In an effort to harmonize the clinical study drug supply labeling requirements, Chapter X of the Regulation provides rules for clinical labeling.  Further, to fill perceived gaps in individual member state requirements, annex VI was added to the regulation with additional detail about clinical labeling requirements.

EU Regulation No. 536/2014 Annex VI defines the clinical labeling requirements for both investigational medicinal products (IMPs) and auxiliary medicinal products (AMPs) and the labeling requirements differ for each.  Further, the clinical labeling requirements vary based on the medicinal products regulatory commercial approval status.  Specifically, medicinal products authorized by government ministries of health for commercial sales have medicinal product labeling rules that differ from those that are not authorized for commercial sale.

Because the definitions of investigational products, auxiliary products and authorized products have implications to their respective labeling requirements, the Regulation’s definitions are shown below in table 1.

Table 1
Investigational medicinal products A medicinal product which is being tested, or used as a reference, including as a placebo, in a clinical trial.
Auxiliary medicinal product A medicinal product used for the needs of a clinical trial as described in the protocol, but not as an investigational medicinal product, such as background treatment, challenge agents, rescue medication, or used to assess end-points in a clinical trial.
Authorised IMP or AMP A medicinal product authorized in accordance with regulation (EC) N°726/2004 or Dir 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an IMP or an AMP.

Note: Auxiliary medicinal products should not include concomitant medications, that is medications unrelated to the clinical trial and not relevant for the design of the clinical trial. (CTR (whereas 54)).

The Regulation states that IMP and AMP should be appropriately labelled to ensure; subject safety, reliability and robustness of data, and allow the distribution to clinical sites. To deliver on this remit, the Regulation specifies rules for clinical labeling in both article 66 and annex VI of the regulation. The advantages of harmonizing medicinal product labeling regulations across EU member states are intuitively obvious.

Along with the advantage of standardized label content, another advantage of the Regulation is that it provides clarity around the clinical labeling requirements for authorized AMPs. In the case of authorized AMPs, no additional labeling is required as long as the authorized AMPs commercial label is compliant with Title V of Directive 2001/83/EC. Said another way, authorized AMPs that are dispensed to patients in their commercial presentation inclusive of the commercial EU member state label do not require ancillary labeling with any additional clinical trial information.

There is no specific requirement in article 67 of the Regulation that authorized IMPs contain labeling other that than the EU member states commercial label. However, the Regulation states that specific circumstances provided for in the protocol may require additional information to ensure subject safety or data robustness. The Regulation lacks a definition of these circumstances nor does it provide examples, and therefore, trial sponsors are left to make their own interpretation. With that being said, based on the type of information that must be on the label in these “specific circumstances”, the reader can infer that the regulation is referring to studies in which the patients are leaving the clinical setting with the authorized IMP. Table 2 lists the information that must be on the authorized IMP label in these special circumstances.

Table 2
Name of the main contact
Clinical trial reference code allowing identification of the clinical trial site, investigator, sponsor and subject
‘For clinical trial use only’ or similar wording

For Unauthorized IMP and AMP, article 66 states in general terms that the following information shall appear on the label:

  • Information to identify contacts persons for the trial
  • Information to identify the trial
  • Information to identify the medicinal product
  • Information about the use of the medicinal product

The Annex VI (LABELING OF INVESTIGATIONAL MEDICINAL PRODUCTS AND AUXILIARY MEDICINAL PRODUCTS) provides a much more specific list of required label content. Table 3 provides a summary each section in Annex VI and readers are encouraged to review the actual Annex VI to better understand the details.

Table 3
UNAUTHORIZED INVESTIGATIONAL MPs General rules, listing all the particulars that shall appear on the immediate and also on the outer packaging.

Limited labeling of immediate packaging

  • Immediate and outer packaging provided together. This chapter lists the particulars that should be on the label of the immediate container when the outer container is labeled according to a.
  • Small immediate packaging. This section describes the minimum labeling requirements for a small container where all requirements of chapter A cannot fit.
UNAUTHORIZED AUXILIARY MPs Section listing all the particulars that shall appear on the immediate and also on the outer container of “auxiliary” MPs
ADDITIONAL LABELING FOR AUTHORIZED IMPs This section describes the minimum requirements for “approved” products used in clinical trials.
REPLACING OF INFORMATION In this section are listed the particulars that (in the different cases above mentioned) could be omitted if made available by other means, like a centralized information system, assuming do not affect the safety of subjects enrolled and the robustness of data of the clinical study.

Notwithstanding the above, additional mandatory information that cannot be omitted is listed below:

  • Route of administration
  • Batch or code number
  • Subject ID number (except for Auxiliary MP)
  • Period of use

In general terms, the new Regulation seems can be perceived as more restrictive then current Vol.4 Annex 13 requirements; for example, the provisions for clinical labeling of the period of use to the immediate packaging have been expanded and, in addition, the use of a centralized electronic information system has been eliminated in this context.

First of all, the definition of the “period of use” is limited to the “expiry date” or “re-test date” and
does not include the “use by date” any more.

Clinical labeling requirements for the “period of use” do not only apply to the outer (secondary) packaging but also apply to the immediate (primary) packaging.. This aspect could have a high level impact: this way we can foresee that periodic updates of the “period of use”, commonly applied in the course of a clinical study when new stability data becomes available, will be much more complex because they won’t be limited to the outer packaging. In addition, it will increase the risks for mix-ups of products when these operations are performed at clinical sites; in many cases a single outer container contains multiple primary packs and the outer packaging needs to be opened to taken out the inner containers to be relabeled.

According to the new Regulations the required elements for the “period of use” cannot be made available any more through a centralized electronic information system. (annex VI, D) In accordance to current “Annex 13” provisions, for many trials, the “Retest/Expiry date” has been successfully omitted even on the outer package, because it could be controlled more safely by an electronic information system, namely the IRT (Interactive Response Technology alias IVRS/IWRS).

By:  Massimo Eli, Clinical Supply Chain Regional Lead for Europe at Merck/MSD
Massimo has a degree in Pharmaceutical Chemistry and Technology and postgraduate diplomas in Toxicology and in Industrial Pharmacy.

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Ted Bradley (Pfizer) – IP COP Task Team Contributor.
Hans von Steiger (Pfizer) – Regulation Introduction Author
Magali Busqet (Sanofi) – IP COP Task Team Contributor
Massimo Eli (Merck) – IP COP Task Team Contributor
Chuck Gentile (Sanofi) – IP COP Task Team Contributor
Juliette Kirk (Pfizer) – IP COP Regulatory Consult
Kirsteen Magee (Mylan) – IP COP Task Team Contributor
Marianne Oth (Eli Lilly) – IP COP Task Team Contributor
Martin Waldherr (Roche) – IP COP Task Team Contributor