The topics are grouped in main sections, within each section there is a series of contributions set in ‘accordion’ (expanding when you click on the item’s headline).
This is a continuous project that will be updated regularly, also based on your feedback, comments and suggestions. On occasion we may invite others to contribute.
European Union (EU) pharmaceutical legislation known as the Clinical Trials Regulation (CTR) entered into application on 31 January 2022. It aims to ensure the EU offers an attractive and favourable environment for carrying out clinical research on a large scale, with high standards of public transparency and safety for clinical trial participants.
EudraLex (“The rules governing medicinal products in the European Union”) Volume 10 – “Clinical trials” provides detailed itemised guidance on the rulings for CT under the EU CTR:
Chapter I – Application and application documents
Chapter II – Safety reporting
Chapter III – Quality
Chapter IV – Inspections
Chapter V – Additional documents
Chapter VI – Legislation
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC
Commission Implementing Regulation (EU) 2017/556 of 24 March 2017 on detailed arrangements for the good clinical practice inspection procedures pursuant to Regulation (EU) No 536/2014 of the European Parliament and of the Council
Commission Delegated Regulation (EU) 2017/1569 (for linguistic versions, click here) of 23 May 2017 supplementing Regulation (EU) 536/2014 of the European Parliament and of the Council by specifying principles and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections (applicable as from the date of entry into application of Regulation (EU) No 536/2014 on Clinical Trials)
Commission Implementing Regulation (EU) 2022/20 of 7 January 2022 laying down rules for the application of Regulation (EU) No 536/2014 of the European Parliament and of the Council as regards setting up the rules and procedures for the cooperation of the Member States in safety assessment of clinical trials (Text with EEA relevance)
{15.Jun.2018 U: 15.Mar.2023 | ACPS-CdM}
European Union (EU) pharmaceutical legislation known as the Clinical Trials Regulation (CTR) entered into application on 31 January 2022. It aims to ensure the EU offers an attractive and favourable environment for carrying out clinical research on a large scale, with high standards of public transparency and safety for clinical trial participants.
{19.Apr.2023 | ACPS-CdM}
European Union (EU) pharmaceutical legislation known as the Clinical Trials Regulation (CTR) entered into application on 31 January 2022. It aims to ensure the EU offers an attractive and favourable environment for carrying out clinical research on a large scale, with high standards of public transparency and safety for clinical trial participants.
EMA provides help for Sponsors getting started:
Also, Sponsor users who want to be trained on CTIS have the opportunity to express their interest in gaining access to the CTIS Training Environment, by filling a survey. The training environment is a simulation of CTIS used in production and allows users to get familiar with system functionalities in a safe environment.
{15.Mar.2023 | ACPS-CdM}
In March 2022, the ‘CTIS highlights’ newsletter became the ‘Clinical Trials highlights’ newsletter. It will continue to cover CTIS but will also include topics such as the business change programme ACT EU.
{01.May.2023 | ACPS-CdM}
European Union (EU) pharmaceutical legislation known as the Clinical Trials Regulation (CTR) entered into application on 31 January 2022. It aims to ensure the EU offers an attractive and favourable environment for carrying out clinical research on a large scale, with high standards of public transparency and safety for clinical trial participants.
EMA is delivering an online modular training programme to help clinical trial sponsors, national competent authorities, ethics committees, European Commission and EMA staff prepare for using the Clinical Trials Information System (CTIS). The training programme consists of several modules, covering the full lifecycle of clinical trial submission, authorisation and supervision.
{15.Mar.2023 | ACPS-CdM}
European Union (EU) pharmaceutical legislation known as the Clinical Trials Regulation (CTR) entered into application on 31 January 2022. It aims to ensure the EU offers an attractive and favourable environment for carrying out clinical research on a large scale, with high standards of public transparency and safety for clinical trial participants. In this way, the Regulation repealed the Clinical Trials Directive (EC) No. 2001/20/EC (CTD) and national implementing legislation in the EU Member States, which regulated clinical trials in the EU until the Regulation’s entry into application. A transition period applies to clinical trial submission under the Regulation..
