CTR Implementation - A QP's Perspective
Introduction
On 31 January 2025, the transition from the Clinical Trial Directive 2001/20/EC (CTD)1 to the Clinical Trial Regulation (EU) No 536/20142 (CTR) will end3. We have been observing this difficult birth for more than a decade. We have learned that a regulation could be in two seemingly contradicting lifecycle states simultaneously: "in force" and "not applicable". Applicability was finally reached on 31 January 2022; since then, we have been in the transitioning phase.
The professional guild of Qualified Persons watches these developments closely4, and with a specific perspective: " The qualified person … shall be responsible for … verifying that each production batch has been manufactured and checked in compliance with … the information provided pursuant to Article 25 of Regulation (EU) No 536/2014"5 meaning the "Data submitted in the application dossier"6 (similar references are found in Annex 167 and Annex 138 to the EU GMP Guide).
Expectations
The QP community was looking forward to the CTR becoming applicable.
The main promises were9,10 :
- A consistent ruleset on Clinical Trials across the EU.
- An environment that is favorable for conducting Clinical Trials11.
- Streamlined applications via a
- Single entry point or EU portal, a
- Centralized Database, with
- One single set of documents, assessed in
- One harmonized review and authorization procedure.
- Better transparency of clinical trials and trial outcomes through public access to the database.
As a QP, my hopes were particularly on the single set of documents and the harmonized authorization procedure. I am aware that hereby, I am inadvertently admitting occasional challenges in verifying what information, including amendments, was approved at a certain point in time in each participating member state for a certain Clinical Trial submitted per CTD - despite sophisticated systems and considerable efforts.
Experiences
Will reality live up to our expectations and the implied promises?
I would probably best describe our experiences as mixed.
Initial Difficulties
Learning Curve
Every change process is challenging, and the magnitude of this effort is obvious.
We are still on a steep learning trajectory, and our experience is still limited. We are all learning and improving, including the authorities and the CTIS database.
It took a while for us QPs to safely identify the new documents, name them correctly, and find the required information in them.
Documents that I consider relevant for the QP release are:
- Approval screenshot with conclusions from the CTIS database,
- Assessment Report Part I,
- Application form,
- RFI documentation,
- Conditions and Commitments,
- Labels,
- Relevant Q-IMPD sections.
Authorities undergo the same development: different Member States and assessors may produce different outcomes.
Thus, we see things improving rapidly.
The learning curve is also reflected in the change history of the involved guidance documents, e.g., the CTR Q&A, which reached version 6.8 within 26 months.
Who has access to CTIS?
Only a limited number of people have access to the database. Initially, this led to situations where people needing certain CTIS documents (e.g., a QP requesting the part 1 assessment report of an IIT) faced significant difficulties getting them.
Approval timelines not met
There are defined approval timelines under CTR12, e.g., 60-10613 days for a new application and 22 14 days for a transitioning application under the expedited administrative procedure. Approval timelines were not met in the beginning and, in some cases, are not met today.
Database errors
Another learning curve example is a mistake in the database that often provided an incorrect MIA number of the site of certification and import in the application form15.
Transparency requirements
As QPs, the ambassadors of GMP in our organizations, we were struggling with the request to provide redacted QP declarations, without name and signature, together with the usual signed QP declaration. Sharing an unauthorized document is a GMP violation. The rationale for the request was that the QP declarations were published in the EU database and publishing personal data like the QP's name or electronic signature is against data protection rules. Fortunately, with the revised CTIS transparency rules of 05-Oct-202316, the QP declaration will no longer be published.
Note: Redaction was also used for Company Confidential Information (CCI); thus, this aspect did not affect me as a QP.
Transition
Trials under CTD need to be transitioned to CTR. This transitioning of all running clinical studies is a significant effort. For Roche alone, this means 150 Roche-sponsored studies and about the same number of IITs and Collaborations that are to be transitioned. Due to good planning, execution, and monitoring, we are making good progress. Thus, the threat is imminent since after 31 January 2025, the continuation of a clinical trial without transitioning would be "considered non-compliant and in breach of the CTR"17, or simply put, illegal.
