Pitfalls in the clinical trial submission process according to CTR
By Manuela Pöhlmann & Cornelia Bauer
On January 31, 2022, the long-awaited Clinical Trials Information System (CTIS) portal for submissions under the Clinical Trial Regulation (EU) No. 536/2014 (CTR) went online.[1] Since then, many of us have already gained first experiences with the portal – especially since all new clinical trials now have to be submitted via this portal and the deadline for the transition to CTR of ongoing clinical trials is clearly approaching.
What experiences have we had with the new portal so far? Well, it certainly brings benefits in many ways – especially for large clinical trials with several participating countries from the EU/European Economic Area (EEA).
However, experience also shows that the submission processes of clinical trials according to CTR via the CTIS portal should not be underestimated.
New concept of low interventional clinical trials
But let’s start from the beginning: What some have not yet realized is that we have received a new type of study under the CTR: The so-called “low interventional clinical trial”. This includes studies of approved investigational medicinal products (excluding placebos) that are used in accordance with the terms of the marketing authorisation (or evidence-based use supported by published evidence on the safety and efficacy of these investigational medicinal products). However, the difference to non-interventional clinical trials is that there are additional diagnosis/monitoring procedures allowed, which do not pose more than minimal additional risk or burden compared to normal clinical practice.[2] This difference is of great importance for the conduct of the study, because low interventional clinical trials are subject to CTR and must therefore – with the exception of a few facilitations – meet all the requirements of CTR. Among other things, low interventional clinical trials must be submitted via the CTIS portal and also the regulatory progress of the study must be recorded and managed through the portal. As a consequence, the categorization as low interventional clinical trial results in a high level of bureaucracy and thus significantly higher costs. Therefore, the necessity of study examinations that deviates from normal clinical practice should be well considered during study planning and a conscious decision should be made for or against a low interventional clinical trial design.
Forward planning is a key factor
Forward planning of clinical trials will become even more important under CTR. Especially in the case of multinational clinical trials or in the case of several upcoming substantial modifications, timing and strategic planning have become unavoidable. Since the CTIS portal gives us various options for the initial submission approach (part I alone and part II later, part I and part II for all countries together, part I for all planned countries together with part II for some of the planned countries and for the remaining countries later), it should be carefully weighed up in advance, which strategy is most appropriate for the specific study.[3] On the one hand, a good strategy can save a lot of time and can result in a swift receipt of regulatory greenlight for many European countries at once. On the other hand, a poor strategic choice may lead to a considerable time delay for the study start. The timing of substantial modification submissions has also become more important – especially for multinational clinical trials. While it was possible under the CTD to submit a further substantial amendment while a previously submitted amendment with different scope was still under review, the CTIS portal sets strict restrictions here. With only a very few exceptions, submissions of substantial modifications can only be submitted as one application together or one after the other, i.e. a new substantial modification may only be submitted once the previous substantial modification has been approved. Considering the possibly long processing time for substantial modifications, issues can arise here. An obvious example would be a belated submission of an urgent PI change due to an ongoing assessment of another, previously submitted substantial modification.[4]
Furthermore, the much stricter deadlines for answering queries, the so-called “request for information” (RFI), as well as new reporting obligations (e.g. recruitment start) should be taken into account when it comes to internal organization.[5]
If you now engage yourself in the submission process under the CTR, you will quickly come across other pitfalls that you should be aware for a successful submission.
New documents and templates
Above all, during study start up planning attention should be paid to the fact that various new documents under the CTR might be required for submission purposes. These include, for example, the following documents: „Compliance with applicable rules for biological samples“, „site suitability list“ for all participating study sites, GCP training certificates for principal investigators (depending on the country requirements, with evidence of knowledge of the new CTR legal basis).[6] In addition, in some countries a synopsis in layperson language is requested, which should be maximum of two pages long.
At the end of the study, in addition to the “summary of results”, a “summary of results in layperson language” with maximum of two pages must be submitted as well – within one year (or six months for paediatric studies) after study end within the EU/EEA (regarding the layman summary, we would also like to refer to our blog post “EU CTR: How to write a good Lay Summary of clinical study results”). For multinational clinical trials that are also conducted outside the EU/EEA, this deadline can become a stumbling block. The reason for this is that the deadline for these submission processes according to CTR is not calculated based on the time point of the global end of the study, but based on the end of the study in all participating countries of the EU/EEA. If the study continues in one or more countries outside the EU/EEA, the deadline remains unchanged. For the submission of the “summary of results” and the “layman summary” the deadline might then be very tight or even impossible to reach. In the latter case, the protocol should specify the prospected delivery date together with a justification for belated provision.