The CTR resolves the issue that the national laws, which regulated the implementation of CTD and GCP on a national level led to different interpretations on how GCXP standards had to be adhered to.
ECRIN-Campus provides guidance in this complexity; it provides specification of the legal requirements for clinical trials with medicinal products, medical devices and nutraceuticals by country:
{16.Jun.2018 | ACPS-CdM}
Clinical trials call upon a complex network of resources i.e. parties contracted by the sponsor (e.g. CROs) and parties subcontracted by such delegates. The EU Clinical Trials Regulation 536/2014 (CTR) Art. 71 replacing the EU Clinical Trials Directive (CTD), EU GCP Directive 2001/20/EC Section 3 Art. 7.1 and ICH GCP E6(R2) Art. 5.2.1-5.2.4 [EMA/CHMP/ICH/135/1995] provide guidance in this regard specifying that:
All parties pertinent to the quality management and GCP-compliance of the trial should be identifiable in the Clinical Trial Application. In this way, it is ensured that the delegates are identifiable also with the purpose to ensure that the quality management of their contribution is accessible for inspection.
Delegation may constitute a relevant quality risk, particularly if several parties are involved with partly overlapping functions and authorities. It is therefore recommended to take due precautions to prevent, control, and remedy possible defects that might arise, e.g.:
See also:
{13.Mar.2018 U: 20.12.2022 | ACPS-CdM}
Clinical trials call upon a complex network of resources, i.e. parties contracted by the sponsor (e.g. contract research organisations [CROs]) and parties subcontracted by such delegates (e.g. hospitals, clinics, investigators, laboratories, site management organisations [SMOs], monitors, etc.). Therefore, it is imperative that the sponsor has systems and procedures in place to ensure adequate oversight of the quality management of the trial’s tasks & duties irrespective of their primary assignment (sponsor or CRO).
ICH GCP E6(R2) [ICH GCP E6(R2) Art. 5.2.1-5.2.4 [EMA/CHMP/ICH/135/1995]
ICH GCP E6(R2) – 5.2.1. “A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control”
ICH GCP E6(R2) – 5.2.2. “Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing – ADDENDUM: The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”
ICH GCP E6(R2) – 5.2.3. “Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor.”
ICH GCP E6(R2) – 5.2.4 “All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial related duties and functions of a sponsor”.
EU Perspective
EU GCP Directive 2001/20/EC Section 3 Art. 7.1 and provide Guidance in this regard, specifying that:
“… the sponsor shall remain responsible for ensuring that the conduct of the trials and the final data generated by those trials comply with Directive 2001/20/EC as well as the EU GCP Directive”
EU Clinical Trial Regulation Chapter XI Art. 71: “Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organisation. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial”
US FDA Perspective
FDA Guidance for Industry: Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring (Aug.2013)
Oversight Tools & Solutions
Several tools can be put in place to plan, establish and document oversight as an essential and self-evident core theme of any study’s risk-based quality management: vendor/system audits; review of the qualification and quality management of the subcontractors; set-up and management of a global risk-based quality management plan encompassing all services (irrespective of their primary assignment); task assignment and contract review extended to the subcontractors; co-monitoring (also) of the subcontracted services; CRO’s and SMO’s obligation to escalate quality limiting findings, etc.
In consequence: Sponsor oversight is not just the initial vendor qualification/selection process of a CRO to whom the trial can be entrusted by means of a full-service agreement. The sponsor’s oversight should encompass the full trial. Using a risk-oriented “for purpose” approach, the necessary measures should be well balanced to ensure due quality without loss of cost and time efficiency.
Recommended Reading
{02.02.2021 U: 19.Apr.2023 | ACPS-CdM}
The replacement of CTD and the national laws to ensure the orderly implementation of GCP by the EU CTR does not change the need for GCP-training and GCP-certification of medical investigators.
