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LIBRARY: CT-Management & GxP-Compliance

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.

EU CT Set-Up

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:

  • „... 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
  • „… Any trial-related duty and function that is transferred to and assumed by a delegate (e.g. CRO) should be specified in writing“.
  • „… 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)“.

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.:

  • Delegation should be addressed in the risk-based Quality Management Plan of the trial.
  • The delegating party is responsible for the selection and documentation of the qualification of the delegate.
  • The delegating party is responsible for the QC/QA of the delegate’s contribution; this may require a system audit as part of the pre-study qualification and due measures for on-trial QC.
  • Delegation should be specified and regulated in writing. Contracts should be accessible to the sponsor in the event the delegate is subcontracted by a primary delegate (e.g. CRO).
  • Delegation should be specified and documented in the Trial Master File (TMF); this may involve the documentation of the qualification of the delegate, documentation of the delegate’s Quality Management System (incl. SOPs and/or reference to the deposit of the delegate’s SOPs) and documentation of the QA/QC of the delegate’s contribution. TMF-Specification should also address which SOPs are/were applicable for a given task.
  • Delegates with GCP-pertinent contributions should be named in the Trial Application, Clinical Trial Protocol, and Clinical Trial Report.
  • A unique Task Assignment List should be in place that specifies the full scope of delegation with sufficient granularity (e.g. for the Clinical trial Protocol: who is responsible for writing the draft, reviewing the draft, finalising, signing and releasing the CTP?)
  • The Task Assignment List should be accessible to all delegates to avoid misunderstandings about who is responsible for what.

{13.Mar.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.

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 Authorisation / Registration / Notification; Submission of Application; Submission Format; Language of Submission; Submission Fees; Timelines Authorisation; 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 Authorisation; 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 | 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}

CLINICAL TRIAL (QUALITY) MANAGEMENT

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}

NHS CLINICAL TRIALS TOOLKIT

[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}

EU General Data Protection Regulation (GDPR)

Recommended reading:

ACPS Comments & Recommendations

  • UNDER CONSTRICTION – More to come

{13.May.2018 | ACPS-CdM}

Good Documentation Practice | TMF-Management

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“) Section 6.4:

« 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. »

{13.Apr.2018 | ACPS-CdM}

Essential trial documentation is to be kept in two distinct files:
i) the Trial Master File (TMF) kept by the sponsor and
ii) the Investigator Site/Study File (ISF) kept by the investigator.

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 well-established approach in accordance with ICH E6 GCP (Art. 82-84) and the EU Clinical Trial Directive is strengthened by the EU Clinical Trials Regulation  536/2014 (Recital 52 and Art. 57-58) and 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) 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 of TMF and ISF is particularly relevant to Data Privacy & Protection. This is exemplified in 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) Section 4.1: « In organising the TMFs, it is essential to segregate some documents that are generated or held by the sponsor from those of the investigator and vice versa (ICH E6 GCP Sections 8.2-8.4 | Recommendations on the content of the trial master file and archiving Sections 3.1, 3.2 and 3.3), as some documentation held by the investigator should not be provided to the sponsor, for example those documents that would result in breach of subject confidentiality (Directive 2005/28/EC Article 5, Directive 2001/20/EC Article 3 [2] c and ICH E6 GCP Art. 2.11) ».

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 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.

Although ’soft‘, segregation of the TMF and ISF is an important quality mark in Good Documentation Practices. Considering the very long time such information needs to be orderly archived by sponsor and investigator (see previous), this results in complex logistic challenges to the investigator for which the sponsor can provide little remedy (see next).

{19.May.2018 | ACPS-CdM}.

UNDER CONSTRUCTION

{15.May.2018 | ACPS-CdM}.

EU GMP for CT

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.Jun.2018 }

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:

  • primary: dosing unit
  • secondary: all dosing units by PERIOD (no need for assignment by investigator; assignment is made centrally at the level of the IMP-Site)
  • tertiary: all doses by subject
  • labelled at each level acc. EudraLex Volume 4 Annex 13 Art. 26-30 that follow on Directive 2003/94/EC.

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:

  • Reference sample: « a sample of a batch of starting material, packaging material, product contained in its primary packaging or finished product which is stored for the purpose of being analysed should the need arise. Where stability permits, reference samples from critical intermediate stages (e.g. those requiring analytical testing and release) or intermediates, which are transported outside of the manufacturer’s control, should be kept. »
  • Retention sample: « a sample of a packaged unit from a batch of finished product for each packaging run/trial period. It is stored for identification purposes. For example, presentation, packaging, labelling, leaflet, batch number, expiry date should the need arise. »
  • « In many instances the reference and retention samples will be presented identically, i.e. as fully packaged units. In such circumstances, reference and retention samples may be regarded as interchangeable.»

EudraLex Volume 4 Annex 13 Art. 36-37 provide for following rules and specifications:

  • « Reference and retention samples of investigational medicinal product, including blinded product should be kept for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is the longer. Consideration should be given to keeping retention samples until the clinical report has been prepared to enable confirmation of product identity in the event of, and as part of an investigation into inconsistent trial results.»
  • « The storage location of Reference and Retention samples should be defined in a Technical Agreement between the sponsor and manufacturer(s) and should allow timely access by the competent authorities.
    • Reference samples of finished product should be stored within the EEA or in a third country where appropriate arrangements have been made by the Community with the exporting country to ensure that the manufacturer of the investigational medicinal product applies standards of good manufacturing practice at least equivalent to those laid down by the Community. In exceptional circumstances the reference samples of the finished product may be stored by the manufacturer in another third country, in which case this should be justified, and documented in a technical agreement between the sponsor, importer in the EEA and that third country manufacturer.
      The reference sample should be of sufficient size to permit the carrying out, on, at least, two occasions, of the full analytical controls on the batch in accordance with the IMP dossier submitted for authorisation to conduct the clinical trial.
    • In the case of retention samples, it is acceptable to store information related to the final packaging as written or electronic records if such records provide sufficient information. In the case of the latter, the system should comply with the requirements of Annex 11. »

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]):

  • For an ANDA, reserve samples of both the test article and the reference standard should be retained at the study site for a period of 5 years.
  • Retention samples should be kept at the testing facility where the study was conducted.
  • The study sponsor should provide the testing facility with a supply of the test article and the reference standard sufficient to complete the study and retain the appropriate number of dosage units as reserve samples.
  • The study sponsor should not separate out the samples to be reserved prior to sending the batches to the testing facility.
  • The testing facility will randomly select the reserve samples from the supply sent by the sponsor. This is to ensure that reserve samples are in fact representative of the same batches provided by the study sponsor for the testing. The testing facility should retain enough quantify to permit FDA to perform five times all of the release tests required in the application.

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:

  • The IMPs-Site processes individualised medication boxes:
    • primary: dosing unit
    • secondary: all dosing units by TREATMENT
    • tertiary: all doses by a medication ID-number
  • The IMP-site provides the investigational sites with sufficient medication boxes to meet two needs:
    • to dose all subjects and their possible replacements and
    • to retain additional, identically labelled medication sets sufficient to retain the “five times quantity”
    • there is no difference in the medication ID-code between supplies intended to be used and supplies to be retained!
  • The investigator
    • randomly selects the medication box (identified by its medication-ID) to be assigned to each individual subject and
    • assigns the subject at random to one of the XO-sequences according to the randomisation plan
  • The site retains the remaining medication boxes as retention samples

{13.Mar.2018 | ACPS-CdM}.