Progress since EMA introduced the Expedited Transition Procedure. The Expedited Transition Procedure is based on previously submitted documentation - no modifications are submitted with the transitioning application.
Thus, for a multi-national trial, the protocol, IMPD, and IB must be either the same in all countries or have to be harmonized via a substantial amendment before the transition or can be consolidated with the transition by reflecting the common core provisions and capturing the differences regarding the nationally authorised trials.18
Pre-transition harmonization proves to be time-consuming and affects the transition date.
A timeline of 22 days is foreseen for approval under the expedited administrative procedure. The record that we observed in Roche was 54 days19.
In general, it is not foreseen to cross-refer to CTD studies20 (see also under Challenging Surprises). Luckily, this was recently changed and is now acceptable for the transitioning application of IITs21.
The transition does not require updating the labels to reflect CTR requirements with the transitioning application. This should occur with the first substantial modification after the transition. This obviously simplifies the transition and removes labeling logistics from the critical path.
Positive Surprises
Apart from the observed difficulties, several aspects are very positive:
- We indeed have a single set of documents - in contrast to having one set per EU member state (on average 7 EU countries per study). However, later in this publication, I will highlight where authorities fail to deliver the initial promises (e.g., multiple sets of cmc data are allowed, and country-specific changes to QP declarations).
- A change that we had been looking forward to was that the label is a required element of the part I documentation. For the first time, I, as a QP, have undoubted evidence that a certain label was submitted and approved in all EU countries.
- An unexpected benefit was the clear visibility of any Requests for Information (RFI) from the authorities and the respective company responses (Q&A).
It is immediately visible in the approval screenshot and the assessment report.
Before CTR, the visibility of Q&A for the QP was dependent on my ability to read the local language approval letters and Q&A documentation or dependent on the working style of the involved regulatory coworkers (the information was always available but not necessarily in plain sight for the QP). - The same applies to a potential "approval subject to conditions." These are fully transparent and traceable to prior Q&As.
- We have a consistent and predictable approval timeline for all EU studies (106 days, including validation questions and RFI). And ethics approval is already included. On the downside, for most countries, this is longer than before.
In general, we very much appreciate that the authorities were open to input from industry (e.g., implementing the IMPD-Q-only submission or, finally, allowing the transition of Investigator Initiated Trials (IITs) with a Cross-reference to a CTD study, see below).
We see another promising discussion with single health authorities22. Some Member States had been applying much quicker approval timelines under CTD than those defined under CTR. There are experiments with "fast-track submissions" under CTR. This would be very promising, particularly for Phase 1 trials.
Challenging Surprises
Cross-referencing to CTD trials is not allowed
A seemingly minor detail created a massive roadblock in the beginning. Cross-references to CTD trials were not allowed for CTR trials. Under CTD, cross-references were the main mechanism that made IITs and Collaborations possible without disclosing company-confidential information (CCI) to the Sponsor. CTIS does not allow submitting an IMPD to another Sponsor's trial without disclosing the IMPD to the sponsor.
As a consequence, no new IITs with development products were initiated for a significant time. Then, the concept of the IMPD-Q-only submission was proposed. The product owner can submit the IMPD-Q using a different EU CT number than the Sponsor's trial. While this was received with great relief, this concept came with new challenges:
- Both submissions from the Sponsor and product owner must occur within 24 hours,
- Transparent referencing is required for both submissions,
- It is quite difficult to make sure the information in both submissions is aligned (and we saw some learning curve here),
- Interestingly, the IMPD-Q-only submission does not foresee substantial modifications. Changes are implemented via withdrawals and resubmissions. Again, matching information must be provided in both submissions,
- These new aspects need to be covered contractually between sponsor and PO (product owner).
QP declarations - new requirements
In the section above, we cherished the "Single Set of Documents." Thus, we see multiple country-specific requests for documents that should not be required per the CTR Q&A.
In theory, no more QP Declarations are required for Active Pharmaceutical Ingredient sites, and no more QP declarations are required for MRA Sites23.
