introduction - university of birmingham · web view2016/03/01 · note: the essential documents...

Essential Documents Checklist - CTIMPs

IntroductionEssential 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.

InstructionsThis checklist can be used as a tool to identify which essential documents should be filed in Trial Master File (TMF) and Investigator Site File, and also which documents are required for inclusion in the Sponsor file.

The essential documents listed below may not be applicable to all trials. Where essential documents are missing or not applicable please document the reason for this, e.g. by including a note in the comments field.

Trial Master Files and Investigator Site Files may contain additional documents that are not in this list but are relevant to the management of a trial. For some trials (e.g. single site) it may be appropriate to merge Trial Master File and Investigator Site File. Please make a note if this is this case.

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.

A Trial Master File should be established at the beginning of the trial. A final close-out of a trial can only be done when a review of both the Investigator Site File and Trial Master File has been performed to confirm 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).

Upon request of the monitor, auditor, Ethics Committee, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records according to Community and national legislation.

Note: the Essential documents checklist has all documents as listed in ICH GCP and the EU recommendation on the content of the Trial Master File and Archiving. Document titles may be reworded e.g. to make them UK specific; any changes are highlighted in italics. This checklist also lists documents that are

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expected to be part of the Trial Master File, and are based on UK specific requirements and/or University of Birmingham specific procedures; these are highlighted in grey. Documents are largely grouped on topic.

Essential documents checklist:Title Of Document Purpose Investigat

or FileTMF Sponsor

FileComment

Where applicable, any translations and back translations of essential documents

To clarify which documents have been translated, and to provide evidence that the translation was appropriate.

X X (if related to documents kept in Sponsor File)

Risk assessment documentation To document the process and outcome of risk assessment, and how this informed the trial set up and management.

X

Any plans and guidelines, e.g. Monitor Plan, Communication Plan, Statistical Analysis Plan

To document the systems put in place to address trial risks and to ensure quality data is generated and the subjects’ safety and wellbeing is safeguarded.

X

Investigator’s Brochure or Summary of Products Characteristics and updates

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

X X

Signed Protocol and amendments, if any, and sample Case Report Form (CRF) and any revisions

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

X(PI signed)

X(PI and CI signed)

X(unsigned)

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Title Of Document Purpose Investigator File

TMF Sponsor File

Comment

Information given to trial subject and any revisions thereof:

- Master Informed Consent Form To document the informed consent

X 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 X

- Advertisement for subject recruitment (if used)

To document that recruitment measures are appropriate and not coercive

X X X

Financial aspects of the trial(including funding application/award letter)

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

X X (auto)

Insurance statement(where required; for CTIMPs insurance/indemnity cover is a legal requirement)

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

X X X (auto)

Signed Agreement between involved parties, e.g.:

- Investigator/Institution and Sponsor (Clinical Trial Site Agreements)

To document agreements X X X

- Investigator/Institution and third parties, eg. Vendors, coordinating

To document agreements X X(where

X

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TMF Sponsor File

Comment

centre etc required)

- Clinical Trials Task Delegation Log CI-CTU

To document agreements X X X

- Charter signed by Data Monitoring Committee members

To document expectations of both parties, e.g. via a charter

X

- Sponsor and Chief Investigator

To document expectations of both parties, e.g. via CI Declaration Form or CI Agreement

X X

Letter of Sponsorship To document that the Sponsor has agreed to take on Sponsorship responsibilities for the trial

X X X(auto)

Dated, documented Favourable Opinion of Research Ethics Committee (REC) of the following including any revisions:

- Protocol and any amendments

- Informed Consent Form(s)

- Any other written information to be provided to the subject(s)

- Advertisement for subject recruitment (if used)

- Subject compensation (if

To document that the trial has been subject to REC review and given favourable opinion. To identify the version number and date of the document(s).To document that the favourable opinion is maintained throughout the trial. Documents include the application form and correspondence.

X X X

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TMF Sponsor File

Comment

any)- Any other documents

given Approval/ Favourable Opinion

Along with REC composition for each Favourable Ethical Opinion

NHS permissions (if applicable) including application, approval letter and correspondence

To document NHS permission was gained for an individual NHS site to participate in the trial

X X X

Regulatory Authority(ies)Clinical Trial Authorisation, including maintaining authorisation following changes to the trial.(where required)

To document appropriate authorisation by the regulatory authority(ies) has been obtained prior to initiation of the trial in compliance with the applicable regulatory requirement(s), and to document that the authorisation is maintained throughout the trial. Documents include the application form and correspondence.

X X X

Other relevant approvals, e.g. ARSAC, HBRC including maintaining approval following changes to the trial. application forms, approval letters and correspondence,(where required)

To document any other appropriate approvals has been obtained prior to initiation, and to document that the authorisation is maintained throughout the trial. Documents include the application form and correspondence.

X X X

Interim or Annual Reports to REC Interim or annual reports X X X

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TMF Sponsor File

Comment

and Authority(ies) (where required)

provided to REC in accordance with 4.10 (ICH GCP) and to authority(ies)

Curriculum Vitae and/or other relevant documents evidencing qualifications of Investigator(s) and Sub-Investigator(s) including any revisions and Curriculum Vitae for new Investigators

To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects This includes GCP training. It is recommended that you sign and date the documents as this will allow the reviewer to assess how recent the information is.

