EU Clinical Trial Regulation: Investigational Medicinal Product Labeling

In this blog post, Gemma Puckey, senior manager of regulatory affairs, explains the impact of the European Union (EU) Clinical Trial Regulation (CTR) 536/2014, specifically Annex VI, on labeling of Investigational Medicinal Products (IMPs). Sponsors need to consider these new labeling requirements when developing clinical trial supply strategies ahead of the CTR’s application date, January 31, 2022.

Understanding the key changes

Following application of the EU CTR,¹ Annex VI will replace the currently applicable Annex 13.² Although both contain detailed requirements and guidance for the labelling of Investigational Medicinal Products (IMP), Annex VI is more restrictive:

• It introduces labelling requirements for Auxiliary Medicinal Products (AMPs). AMPs are defined by CTR as “medicinal products used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product.”
• In the case of blinded trials, there is a new requirement to ensure the name of both the substance and comparator or placebo appear on the label.
• It restricts the current option to omit information that is available by other means; for example, by use of a centralized electronic randomization system.
• There is a new requirement to include the expiry date on the inner packaging without exception.

The impact

The most significant change introduced by Annex VI, and that of most concern to the industry,^3,4 is the requirement for the expiry date to be included on both the primary and secondary packaging components. The omission of this date from any label is specifically prevented by paragraph nine of Annex VI.

Space on primary packaging components is often limited. Assuming there is space, adding the expiry date to the primary packaging during initial printing is achievable. However, for IMPs shipped in bulk, extending the expiry date as the clinical trial progresses and more stability data becomes available is more problematic:

• If full re-labeling and repackaging is necessary, the IMP would need to be reshipped to a central, appropriately authorized manufacturing site; extending the expiry date at site will no longer be an option.
• The secondary packaging component would need to be opened to apply an updated label, which could compromise the quality of the IMP, particularly those that require cold storage or protection from light.
• Tamper seals may need to be broken and completely replaced; this is of concern for seals that are critical to product stability and overall integrity of the IMP.
• There may be increased risk of error in blinded trials during the manual process of removing the primary package from a secondary container because IMPs are not distinguishable from one another.
• Expired IMP may need to be destroyed at site and compound remade, an expensive and time-consuming process. 

Considerations and potential solutions

To avoid these potential impacts, and in preparation for the CTR, we recommend sponsors consider the following when developing labelling and clinical trial supply strategies:

• Stability data: Amount of IMP available, and given the length and size of the trial, whether an update to the expiry date will be required.
• Cost: Extension of the expiry date by use of a central manufacturing site and intensified Qualified Person (QP) effort versus wastage cost if IMP is destroyed at site.
• Exploration of a new clinical trial supply strategy: For example, production of smaller but more frequent batches of primary packaging to avoid the need for expiry date extensions. (This would need to be part of a broader discussion, taking into consideration the complexities of the study design.)
• Change in packaging type: Use of a single packing component to remove the need to break a tamper-proof pack.
• Use of an alternative packaging campaign: Separation of supply between countries that require the expiry on the primary packaging as per their local legislation and those that do not.

Inevitably, there is still uncertainty surrounding the practicalities of implementing the requirements of the CTR, and the additional complexities imposed by Annex VI are no exception. While you may find it daunting to commit to significant changes to current labelling and clinical trial supply strategies, our recommendation is to prepare now. Our approach is to actively work with and on behalf of clients to implement the necessary strategies, so all are ready for the rapidly approaching CTR go-live date of January 31, 2022.