Thus, single member states concerned requested those QP declarations that are explicitly not required, in particular for 3rd country Biologics Drug Substance manufacturers and even for Cell Bank manufacturers. Pushback, referencing EMA's own guidance, resulted in even more RFIs, so the best tactics appeared to give in.
From a strategic point of view, we urge the authorities to align and adhere to their own guidance.
Requests for Information (RFIs)
RFIs are a topic of discussion:
- Above, I appreciated the new transparency;
- On the other hand, the same information appeared multiple times redundantly;
- We saw identical RFIs coming from multiple member states without any consolidation;
- Since replying to those RFIs is subject to strict timelines, this contrasts with answering the same questions multiple times.
Multiple sets of cmc data are still possible
An unexpected blow was that in contrast to the "Single Set of Documents" paradigm, differences in part I documents in single member states are still possible.
CTR Q&A states, "… each Member State Concerned takes an individual decision and can disagree with a positive conclusion by the RMS. … several versions of the part I documents may exist"24.
So far, we only observed different study protocol versions in the same trial, e.g., one study arm was not approved in a certain member state. Thus, this is release-relevant since we should not release the respective product for this country.
Taking the CTR Q&A literally, we cannot exclude that we could also have different IMPD versions in the same trial. We are observing this closely, and we do not want to return to country-specific regulatory compliance assessments.
Study Start
Another source of discussion was that, in theory, a study could start after a member state issues a positive decision on parts I and II 25. Our process foresees the release of medication once the RMS and all MSCs have documented their part I and II approval.
Labeling
Labeling requirements are defined in the CTR, chapter 10, articles 66 to 69, and CTR Annex VI. Upon the CTR's initial publication, the new requirement to print the period of use on the immediate packaging was discussed intensely. Luckily, once the CTR came into force, corrections began, and Annex VI26 was revised. In short, the period of use is handled like with the old Annex 1327.
After 31.01.2025, labels are required to comply with Annex VI. For transitioned trials, CTR-compliant Labels shall be submitted using the first substantial modification after the transition. After new labels are approved, any superseded label should no longer be used.
A related practical aspect: For IITs, we often have the EudraCT number on labels, which will be outdated after the transition. Accordingly, we are switching to the EU CT number. Submission will be with the first SM after transition.
The CTR allows the member states to determine the language of the labelling28. Annex II to the CTR Q&A provides further clarification: "EN labelling is acceptable for an IMP that is only administered by the physician (or qualified health professional) and not handed to the patient."
While this was practiced before, it is now legally defined - contrasting the old Annex 1329.
Another new aspect is that commercial products may be used without labelling if the study concepts allow this30.
Finally, per the CTR, hospitals are entitled to perform re-labeling or re-packaging activities for use in other hospitals in the same Clinical Trial and Member State31 without having an MIA. For example, they could label commercial products with the required additional particulars "(a) name of the main contact; (b) clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor, and subject; (c) 'For clinical trial use only' or similar wording."32
As a QP, I cannot say that I like the proposed freedom: I primarily see
- A lack of supply chain control,
- Higher costs for local sourcing,
- Potential for misuse of medication outside the intended Clinical Trial,
- Difficulties in performing drug accountability,
- And the potential to negatively affect the reliability of study data.
On the other hand, considering the typical desperation of Clinical Colleagues when confronted with IMP lead times of three to seven months, I understand the intention. There are scenarios where, subject to appropriate controls, this approach can make sense.
Supply Strategy
In the turmoil of implementing CTR submissions and switching all running studies, it went almost unnoticed that the CTR includes several aspects with a potentially significant impact on our IMP supply strategy.
Relabelling at hospitals
The possibility of relabelling at hospitals33 would allow us to source comparators at the said hospitals, perform relabelling, and distribute the product within the same country for the same trial. Such a concept would undoubtedly be a paradigm change for our supply strategy. I did express my hesitation above.
Submission per Active Substance or ATC code
Commercial products can be submitted "per active substance or ATC code"34. This would allow, for example, changing between different Generic Comparators or AxMPs (with different Marketing Authorization Numbers) without any submission.
