New packaging solutions for life sciences, all at PACK EXPO in Chicago
Discover new packaging solutions from hundreds of suppliers specializing in life sciences, all under one roof at PACK EXPO International in Chicago.

Manage Challenges from the EU 536/2014 Clinical Trials Regulation

Plan ahead for study startup timelines, expiry labeling on primary packaging solutions, and study administration methods.

Regulation EU No 536/2014 on clinical trials will come many changes that will impact study startup processes and timelines, expiry labeling on primary and secondary packaging, and study administration methods such as direct-to-patient.
Regulation EU No 536/2014 on clinical trials will come many changes that will impact study startup processes and timelines, expiry labeling on primary and secondary packaging, and study administration methods such as direct-to-patient.

Regulation EU No 536/2014 on clinical trials—a binding legislative act for each member state, overruling national law—came into force on January 31, 2022, to simplify clinical trial preparation and activation. With it will come many changes that will impact study startup processes and timelines, expiry labeling on primary and secondary packaging, and study administration methods such as direct-to-patient.

An XTalks webinar panel discussion, “How to Avoid Significant Delays in Multi-Country Studies Due to EU 536/2014 Clinical Trial Regulation,” made note that before the regulation, most tasks required to start enrolling patients could largely be planned and managed independently, with minimal coordination between study, country, and site project managers. This previous method put the focus on the first country and site approved, knowing additional activities would follow, which made for decentralized, unsophisticated planning and management. The regulation, however, represents a paradigm shift to last country and site ready, with any missing content required for the study, country, or site approval delaying all countries and sites. This can significantly impact study timelines.

Listen to article   unPACKED with Packaging World Podcast: Did 2020 Change Packaging Forever?

Elvin Thalund, director, industry strategy, Oracle Health Sciences explained in the webinar that the previous study startup dynamic, at least as far as it concerns European countries and sites, required clinical sponsors to contact potentially over a hundred different regulatory agencies to get the study up and running, whereas the new setup will require only one or two submissions through the clinical trials information system (CTIS).

Though this simplifies one aspect of study startup and won’t allow each member state to enact its own laws and interpretations of directives, creating specific challenges for clinical sponsors as done previously, it does require more time before clients can begin enrollment. Where the previous method took six to eight and a half months, the new method will take eight to 11 months to identify sites, select sites based on feasibility and need, and activate them. This is because the new EU regulation will not allow the selection process and activation process to run in parallel.

Instead, the new regulation splits the submission process into two parts:

  • Part 1: the reporting country, which is an EU regulatory submission, requiring submission of study material and product material
  • Part 2: the member states concerned, which is a country regulatory submission, country IRB or IEC submission that requires submission of recruitment material, patient material, principal investigator, facility information, indemnity, and localized study material

The critical elements, as noted by Thalund, are first the product, study, and localized study material; and then the principal investigator and facility information. As a regulation, the timeline is inflexible and fixed and aligned across all member states, causing clinical sponsors to adapt in order to operate within the framework.

As a regulation, the timeline is inflexible and fixed and aligned across all member states, causing clinical sponsors to adapt in order to operate within the framework.As a regulation, the timeline is inflexible and fixed and aligned across all member states, causing clinical sponsors to adapt in order to operate within the framework.If the timelines are not met by the clinical sponsor, then the submission lapses and delays and can even require a restart. So if Part 1 timeline is missed, it affects the whole trial timeline, and if a Part 2 timeline is missed, it only affects the country of that particular submission. Though if that country is critical for the study, it obviously will affect the entire study.

Other important factors that can affect study timeline are the individual member states’ final decisions as each can reject Part 1 and Part 2 decisions, and substantial modifications, which must be submitted after the initial Part 1 submission is complete. The regulation does not allow for partial approvals as well.

Pierre Omnes, executive director, site start up and regulatory, Syneos Health, explained that individual Part 2 applications can be submitted at different times based on the amount of information available for the desired sites after the conclusion of the Part 1 acceptance. He cautioned to include as many countries in Part 1 as you think will be useful first as you don’t need to wait for the decisions to be granted in all countries to submit Part 2 applications, as long as they were included in Part 1. To include a country not listed in Part 1, you must follow the additional member state procedure, which has different criteria.

Regulations and packaging considerations with expiry labels

In the first part of a webinar series, “The Evolution of Clinical Trial Packaging,” put on by Essentra Packaging—a global manufacturer of cartons, leaflets, and labels that specializes in the pharmaceutical industry, as well as  beauty and personal care—called “The Implications on Clinical Trials Labeling Due to Annex VI Changes and Patientricity,” changes, issues, and possible solutions for Annex VI expiry labeling were discussed.

When the EU 536/2014 Clinical Trial Regulation was born, Annex VI had an unintended effect on expiry labels which presents various challenges to sponsors. Annex VI chapter nine stipulates that the expiration date is required to be printed on the label.

Joe Monteiro, technical account manager, clinical trials, Essentra Packaging, listed in the webinar a number of challenges that this poses for sponsors:Joe Monteiro, technical account manager, clinical trials, Essentra Packaging, listed in the webinar a number of challenges that this poses for sponsors.Joe Monteiro, technical account manager, clinical trials, Essentra Packaging, listed in the webinar a number of challenges that this poses for sponsors.

  • Increased cost of rework, especially around kits, which have multiple primary containers per kit, each required to have an updated expiry label
  • Purchase of new labels for relabeling, which must be performed in a controlled GMP-compliant environment under quality QP release—this also brings depos under careful consideration concerning site capability
  • Added cost of releasing supplies
  • Potential for labels on the outer pack being broken during relabeling, increasing risk of damaged packs
  • Biological drugs taken out of cold storage for pack labeling, which increases the risk of damage to the drug
  • Careful selection of label materials and adhesives for cold temperature applications
  • Consideration of space available on small primary containers, such as syringes and vials—consider future proofing the design for relabeling
  • Potential for added waste and delays to the additional packaging requirements that Annex VI may present
Explore new technology from hundreds of life sciences suppliers.
At PACK EXPO International, you’ll find innovations from hundreds of exhibitors that specialize in pharmaceuticals, biologics, nutraceuticals, medical devices and more. No other show delivers as many solutions to keep your products safe and effective.
Read More
Explore new technology from hundreds of life sciences suppliers.