Compliance and Challenges in Global Clinical Trial Labelling

Clinical trial labelling represents a fundamental aspect of regulatory compliance, patient safety, and operational efficiency in global studies. The European Union (EU) has implemented comprehensive regulations, including Regulation EU No 536/2014 and the Detailed Commission Guideline of 8 December 2017, to standardize clinical trial processes across member states. This article explores the essential elements of compliance with these regulations and strategies to ensure efficient labelling processes in multinational studies.

Regulation EU No 536/2014: Overview and Key Labelling Requirements

The EU Clinical Trials Regulation (CTR) No 536/2014, effective from 31 January 2022, seeks to harmonize and streamline clinical trial approvals and supervision across the EU. The regulation enhances transparency, simplifies reporting requirements, and strengthens safety measures. Key labelling requirements under CTR No 536/2014 include:

• Harmonised Labelling: Consistent labelling standards across all EU member states.
• Legibility and Language Requirements: Labels must be clear, legible, and available in the national language of the participating countries.
• Essential Labelling Information: Includes the name and contact details of the sponsor, protocol number, unique trial subject identification code, storage conditions, relevant warnings, and expiry date.
• Multi-language Labelling Challenges: Trials spanning multiple EU countries must comply with language requirements for patient safety and regulatory acceptance.

Detailed Commission Guideline of 8 December 2017: Clarifications on Labelling Compliance

The Detailed Commission Guideline of 8 December 2017 offers further interpretation and clarifications on clinical trial labelling under the new regulation, providing guidance on aspects such as:

• Secondary Packaging and Relabelling: Flexibility in labelling for secondary packaging and the requirement for relabelling in case of expiry date extensions.
• Expiration Date Format and Placement: Standardised formats to avoid misinterpretation across different regulatory authorities, with clear placement of expiry dates on both the primary and secondary packaging.
• Labelling of Blinded and Unblinded Studies: Additional considerations for blinding integrity in double-blind trials and specific labelling instructions for open-label trials.
• Exemptions for Certain Trials: Labelling waivers for low-risk, non-interventional trials and reduced labelling requirements for auxiliary medicinal products (AMPs).

Country-Specific Requirements in Global Clinical Trials

While the EU has harmonized its approach, global clinical trials must also comply with additional country-specific regulations outside the EU. Each jurisdiction may have unique labelling, language, and packaging mandates. Key examples include:

• United States (FDA Requirements): Compliance with 21 CFR Part 312, mandatory inclusion of the IND number, specific warnings, and English as the primary language.
• China (NMPA Regulations): Chinese language translations, strict storage conditions, and the use of QR codes and electronic tracking systems.
• Japan (PMDA Requirements): Katakana script translations, explicit temperature control instructions, and shorter stability periods necessitating frequent relabelling.
• Latin America (ANVISA, COFEPRIS, INVIMA Regulations): Portuguese and Spanish translations, country-specific registration numbers, and potential ethics committee approvals for labelling modifications post-trial initiation.

Expiry Date Extension Requirements and Relabelling Strategies

Managing expiry date extensions efficiently presents a significant challenge in global clinical trial labelling. Regulatory bodies impose strict guidelines on handling expiry date changes to ensure participants receive only valid and effective medication. Key strategies include:

• EU Expiry Date Extension Compliance: The Detailed Commission Guideline of 8 December 2017 allows for Just-In-Time (JIT) labelling, regulatory notification vs. approval, and repackaging and re-inspection.
• Global Approaches to Expiry Date Extensions: Use of tamper-proof relabelling, regulatory pre-approvals, and considerations for cold chain products.

Best Practices for Global Clinical Trial Labelling Compliance

To ensure compliance with EU CTR No 536/2014, the Detailed Commission Guideline of 8 December 2017, and global country-specific regulations, sponsors should adopt several best practices:

• Use Centralised and Standardised Labelling Templates: Implement a universal labelling template that meets both EU and country-specific regulations while ensuring flexibility for regional adaptations.
• Plan for Expiry Date Extensions in Advance: Use stability studies to predict and justify expiry date extensions and implement Just-in-Time (JIT) labelling to reduce relabelling needs.
• Ensure Cross-Functional Coordination: Regulatory teams must collaborate closely with supply chain, packaging, and quality assurance to stay updated on evolving regulations.
• Use Multi-Language Labelling Software and Booklet labels: Automate translations and regulatory compliance checks, and use booklet labels to provide compliance for all countries grouped by languages.

Global clinical trial labelling is a complex yet crucial component of regulatory compliance. Ensuring adherence to EU Regulation No 536/2014, the Detailed Commission Guideline of 8 December 2017, and country-specific requirements demands meticulous planning, standardized processes, and technological advancements. By leveraging digital labelling, Just-in-Time strategies, and robust compliance frameworks, sponsors can optimize clinical trial labelling while maintaining global regulatory adherence.

Future advancements in e-labelling and AI-driven compliance monitoring are expected to further streamline labelling processes, enhancing efficiency and patient safety in global studies.