Since we frequently see supply shortages of generic products, a seamless replacement of an unavailable Comparator or AxMP could be very beneficial.
Interestingly, this possibility did already exist under CTD; however, it was not widely used: The application form standard under CTD35, in section D.2.2., used a disclaimer "(where) the protocol allows that any brand of the IMP with a Marketing Authorisation in that Member State be administered to the trial subjects." This disclaimer excluded nationally authorised products from usage in other countries and removed many standard-of-care products from the scope.
Noteworthy Facts
In the section below, I listed several facts that may sound as if they were outside the horizon of a Qualified Person. I think they are noteworthy - please check for yourself:
AxMPs
In line with the CTR implementation, the guidance on AxMPs was recently revised36, providing changes to the definition (IMP vs. AxMP), requirements for authorized and non-authorized AxMPs, labelling, and submission documentation. The impact of this document is still being discussed, e.g.37
Conditions
A Clinical Trial Application can be authorized, authorized subject to conditions, or rejected38.
Per default, a condition will not prevent the start of the trial. Thus, in exceptional cases, the study start can be delayed until the condition is met. So far, we found conditions written clearly, leaving no doubt if a condition implies approval or delay. For a QP, this can be a crucial distinction: It means that I can either certify the study medication or not.
Mother and Daughter Trials
The concept of cross-referencing now uses a new terminology: "mother" and "daughter" trials39. An approved IMPD-Q in a mother trial automatically leads to approval in all daughter trials. This requires that all Member States Concerned in the daughter trial participate in the mother trial. A new mother trial must be selected when the first trial ends. While cross-referencing is a rather manual process in CTIS, the benefits of having only one IMPD-Q for all trials could outweigh the extra administrative effort.
Substantial modifications
The term "substantial modification" (SM) now replaces the "substantial amendment." The definition is very broad: "They are likely to have a significant impact on: the safety or rights of the subjects and/or the reliability and robustness of the data generated in the clinical trial"40. In addition, the CTR Q&A provides an insightful list of examples41 in addition to the known guidances42,43. A new limitation exists: only one SM is possible at a time. To submit an additional SM, you must wait for the first one to be approved (or withdraw it) - this is obviously a significant drawback for our regulatory colleagues.
Changes relevant to the supervision of the trial (Art 81.9 change)
The Article 81.9 change represents a new concept for changes relevant to the trial's supervision. This change will involve providing updating certain information in the CTIS database, but no approval is required.
Non-substantial modifications (NSM)
The concept of a non-substantial amendment remains, but it is now called a non-substantial modification (NSM). It means a change that involves, e.g., an editorial update to study documents. Such an NSM will be implemented with the next substantial modification43 of the respective document45.
Addition of a new member state concerned (MSC)
There is a new submission type to add member states concerned (MSC). It requires approval from Parts I and II by the new MSC. Expected timeline: 52-83 days46.
Temporary halt and restart of a trial
A temporary halt47 means an interruption of a trial that is not described in the protocol. It is executed by the Sponsor and implies the intent to resume the trial. A temporary halt is notified to the authorities, e.g., with an Urgent Safety Measure. The restart is typically a Substantial Modification (SM). CTR says restart is an SM "if the reasons for the temporary halt have the potential to affect the benefit/risk balance (i.e., concern related to safety, lack of efficacy or IMP quality defect)."
If this is not the case (e.g., an IMP shortage), the restart can be notified (under CTD, the restart was always a substantial amendment).
Why is this important for a QP? A temporary halt can imply a stop of certification.
It may be necessary to revoke certifications, reject products, or even initiate a recall.
After the decision to restart a trial and before resuming certification, a QP typically needs to wait for the approval of the respective SM (or verify that it is not required). Note: No other restart activities may occur before the approval of the SM, in particular, the start of recruitment48.
Urgent Safety Measure (USM)
The USM49 is a means to notify the member states concerned through the EU portal where an unexpected event is likely to seriously affect the benefit-risk balance. The USM describes the event and the measures taken. A USM may involve a temporary halt and an SM before restart. The impact on QP certification is described above.