In Germany, this is and will remain under the authority of the Ethics Committee(s) and the respective Chamber of Physicians. The Chamber(s) define the training curricula and regulate the need for refresh training every three years or in the event of any novel GCP-ruling:
{08.Oct.2020 – U: 22.12.2022 | ACPS-CdM}
{01.Oct.2020 U: 27.Mar.2022 & 27.Dec.2022 | ACPS-CdM}
BABE-Studies are highly cost-sensitive. EU & US Sponsors are obviously seeking to keep BABE-budgets low also by relying on non-ICH sites for the conduct of their trials even although these studies are aimed to endorse applications for marketing authorisation in the EU or US. The drift from the EU to non-ICH CROs also reflects rapidly increasing trial costs in eastern- and southeastern-EU, the complexity of the EU CT application process, increasing frustration about the lengthy CA reviews in most EU member states, the hurdle of needing an extensive IMPD (or IMPD-Q) for novel, i.e. non-authorised IMPs, etc.
There is a reasonably justified expectation that non-ICH may offer good quality faster and at a lower cost. On the other hand, there have been horrifying cases of serious GCP-infringements at non-ICH sites ultimately leading to the withdrawal of hundreds of products from the EU markets (see EMA on GVK Biosciences , Quest Life Science, and Micro Therapeutic Research).
In the EU, clinical trials that are part of an application for marketing authorisation (MA) in the EU (whether part of a centralised or decentralised procedure) are required to meet internationally agreed ethical and data quality standards or their equivalent. These objectives need to be addressed before and during the conduct of the clinical trials and not only by assessment and inspection at the time of MA evaluation, by which point the trials have been completed, in some cases several years earlier.
The best approach for achieving these objectives is to ensure that a robust framework exists for the oversight and quality management of clinical trials, no matter where in the world the clinical investigators’ sites are located and patients recruited (EMA/121340/2011 The European Medicines Agency Working Group on Clinical Trials conducted outside of the EU/EEA – Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities, Apr.2012).
Also, Paragraph §8 of the Preamble (Introduction and General Principles) of Annex 1 to Directive 2001/83/EC (“Community Code”):
» regardless of where they are conducted, all clinical trials included in applications for MAA for human medicines in the European Economic Area must have been carried out in accordance with the requirements set out in Annex 1 of Directive 2001/83/EC. This means that:
a) clinical trials conducted within the EEA have to comply with European Union (EU) clinical-trial legislation (Directive 2001/20/EC) and that
b) those conducted outside the EEA have to comply with ethical principles equivalent to those set out in the EEA, including adhering to international good clinical practice (GCP) and the Declaration of Helsinki.
In consequence, the sponsor is expected to
In addition, clinical trials set in a foreign environment generally involve important challenges: linguistically (patient information, declaration of consent, and sources of CRF-data ought to be in the national language; liaison with the ethics committee and competent authority are likely to be in the national language), culturally (dietary habits, constraints on the participation of females in studies, etc.).
{03.Mar.2021 U: 27.Mar.2022 | ACPS-CdM}
Legally, FDA has the authority to accept foreign data as the sole basis for marketing approval.
CFR 314.106(b) sets out these requirements:
FDA may reject an NDA filing if there is “inadequate evaluation for safety and/or effectiveness of the population intended to use the drug, including pertinent subsets, such as gender, age, and racial subsets.” (CFR 314.101(d)(3)). See:
Guidance for Industry and FDA Staff – FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND – Frequently Asked Questions (Mar.2012)
Further reading: e.g. IQVIA: Global Approaches To Drug Development: When Ex-Us Clinical Data Can Support Us Drug Approvals
{20.Mar.2023 | ACPS-CdM}
The first version of the ICH E6 Good Clinical Practice (GCP) Guideline was finalised in 1996 describing the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. GCP covers aspects of monitoring, reporting and archiving of clinical trials, and incorporates addenda on the Essential Documents and on the Investigator’s Brochure.
This Harmonised Guideline has been amended in 2016 with an integrated Addendum to encourage implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting, while continuing to ensure human subject protection and reliability of trial results. Standards regarding electronic records and essential documents intended to increase clinical trial quality and efficiency have also been updated.
