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).

ADDENDUM

The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval. Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial. The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

 

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 DocumentPurposeLocated in Files of
   Investigator/
Institution
Sponsor
8.2.1INVESTIGATOR’S BROCHURETo document that relevant and current scientific information about the investigational product has been provided to the investigatorXX
8.2.2SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)To document investigator and sponsor agreement to the protocol/amendment(s) and CRFXX
8.2.3INFORMATION GIVEN TO TRIAL SUBJECT
- INFORMED CONSENT FORM
(including all applicable translations)
To document the informed consentXX
 - ANY OTHER WRITTEN INFORMATIONTo document that subjects will be given appropriate written information (content and wording) to support their ability to give fully informed consentXX
 - ADVERTISEMENT FOR SUBJECT RECRUITMENT (if used)To document that recruitment measures are appropriate and not coerciveX 
8.2.4FINANCIAL ASPECTS OF THE TRIALTo document the financial agreement between the investigator/institution and the sponsor for the trial
 
XX
8.2.5INSURANCE STATEMENT
(where required)
To document that compensation to subject(s) for trial-related injury will be availableXX
8.2.6SIGNED 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 agreementsX
 
X
X
X
X
(where required)
X
X
8.2.7DATED, 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)
XX
8.2.8INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITIONTo document that the IRB/IEC is constituted in agreement with GCPXX
(where required)
8.2.9REGULATORY 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)
8.2.10CURRICULUM 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 subjectsXX
8.2.11NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOLTo document normal values and/or ranges of the testsXX
8.2.12MEDICAL/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 resultsX
(where required)
X
8.2.13SAMPLE 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
8.2.14INSTRUCTIONS 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 materialsXX
8.2.15SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALSTo 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 accountabilityXX
8.2.16CERTIFICATE(S) OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPEDTo document identity, purity, and strength of investigational product(s) to be used in the trial
 
 X
8.2.17DECODING PROCEDURES FOR BLINDED TRIALSTo 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)
8.2.18MASTER RANDOMISATION LISTTo document method for randomisation of trial population X
(third party if applicable)
 
8.2.19PRE-TRIAL MONITORING REPORTTo document that the site is suitable for the trial (may be combined with 8.2.20) X
8.2.20TRIAL INITIATION MONITORING REPORTTo document that trial procedures were reviewed with the investigator and the investigator’s trial staff ( may be combined with 8.2.19)XX

    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 DocumentPurposeLocated 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 XX
8.3.2ANY 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 trialXX
8.3.3DATED, 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).XX
8.3.4REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFICATIONS WHERE REQUIRED FOR:
- protocol amendment(s) and other documents
To document compliance with applicable regulatory requirementsX
(where required)
X
8.3.5CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB-INVESTIGATOR(S)(see 8.2.10)
 
XX
8.3.6UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOLTo document normal values and ranges that are revised during the trial (see 8.2.11)XX
8.3.7UPDATES 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
8.3.8DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT(see 8.2.15.)XX
8.3.9CERTIFICATE(S) OF ANALYSIS FOR NEW BATCHES OF INVESTIGATIONAL PRODUCTS(see 8.2.16) X
8.3.10MONITORING VISIT REPORTSTo document site visits by, and findings of, the monitor X
8.3.11RELEVANT 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) reportingXX
8.3.12SIGNED INFORMED CONSENT FORMSTo 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 
8.3.13SOURCE DOCUMENTSTo 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 subjectX 
8.3.14SIGNED, DATED AND COMPLETED
CASE REPORT FORMS (CRF)
To document that the investigator or authorised member of the investigator’s staff confirms the observations recordedX
(copy)
X
(original)
8.3.15DOCUMENTATION OF CRF CORRECTIONSTo document all changes/additions or corrections made to CRF after initial data were recordedX
(copy)
X
(original)
8.3.16NOTIFICATION BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS AND RELATED REPORTSNotification by originating investigator to sponsor of serious adverse events and related reports in accordance with 4.11XX
8.3.17NOTIFICATION 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 INFORMATIONNotification 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 4.11.2X
(where required)
X
8.3.18NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATIONNotification by sponsor to investigators of safety information in accordance with 5.16.2XX
8.3.19INTERIM 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 5.17.3XX
(where required)
8.3.20SUBJECT SCREENING LOGTo document identification of subjects who entered pre-trial screeningXX
(where required)
8.3.21SUBJECT IDENTIFICATION CODE LISTTo 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 subjectX 
8.3.22SUBJECT ENROLMENT LOGTo document chronological enrolment of subjects by trial number
 
X 
8.3.23INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITETo document that investigational product(s) have been used according to the protocolXX
8.3.24SIGNATURE SHEETTo document signatures and initials of all persons authorised to make entries and/or corrections on CRFsXX
8.3.25RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)To document location and identification of retained samples if assays need to be repeatedXX

 

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 DocumentPurposeLocated in Files of
   Investigator/
Institution
Sponsor
8.4.1INVESTIGATIONAL PRODUCT(S) ACCOUNTABILITY AT SITETo 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 sponsorXX
8.4.2DOCUMENTATION OF INVESTIGATIONAL PRODUCT DESTRUCTIONTo document destruction of unused investigational products by sponsor or at site
 
X
(if destroyed at site)
X
8.4.3COMPLETED SUBJECT IDENTIFICATION CODE LISTTo 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 timeX 
8.4.4AUDIT CERTIFICATE (if available)To document that audit was performed X
8.4.5FINAL TRIAL CLOSE-OUT MONITORING REPORTTo document that all activities required for trial close-out are completed, and copies of essential documents are held in the appropriate files X
8.4.6TREATMENT ALLOCATION AND
DECODING DOCUMENTATION
Returned to sponsor to document any decoding that may have occurred X
8.4.7FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)To document completion of the trialX 
8.4.8CLINICAL STUDY REPORT
 
To document results and interpretation of trialX
(if applicable)
X

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