Financing and Sponsorship
While it is a Sponsor's responsibility to set up the financing of a Clinical Trial, the sole financing of a trial does not imply sponsorship50 or Sponsor liabilities, accordingly. This is primarily interesting for a company that supports IITs. Thus, also for a QP of the manufacturer's organization, it is important to delineate their own responsibilities from those of the Sponsor51.
Conclusion
The CTR is probably the most significant regulatory development for Clinical Trials and IMPs in the last two decades - or my professional experience as a QP. It profoundly impacts my work as a QP (all pharmaceutical industry in the EU). Some of these developments were not visible at first glance and are still unfolding. Diving into the details of these many impacts, increasing my understanding, discussing them with other QPs, and finally summarizing it for my peer group was a rewarding exercise in itself - I hope you find this useful as well.
Autor:
Dr. Andreas Schwinn,
Senior QP, Roche Pharma AG, Grenzach-Wyhlen, Germany
German QP Association (GQPA), Leadership Team
Note: This publication represents the author's personal opinions. It uses information gathered from QP colleagues in the German QP Association, and experience gathered as a QP of Roche Pharma AG. It does not reflect official statements of the GQPA, Roche Pharma AG, or F. Hoffmann-La Roche, Inc.
Thanks a lot to the reviewers of this document:
Dr. Rina Gamboni, F. Hoffmann-La Roche, Inc.
Henriette Granse, Roche Pharma AG
Tillmann Lindenblatt, Fisher Clinical Services GmbH
Dr. Natalia Lugli, F. Hoffmann-La Roche, Inc.
Dr. Gabriele Oleschko, Merck KgaA
Note:
1 CTD: DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
2CTR: 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.
3 There are discussions of an extension of the transition timeline.
4 EU Clinical Trial Regulation - experience so far, Claudius Pop Oral presentation, QP Forum / IMP Pre-Conference Session, Vienna, October 11th, 2023.
5DELEGATED REGULATION (EU) 2017/1569, Article 12. DELEGATED REGULATION (EU) 2017/1569 of 23 May 2017, supplementing Regulation (EU) No 536/2014 of the European Parliament and of the Council by specifying principles of and guidelines for good manufacturing practice for investigational medicinal products for human use and arrangements for inspections, Official Journal of the European Union, 16.09.2017.
6 CTR, Article 25.
7Annex 16: General Principles. EudraLex Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 16: Certification by a Qualified Person and Batch Release, Brussels, 12 October 2015.
8New Annex 13: 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 final, Brussels, 08.12.2017, lines: 510-513.
9 CTR practice guide: Clinical Trials Regulation (EU) No 536/2014 in practice, The rules governing medicinal products in the European Union, VOLUME 10 - Guidance documents applying to clinical trials, March 2024, version 05.
10 CTR Q&A: CLINICAL TRIALS REGULATION (EU) NO 536/2014, QUESTIONS & ANSWERS, VERSION 6.9, he rules governing medicinal products in the European Union VOLUME 10 - Guidance documents applying to clinical trials, July 2024, section 1.1.
11 This article was initially based on the CTR Q&A 6.8, all references have been updated to 6.9..
12CTIS Evaluation Timelines, CTIS Training Programme, EMA, Version 2.0 - February 2024.
13 106 days includes 15 days for validation questions and 31 days for part I and II RFIs.
14 Note: if there are RFIs, the regular timelines apply.
15 See CTIS Application Form under: Compliance with GMP for the medicinal product / Authorisation number of manufacturing and import. The MIA number is taken from one of the uploaded MIAs, thus, not necessarily the site of certification and import.
16Transparency Rules: Revised CTIS Transparency Rules, Revised CTIS Transparency Rules, EMA/263067/2023
17CTR transition guidance: Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, May 2024, Version 4, page 3, section 1.
18CTCG Best Practice Guide for sponsors of multinational clinical trials with different Part I document versions approved in different Member States under the Directive 2001/20/EC that will transition to the Regulation (EU) No. 536/2014.