National requirements
The CTR / CTIS portal has definitely brought us a significant advantage: Submissions within the EU/EEA has become much more standardized and therefore easier. Nevertheless, the CTR gives the member states the opportunity to set country-specific requirements in some areas – which was well implemented by some states. Therefore, it is advisable to investigate about the country-specific requirements in advance. These can range from translations (e.g. Greek translation of protocol for submission in Greece[7]) to additional documents (e.g. Poland requires proof of insurance in addition to the minimum dossier when transitioning a clinical trial[8]).
In Germany and Austria a so-called “deputy investigator” is requested in addition to the principal investigator according to national recommendations.[9], [10] As a consequence, an appropriately qualified deputy should be trained and documented at study sites in both countries. In previous submission processes, even RFIs regarding the qualification documentation of deputy investigator have been raised. The legal basis for this kind of RFI is not entirely clear. On the one hand, the definition of a “deputy investigator” does not exist in the CTR. On the other hand, Annex I of the CTR requires “description of the qualification of the investigators in a current curriculum vitae and other relevant documents”, which may refer to further investigators besides the principal investigator.[11] Therefore, such a request is quite explainable and must be taken into account when conducting the study. As far as submission is concerned, however, it is possible to avoid the submission of qualification documentation for the “deputy investigators” provided the “site suitability list” is filled out wisely.
Further pitfalls
- xEVMPD registration: IMP and also partly AxMP must be registered in xEVMPD in advance. Multiple registrations must be avoided and the accuracy of the entry is crucial. The CTIS portal accesses the xEVMPD directly as soon as the “Submit” button is pressed. This means that it is not possible to check the entry in xEVMPD via CTIS in advance.
- IMPD, if the sponsor is not the manufacturer and does not have access to the IMPD-Q documentation: If it is not possible to simply reference the quality documentation of another clinical trial with the same IMPD under CTIS, the CTR provides an “IMPD-Q only” submission option. In this case, the manufacturer of the investigational product submit a separate initial “IMPD-Q only” application to ensure that no other party has access to the IMPD-Q documentation and RFIs, if applicable. For this approach some requirements must be met (e.g. the “IMPD-Q only submission” by the manufacturer must be made at the same time as the submission of the clinical trial by the sponsor), which may lead to an increased workload.[12]
- OMS (Organisation Management Service): Besides the sponsor’s organisational OMS number, also OMS numbers of study sites and “third parties” associated with the trial might be required for the completion of the CTIS application form. It is beneficial to obtain these OMS numbers in advance. Some trial sites and “third parties” are unable to apply for OMS numbers. In these cases, a workaround has been implemented in CTIS, which allows to create these organizations “locally” in CTIS for a specific study. However, one disadvantage of this approach is that you can only change the organization details by deleting and re-adding the organization.[13]
- Timelines in CTIS: The timelines for CTR applications do not correspond to the timelines in real life. The background for this is that the calculation of “due dates” in CTIS is based on the “Regulation (EEC, Euratom) No 1182/71 of the Council of 3 June 1971 determining the rules applicable to periods, dates and time limits”. This can significantly extend the timelines until the decision (e.g. for the initial submission of a multinational clinical trial the maximum timeline of 106 days may increase up to more than 120 days).[14]
Data protection and confidentiality of commercial information
A final point which should be mentioned here, are the so-called transparency rules, which have already caused a lot of discussions in the context of the implementation of the CTR. To create more transparency for the public, many submitted documents and extensive information of the clinical trial are published via CTIS, which has not been the case under the CTD. Therefore, forward planning is very important when it comes to the protection of personal data and commercial information.
There have been many changes to the transparency rules recently, which facilitated the process for sponsors tremendously.[15] With this topic as an example, you can see that the processes in CTIS are not yet final and you have to constantly identify changes in regulatory requirements and recommendations. Taking into account the high amount of guidance and information documents on CTR / CTIS topics, it might be indeed sometimes challenging but nevertheless, very important to stay up to date.
