Background

From 2004 to 2014, clinical trials in the EU and countries in the European Economic Area (collectively known as EU/EEA Countries) were subject to the EU Clinical Trial Directive 2001/20/EC (CTD) which set rules for conducting clinical trials and protecting human research subjects. While the CTD aimed to improve consistency in the regulation and conduct of clinical trials throughout Europe, individual countries independently interpreted and implemented the CTD’s guidelines, resulting in fragmented and inefficient assessments, authorizations and ethics reviews for multinational clinical trials. The result: increased red tape and expense for clinical trial sponsors.

In 2014, seeking to modernize and streamline the rules governing clinical trials and strengthen Europe’s position as an attractive location for clinical trials, the European Parliament and EU Council approved the Clinical Trials Regulation EU-CTR No 536/2014 (CTR). The CTR harmonizes clinical trial regulations in the EU, improves information sharing and calls for coordinated decision making among EU/EEA Countries. It also seeks to increase subject safety and transparency. Yet, full implementation of the CTR was significantly delayed due to obstacles in the development and testing of the Clinical Trial Information System (CTIS), a key component of the CTR.

The CTIS is a single point of entry and database accessible to clinical trial sponsors, regulators and the public. It serves as a paperless system for the submission of clinical trial applications, evaluation of clinical trial data, regulatory oversight, communications and safety reporting for all clinical trials in EU/EEA Countries. The CTIS will allow for the authorization of clinical trials in up to 30 EU/EEA Countries with a single application.

Nearly seven years after approval of the CTR, the European Medicines Agency (EMA) announced in January 2022 that the CTIS would go live on Jan. 31, 2022, and initiated a transition period toward full implementation of the CTR:

• Year 1 (Jan. 31, 2022 – Jan. 31, 2023): Clinical trial applications may be submitted under the CTD or the CTR.
• Years 2-3 (Jan. 31, 2023 – Jan. 31, 2025): Initial clinical trial applications will be subject to the CTR and must be created and submitted for review via the CTIS.
• After Jan. 31, 2025: All new and ongoing clinical trials must be fully compliant with the CTR.[1]

The CTR presents an enormous shift in the conduct of clinical trials in the EU and creates a streamlined, more cost-efficient drug development process for sponsors. Academic medical centers carrying out investigator-initiated studies may pursue acceptance of “low-intervention” clinical trials with simplified authorization and safety reporting requirements at a decreased cost.

As with all new processes, sponsors planning to initiate or continue clinical trials after the CTR transition must learn to navigate CTR’s requirements. Below are some key aspects of the CTR as it becomes fully implemented with the official go-live of the CTIS.

The CTIS

The EMA will oversee the database housing all data and information required to be submitted under the CTR.[2] Sponsors, regulatory authorities and the general public will be able to access information and data on the CTIS.

1. Sponsors. Sponsors will have access to a secure workspace to (among other functions): submit clinical trial applications and documentation required for regulatory approval of new and modified clinical trials and to respond to requests from regulators; issue CTR-required clinical trial notifications; report Suspected Unexpected Serious Adverse Events (SUSARs); and submit Annual Safety Reports.[3]
2. Authorities. EU regulatory authorities including the European Commission will also utilize a secure workspace to (among other functions): evaluate and coordinate multi-country review of clinical trials; submit requests for information and clinical trial application decisions; issue corrective measures; collaborate with regulatory authorities from other EU/EEA Countries; and assess safety reports.
3. General Public. Detailed, searchable information regarding all clinical trials carried out in EU/EEA Countries will be available to the general public in all official EU languages, subject to redactions for confidentiality pursuant to the CTR’s disclosure policies.[4]^{, [5]}

