Source: https://www.acps-network.com/lib-ctm/
Timestamp: 2018-08-18 02:43:13
Document Index: 441032902

Matched Legal Cases: ['Art. 7', 'Art. 5', 'Art. 82', 'Art. 57', 'Art. 3', 'Art. 2', 'Art 63', 'Art. 26', 'Art. 36', 'Art. 36', 'Art. 11']

Library: CT-Management & GxP-Compliance - ACPS - Applied Clinical Pharmacology Services %
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
Lost in delegation?
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}
EudraCT-Application | Provisions by EU Member State [ECRIN-Campus]
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}
EudraCT-Application | Germany
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
In addition, a summary plus related checklists can be downloaded here: ACPS-Library-CTM-EudraCT-Application-DE
EudraCT-Application | The Netherlands
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).
[WHO] WHO GCP
WHO Technical Report Series, No. 850 – Annex 3: Guidelines for good clinical practice (GCP) for trials on pharmaceutical products
WHO Handbook for Good Clinical Practice – Guidance for implementation (2005)
WHO Technical Report Series, No. 957 – Annex 7: Guidelines for the preparation of a contract research organization master file (2010)
WHO Technical Report Series, No. 996 – Annex 5: WHO guidance on good data and record management practices (2016) [GDRMP guidance]
Essential Medicines and Health Products: Prequalification of medicines | Principles and guidelines pertinent to the WHO’s inspection
{20.Jun.2018 | ACPS-CdM}
[EU] ECRIN Toolbox
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.
ECRIN IA – Guideline on risk management for clinical research Version 1.0 (2015)
and Djurisic S, Rath A, Gaber S, Garattini S, Bertele V, Ngwabyt SN, Hivert V, Neugebauer EAM, Laville M, Hiesmayr M, Demotes-Mainard J, Kubiak C, Jakobsen JC,10, Gluud C. Barriers to the conduct of randomised clinical trials within all disease areas. Trials. 2017 Aug 1;18(1):360.
ECRIN guidance document on risk assessments
ECRIN Risk-Based Monitoring Toolbox
{18.Jun.2018 | ACPS-CdM}
[UK] Trial Managers’ Network
UKTMN – UK Trial Managers Network
UKTMN Guide to Efficient Trial Management (2014)
PHARMACY GCP COMPLANCE CHECKLIST
NIHR Checklist for TMF
NIHR Task, Knowledge and Competency Framework for Trial Managers
SOP Implementation of Urgent Safety Measures
{15.May.2018 | ACPS-CdM}
[UK] NHS/NIHR Clinical Trials Toolkit
[UK NHS specific – in some aspects outdated; nevertheless, contains some useful manuals, training & teaching tools]
Toolkits RoadMap | Getting started
HRA Guidance Specific questions that need answering when considering the design of clinical trials
Planning a Randomised Controlled Trial (RTC) – Points to Consider
Medical Research Council (MRC). A framework for the development and evaluation of RCTs for complex interventions to improve health (2000)
O’Cathain A, Hoddinott P, Lewin S, Thomas KJ, Young B, Adamson J, Jansen YJ, Mills N, Moore G, Donovan JL. Maximising the impact of qualitative research in feasibility studies for randomised controlled trials: guidance for researchers. Pilot Feasibility Stud. 2015 Sep 7;1:32
NIHR Clinical Trials Guide for Trainees
NIHR Additional guidance for applicants including a clinical trial, pilot study or feasibility as part of a personal award application
Avery KN, Williamson PR, Gamble C, O’Connell Francischetto E, Metcalfe C, Davidson P, Williams H, Blazeby JM; members of the Internal Pilot Trials Workshop supported by the Hubs for Trials Methodology Research. Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot studies. BMJ Open. 2017 Feb 17;7(2):e013537.
Association of Medical Research Charities (AMRC) and NIHR Medicines for Children Research Network (MCRN): AMRC/NIHR Points to consider when assessing the feasibility of research
MRC/DH/MHRA Joint Project – Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products
NHS Research & Development Forum – Sponsorship Principles
NHS Protocol guidance and template for use in a Clinical Trial of an Investigational Medicinal Product (CTIMP)
NHS Protocol guidance and template for use in qualitative research
Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Doré C, Williamson PR, Altman DG, Montgomery A, Lim P, Berlin J, Senn S, Day S, Barbachano Y, Loder E. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials. JAMA. 2017 Dec 19;318(23):2337-2343.