X X X (CI only)

Signature Sheet To document signatures and initials of all persons authorised to make entries and/or corrections on CRFsThis may be combined with the delegation of responsibilities log.

X X

Delegation of responsibilities log To document what duties have been delegated by the site PI to site staff. This may be combined with the Signature Sheet.

X X

Normal value(s)/range(s) for medical/laboratory/technical procedure(s) and/or test(s) included in the Protocol, including any updates

To document normal values and/or ranges of the tests

X X

Medical/laboratory/technical To document competence of X X

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TMF Sponsor File

Comment

procedures/tests, including any updates

- certification or- accreditation or- established quality control

and/or external quality assessment or

- - other validation (where required)

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

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

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

Instructions for handling of Investigational Product(s) and trial-related materials and any updates(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

Shipping records for Investigational Product(s) and trial-related materials and any updates*

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

X X

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TMF Sponsor File

Comment

conditions, and accountability

Certificate(s) of Analysis of Investigational Product(s) shipped including Certificates of Analysis for new batches and QP release

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

X

Proof of Investigational Product(s) storage condition monitoring*

To document that the required storage conditions of the Investigational Product(s) are maintained at site.Note that this is especially important where storage conditions vary from normal practice, e.g. use of refrigerator/freezer.

X X

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

Documentation of Investigational Product destruction*

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

X(if destroyed at site)

X

Decoding procedures for blinded trials

To document how, in case of an emergency, identity of blinded

X X(third party if

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TMF Sponsor File

Comment

investigational product can be revealed without breaking the blind for the remaining subjects' treatment

applicable)

Master Randomisation List To document method for randomisation of trial populationNote this may be a programme rather than a list, and may be held by the Trial Statistician. In this case, a Note to File should be added to the TMF, document the name and contact details of the Trial Statistician, and the parameters of the randomisation.

X(third party if applicable)

Treatment allocation anddecoding documentation

Returned to sponsor to document any decoding that may have occurred

X

Pre-trial Monitoring Report (may be combined with Trial Initiation Monitoring Report)

To document that the site is suitable for the trial

X

Trial Initiation Monitoring Report (may be combined with Pre-trial Monitoring Report)

To document that trial procedures were reviewed with the investigator and the investigator’s trial staff

X X

Monitoring Visit Reports To document site visits by, and findings of, the monitor

X

Final Trial Close-Out Monitoring Report

To document that all activities required for trial close-out are

X

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TMF Sponsor File

Comment

completed, and copies of essential documents are held in the appropriate files

Audit Certificate (if available) To document that audit was performed

X

Relevant communications other than site visits

- Letters- Emails- Meeting notes- Notes of telephone calls

To document any agreements or significant discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) reporting.Note this may include communications amongst the Trial Management Group members, between Trial Management Group and Data Monitoring Committee etceteras, including meeting minutes.

X(where required)

X

Subject Screening Log To document identification of subjects who entered pre-trial screening

X X(where required)

Up to date Subject Identification Code List

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

X

Subject Enrolment Log To document chronological enrolment of subjects by trial

X

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TMF Sponsor File

Comment

number

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

X X (where applicable)

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

Sample Case Report Forms and any updates thereof

To record trial related observations.

X X

Signed, dated and completedCase Report Forms (CRF)

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

X(copy)

X(original)

Documentation of CRF corrections

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

X(copy)

X(original)

Analytical data and supporting records relating to clinical trial analysis

To enable the conduct and quality of the data to be evaluated to ensure that the research has been conducted in accordance with GCP and all

X

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TMF Sponsor File

Comment

applicable regulations.

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

X X

Notification by Sponsor and/or Investigator, where applicable, to Regulatory Authority(ies) and REC(s) of Unexpected Serious Adverse Drug Reactions (in CTIMPs: SUSARs) 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 and of other safety information

X(where required)

X X

Notification by Sponsor to Investigators of safety information

Notification by sponsor to Investigator of safety information.

X X

Final report by Investigator to REC where required, and where applicable, to the Regulatory Authority(ies)

To document completion of the trial

X X

End of Study Declarations submitted to Authority and REC at the end of the trial

To document completion of the trial

X X

Clinical Study Report To document results and interpretation of trial

X (if applicable)

X X

Notes:

* Many non-commercial trials use pharmacy supplies of medicinal products that have a marketing authorisation and the tracking of product batches, shipping conditions and accountability, storage and dispensing instructions and the need for reconciliation between medicinal products supplied, used and returned

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before destruction as well as the process for destruction will be part of the pharmacy’s standard operating procedures for handling clinical trial materials. If this applies, provided the pharmacy SOP conforms to the applicable legislation and guidance, including retention of records, it may be noted in the TMF and ISF.Columns marked ‘X (auto)’: the underlying processes are dealt with by the UoB central offices (Research Governance Team, Research Finance Office) and the information will be automatically captured in the Sponsor Files.

References European Committee, 2006. Recommendation of the content of the Trial Master File and Archiving. [Online]

Available at: http://ec.europa.eu/health/files/eudralex/vol-10/v10_chap5_en.pdf[Accessed 14 January 2016].

International Conference for Harmonisation, 1996. ICH GCP. [Online] Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf[Accessed 14 January 2016].

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