EU Clinical Trail Regulation: Annex VI Period of Using Labeling Requirements
Guidance from ISPE's Investigational Medicinal Products Community of Practice
Introduced on 16 April 2014, the European Union clinical trial regulation No. 536/20141–2 is expected to be implemented by October 2018.1,2 One of its most significant changes is found in Annex VI, which covers the labeling requirements for authorized and unauthorized investigational medicinal products (IMPs) and auxiliary medicinal products used in EU clinical trials.
In general, the new requirements are more restrictive than those of the still-applicable Volume 4, Annex 13 guidelines on good manufacturing practice.3 One of the most important changes—and the focus of this article—is that the regulation will no longer permit the period of use to be omitted from the immediate packaging under defined circumstances (immediate and outer packaging provided together and/or small immediate packaging).
In addition to industry concerns for patient safety and study validity,4,5 this change will create serious technical challenges for pharmaceutical companies when it comes to IMP packaging—particularly retest date extension labeling operations. When an IMP’s retest date is extended based on new stability data, all patient kits containing this IMP must be given an additional label showing the new retest date as well as a unique identifier (e.g., study number). In this article we describe this process as “retest date extensions.”
The main concern is that the retest date must be printed on the immediate packaging label; as a result, patient kits will have to be opened during retest date extension labeling. This change has the following major negative implications:
- Efficacy and quality: IMP storage conditions (e.g., cold storage, protection from light) may be compromised if the outer container is opened for retest extension labeling.
- Risk of error/tamper evidence: Retest date extensions on the inner container in blinded trials create a severe risk of error, since blinded treatments cannot be differentiated. Tamper-evidence seals would also need to be broken for extensions on the inner container. As a result, patients would either receive medication with broken tamper seals or the outer packaging would have to be replaced completely to reestablish an unbroken tamper seal.
- Legibility: Space on immediate containers is often very limited. Adding retest date labels may alter the legibility of the original label as well as other important information mandated by Annex VI.
- Waste and environmental impact: Small immediate containers like ampoules or injection devices (e.g., prefilled syringes) may not provide enough space for retest date extension labels. In these cases, clinical trial materials might have to be discarded rather than extended, increasing waste and environmental impact.
- Supply continuity: Additional labeling of the immediate container will increase retest date extension processing time and might generate the necessity for additional transportation (e.g., to avoid impact to storage conditions during labeling operations). This could delay clinical trial execution or even extend the trial duration and thus affect market authorization application timelines.
- Cost: In addition to increasing material overage (and waste), retest labeling of the immediate container will also directly increase costs associated with labeling operations. All depots and sites within the clinical supply chain will have to be paid for the additional effort of labeling the immediate container during extension operations.
For a more detailed description of these concerns and an example of the advocacy efforts in this space, please refer to the EFPIA position paper.4
Another potential concern is a restriction on the use of interactive response technologies (IRTs). The extent to which these technologies can be used for supply management in clinical trials will be severely limited. Omitting the retest date from labels managed by an IRT will no longer be allowed under the new regulation. The industry considers this a retrograde and innovation-inhibiting step that will limit the flexibility of managing a clinical trial.
The current understanding is the regulation would not be amended prior to implementation, but there is some hope that Annex VI could be influenced post-EU implementation.
In the following bullet points, we want to discuss some potential options on how to deal with the new requirements in Annex VI around labeling and also make readers aware of some potential pitfalls when adjusting their clinical supply chains.
- For packaging of solid dosage forms, it is possible to avoid printing and extension of the period of use on the immediate and outer container by avoiding multiple levels of packaging. This can be achieved by using (for example) high-density polyethylene bottles or blister cards. In both cases, no second level of packaging is needed, thus making extension operations a lot safer, regardless of the location of the medication within the supply chain (depots, sites, etc.).
- Consider avoiding tamper-evidence seals on multilevel patient kits, as they would have to be broken to allow retest date extensions on the immediate container. This means that either patients would receive kits with broken seals or the outer packaging would have to be resealed or even replaced completely. As tamper-evidence seals are an important indicator for patient kit integrity, the risks and benefits of such a decision should be considered carefully.
