Where did the EU Clinical Trial Regulation come from?
The EU Clinical Trial Regulation (EU-CTR) was approved in April 2014 and published in the Official Journal of the European Union on 27 May 2014. It entered into force on 16 June 2014 – but will apply no earlier than 28 May 2016.
The new legislation, once adopted, will take the form of a Regulation to ensure a greater level of harmonisation of the rules of conducting clinical trials throughout the EU.
What legislation does it replace?
It replaces the EU Clinical Trials Directive (EUCTD), which was approved in 2001 and implemented in May 2004. The EUCTD had approximation of the laws, regulations and administrative provisions of the member states relating to the principles of Good Clinical Practice (GCP) in the conduct of clinical trials on medicinal products for human use.
On 17 July 2012, following significant prior discussion, the European Commission published the draft EU Clinical Trial Regulation to repeal the Directive.
What were the problems with the old legislation?
It was criticised by companies, researchers and a range of stakeholders because of its disharmonised interpretation – as the EUCTD had been implemented differently in different member states – and because it increased associated costs, delays, and the administrative and regulatory burdens of doing clinical trials in different member states.
What will the advantages of the new regulation be for pharma companies?
The regulation will introduce and include a number of key provisions. There is an authorisation procedure for clinical trials based on a single submission dossier via a single EU portal, an assessment procedure leading to a single decision on all aspects per member state, rules on the protection of subjects and informed consent, and transparency requirements.
Other aspects include more detailed safety provisions, new indemnity provisions and a category for low interventional trials. The new regulation also intends to make it easier for pharma companies to conduct multinational clinical trials, which we believe would ultimately increase the number of studies conducted within the EU.
Does the new regulation address issues the ABPI has been lobbying for?
The new regulation, once adopted, will aim to ensure a greater level of harmonisation of the rules of conducting clinical trials throughout the EU. It has seven annexes which cover more detailed topics such as the content of the Clinical Trial Authorisation (CTA) dossier, Investigational Medicinal Product (IMP) labelling, and safety reporting.
There are also transparency requirements relating to the publishing of clinical trial results as well as the functionality of an EU portal and database to support companies in doing this. (The regulation says that information from clinical trial study reports should not be considered commercially confidential, thus removing any legal framework for pharma to not publish its data.)
The ABPI is committed to greater clinical trial transparency and we believe that clinical trial results should be posted by companies in publicly accessible registries and databases, and published in the scientific literature, in a timely manner.
The regulation makes certain stipulations about transparency – is the ABPI in favour of this?
The ABPI Code of Practice stipulates that current and future trials must be registered within 21 days of enrolling the first patient, and results must be published within one year of marketing authorisation, or one year from completion for marketed products.
In addition, all pharmaceutical companies must submit all relevant data to regulators as part of the approval process for new medicines. Follow up work is currently being undertaken for the disclosure monitoring of products approved by EMA in 2012.
The project will demonstrate progress in the area of clinical trial transparency and also help to prepare companies for the transparency requirements in the proposed new EU-CTR.
The regulation applies across the EU, but are there any special requirements that UK companies should be aware of?
In the UK, the Health Research Authority (HRA) is committed to transparency and has an interest in the conduct of research specifically for the consideration of registration, dissemination, publication, access to data, access to tissue and informing participants of the outcome of studies.
The HRA is also responsible for protecting and promoting the interests of patients and the public in health research seeking to improve public confidence in research in the UK. In doing this the HRA has set out to promote transparency with the following requirements:
• Registration of all clinical trials before the first participant is recruited. This is a condition of the Research Ethics Committee (REC) opinion, and failure to do so within six weeks of the first UK participant being recruited is a breach of the favourable ethical opinion – unless a notice to defer registration has been granted by the HRA.
• Sponsor declaration on a new application to a REC, to comply with duties of the sponsor including conduct of research and for sponsors to specifically declare that the HRA registration requirements have been met.
• From April 2015 there will be an extension of registration requirements to all trials in active recruitment in the UK.
The HRA has introduced a simple mechanism for deferral of registration where there are concerns of commercial confidentiality, based on assurances that the studies will be registered later and this is a deferral with a commitment to register later, not an exemption. But the need to maintain UK competitiveness has been recognised, in particular for the early-phase trials industry.
The HRA requirements are consistent with EU legislation for clinical trials of medicines in patients, and they extend the requirements for other clinical trials.
But the simple deferral option maintains UK competitiveness and also prepares the early trial community for the requirements that will be in the new EU regulation.
Has the ABPI responded to the EMA’s public consultation on the regulation? What were its recommendations?
The consultation was sent out to our members and networks for review, and feedback was through the European Federation of Pharmaceutical Industries and Associations EFPIA, who collated the response on behalf of industry.
The recommendations included comments on various aspects of the public consultation on application of transparency rules of EU-CTR.
On the proposed timeline for disclosure of Phase I information and results it was suggested that more deliberation and discussion is necessary regarding an acceptable mechanism and deferral period for release of Phase I trial summary results.
Under the alignment of EMA policies and processes, it was recommended for a statement to be prominently displayed, for example with search results and when downloading or printing data.
With regards to disclosing names of investigators listed in the Clinical Study Reports (CSR) at the time of posting, the response was that it is proposed that no personal information be made public on personnel identified in the CSR.
For the database functionality and decision making processes to be applied when invoking the use of ‘overriding public interest’, the suggestions was that it should allow for consultation prior to disclosure of commercially confidential information in order to ensure a balanced decision that takes into account any risk of loss of commercially confidential information.
Also, a process should to be implemented to streamline and make consistent CSRs submitted as part of the marketing authorisation applications process, as there will be duplication of submitting CSRs to the EMA over time.
Are there any downsides or potential problems with the new regulation?
The EU Portal and Database, which will act as both the single interface for Clinical Trial Authorisation dossier submission and their associated processes, and will be the single data repository for associated documents, will be developed by the EMA with the member states.
The full functionality will be verified via an independent audit and the European Commission will publicise its completion.
The EU-CTR will apply six months after, so any delay in developing the EU Portal and Database will delay the application of the EU-CTR.
What do companies have to do to gear up for the implementation of the regulation?
The best approach will depend on the company as there is no right way to implement a large piece of legislation like the EU-CTR. But there are some useful pointers on making as smooth a transition as possible which include developing an internal communication plan to keep staff informed at operational and senior levels in the EU and globally.
Raising awareness across the organisation could be a good way to start the implementation process.
The following points could also be useful ways in facilitating the process:
• Formation of a cross-functional team to develop a structure that keeps all affected functions informed of upcoming changes and engaged in discussions. This could also include operational teams performing initial impact analyses and subsequently proposing changes to company processes.
• Identify staff to engage externally as well as internally to make sure the latest information is available throughout the implementation phase.
• Monitor member state level implementation as each member state may need to adapt national systems to achieve a ‘single opinion’.
Dr Virginia Acha is the executive director of research and medical innovation at the ABPI