EC Application & Oversight
Research Ethics Committee – Standard Operating Procedures v.7.2 (Mar.2018)
MRC/DH joint project to codify good practice in publicly-funded UK clinical trials with medicines | Workstream 4: Trial Management and Monitoring: GCP in non-commercial trials
MRC/DH joint project to codify good practice in publicly-funded UK clinical trials with medicines | Workstream 4: Trial Management and Monitoring: B) Summary of Trial Management Systems (TMS)
MRC/DH joint project to codify good practice in publicly-funded UK clinical trials with medicines | Workstream 4: Trial Management and Monitoring: C) Monitoring Procedures
Trial Scenarios for Monitoring – Pilot randomised trial of streptokinase, aspirin and heparin in acute myocardial infarction
Trial Monitoring Option Checklist
MHRA Guidance For The Notification Of Serious Breaches Of GCP Or The Trial Protocol
IMP-Management
Clinical Trials Toolkit – Trial Supplies (2018)
MRC/DH joint project to codify good practice in publicly-funded UK clinical trials with medicines – Workstream 6: Pharmacovigilance (2012)
MHRA produced FAQs for Trial Master Files (TMF) and Archiving (2012)
{ACPS-CdM & -LT | 15.Jun.2018}
[US] CTTI - Clinical Trials Transformation Initiative
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):
CTTI Recommendations: Good Clinical Practice (GCP) Training For Investigators
& Arango J, Chuck T, Ellenberg SS, Foltz B, Gorman C, Hinrichs H, McHale S, Merchant K, Seltzer J, Shapley S, Wild G. Good Clinical Practice Training: Identifying Key Elements and Strategies for Increasing Training Efficiency. Ther Innov Regul Sci. 2016 Jul;50(4):480-486.
CTTI Recommendations: Informed Consent
CTTI Recommendations: IND Safety Assessment And Communication
CTTI Recommendations on Data Monitoring Committees
CTTI Recommendations: Quality By Design (« Applying a Quality by Design (QbD) approach to clinical trials helps prospectively identify important errors that could jeopardize the ability to protect patients during the trial and to obtain reliable results and meaningful information from the trial. “Quality in clinical trials”, therefore, is defined as the absence of errors that matter »)
CTTI Quality By Design Project – Critical To Quality (CTQ) Factors – Principles Document
CTTI Recommendations: Effective And Efficient Monitoring As A Component Of Quality Assurance In The Conduct Of Clinical Trials
CTTI QbD (Quality By Design) Toolkit
GDPR: General Data Protection Regulation 2016/679
Useful Links for direct well-structured access:
GDPR [EN] – Recitals
DE: Datenschutz-Grundverordnung DSGVO – Erwägungsgründe
DE: Datenschutz-Grundverordnung DSGVO
DE: Bundesdatenschutzgesetz BDSG
DE: Vergleich des neuen mit dem alten BDSG (XLS for download) – from Synopse: EU-DSGVO, BDSG (alt) und BDSG (neu) gegenübergestellt
GDPR: Implications for Clinical Trials
Chassang G. The impact of the EU general data protection regulation on scientific research. eCancer medical science. 2017 Jan 3;11:709.
Rumbold JM, Pierscionek B. The Effect of the General Data Protection Regulation on Medical Research. J Med Internet Res. 2017 Feb 24;19(2):e4
ACPS Comments & Recommendations
UNDER CONSTRICTION – More to come
{13.May.2018 | ACPS-CdM}
Good Documentation Practice | TMF-Management
Archiving: How long?
{13.Apr.2018 | ACPS-CdM}
Segregation of TMF and ISF
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}.
Can the sponsor handle archiving of the ISF?
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) and 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) – 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.
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:
archiving provisions are explicitly specified in the contractual agreement between sponsor and investigator
at study close-out, the Monitor i) checks the ISF for completeness, ii) collects the ISF-TOC and iii) prepares the ISF for closure and archiving (in a sealed box)
Copies of the ISF-TOC and documentation of closure (signed by the Monitor and Investigator) are retained by both the sponsor and the investigator; the sponsor documents the provisions for the orderly archiving of the investigators’ ISF in the TMF
the sponsor or investigator identifies a suitable off-site professional archiving facility and makes an arrangement with this archiving service provider to receive and store trial sites’ ISF that are sent to the facility by the sites’ investigators
this agreement also specifies that the ISF-archive at the facility remains under the sole control of the investigator although the sponsor may pay the related costs
the sponsor may assists the investigators re. the safe transfer of the sealed ISF-container from the trial site to the archiving facility
in the event that the ISF-documentation would need to be accessed for QA/QC, the investigator is the prime and sole contact to this purpose
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.2018 | ACPS-CdM}.
EU GMP for CT
GMP for IMP, NIMP & AxMP
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
Good manufacturing practices for manufacture of investigational medicinal products (February 2010) i.e. Eudralex Volume 4 Annex 13
EU Clinical Trial Regulation 536/2014 Art 63(1) and 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) [applicable as from the date of entry into application of Regulation (EU) No 536/2014 on Clinical Trials]
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
and the related/resulting tools & templates:
and Template for the “written confirmation” for active substances exported to the European Union for medicinal products for human use (Version 2, January 2013)
Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (2006 i.e. under EU Clinical Trial Directive 2001/20/EC)
to be replaced by Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (revision 1 – October 2017) pursuant to EU Clinical trial Regulation 536/2014
Guidance Documents Applying To Clinical Trials Guidance On Investigational Medicinal Products (IMPs) And ‘Non Investigational Medicinal Products’ (NIMPs) (Rev. 1, March 2011 – SANCO/C/8/SF/cg/a.5.001(2011)332855) under EU Clinical Trial Directive 2001/20/EC)
to be replaced (?) by Auxiliary medicinal products in clinical trials (rev. 2, June 2017) pursuant to EU Clinical trial Regulation 536/2014
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 }
IMP: Reference, Retention & Reserve supply samples
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.
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:
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!
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}.