EU Clinical Trials Regulation: The Application Process
One of the major changes introduced by the European Union (EU) regulation 536/2014 is an application procedure that will require sponsors to apply for authorization to conduct an interventional/low-intervention clinical trial (CT) via a new EU portal.3 The regulation’s effective date is dependent on the availability of the portal and its associated database, which are now in development and subject to user acceptance testing by EMA stakeholders. According to the most recent European Medicines Agency (EMA) confirmation,1 the regulation will be applicable by no later than October 2018.
While this is a major change, it is also seen by many as a key benefit. The regulation introduces a single approach for the application and maintenance of a CT authorization, and applies to both single or multiple member state trials. This procedure not only combines the content of what can be currently referred to as the “regulatory” and “ethics” applications, but also combines the scientific, technical, and ethical review necessary to receive approval to conduct a CT in the EU. In addition, the regulation defines procedural timelines, harmonizes document requirements, and aims to reduce the administrative burden of applications.2
Note: This article does not cover notifications of milestones or unexpected events that are required by the new regulation.
The application content and assessment are divided into two parts: Part I contains scientific and medicinal product documentation; Part II contains the national and patient-level documentation (see Table A).
There is provision for cross-referencing to existing applications, which will further reduce the current administrative burden of EU CT applications.
Process and timelines
For many sponsors, the application process may require internal administration to support sponsor registration and role allocation where required by the CT arrangements (e.g., allocating work to contract resource organizations, affiliates, or personnel). User training will be essential; it is expected that the EMA will offer system training.
We will learn more as development of the portal and database progress, but we do know that there will be provision for both compiling an application within a workspace facility and for uploading an application that has been compiled outside of the system.
The application is submitted via the portal to all concerned member states (CMSs) in which the sponsor intends to conduct the CT (Figure 1). At the time of application, the sponsor proposes a reporting member state (RMS), who will be confirmed by day 6 following submission. The sponsor’s RMS proposal may not always be accommodated, and in these cases the member state that has either self-nominated or been selected will instead be the RMS.
Following submission, there is a validation period to assess whether the application is complete and whether the application is in scope of the regulation. During this period the member states may request additional information from the sponsor. Member state requests for information during validation should be sent within 10 days of the submission. A 15-day extension can be allocated if needed to resolve issues; this provides an additional 10 days for the sponsor to respond/update the application and 5 days for member state confirmation, based on the information provided. The validation date is the date the RMS notifies the sponsor of the end of validation, or the natural end of the 10 or 10 + 15 days, whichever comes first.
The regulation requires strict adherence to the maximum timelines for each phase of the application procedure and has provisions to ensure that delays from any party do not hold up the process. If the RMS does not provide validation feedback within the defined time frame, for example, this will be considered a tacit validation of the application. If a sponsor fails to reply to a request for information by the deadline, this will lead to the automatic (tacit) withdrawal of the application in all CMSs. The portal will determine when the milestones such as the validation date have been met. Table B provides a summary of the CT application procedural timelines.
|Part I||Part II|
|Application form||Informed consent form and subject
|Cover letter (including sponsor’s
justification for the classification as a low intervention
CT, if necessary
|Investigator’s brochure||Suitability of investigators and facilities|
|Good manufacturing practice
|Proof of insurance or indemnification|
|Investigational medicinal product dossier/
Auxiliary medicinal product dossier
|Data protection rules|
|Scientific advice||Proof of fee payment|
|EU Paediatric Investigation Plan decision||Note: Precise content will be determined
by each member state
|Example of investigational and auxiliary
medicinal product labeling
The EU ct regulation introduces a new procedure, new timelines, and revised application content. although it may increase or decrease the overall timelines in some member states, it will bring with it increased predictability for ct start-up in the EU.
The RMS assesses Part I of the application in accordance with the aspects described within Article 6 (1b)2 of the regulation, and authors an assessment report that includes determination that the conduct of the CT is either:
- Acceptable subject to specific conditions
- Not acceptable
For a multistate CT application, the 45-day assessment process includes:
- RMS releases draft assessment report to CMSs
- CMSs coordinated review of the draft report
- RMS sends final assessment report, including CMS considerations and how they have been addressed
If further information is required, the RMS will issue a request for information to the sponsor via the portal. If this occurs, the 45-day assessment period will be extended by 31 days to incorporate the sponsor response (via the portal) and RMS/CMS assessment of the new information. The 31-day period includes 12 days for the sponsor to respond. If the sponsor exceeds this time frame, the application will be considered as lapsed (or a tacit withdrawal). This forces sponsors to adhere to the deadline or face having to resubmit.
The reporting date is the date the final assessment report is sent via the portal to the sponsor and CMSs. It will occur within 45 days of the validation date unless there are requests for information and/or the CT is for an advanced therapeutic medicinal product (ATMP) or biologic. The assessment period for CTs concerning ATMPs or biologics may be extended by up to 50 days to allow consultation with experts.
Assessment Of Part II
Part II will be assessed individually by each MS and in accordance with Article 7(1)(3). The assessment will be performed by an ethics committee and in accordance with the national law of the MS within the overall timelines defined by the regulation. Each CMS will submit an assessment report listing their conclusions to the sponsor (via the portal) within 45 days of the validation date. Within the 45-day period MSs can request further information from the sponsor regarding aspects covered by Article 7(1). In addition, as per the Part I provisions, the 45-day period can be extended by 31 days to allow the sponsor to respond to MS requests and the requesting MS(s) to assess the information.
