8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

8.1 Introduction

Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a 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.

Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor’s independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected.

The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable.

Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor’s office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files.

Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).

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

 

Title of Document

Purpose

Located in Files of

     

Investigator/

Institution

Sponsor

8.2.1

INVESTIGATOR’S BROCHURE

To document that relevant and current scientific information about the investigational product has been provided to the investigator

X

X

8.2.2

SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)

To document investigator and sponsor agreement to the protocol/amendment(s) and CRF

X

X

8.2.3

INFORMATION GIVEN TO TRIAL SUBJECT

- INFORMED CONSENT FORM

(including all applicable translations)

 

 

To document the informed consent

X

X

 

- ANY OTHER WRITTEN INFORMATION

To document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consent

X

X

 

- ADVERTISEMENT FOR SUBJECT RECRUITMENT (if used)

To document that recruitment measures are appropriate and not coercive

X

 

8.2.4

FINANCIAL ASPECTS OF THE TRIAL

To document the financial agreement between the investigator/institution and the sponsor for the trial

 

X

X

8.2.5

INSURANCE STATEMENT

(where required)

To document that compensation to subject(s) for trial-related injury will be available

X

X

8.2.6

SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.:

- investigator/institution and sponsor

- investigator/institution and CRO

- sponsor and CRO

- investigator/institution and authority(ies) (where required)

To document agreements

 

X

X

 

X

 

X

X

(where required)

X

X

8.2.7

DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:

- 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

To document that the trial has been subject to

IRB/IEC review and given approval/favourable opinion. To identify the version number and date of the document(s)

X

X

8.2.8

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITION

To document that the IRB/IEC is constituted in agreement with GCP

X

X

(where required)

8.2.9

REGULATORY AUTHORITY(IES)

AUTHORISATION/APPROVAL/

NOTIFICATION OF PROTOCOL

(where required)

To document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirement(s)

X

(where required)

X

(where required)

8.2.10

CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)

To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects

X

X

8.2.11

NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL

To document normal values and/or ranges of the tests

X

X

8.2.12

MEDICAL/LABORATORY/TECHNICAL PROCEDURES /TESTS

- certification or

- accreditation or

- established quality control and/or external quality assessment or

- other validation (where required)

 

To document competence of facility to perform required test(s) , and support reliability of results

X

(where required)

X

8.2.13

SAMPLE OF LABEL(S) ATTACHED TO INVESTIGATIONAL PRODUCT CONTAINER(S)

To document compliance with applicable labelling regulations and appropriateness of instructions provided to the subjects

 

X

8.2.14

INSTRUCTIONS FOR HANDLING OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS

(if not included in protocol or Investigator’s Brochure)

To document instructions needed to ensure proper storage, packaging, dispensing and disposition of investigational products and trial-related materials

X

X

8.2.15

SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS

To document shipment dates, batch numbers and method of shipment of investigational product(s) and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability

X

X

8.2.16

CERTIFICATE(S) OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPED

To document identity, purity, and strength of investigational product(s) to be used in the trial

 

 

X

8.2.17

DECODING PROCEDURES FOR BLINDED TRIALS

To document how, in case of an emergency, identity of blinded investigational product can be revealed without breaking the blind for the remaining subjects’ treatment

 

X

 

X

(third party if applicable)

8.2.18

MASTER RANDOMISATION LIST

To document method for randomisation of trial population

 

X

(third party if applicable)

 

8.2.19

PRE-TRIAL MONITORING REPORT

To document that the site is suitable for the trial (may be combined with 8.2.20)

 

X

8.2.20

TRIAL INITIATION MONITORING REPORT

To document that trial procedures were reviewed with the investigator and the investigator’s trial staff ( may be combined with 8.2.19)

X

X

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

 

Title of Document

Purpose

Located in Files of

     

Investigator/

Institution

Sponsor

8.3.1

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

8.3.2

ANY REVISION TO:

- protocol/amendment(s) and CRF

- informed consent form

- any other written information provided to subjects

- advertisement for subject recruitment

(if used)

To document revisions of these trial related documents that take effect during trial

X

X

8.3.3

DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB) /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:

- protocol amendment(s)

- revision(s) of:

- informed consent form

- any other written information to be provided to the subject

- advertisement for subject recruitment

(if used)

- any other documents given approval/favourable opinion

- continuing review of trial (where required)

To document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were given approval/favourable opinion. To identify the version number and date of the document(s).