{ACPS-CdM: 20.Mar.2023}
{01.May.2023 | ACPS-CdM}
The E6(R3) EWG is working on the revision of the E6(R2) Guideline “Good Clinical Practice” (GCP) with a view to addressing the application of GCP principles to the increasingly diverse trial types and data sources being employed to support regulatory and healthcare related decision-making on drugs, and provide flexibility whenever appropriate to facilitate the use of technological innovations in clinical trials. Additional information may also be found in ICH Reflection Paper on “GCP Renovation” on the ICH Reflection Paper page.
{01.May.2023 | ACPS-CdM}
The ICH M11 draft Guideline on Clinical electronic Structured Harmonised Protocol (CeSHarP), Technical Specification and Template reached Step 2 of the ICH process on 27 September 2022. This new guideline is proposed to provide comprehensive clinical protocol organisation with standardised content, with:
See also:
this extensive publication exemplifies the need for “good” CTP: Clinical Study Protocols – The Pillars Of Clinical Development
{ACPS-CdM: 20.Mar.2023}
This new guideline is proposed to provide comprehensive clinical protocol organisation with standardised content, with:
{10.Mar.2023 U: 01.May.2023 | ACPS-CdM}
{20.Mar.2021 U | ACPS-CdM}
Several tools are available on-line that provide guidance for state-of-the-art management and monitoring of clinical trials also from a risk-based fit-for-purpose quality management perspective.
All refer to ICH E6 GCP as binding standard; however, in spite of “harmonisation”, rulings may differ by country and region; this is very obvious comparing EU with US, but is also reflected by different trial regulations across EU.
In the following, tools & links are listed that ACPS finds particularly useful – Note: in some cases, these are not (yet) compliant with ICH E6(R2) GCP; also, in the EU (exempt UK?) rulings are bound to change pursuant to the new EU Trial Regulation 536/2014 (which will become effective in a not yet foreseeable future).
{20.Jun.2018 U: 20.Jan.2021| ACPS-CdM}
The European Clinical Research Infrastructure Network (ECRIN) is a public, non-profit organisation that links scientific partners and networks across Europe to facilitate multinational clinical research (Members: Czech Republic, France, Germany, Hungary, Italy, Norway, Portugal and Spain: Observer: Switzerland). It provides sponsors and investigators with advice, management services and tools to overcome hurdles to multinational trials and enhance collaboration.
{18.Jun.2018 U: 27.Dec.2022 | ACPS-CdM}
UKTMN – UK Trial Managers Network
{15.May.2018 | ACPS-CdM}
[UK NHS specific – in some aspects outdated; nevertheless, contains some useful manuals, training & teaching tools]
Toolkits RoadMap | Getting started
Trial Planning & Design
Feasibility assessment
Risk Assessment (potential hazards)
Sponsorship
Protocol Development
EC Application & Oversight
Trial Management & Monitoring
GCP & Serious Breach Reporting
IMP-Management
Pharmacovigilance
Essential Trial Documentation
{ACPS-CdM & -LT | 15.Jun.2018}
CTTI (Clinical Trials Transformation Initiative) was launched 2007 by a joint effort of Duke University and the U.S. Food and Drug Administration (FDA) to found a multi-stakeholder organization in response to the growing need for evidence-based answers to therapeutic questions and the obvious concern that clinical trials became too expensive and inefficient to fulfil this need. CTTI pursues the mission “To develop and drive adoption of practices that will increase the quality and efficiency of clinical trials” whilst aiming for “a high quality clinical trial system that is patient-centred and efficient, enabling reliable and timely access to evidence-based therapeutic prevention and treatment options”.
This has resulted in a wide range of concepts & tools for optimised while (quality) risk-based management of clinical trials, some of which are listed in the following (Note: although US-focused, several of these tools also apply to other regions):
{15.May.2018 | ACPS-CdM}
WHO
{04.Mar.2021 | ACPS-CdM}
The GCP Inspectors Working Group has developed procedures for the coordination, preparation, conduct and reporting of GCP inspections carried out in the context of the Centralised Procedure. These inspections are adopted by the CHMP and may be routine or may be triggered by issues arising during the assessment of the dossier or by other information such as previous inspection experience. They are usually requested during the initial review of a Marketing Authorisation Application but could arise post-authorisation (e.g. inspection of studies conducted or completed as part of the condition of marketing authorisation, or because of concerns arising about the studies previously submitted).