19 Transitioning ongoing Studies from CTD to CTR, Roche's strategy and experience transitioning a large portfolio of CTD studies to the CTR in time by the end of the transition period, Author: Sandrine Verstraete, Co-Authors: Samia Dridi, Natalia Lugli, Valentina Geisseler-Homann, Duncan Terrett, Rina Gamboni, Joanna Gaspar-Neves, F. Hoffmann-La Roche Ltd, Basel (Switzerland), Poster Presentation, DIA Europe, Brussels, 12-14 March 2024.
20 CTR Q&A, section 3.8, answer 170.
21 CTR Q&A, section 2.15, answer 124.
22 Regulatory aspects of the implementation of CTR and work in CTIS: updates and clarifications specific for early phase, tips for a smooth validation, Anne LENAERS, FAMHP, Brussels, 15.09.2023
23 CTR Q&A, Section 8.4, Answer 415.
24 CTR Q&A, section 3.15, answers 199.
25 CTR Q&A, section 2.5, answer 92.
26Commission Delegated Regulation (EU) 2022/2239, of 6 September 2022, amending Regulation (EU) No 536/2014 of the European Parliament and of the Council as regards labelling requirements for unauthorised investigational and unauthorised auxiliary medicinal products for human use, Official Journal of the European Union, 15.11.2022
27Old Annex 13: EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13, Investigational Medicinal Products, Brussels, 03 February 2010, ENTR/F/2/AM/an D(2010) 3374.
28 CTR, Article 69.
29 Old Annex 13, article 28.
30 CTR, Article 67, 1. (b).
31 CTR, Article 61, paragraph 5. (a).
32 CTR, Article 67, paragraph 2. and CTR, Annex VI, Section C.
33 CTR, Article 61, paragraph 5. (a).
34 CTR Q&A, section 3.16, answer 201 and CTR Q&A, Annex V.
35CTD Application Form: Annex 1 Clinical Trial Application Form, REQUEST FOR AUTHORISATION OF A CLINICAL TRIAL ON A MEDICINAL PRODUCT FOR HUMAN USE TO THE COMPETENT AUTHORITIES AND FOR OPINION OF THE ETHICS COMMITTEES IN THE COMMUNITY.
36Auxiliary Medicinal Products in Clinical Trials, Recommendations on the use of Auxiliary Medicinal Products in Clinical Trials written and endorsed by the Clinical Trials Coordination and Advisory Group (CTAG), 01 March 2024
37CTIS Bitesize Talk: Alternate IMPD-Q and New guidance AxMP, YouTube video, 19.32 - 1:14:32, European Medicines Agency, 30.04.2024
38 CTR Q&A, section 2.8, answers 100 - 104.
39 CTR Q&A section 3.8, answers 169 - 174.
40 CTR Q&A, section 3.1, answer 127.
41 CTR Q&A, Annex IV.
42Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials, 27 January 2022, EMA/CHMP/BWP/534898/2008 Rev. 2, Committee for Medicinal Products for Human Use (CHMP)
43Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials, 27 January 2022, EMA/CHMP/QWP/545525/2017 Rev. 2, Committee for Medicinal Products for Human Use (CHMP)
44 CTR Q&A, section 3.4, answer 140+141.
45 CTR Benefits and Challenges from the sponsors perspective, Author: Natalia Lugli, Co-Authors: Samia Dridi, Rina Gamboni, Joana Gaspar Neves, Valentina Homann, Duncan Terrett, Sandrine Verstraete, F. Hoffmann-La Roche Ltd | Pharma Drug Regulatory Affairs, Poster Presentation, DIA Europe, Brussels, 12-14 March 2024.
46 CTR Q&A, section 2.10, answers 113-115.
47 CTR Q&A, section 10.4, answers 44038 - 442.
48 CTR Q&A, section, 10.1, answer 431.
49 CTR, article 54.
50 CTR Q&A, section 5.3, answer 221-223.
51Guideline on the responsibilities of the sponsor with regard to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice, 14 September 2022, EMA/INS/GMP/258937/2022.
