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.
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. 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 section G.5 of the Clinical Trial Application Form (Annex 1 of Eudralex 10 CT-1). 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: 28.Oct.2020 | ACPS-CdM}
EU Clinical Trial Regulation 536/2014 is bound to come to effect in a not yet foreseeable future. In the meantime, trial applications in the EU continue to remain subject to the national provisions that regulate the implementation of EU Clinical Trial Directive 2001/20/EC and EU GCP Directive 2005/28/EC.
The interpretations of these directives and of ICH E6 GCP, which they implement as binding standard, differ by country: e.g. in some countries the application file for the competent authority (CA) and the ethics committee (EC) are the same, in some they are essentially different.
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:
Competent Authority (Contact details; Trial Authorization / Registration / Notification; Submission of Application; Submission Format; Language of Submission; Submission Fees; Timelines Authorization; Amendments / Substantial Amendments; Safety Reporting; End of Trial) |
Ethics Committee (Contact details; Single-Centre Studies – Ethical Review; Submission of Application; Submission Format; Language of Submission; Submission Fees; Timelines Authorization; Amendments / Substantial Amendments; Safety Reporting; End of Trial; Special definitions & regulations) |
Study specific requirements (Sponsor; Informed Consent, Vulnerable populations; Information of trial participants of trial outcome; Data protection; Insurance) |
Legislation (Applicable Legislation & Conventions; Clinical Trials on IMPs in Humans; Gene Therapy; Data protection)
Definitions (IMP & IMP-study).
{16.Jun.2018 | ACPS-CdM}
EU Clinical Trial Regulation 536/2014 is bound to come to effect in a not yet foreseeable future.
In the meantime, trial applications in the EU continue to remain subject to the national provisions that regulate the implementation of EU Clinical Trial Directive 2001/20/EC and EU GCP Directive 2005/28/EC .
In Germany, this is regulated by the German Drug Law (AMG “Arzneimittelgesetz”) and the resulting German GCP Implementing Ordinance (“GCP-Verordnung [GCP-V]“). This results in a series or rulings and standards that affect the application of Clinical Trials for review and approval by the Competent Authority (CA: BfArM [“Bundesinstitut für Arzneimittel”] | PEI [“Paul-Ehrlich-Institut”]) and Ethics Committee(s).
Detailed information on the proceedings and requirements can be found under:
BfArM Genehmigungsverfahren
PEI Anträge auf klinische Prüfungen
Struktur für die Einreichungsunterlagen bei elektronischer Einreichung von Anträgen auf klinische Prüfung beim BfArM/PEI
In addition, a summary plus related checklists can be downloaded here: ACPS-Library-CTM-EudraCT-Application-DE
{13.Mar.2018 – U: 08.Oct.2020 | ACPS-CdM}
EU Clinical Trial Regulation 536/2014 is bound to come to effect in a not yet foreseeable future.
In the meantime, trial applications in the EU continue to remain subject to the national provisions that regulate the implementation of EU Clinical Trial Directive 2001/20/EC and EU GCP Directive 2005/28/EC .
In Germany, this is regulated by the German Drug Law (AMG “Arzneimittelgesetz”) and the resulting German GCP Implementing Ordinance (“GCP-Verordnung [GCP-V]“). This results in a series or rulings and standards that affect the application of Clinical Trials for review and approval by the Competent Authority (CA: BfArM [“Bundesinstitut für Arzneimittel”] | PEI [“Paul-Ehrlich-Institut”]) and Ethics Committee(s).
In Germany, GCP-training and GCP-certification of medical investigators is and will remain under 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 | ACPS-CdM}
Precious templates – see: CCMO – Centrale Commissie Mensgebondene Onderzoek – Standaardonderzoeksdossier
Updated template for Patient Information & Consent (PIF) [May.2018] by the Werkgroep Proefpersonen of the DCRF (Dutch Clinical Research Foundation): Template | Guidance
{11.May.2018 | ACPS-CdM}
{01.Oct.2020 | 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 | 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 | 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}
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. «
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 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 Tools:
Miscellaneous Resources:
{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. «
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:
« For trials conducted under Directive 2001/20 EC, the sponsor and the investigator must ensure that the documents contained, or which have been contained, in the TMF are retained for at least 5 years after the conclusion of the trial (GCP-Directive Article 17) or in accordance with national regulations (e.g. in Germany GCP-V §13(10): 10 years).
« For trials conducted under Regulation 536/2014, per Art. 58: “unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical TMF for at least 25 years after the end of the clinical trial. »
Directive 2003/63/EC (i.e. Amendment M2 of the Community Code 2001/83/EC introducing the revised Annex 1):
« Trials where the data are used to support a marketing authorisation have further requirements and must be retained for at least 15 years after completion or discontinuation of the trial or for at least two years after the granting of the last marketing authorisation in the EC (when there are no pending or contemplated marketing applications in the EC) or for at least two years after formal discontinuation of clinical development of the investigational product. »
« Directive 2003/63/EC states that the sponsor or other owner of the data must retain some of the documentation for as long as the product is authorised: « … Additionally, this documentation must include (as a minimum) the trial protocol (which must include the rationale, objectives and statistical design and methodology of the trial, with conditions under which it is performed and managed, details of the investigational product, the reference medicinal product and/or the placebo used), any standard operating procedures used for conducting the trial, all written opinions on the protocol and procedures, the investigator’s brochure, case report forms on each trial subject, final report and audit certificate(s), if available, staff training records. Finally, the final report must also be retained by the sponsor or subsequent owner, for five years after the medicinal product is no longer authorised. »
{08.Nov..2018 | 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}.
GMP for investigational (IMP), non-investigational medicinal products (NIMP) and Auxilliary medicinal products (AxMP) used in clinical trials (CT) is regulated (as specified in EudraLex Volume 10 Chapter III) by
These guidelines also include important information with regard to the Quality Documentation (NIMPD-Q) to be provided for NIMP and the need for orderly labelling of NIMP-supplies.
{ACPS-CdM | 13.Mar.2018 | Update: 12.Apr.2020 }
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 with regard to 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
In addition, 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, and FDA Guidance for Industry: Handling and Retention of BA and BE Testing Samples [2004]):
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:
{13.Mar.2018 | ACPS-CdM}.