The EMA has established and maintains a website platform that is specifically dedicated to the guidelines re. GCP Inspections for clinical trials including bioequivalence studies. In addition, attention is drawn to two important aspects of prime interest:
{04.Mar.2021 U: 23.Dec.2022 | ACPS-CdM}
Key Reports
{04.Mar.2021 | ACPS-CdM}
Useful Links for direct well-structured access:
{15.May.2018 | ACPS-CdM}
Recommended reading:
{13.Aug.2019 | ACPS-CdM}
EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)” Section 2: » A TMF is the collection of essential documents that is used by sponsors, CROs and investigators/institutions for the management of the trial and by monitors, auditors and inspectors to review and verify whether the sponsor and the investigators/institutions have conducted the trial in line with the applicable regulatory requirements and the principles and standards of GCP. «
Accordingly, the Essential Documentation of a trial (the Trial Master File) is a Documentation System with at least two parts:
i) the Trial Master File (TMF) kept by the sponsor and
ii) the Investigator Site/Study File (ISF) kept by the investigator.
On several accounts, these two parts overlap and are complementary – see EMA/INS/GCP/856758/2018 Section 5.2: » Some copies of documents in the TMF do not replace the original and therefore do not require certification (e.g. original wet-ink signed contracts held at the legal departments of the sponsor and the investigator/institutions and copies in the sponsor and investigator/institution TMF; original delegation log in investigator/institution TMF and copy in sponsor TMF). The creation of such copies for a TMF should be defined in a written procedure. The procedure should ensure that the copy is of sufficient quality for the intended purpose «
On the other hand, although they overlap, the ISF contains information that ought not to be kept in the TMF, whereas the TMF may contain information that is of little – if any – use to the investigator.
This segregation is an essential feature of the management of the essential trial documentation in accordance with ICH E6 GCP (Art. 8.2-8.4), the EU Clinical Trial Directive, the EU Clinical Trials Regulation 536/2014 (Recital 52 and Art. 57-58), EMA/INS/GCP/636736/2012 , EMA/15975/2016, and EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)” – Dec.2018) Art 3.1: « … In organising the TMFs, it is essential to segregate some documents that are generated or held by the sponsor only, from those that are generated or held by the investigator only, and vice versa »
Segregation serves securing confidentiality of the information that links the trial data controlled and processed by the sponsor with the patient’s identity that it is to be kept confidentially by the investigator (e.g. in the Subject Identification Code Log, the signed Informed Consent forms, and the medical source files). In this way, data are “pseudonymised” at the level of the investigator, but become “anonymous” at the level of the sponsor unless access to the subject identification information would be taken.
The subject identification information is to be kept securely and confidentially in the ISF; access to this information by the sponsor ought to be restricted and controlled.
On-trial, access to the Subject Identification Information in the ISF is a mandatory aspect of the QC-verification of data and compliance.
Off-trial, conditional access to this information should be possible for QA/QC inspection of GCP-compliant conduct, analysis, and reporting of the trial.
Other access is not permissible (particularly if it could affect data processing) since it would violate the rulings on data protection, but cannot be entirely excluded. Although not intended, such undue access to subject identification information is ‘possible’; therefore, trial subject data remain “pseudonymised” also at the level of the sponsor.
More restrictive rulings on access to the Subject Identification Information might help keeping trial data “anonymous”; this could be achieved by imposing prohibitive rulings on access to the identification information once the database is closed; in such case, the information could only be accessed after database closure by sponsor-independent inspectors and not by sponsor-based or sponsor-assigned auditors.
Segregation of the TMF and ISF and their orderly post-study archiving are essential quality marks in Good Documentation Practices. Considering the very long time such information needs to be orderly archived by sponsor and investigator (see next), this results in complex logistic challenges to the investigator for which the sponsor can provide little remedy (see next).
