Regulating Clinical Trials

Pharmaceutical Technology, Pharmaceutical Technology, April 2022, Volume 46, Issue 4

In January 2022, Europe started to implement EU-CTR, a new regulatory framework for clinical trials, but what does this mean for pharma clinical research?

On 31 Jan. 2022, the European Union (EU) initiated the three-year transition for member states to submit clinical trials under a new legal framework Clinical Trial Regulation 536/2014 (EU‑CTR) which replaces Clinical Trial Directive 2001/20/EC (EU-CTD) while increasing transparency and harmonizes the submission, assessment, and supervision processes for clinical trials in the EU (1,2). Between now and 31 Jan. 2023, sponsors can submit clinical trials under EU-CTD or EU-CTR; thereafter, all trial applications will be subject to EU-CTR (3).

Key differences between EU-CTR and EU-CTD

The EU-CTR aims to provide a more transparent and streamlined process whereby each multinational application will be required to submit a single National Competent Authority (NCA) or Ethics Committee (EC) per member state to run a clinical trial in several EU countries (Table I). This means that the sponsors’ regulatory team needs to collaborate with contract research organization (CRO) early to determine the roles and responsibilities of each party and carefully select the most appropriate reporting state as they will be responsible for coordinating the assessment throughout the trials’ lifecycle. The success of a clinical trial application is highly dependent on the quality of the submission and if a reporting member state refuses the Part I scientific/technical application, it is refused for all member states.

The Clinical Trial Information System (CTIS) replaces EudraCT enabling sponsors to centralize their electronic submission and allows for greater transparency and sharing of data throughout the development process. All communication is via the CTIS and all requests for information must be answered within 12 calendar days or the application lapses. Therefore, sponsor regulatory teams will need to monitor and coordinate responses to CTIS communications and synchronize activities for lifecycle planning because ongoing assessment in one member state prevents further substantial modifications to part I and/or II for all member states (4).

As with the implementation of any new information management system, sponsors may need to upgrade their IT infrastructure to make sure they are fully operational and to train and support staff, to ensure they are familiar with the CTIS interface and have assigned roles for application submissions and safety reporting (3).

Like the EU-CTD, the new EU-CTR are limited to interventional clinical trials; nevertheless, several new definitions have been included such as “low intervention clinical trials” to differentiate studies that pose minimal patient risk. Thus, sponsors of low interventional clinical trials can adopt a risk-based approach and may be required to submit Summary of Product Characteristics (SmPC) (5) rather than an Investigational Medical Product (IMP) Dossier (6) and face less stringent rules on monitoring, the release of the IMP (7,8), and content included within the Trial Master File (TMP) (9).

The EU-CTR has updated the definition of a legally designated representative (LDR) to include “a natural or legal person, authority, or body which according to member state law is empowered to give informed consent on behalf of the subject who is incapacitated or a minor.” In addition, substantial changes have been made to provisions for informed consent and detailed guidance is provided for:

  • broad consent
  • simplified consent for cluster trials
  • consent for minors or incapacitated people
  • consent for pregnant or breastfeeding women
  • consent for other vulnerable populations
  • consent during trials in emergency settings (3).

Implications for the UK

EU-CTR do not apply to the United Kingdom (UK) since Brexit. Prior to their implementation in January 2022 the UK launched a public consultation. The UK Government has presented a series of proposals that provide a more modern and flexible approach than the EU-CTR (10). The UK consultation closed on 14 March 2022. Proposed legislative changes aim to update and strengthen the current clinical trial legislation to:

  • Promote public health and ensure protection of participants remains at the heart of legislation
  • Remove obstacles to innovation, whilst maintaining robust oversight of the safety of trials
  • Streamline the regulation of clinical trials and reduce unnecessary burden to those running trials by embedding risk proportionality into the framework
  • Facilitate the evaluation and development of new or better medicines to reduce the burden of disease on patients and society
  • Ensure the legislation builds international interoperability so that the UK remains a preferred site to conduct multi-national trials (10).

Future outlook

The new EU-CTR aims to address many of the limitations incurred with the EU-CTD, helping to streamline clinical trial applications, processing while improving transparency and securing the EUs competitiveness within the clinical trial arena. As the EU-CTR will be phased in over the next three-years, sponsors will need to determine the best route of adoption and ensure their regulatory teams have put in place operational procedures, IT management systems, and training and support, to enable them to conduct clinical trials and provide request for information (RFI) via CTIS in a timely manner.

Whilst the UK lags the EU in terms of its clinical trial regulations, it will have the opportunity to watch and learn from the roll out of EU-CDT and ensure that the new UK legislation provides a flexible, streamlined approach to clinical trial applications. Increased transparency, participant protection and broadening opportunities for greater risk stratification and diversity should enable the UK to compete within the global clinical trial arena and enable them to remain a leading global centre in research design, and delivery across all types and phases of clinical trials alongside their EU counterparts.

References

1. EMA, “Regulatory Harmonization of Clinical Trials in the EU: Clinical Trials Regulation to Enter into Application and New Clinical Trials Information System to be Launched,” Press Release, 25 Jan. 2022.
2. EC, Clinical trials—Directive 2001/20/EC, Public Health Directive, ec.europa.eu [Accessed 28 March 2022].
3. K. Bonnarens, “Clinical Trial Regulation 536/2014 Objectives, Key Changes, and Transitional Arrangements,” Presentation, ec.europa.eu (January 2022).
4. A. Khera and S. Bly, “Understanding the new EU Clinical Trial Regulation,” Article, European Pharmaceutical Review, 28 Jan. 2022.
5. R. Pankow, et al., “EU Clinical Trial Regulation: Get Ready, Set, Go!” Article, Global Forum (January 2021).
6. EMA, Summary of Product Characteristics, Glossary, ema.europa.eu [Accessed 28 March 2022].
7. European Investigational Medicinal Product Dossiers, Investigational Medicinal Product Dossier—IMPD Guidance, Guidance Document, IMP-dossier.eu [Accessed 28 March 2022].
8. EMA, Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials, Guidance Document, ema.europa.eu (September 2018).
9. EMA, Guideline on the Content, Management, and Archiving of the Clinical Trial Master File (Paper and/or Electronic), Guidance Document, ema.europa.eu (December 2018).
10. UK Government, Consultation on Proposals for Legislative Changes for Clinical Trials, Guidance, gov.uk (January 2022).

About the author

Cheryl Barton is director of PharmaVision, info@pharmavision.co.uk.

Article details

Pharmaceutical Technology Europe
Vol. 34, No. 4
April 2022
Pages: 7–8

Citation

When referring to this article, please cite it as C. Barton, “Regulating Clinical Trials,” Pharmaceutical Technology Europe 34 (4) 2022.