- Very small vials and ampoules have a limited area in which to place retest date extension labels. Flag labels could provide the additional space needed; this technology is already well established.
- Retest date extensions can become risky in blinded trials. Every immediate container at every site or depot in the trial will have to be removed from its outer packaging, creating a high risk of errors (mix-up of study medication). One possibility to mitigate this risk would be to add a unique identifier on all immediate and outer packaging. This could be the blinded container number, a randomization number, an RFID tag, or a 3D matrix on both the inner and outer packaging. This would help limit the possibility of mix-ups when applying the retest date extension label.
Why try to “control” contamination? why not just eliminate it? This change will create serious technical challenges for pharmaceutical companies when it comes to imp packaging—particularly retest date extension labeling operation.
To avoid the abovementioned issues, we also want to discuss some potential options for dealing with the new Annex VI labeling requirements. Several are being discussed in the pharmaceutical industry:
- Limit the size of packaging campaigns and hold stock levels in the supply chain to a level that will avoid the need for retest date extensions. Alternatively, packaging campaigns could be separated between EU (with retest date on the immediate container) and non-EU (without retest date on the immediate container) supplies. Because both of these options would require more packaging campaigns and very good stock monitoring, study costs would undoubtedly increase.
- In some cases, packaging design could be adjusted to simplify the retest date relabeling operations for immediate containers (e.g., pack one vial per kit instead of four). This would also add complexity and increase workload on stock level management.
- Print the period of use on the immediate and outer container during initial packaging, but limit extensions to the outer packaging. This would need to be stated clearly on the immediate packaging label as well as in the study protocol. There is currently no guidance to indicate whether such an approach would be accepted by EU authorities.
- Labeling of secondary packaging and patient kits only occurs after a request for medication is received from a clinical site. This “just-in-time labeling” would very likely be done at regional packaging sites to avoid long transportation lead times, and would require a harmonized quality control system and trained staff at the regional/local packaging sites and/or regional/local depots.
- Electronic replacement labels might, in the future, eliminate the need for physical retest date extensions. While there have been some promising developments in the field and industry working groups are exploring this new technology, eLabels have not yet gained regulatory approval. Because current regulations state that the retest date must appear on each label in manner that avoids any ambiguity, it is not clear if eLabels will be accepted by EU authorities.
In summary, several modifications to current practice can be considered in preparation for the implementation of Annex VI of the EU clinical trial regulation. The strategies suggested here will need to be discussed and agreed by organizations wanting to conduct or support clinical trials in the EU.
- 1. EUR-Lex. Document 32014R0536. “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://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=uriserv%3AOJ.L_.2014.158.01.0001.01.ENG
- 2. International Society for Pharmaceutical Engineering. iSPEAK blog. “Introduction to EU Clinical Trial Regulation No. 536/2014.” 9 March 2016. https://ispe.org/pharmaceutical-engineering/ispeak/introduction-eu-clinical-trial-regulation-no-5362014
- 3. European Commission. Enterprise and Industry Directorate-General. EudraLex, Volume 4, Annex 13: “Investigational Medicinal Products.” 3 February 2010. http://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2009_06_annex13.pdf
- 4. a. b. European Federation of Pharmaceutical Industries and Associations. EFPIA Position Paper EU Clinical Trial Regulation Annex VI: Labelling of Investigational Medicinal Products and Auxiliary Medicinal Products—Impact on Patient Safety and Validity of Study Data. 20 October 2014. http://www.efpia.eu/documents/127/48/EFPIA-position-paper-EU-Clinical-Trial-Regulation-Annex-VI-Labelling-of-investigational-medicinal-products-and-auxiliarymedicinal-products-Impact-on-patient-safety-and-validity-of-study-data
- 5. ———. “Re-Test or Expiry Date Labelling in Clinical Trials.” YouTube video. 16 October 2014.https://www.youtube.com/watch?v=5bPZb_Ezg1Y.