Clinical Trial Assessment & Acceptance

1. Single Application. Sponsors will submit a single application dossier for authorization of the clinical trial in the intended member states (Member States Concerned or MSCs) via the CTIS.[6] The application dossier contains two parts: Part I details the scientific and methodological aspects of the clinical trial.[7] Part II addresses the ethical aspects of the clinical trial.[8]
2. Reporting Member State. A “Reporting Member State” will be designated to lead the assessment of Part I of the application dossier.[9] The Reporting Member State will validate the application[10], prepare an initial assessment report, coordinate the review of the clinical trial by the other MSCs and submit a final assessment report to the CTIS.[11]
3. Ethics Committee Review. Part II of the application dossier is reviewed by an ethics committee in each MSC.[12] The ethics committee will issue an assessment report indicating that it (1) accepts the clinical trial; (2) accepts with conditions; or (3) refuses the clinical trial.[13] The clinical trial may not be conducted in any country in which the clinical trial receives a negative assessment report from the reviewing ethics committee.[14]
4. Clinical Trial Decisions. The Reporting Member State’s final assessment report must include its conclusion as to whether Part I of the application is 1) acceptable; 2) acceptable subject to conditions; or 3) not acceptable.[15] The Reporting Member State’s assessment report is binding on all MSCs, unless an MSC declines to accept the Reporting Member State’s assessment report on one of the following grounds: 1) patients participating in the clinical trial would receive inferior treatment to standard clinical practice; 2) violation of national rules regarding cells or narcotics; or 3) concerns about the safety or data reliability.[16] If the Reporting Member State issues a negative assessment report, then it is negative for all MSCs and the clinical trial may not proceed.[17] A clinical trial may only proceed in countries in which both assessment reports are positive.[18]

Review Timelines

1. Application Review. The CTR contains strict review timelines for the application dossier. The Reporting Member State must validate the application for completeness within 10 days from submission.[19] For multi-national clinical trials, the Reporting Member State will lead the assessment process in accordance with the following timeline:
   • Initial Assessment Phase: Within 26 days of validation, the Reporting Member State will complete an initial draft of the Part I assessment report and circulate it for review by the other MSCs.[20]
   • Coordinated Review Phase: Within 12 days of the end of the initial assessment phase, all MSCs will jointly review the draft Part I assessment report and provide feedback.[21]
   • Consolidation Phase: Within 7 days from the end of the coordinated review phase, the Reporting Member State will record the considerations of the other MSCs (and how such considerations were addressed) and will submit the finalized Part I assessment report via the CTIS. [22]
2. An additional 50 days may be added to the review period for complex clinical trials involving Advanced Therapy Medicinal Products such as gene therapies and tissue-engineered products. [23]
3. Within 5 days from the date of submission of the final Part I assessment report, each MSC must notify the sponsor through the CTIS as to whether the clinical trial is accepted, accepted with conditions or whether acceptance is refused. If the MSC fails to provide its decision within this five-day timeframe, then it is deemed to have approved the conclusion of the Part 1 assessment report. [24]
4. Each MSC must complete its assessment of Part II (e.g. ethics review) within 45 days from the validation date. [25]
5. Sponsor Responses to Requests for Information. The sponsor must respond to any requests by the Reporting Member State for additional information (RFIs) necessary for the evaluation of the clinical trial within a period of time set by the Reporting Member State (for Part I), or the MSC (for Part II) not to exceed 12 days from the date of the request.[26] If a sponsor fails to timely respond to an RFI, the application will automatically lapse.[27]

Increased Transparency

The CTR increases clinical trial transparency by implementing strict rules regarding safety and results reporting, records keeping and disclosure.

1. Public Disclosure of Clinical Trial Information and Documents. In a significant change from the CTD, the CTR requires that all clinical trial data and documents in the CTIS be made public (including all applications on which an acceptance decision has been issued and study protocols), with limited exceptions for information that is:
   • personal data;
   • commercially confidential;[28]
   • a confidential communication between MSCs during the assessment of the clinical trial; or
   • is necessary to ensure the effective supervision of the trial.[29]
2. Milestone Notifications. Sponsors must issue certain milestone notifications through CTIS, including the following:
   • Notification to each MSC of the start of the trial in the MSC (15 days)
   • Notification to each MSC of the first visit, first patient in the MSC (15 days)
   • Notification to each MSC of the end of recruitment in the MSC (15 days)[30]
3. Results Reporting. Clinical trial results must be reported within one year from the end of the clinical trial.[31]
4. Breach Reporting. Sponsors must report to MSCs serious breaches of the clinical trial protocol or the CTR within seven days of becoming aware of the breach.[32]^{, [33]}
5. Results Reporting Must be in Layperson Terms. Sponsors must provide a lay summary for all clinical trials regardless of the clinical trial phase or outcome.[34] The CTR sets forth specifically what must be contained in the results summary.[35]
6. Data Privacy. The CTR’s requirement for broad disclosure of clinical trial information and data places the burden on the sponsor to ensure the privacy and confidentiality of clinical trial subjects’ personal data as required by applicable privacy laws, including the General Data Protection Regulation.