{19.May.2018 – Update: 09.Sep.2019 | ACPS-CdM}.
ICH GCP E6(R2) Section 8.1: » 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. … 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. «
EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)”
Section 2: » A TMF is the collection of essential documents that is used by sponsors, CROs and investigators/institutions for the management of the trial and by monitors, auditors and inspectors to review and verify whether the sponsor and the investigators/institutions have conducted the trial in line with the applicable regulatory requirements and the principles and standards of GCP. «
Section 2: » Documents and records in the TMF should collectively permit confirmation of compliance with the protocol and GCP and the integrity of data collected without the need for additional explanation from the sponsor, CRO or investigator/institution staff «
Minimum content specification of the TMF and ISF is provided by ICH GCP E6(R2) Sections 8.2-8.4.
In practice, this list is usually extended, depending on the specific nature of the IMP, type of study, set-up of the investigational institution, etc. In exceptional cases, less documents might be required than specified in Sections 8.2-8.4 (»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 «).
Several public examples are available that illustrate how TMF/ISF Documentation Systems can be implemented with a reasonable while useful extension of the minimum content specification provided by Section 8.2-8.4 of ICH-GCP E6(R2):
Further reading
{09.Sep.2019 U: 06.Jul.2020; 07.Oct.2020 | ACPS-CdM}
The TMF Reference Model initiative is a sub-group of the Document and Records Management Community of the Drug Information Association (DIA). The TMF Reference Model initiative is governed by the rules and procedures of the DIA, but the work products are not owned, governed, managed, or endorsed by the DIA, per DIA bylaws. The TMF Reference Model is a Public Domain work.
The TMF Reference Model provides standardized taxonomy and metadata and outlines a reference definition of TMF content using standard nomenclature. The Model is not intended to be taken and used “off-the-shelf” but can be adapted to an electronic or paper TMF and does not endorse, nor require, any specific technology for the application. DIA members and industry members are under no obligation to adopt the TMF Reference Model.
Resources for Current Version of TMF Reference Model:
TMF Resources:
TMF Tools
Miscellaneous Resources:
{09.Sep.2019 U: 14.Feb.2021 | ACPS-CdM}
ICH GCP E6(R2) Section 8.1: » 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. … 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. «
EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)” Section 2: » A TMF is the collection of essential documents that is used by sponsors, CROs and investigators/institutions for the management of the trial and by monitors, auditors and inspectors to review and verify whether the sponsor and the investigators/institutions have conducted the trial in line with the applicable regulatory requirements and the principles and standards of GCP. «
In practice, the Essential Documentation of a trial is generally held in its “Trial Master File” is a documentation system with at least two parts: i) the (Sponsor-) Trial Master File (TMF) kept by the sponsor and ii) the Investigator Site/Study File (ISF) kept by the investigator.
Whatever their granularity (even when using the DIA TMF Reference Model – see previous) – in our experience – conventional TMF/ISF based on pragmatic extension of the minimum list of ICH GCP E6(R2) Sections 8.2-8.4 may be criticised upon present-day (E6(R2)-guided) inspection whilst not holding all documents that might be considered pertinent to the documentation of the orderly conduct of the trial and GCP-compliance. In particular, this relates to the need to include the following: personnel data (qualification, certification, job description, training & development plan, etc.); SOPs (Sponsor, CRO, Site, Laboratories, Data Centres); QC/QA-documentation of clinical and bioanalytical laboratories; QC/QA-documentation of Data Management & Analysis; draft versions of core documents (CTP, CTR, etc.) [EMA/INS/GCP/856758/2018 Section 3.5.2], Correspondence [EMA/INS/GCP/856758/2018 Section 3.5.3]; etc.
However, not all TMF-items need not to be held in study specific TMF-binders; instead, it ought to suffice to place a Note-to-File in the Sponsor-TMF-binder that specified items are kept securely and orderly by other qualified and authorised parties and/or at other facilities under a unique reference ID and that direct and immediate access (even if remote) to this documentation is ensured (unless containing personified data).
