EU CTR 536/2014: Key Considerations For CROs And Sponsors
By Rainer Porrmann, PhD, head, clinical trial regulatory management—Western and Central Europe, Accovion GmbH
Since the implementation of EU Directive 2001/20/EC more than 10 years ago, the clinical research community in Europe has discussed potential improvements on those rules. Based on the recognition that the system might have hampered clinical research, the European Parliament and Commission published Regulation 536/2014 in April 2014, which contains significant changes in regards to the application process, definitions, responsibilities, reporting during and after the trial, and clinical trial disclosure.
The Regulation will become applicable no earlier than May 28, 2016, meaning that CROs and sponsors should prepare now to make sure they are ready for all the upcoming changes. Below are a few key considerations to be aware of before the Regulation goes into effect.
Submission Through The Single Portal System And Updated Timelines
Sponsors must submit a single clinical trial application through the new EU Clinical Trial Portal and Database, regardless of the number of states in which the clinical trial will take place. According to the European Commission, the Portal and Database were created in order to “facilitate the application for clinical trials authorization, in particular in case of multinational clinical trials, to the sponsor; the assessment carried out by the Member states authorities; [and] access to clinical trials information by the general public.” The use of the portal will require dedicated staff trained on the system who are provided with access rights.
However, with this new single portal system comes new, shorter timelines. One important timeline to consider is the maximum of 12 days in which you can answer questions from authorities and committees; previously sponsors had up to 90 days. If you fail to provide satisfactory answers to these questions, your application will be rejected.
One way to prepare for these shorter timelines is to take advantage of pre-submission guidance offered by some regulatory authorities. Additionally, sponsors should make relevant employees and involved departments aware of the timelines and submission dates so that they are prepared to answer questions (which might also require updates of SOPs). Finally, sponsors should plan their trial submission dates around holidays to ensure that there will be enough resources available to answer authority questions.
Two-Part Assessment Procedure For Clinical Trial Applications
The new assessment procedure for clinical trial applications is divided into two parts: Part I and Part II. While Part I is assessed by all relevant Member States together, Part II is assessed by each relevant Member State separately. Unlike Part I, Part II takes local aspects of the clinical trial into account. Sponsors can choose to do the Part I assessment first and leave out the Part II assessment initially; the Part II assessment may be completed up to two years later.
Sponsors should consider whether or not the strategy of delaying the Part II assessment makes sense for them. While currently the whole process is typically driven from the clinical department, this change means that the regulatory department should be involved earlier on in the process in order to advise on regulatory strategy.
Opportunity For Co-Sponsorship
This new Regulation offers the possibility of co-sponsorship for a clinical trial. The Regulation specifies that “all sponsors shall have the responsibilities of a sponsor set out in this Regulation, unless the sponsors decide otherwise in a written contract setting out their respective responsibilities.”
Companies who plan to do this should review the section of the Regulation explaining the details, how responsibilities can be split between different parties, and how it should be documented. For example, one sponsor could be responsible for obligations for authorization procedures, while the other sponsor could be a contact point for questions from subjects, investigators, or any CMS, etc.
Definition Of Auxiliary Medicinal Products (AMPs)
The Regulation also provides a definition and more information for auxiliary medicinal products, which are products used for the means of a clinical trial as described in the protocol, but not as an investigational medicinal product, “such as medicinal products used for background treatment, challenge agents, rescue medication, or used to assess end-points in a clinical trial.” Previously, these products were referred to as “non-IMPs” in the Guidance on Investigational Medicinal Products (IMPs) and other medicinal products used in Clinical Trials. Thanks to EU CTR 536/2014, AMPs are covered by law as opposed to just being regulated by a guideline.
If sponsors and CROs are planning on using an AMP in their clinical trials, they should read through the Regulation carefully to ensure that the planned AMP fulfills all the requirements. For example, the Regulation details what kinds of medication can be AMPs, how they should be labeled, where they should be sourced from, etc.
Definition Of Low-Intervention Clinical Trials
Included in the Regulation is a definition of a low-intervention clinical trial, in which authorized products (excluding placebos) are used and no more than a minimal additional risk as compared to normal clinical practice is presented by additional procedures (for example, a trial comparing two authorized medicines). While these low-intervention clinical trials will be subject to the same application procedure as other clinical trials, they will be subject to less stringent rules in regards to “monitoring requirements for the contents of the master file and traceability of investigational medicinal products, as well as the need for a study insurance.”
Now that EU CTR 536/2014 has specified a legal definition of low-intervention clinical trials, sponsors should consider whether their trials can fulfill the Regulation definition, as the lower regulatory obligations for such trials can be beneficial to them.
EU CTR 536/2014 has created a complete change of the system from EU Directive 2001/20/EC. Many functions within the clinical trial landscape will be affected by the changes, so it’s important that companies are trained and prepared for these changes early on. Be sure to read through the Regulation carefully, keeping these particular changes in mind, so that you are ready for the updates come May 2016 at the earliest.
About The Author
Dr phil. nat. Rainer Porrmann studied biology at the University of Frankfurt/Main, Germany and finished his PhD in cell and neurobiology in 1998. He started his career in clinical research in 1999 as a clinical monitor in oncology until he joined Accovion in 2003 as a data and study coordinator. Since 2006, he has focused on the regulatory management of clinical trials. He was involved in the establishment of clinical trial application processes and building up and leading a group of experts in this area. Since 2013, he has headed the department of Clinical Trial Regulatory Management, which belongs to the Clinical Operations group at Accovion – A Clinipace Worldwide Company.