Literatur
[1] European Medicines Agency (n. d.): Clinical trials’ transition to new EU system – one year left, URL: https://euclinicaltrials.eu/about-this-website/
[2] European Commission (07.2024): Questions and Answers Document – Regulation (EU) 536/2014, URL: European Commission (07.2024): Questions and Answers Document – Regulation (EU) 536/2014, URL: https://health.ec.europa.eu/document/download/bd165522-8acf-433a-9ab1-d7dceae58112_en?filename=regulation5362014_qa_en_0.pdf, p. 16, v. 6.9
[3] European Medicines Agency (30.08.2023): CTIS Bitesize Talk : Part I – only applications and Part II requirements in CTIS – presentation, URL: https://www.ema.europa.eu/en/documents/presentation/ctis-bitesize-talk-part-i-only-applications-and-part-ii-requirements-ctis-presentation_en.pdf
[4] European Medicines Agency (31.05.2022): Clinical Trial Information System (CTIS) Bitesize talk: Modifications – presentation, URL: https://www.ema.europa.eu/en/documents/presentation/presentation-clinical-trials-information-system-ctis-bitesize-talk-modifications_en.pdf
[5] European Medicines Agency (02.2024): CTIS Evaluation Timelines, in: CTIS Training Programme, URL: https://www.ema.europa.eu/en/documents/other/clinical-trial-information-system-ctis-evaluation-timelines_en.pdf, V2.0
[6] European Medicines Agency (28.06.2024): Clinical Trials Information System (CTIS) – Sponsor Handbook, in: Clinical Trials Information System (CTIS) Programme, URL: https://www.ema.europa.eu/en/documents/other/clinical-trial-information-system-ctis-sponsor-handbook_en.pdf, EMA/923413/2022, v. 4.0
[7] European Commission (07.2024): Questions and Answers Document – Regulation (EU) 536/2014, URL: https://health.ec.europa.eu/document/download/bd165522-8acf-433a-9ab1-d7dceae58112_en?filename=regulation5362014_qa_en_0.pdf, p. 133, v. 6.9
[8] European Commission (May 2024): Guidance for the Transition of clinical trials from the Clinical Trials Directive to the Clinical Trials Regulation, URL: https://health.ec.europa.eu/document/download/10c83e6b-2587-420d-9204-d49c2f75f476_en?filename=transition_ct_dir-reg_guidance_en.pdf), v. 4
[9] Arbeitskreis Medizinischer Ethik-Kommissionen (10.11.2023): FAQ: Principal Investigator, Investigator, Investigating Team, Trial Site, URL: https://www.akek.de/wp-content/uploads/FAQ-Investigator-related-v1-12_231110.pdf, v1-12
[10] Bundesamt für Sicherheit im Gesundheitswesen (n. d.): URL: https://www.basg.gv.at/gesundheitsberufe/klinische-studien/klinische-pruefungen-von-arzneimitteln-vo/nationale-anforderungen-und-empfehlungen
[11] 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 (16.04.2014), L 158/1
[12] European Commission (07.2024): Questions and Answers Document – Regulation (EU) 536/2014, URL: https://health.ec.europa.eu/document/download/bd165522-8acf-433a-9ab1-d7dceae58112_en?filename=regulation5362014_qa_en_0.pdf, p. 35 ff., v. 6.9
[13] European Medicines Agency (28.06.2024): Clinical Trials Information System (CTIS) – Sponsor Handbook, in: Clinical Trials Information System (CTIS) Programme, URL: https://www.ema.europa.eu/en/documents/other/clinical-trial-information-system-ctis-sponsor-handbook_en.pdf, EMA/923413/2022, v. 4.0
[14] Council of the European Union (03.06.1971): Regulation (EEC, Euratom) No 1182/71 of the Council of 3 June 1971 determining the rules applicable to periods, dates and time limits, L 124,
[15] European Medicines Agency (05.10.2023): Revised CTIS Transparency Rules, URL: https://www.ema.europa.eu/en/documents/other/revised-ctis-transparency-rules_en.pdf
Picture: @ Verrone/AdobeStock.com