Such solution is compliant with EMA/INS/GCP/856758/2018 Section 3.4 » When starting a clinical trial, the sponsor and the investigator/institution should identify and maintain a record of the location(s) of all the potential documentation that is considered to form the TMF, even if several locations, departments, country organisations and systems are involved. There should be a primary TMF system for holding essential documents, which could be entirely electronic, entirely on paper or a hybrid of both. Other systems including central systems may exist that hold essential documents (e.g. a central e-mail repository, SOP-management system, central training records, delegation logs, software validation records and records concerning more than one trial, e.g. investigator’s brochures (IB)) relevant to the trial and should therefore be part of the TMF. The number of these other systems should be minimised with the priority focussed on placing documents in the primary TMF system. Documents applicable to multiple trials do not need to be duplicated in several TMFs. «
{09.Sep.2019 U: 20.Jul.2020 | ACPS-CdM}
Per ICH GCP E6(R2) 1.51: » all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data should be accurate, legible, contemporaneous, original, attributable, complete and consistent. «
The use of electronic data recording and the initiatives to facilitate remote monitoring by allowing remote access to source data and medical records presents an important challenge from a data protection perspective: in our opinion, there is no reason to allow the sponsor access to the intimate information that a good medical record should contain and there is no reason to reduce the medical records to just the size that fits the need for sourcing CRF-reported data.
These concerns have also been recently well expressed by the pertinent regulators:
{10.Oct.2020 | ACPS-CdM}
EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)”) Section 6.3:
Directive 2003/63/EC (i.e. Amendment M2 of the Community Code 2001/83/EC introducing the revised Annex 1):
{08.Nov..2018 U: 03.Feb.2021 | ACPS-CdM}
The essential trial documentation consists of two sections that are distinct and separate: the sponsor’s Trial Master File (TMF) and the Investigator’s Study File (ISF).
As detailed in the previous, the TMF and ISF need to be archived orderly and securely over a long period of time, particularly if the trial is part of the clinical documentation for marketing authorisation application.
The provisions for orderly archiving of the TMF and ISF are well defined: see EMA/15975/2016 (“Guideline on GCP compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials” – 2017), EMA/INS/GCP/636736/2012 (“Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials” – Jun.2015), and EMA/INS/GCP/856758/2018 (“Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic)” – Dec.2018) – see also MHRA produced FAQs for Trial Master Files (TMF) and Archiving (2012).
These provisions are challenging and not easily complied with, also since the mandatory duration of archiving may extend beyond the investigator’s professional lifetime and/or employment at the site where the trial was carried out (see previous).
Therefore, the sponsor may have to provide assistance to the investigator to ensure orderly archiving of the ISF. However, since the ISF needs to remain under the sole control of the investigator, this is subject to important limitations: the sponsor cannot simply collect the ISF for storage at the sponsor’s facilities. This may be resolved as follows:
These provisions apply to the ISF, but not to the medical files. Medical files – as data source – need to by securely archived at the site. Duration of storage is limited and generally subject to national legislation. In general, these files are subject to the rules that apply to all medical patients managed at the site – irrespective of trial participation.
{15.Jul.2019 | ACPS-CdM}.
Under the EU Clinical Trial Directive
EU Rulings for Manufacturing, Import and QP
Manufacturing, import of IMPs and the need for the Quality Management thereof by a Qualified Person (QP) are subject to:
EU GMP-Standards
In the EU, GMP-standards of medicinal products for human use and investigational medicinal products for human use are set by
2-Step Release
IMPs should be retained from use in a trial until after completion of a two-step procedure:
Pertinent regulations specify the qualification requirements for any QP. Rulings do not specify the scope of authority and the type of qualification that the sponsor representative needs to hold who released the IMP on behalf of the sponsor. It may be expected (but is not mandatory) that these two responsibilities are distinct.
