                                                                                                            X
                                                        To document destruction of unused
          DOCUMENTATION OF INVESTIGATIONAL                                                                  (if
8.4.2                                                   investigational products by sponsor or at                         X
          PRODUCT DESTRUCTION                                                                           destroyed
                                                        site
                                                                                                         at site)

                                                        To permit identification of all subjects
                                                        enrolled in the trial in case follow-up is
          COMPLETED SUBJECT IDENTIFICATION
8.4.3                                                   required. List should be kept in a                   X             .
          CODE LIST
                                                        confidential manner and for agreed upon
                                                        time

8.4.4     AUDIT CERTIFICATE (if available)              To document that audit was performed                  .            .

                                                        To document that all activities required for
          FINAL TRIAL CLOSE-OUT MONITORING              trial close-out are completed, and copies of
8.4.5                                                                                                        X             .
          REPORT                                        essential documents are held in the
                                                        appropriate files

          TREATMENT ALLOCATION AND DECODING             Returned to sponsor to document any
8.4.6                                                                                                        X             .
          DOCUMENTATION                                 decoding that may have occurred

          FINAL REPORT BY INVESTIGATOR TO IRB/
          IEC WHERE REQUIRED, AND WHERE
8.4.7                                                   To document completion of the trial                  X             .
          APPLICABLE, TO THE REGULATORY
          AUTHORITY(IES)

                                                        To document results and interpretation of
8.4.8     CLINICAL STUDY REPORT                                                                              X            X
                                                        trial




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