Safety Reporting

1. Instead of reporting suspected unexpected serious adverse reactions (SUSARS) to individual member states, Sponsors will report to the EudraVigilance database. Initial reports of SUSARs must be made within seven days if fatal and 14 days if non-fatal.[36]
2. Urgent Safety Measures must be reported via CTIS within seven days.[37]
3. Sponsors will submit Annual Safety Reports (previously known as the Development Safety Update Report) via the CTIS.[38]

Low Intervention Clinical Trials

The CTR recognizes “Low Interventional Trials,” which pose only minimal additional risk to clinical trial subjects compared to usual clinical care and provides for a risk-based approach to the approval, monitoring and other regulatory requirements for such clinical trials. In order to be classified as a Low Interventional Trial, the clinical trial must meet the following conditions:

1. The Investigational Medicinal Product (IMP), excluding placebos, are authorized; and
2. The clinical trial protocol provides that:
   • The IMP is used in accordance with its marketing authorization; OR
   • The IMP’s use is evidence-based and supported by published scientific evidence on the safety and efficacy of those IMPs in any of the MSCs; AND
3. The additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of the subjects compared to usual clinical practice in the MSCs.[39]

Conclusion

Industry sponsors and academic medical centers carrying out clinical trials in Europe must familiarize themselves with the CTR’s requirements and prepare for the CTR transition to CTIS by adopting regulatory strategies, policies and roles and responsibilities that align with the CTR’s processes and requirements.

---

[1] See EMA Press Release, Regulatory harmonization of clinical trials in the EU: Clinical Trials Regulation to enter into application and new Clinical Trials Information System to be launched (January 25, 2022). Available at: Regulatory harmonisation of clinical trials in the EU: Clinical Trials Regulation to enter into application and new Clinical Trials Information System to be launched | European Medicines Agency (europa.eu).

[2] Clinical Trials – Regulation (EU) No 536/2014, art. 81, 1.

[3] See generally, id. at art. 81, 1.

[4] Id. at art. 81, 4.

[5] EMA Policy on Clinical Data Publication (0070), available at Clinical data publication | European Medicines Agency (europa.eu) (accessed June 9, 2022).

[6] Clinical Trials – Regulation (EU) No 536/2014, art. 5, 1.

[7] Id. at art. 6, 1(a)-(e).

[8] Id. at art. 7.

[9] Id. art. 5, 1.

[10] Id.

[11] See generally id. at art. 6 for responsibilities of the Reporting Member State.

[12] Id. at art. 4.

[13] Id. at art. 8, 3.

[14] Id. art. 8, 4.

[15] Id. at art. 6, 3.

[16] Id. at art. 8, 2.

[17] Id. at art. 8, 5.

[18] See generally id. at art. 8, 3-4.

[19] Id. at art. 5, 3.

[20] Id. at art. 6, 5(a).

[21] Id. at art. 6, 5(b).

[22] Id. at art. 6, 5(c).

[23] Id. at art. 6, 7.

[24] Id. at art. 8, 1.

[25] Id. at art. 7, 2.

[26] Id. at art. 6, 8.

[27] See id. at art. 6, 8 and art. 7, 3.

[28] See [DRAFT] Guidance document on how to approach the protection of personal data and commercially confidential information in documents uploaded and published in the Clinical Trial Information System (CTIS) (published April 7, 2022). Available at: https://www.ema.europa.eu/en/documents/other/draft-guidance-document-how-approach-protection-personal-data-commercially-confidential-information_en.pdf

 (accessed June 10, 2022).

[29] Id. at art. 81, 4.

[30] Id. at art. 36.

[31] Id. at art. 37.

[32] Id. at art. 52, 1.

[33] See EMA Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol (effective January 31, 2022). Available at: Guideline on reporting serious breaches (europa.eu) (accessed June 10, 2022).

[34] Id. at art. 37.

[35] Id. at Annex V.

[36] Id. at Annex 3, Section 2.4.

[37] Id. at art. 54.

[38] Id. at Annex 3, Section 3.

[39] Id. at Preamble, Paragraph 11.

Finis