EU Investigational Medicinal Product Dossier (IMPD)
In the EU, the IMPD is the core product file of the sponsor’s application for trial authorisation. The IMPD is regulated primarily by the specifications of Eudralex Volume X CT-1 Section 2.7 (“IMP Dossier”):
An IMPD is required for any IMP and NIMP. The IMPD may be simplified by cross-referencing its nonclinical (acc. CT-1 2.7.2.3) and clinical sections (acc. CT-1 2.7.2.4) to the Investigator Brochure (or SmPC if authorised), and it may be abbreviated depending if the IMP is already authorised; Table 1 of CT-1 provides detailed guidance on how the IMPD might be abbreviated depending on whether the IMP is already authorised.
Documentation of GMP-compliance & Pharmaceutical Quality Dossier (IMPD-Q)
Documentation of GMP-compliance and documentation of the pharmaceutical substance and product quality are essential parts of the IMP.
The former is regulated by Eudralex Volume X CT-1 Section 2.7.1, the latter by CHMP/QWP/185401/2004 “Guideline On The Requirements To The Chemical And Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products In Clinical Trials” (Mar.2006) [to be replaced by EMA/CHMP/QWP/545525/ 2017 “Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials” (Sep.2017) once the EU Clinical Trial Regulation comes to effect.
These guidelines provide specific instructions also for authorised controls/comparators and test products of bioequivalence studies.
Under the EU Clinical Trial Regulation 536/2014
{13.Mar.2018 Update: 27.Mar.2022 | ACPS-CdM}
EUROPE
In order to avoid error on assignment and maintain due blinding (if applicable) we consider it highly recommendable that IMP-supplies are processed as individual boxes by subject at the IMP-site:
In compliance with EudraLex Volume 4 Annex 13 Art. 36-37 and EudraLex Volume 4 Annex 19 (‘Reference and Retention Samples’ – 2005) there is need to process and retain reference and retention samples of the trial’s supplies:
EudraLex Volume 4 Annex 13 Art. 36-37 provide for following rules and specifications:
Updated Guidelines pursuant to EU Clinical Trial Regulation 536/2014 i.e. EU Detailed Commission Guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014 (C(2017) 8179 – 2017) Chapter 7 (‘Quality Control’) and EU Commission Delegated Regulation 2017/1569 specifying principles and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections (Art. 11) provide less specification, but define the requirements similarly also regarding the retention time of at least two years after completion or formal discontinuation of the trial.
The processing and management of such reference and retention samples is best handled professionally by the IMP-Site under direct supervision including QA/QC by the sponsor. In this way possible quality risks in handling and assigning IMP at investigator level can be minimised.
EU STUDIES WITH US-IMPACT
Special provisions apply for bioequivalence (BE) and bioavailability (BA) studies that might have implications also in the USA. In such case, there is need to provide for retention samples retained at the investigational site in accordance with 21 CFR 320.38 and 320.63. Lack of such retention samples may disqualify the study
(see: FDA-CDER-Statement on Retention Samples, FDA-Clinical Trials and Human Subject Protection: Retention of Bioavailability and Bioequivalence Testing Samples, FDA Guidance for Industry: Handling and Retention of BA and BE Testing Samples [2004] and FDA Guidace for Industry: Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c) [Aug.2020]):
These US regulations for reserve samples of BA/BE-studies reflect on the past day “two-jar” practice that was not uncommon for such (non-blinded) studies: the investigator was provided with two jars, one with reference tables and one with test tablets and it was left to the investigator to make sure that each subject received the right medication as scheduled by period.
It is our understanding (but needs case-by-case check & confirmation) that this US-challenge can be met in the following way when using individualised supplies:
Note: In line with the final rule of 1993 (re. 21 CFR 320.38 and 320.63), the applicant of an NDA or ANDA had to retain a quantity of the test article and reference standard used in BA/BE testing of a least five times the amount of product required for release testing for each in vivo BA and in vivo or in vitro BE study in support of the application. Pursuant to the recent “FDA Guidace for Industry: Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c)” now allows to retain less under well specified conditions (as listed in the guidance’s appendices), e.g. » For drug products that are manufactured in single-dose units, FDA does not intend to enforce the requirement to retain a sufficient quantity to perform five times all the release tests required in the application or supplemental application, so long as the minimum quantity of drug product for sample retention is 30 units each of the test article and reference standard from each shipment is retained «
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