X

X

8.3.4

REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFICATIONS WHERE REQUIRED FOR:

- protocol amendment(s) and other documents

To document compliance with applicable regulatory requirements

X

(where required)

X

8.3.5

CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB-INVESTIGATOR(S)

(see 8.2.10)

 

X

X

8.3.6

UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL

To document normal values and ranges that are revised during the trial (see 8.2.11)

X

X

8.3.7

UPDATES OF MEDICAL/LABORATORY/ TECHNICAL PROCEDURES/TESTS

- certification or

- accreditation or

- established quality control and/or external quality assessment or

- other validation (where required)

To document that tests remain adequate throughout the trial period (see 8.2.12)

X

(where required)

X

8.3.8

DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT

(see 8.2.15.)

X

X

8.3.9

CERTIFICATE(S) OF ANALYSIS FOR NEW BATCHES OF INVESTIGATIONAL PRODUCTS

(see 8.2.16)

 

X

8.3.10

MONITORING VISIT REPORTS

To document site visits by, and findings of, the monitor

 

X

8.3.11

RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS

- letters

- meeting notes

- notes of telephone calls

 

To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting

X

X

8.3.12

SIGNED INFORMED CONSENT FORMS

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

X

 

8.3.13

SOURCE DOCUMENTS

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

X

 

8.3.14

SIGNED, DATED AND COMPLETED

CASE REPORT FORMS (CRF)

To document that the investigator or authorised member of the investigator’s staff confirms the observations recorded

X

(copy)

X

(original)

8.3.15

DOCUMENTATION OF CRF CORRECTIONS

To document all changes/additions or corrections made to CRF after initial data were recorded

X

(copy)

X

(original)

8.3.16

NOTIFICATION BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS AND RELATED REPORTS

Notification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11

X

X

8.3.17

NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION

Notification by sponsor and/or investigator, where applicable, to regulatory authorities and IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other safety information in accordance with 5.16.2 and 4.11.2

X

(where required)

X

8.3.18

NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION

Notification by sponsor to investigators of safety information in accordance with 5.16.2

X

X

8.3.19

INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)

Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in accordance with 5.17.3

X

X

(where required)

8.3.20

SUBJECT SCREENING LOG

To document identification of subjects who entered pre-trial screening

X

X

(where required)

8.3.21

SUBJECT IDENTIFICATION CODE LIST

To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject

X

 

8.3.22

SUBJECT ENROLMENT LOG

To document chronological enrolment of subjects by trial number

 

X

 

8.3.23

INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITE

To document that investigational product(s) have been used according to the protocol

X

X

8.3.24

SIGNATURE SHEET

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

X

X

8.3.25

RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)

To document location and identification of retained samples if assays need to be repeated

X

X

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

 

Title of Document

Purpose

Located in Files of

     

Investigator/

Institution

Sponsor

8.4.1

INVESTIGATIONAL PRODUCT(S) ACCOUNTABILITY AT SITE

To document that the investigational product(s) have been used according to the protocol. To documents the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor

X

X

8.4.2

DOCUMENTATION OF INVESTIGATIONAL PRODUCT DESTRUCTION

To document destruction of unused investigational products by sponsor or at site

 

X

(if destroyed at site)

X

8.4.3

COMPLETED SUBJECT IDENTIFICATION CODE LIST

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

X

 

8.4.4

AUDIT CERTIFICATE (if available)

To document that audit was performed

 

X

8.4.5

FINAL TRIAL CLOSE-OUT MONITORING REPORT

To document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files

 

X

8.4.6

TREATMENT ALLOCATION AND

DECODING DOCUMENTATION

Returned to sponsor to document any decoding that may have occurred

 

X

8.4.7

FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)

To document completion of the trial

X

 

8.4.8

CLINICAL STUDY REPORT

 

To document results and interpretation of trial

X

(if applicable)

X