The sponsor can choose to submit only Part I for assessment, and then submit Part II within two years of the Part I reporting date. If the sponsor does not submit Part II within two years, the Part I application in that MS will lapse.
A sponsor may withdraw an application at any time until the reporting date, but can only withdraw the full application rather than in chosen MSs.
Parts I and II will be assessed in parallel unless the application contains only Part I. If Part II is submitted at a later date following Part I approval, then the MSs cannot request information concerning Part I.
Each MS will notify the sponsor of its single decision covering both Part I and Part II via the portal within 5 days of the Part I assessment reporting date, or within 5 days from the last day of its Part II assessment, whichever is later. This is the notification date. If a CMS does not provide a decision within this time frame then the Part I assessment report conclusion will be considered as the CMS decision on the application—i.e., a tacit approval.
If the RMS Part I assessment concludes that the CT is not acceptable, it shall be deemed to be the conclusion of all CMSs. If the RMS Part I assessment by the RMS concludes that the CT is acceptable or acceptable with conditions, it shall be deemed to be the conclusion of all CMSs.
A CMS can disagree with these conclusions, but only on the grounds of set criteria, including:
- Participation in the CT would lead to a subject receiving an inferior treatment than the normal clinical practice in their MS
- Considerations regarding subject safety, data reliability, and robustness
- Violation of MS rules on use of cell therapy
- Disagreement with RMS conclusion based on safety and data reliability, and robustness considerations as raised during the assessment procedure
- Aspects addressed in Part II of the assessment report are not complied with
- An ethics committee has issued a negative opinion, which in accordance with the law of the CMS is valid for that entire MS
In cases where the CMS disagrees with the RMS conclusions and does not grant approval, that CMS shall provide for an appeal procedure. It has yet to be seen how MSs will interpret and apply these grounds for not accepting RMS conclusions.
|Submission date to validation date||Validation date
to reporting date
to notification date
|Submission date to notification date|
|Initial application||10–25 days||45–76
(+50 days for ATMPs or biologics)
|Addition of a CMS||—Not Applicable—||52–83 days|
|Substantial modification||6–21 days||38–69 days||5 days||49–95 days|
|Some member states may work to shorter timelines for single state applications; UK and Belgium have suggested this would be the case for applications they receive for Phase I CTs.
If the clinical trial is authorized, then the notification date = authorization date.
Adding a new MS
Following the notification date for an initial or substantial modification application, a sponsor can apply to modify a CT application to add an additional MS. Sponsors must wait for approval of the initial CT application and any subsequent substantial modification application before applying to add an additional MS. For such applications, the RMS will remain the same, and the new CMS will assess the application to the same criteria (as if the MS were part of the initial application); the same timelines of 31 days for requests for information apply. Any requests for information will be submitted to the sponsor via the portal and will also be sent to the RMS and existing CMSs. The additional MS must confirm the single decision for their country within 52 to 83 days of the submission.
Just as in the CT directive, only substantial changes (which the regulation calls “modifications”) require approval prior to implementation. The criteria for a substantial modification described within the regulation are similar to those of the CT Directive.
Essentially, changes that are likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the CT are considered “substantial.” Substantial modification can be for Part I, Part II, or both. In terms of the application, the initial application approach applies: The RMS is the same, it includes a validation step, 31 days can be added to the timeline to accommodate requests for information, and a 5-day period follows the reporting date for CMSs to confirm their single decision The RMS will validate the application within 6 days of the submission and the reporting date will be 38 days (or 69 days if there are questions) from the validation date. If a modification affects both Part I and Part II, the assessment of each will be run in parallel in accordance with the timelines for a substantial modification.
An application cannot be submitted if another is ongoing. Tracked-changes versions of the modified documents may be required for the application.
- 3. Official Journal of the European Union. Regulations. “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.” 27 May 2014. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf
- 1. European Medicines Agency. “Delivery Time Frame for the EU Portal and EU Database.” 17 December 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199078.pdf
- 2. European Commission. Clinical Trials. Directive No. 2001/20/EC. 4 April 2001. http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf
The EU CT regulation introduces a new procedure, new timelines, and revised application content. Although it may increase or decrease the overall timelines in some MSs, it will bring with it increased predictability for CT start-up in the EU.
Significant changes are afoot for the MS competent authorities, ethics committees, and sponsors.
- At the MS level, ethics committees and competent authorities will need to agree how to work together to achieve the review outcome within the required timelines.
- At the EU level, MSs will need to agree how to work together to achieve what is required to complete the application review.
- Industry CT sponsors will need to prepare themselves to confirm country selections without negatively affecting planned study start-ups (i.e., avoiding multiple applications to add MSs), respond to application review queries within short timelines, and manage changes so they can be submitted when needed rather than waiting for an ongoing application to complete.
This article was adapted from “EU Clinical Trials Application Process,” published 7 June 2016 on iSPEAK, the Official Information Resource of ISPE, by the Investigational Products CoP:
- Ted Bradley (Pfizer), IP CoP Task Team contributor
- Hans von Steiger (Pfizer), regulation introduction author
- Magali Busqet (Sanofi), IP CoP Task Team contributor
- Massimo Eli (Merck), IP CoP Task Team contributor
- Chuck Gentile (Sanofi), IP CoP Task Team contributor
- Juliette Kirk (Pfizer), IP CoP regulatory consult
- Kirsteen Magee (Mylan), IP CoP Task Team contributor
- Marianne Oth (Eli Lilly), IP CoP Task Team contributor
- Martin Waldherr (Roche), IP CoP Task Team contributor