The implementation of the EU Clinical Trials Regulation, which governs how clinical trials in the EU are run, means there is now a risk that commercially confidential information might be made accessible to the public, even at early stages of the trial. While unwanted disclosure may be preventable in some cases, the onus will be on trial sponsors to request that publication is deferred or waived. We take a look at what this could mean for future patent filings, and summarise the key points that sponsors should keep in mind when conducting clinical trials in the EU.
The new EU Clinical Trials Regulation (“EU-CTR”) came into effect on 31st January 2022, replacing the previous EU Clinical Trials Directive (“EU-CTD”). This new regulation harmonises the clinical trials process in all EU Member States and introduces wide-ranging changes to the way that trials will now be run. The EU-CTR rules will apply to all new clinical trial applications from 31st January 2023, and, from 31st January 2025, all ongoing and new clinical trials conducted in the EU will be subject to the EU-CTR rules.
Clinical trials are, by their nature, conducted in public, and information about them is made publicly accessible in most countries around the world. It is common for disclosures regarding a clinical trial to be cited in proceedings before patent offices and national courts, and often documents regarding an applicant’s own trials are cited against their cases. In Europe this has led to the development of a body of case law that can cause headaches for applicants who have unwittingly disclosed too much to the public ahead of filing new patent applications.
The EU-CTR is changing both the amount of information that is available to the public and the time at which it can be made available. This article focuses on the implications of this new regulation for patent filing strategies and highlights some key points that applicants should be aware of when conducting clinical trials in Europe.
What is changing?
One of the explicit aims of the EU-CTR is to increase public transparency of the way clinical trials are run, including making more information available on what is being tested and the outcomes of trials at every stage. Accordingly, a new publicly accessible database has been created (the Clinical Trials Information System – “CTIS”). Sponsors will upload all documents (e.g. trial protocols, details on the medical product under investigation (“IMP”) and summaries of data) to this database to make them accessible to the Competent Authority (or Authorities) of the Member State(s) in which the clinical trial is being run. The CTIS will be administered by the European Medicines Agency (“EMA”), and will gradually replace the existing EudraCT database.
By default, all documents submitted to the CTIS will also be made publicly available, with very few exceptions. This means that, among others, the following types of documents can be published: the clinical trial protocol, investigator brochures, summary of product characteristics (“SmPC”), assessment reports, summaries of trial results (both scientific summaries and layperson summaries must be provided), and any study modifications that are submitted throughout the lifetime of the trial. The onus will be on the trial sponsor to ensure patient confidentiality is maintained, and to ensure there are no breaches of data protection regulations.
Compared to the previous EU-CTD, much more information will be made available to the public under the new regulation, including information that would not previously have become available even after a trial has concluded. In particular, under the EU-CTD, clinical trial disclosures were much less detailed and often did not necessarily contain information on dosing, the drug or drugs under investigation (e.g. the mechanism of action and/or drug structure), and the overall level of disclosure was similar to that of clinical trials published on the FDA’s “clinicaltrials.gov” website.
In summary, applicants should be aware that very detailed and possibly confidential information has the potential to be publicly disclosed in the course of conducting new clinical trials under the EU-CTR.
When will the details of new clinical trials be published?
By default, all documents and data will be made public at the first opportunity.
There are some exceptions to the default rule to allow publication of certain documents to be waived or deferred. Crucially, if confidentiality is justified under the ground of protecting commercially confidential information, the requirement for publication may be waived or deferred. However, even in this situation, immediate publication will still occur if it is held that there is an overriding public interest in disclosure. Commercially confidential information is expected to potentially include anything that is not in the public domain, if its disclosure may undermine the legitimate economic interest of the sponsor.
Deferred publication must be proactively requested by the sponsor with respect to each new submission to the CTIS and for specific documents and/or data submitted. Again, the onus is on the sponsor to ensure that deferred publication is requested for any documents containing commercially confidential information, and that redacted versions of documents are provided if necessary.
Even where deferral is granted by the EMA, it seems unlikely that this will prevent publication on a permanent basis. Publication of any documents containing commercially confidential information can only be deferred for a fixed period of time set by the EMA. The time limit for deferral will depend on the trial category, which takes into account the nature of the trial, the IMPs used in a trial, and how they are used. For early-stage trials (e.g. Phase I trials), publication of certain commercially confidential information might be deferred by whichever is the earliest of up to seven years after the end of the trial, or up until the medicinal product is authorised. This time frame is increasingly short for later stage trials, and is available for Phase IV trials only if the sponsor can provide good reasons for the deferral. However, certain categories of information have different disclosure timelines. For example, the clinical trial results summary is to be published within 12 months of the end of the trial in the EU, unless it is later for scientifically justified reasons or the sponsor is granted a deferral of up to a further 18 months (with the proviso that publication will occur when the marketing authorisation is granted). The 18-month deferral is said to be based on the 18-month delay between filing a priority document and publication of the later PCT application, suggesting that deferral in this situation is intended to assist with patent filing strategies. Deferrals may not be available at all for documents submitted in relation to trials involving paediatric subjects or that are listed in a Paediatric Investigation Plan. So, understanding when documents may become available via CTIS will require careful discussion with experts in the regulatory process.
The EMA has also indicated that the use of deferrals will be monitored and should not exceed what is really needed. Accordingly, there is a possibility that requests for deferral could be denied if they are deemed unnecessary or excessive.
Why does the timing of these disclosures matter?
Clinical trial disclosures can be problematic as prior art in both patent prosecution and in post-grant proceedings (including litigation). In Europe, clinical trial disclosures and related press releases are frequently raised by third parties in post-grant opposition proceedings, where competitors have a keen interest in finding and using a patent proprietor’s own disclosures to attack patents protecting valuable drug products.
There is existing EPO case law that can make published clinical trial protocols challenging to overcome as prior art. For example, in T 2506/12 the Board said that clinical trials are “routine tests”, and so finding out if a suggested active ingredient has a useful therapeutic effect would be a “straightforward” task for the skilled person. Similarly, in T 239/16 the Board found that the skilled person would have an “expectation of success” simply by learning that a clinical trial was being carried out – in other words, the skilled person would expect the clinical trial to be successful, even if no data were available to them. These cases are fact specific, and in other cases mere disclosure of an on-going clinical trial of a drug was not enough to make the therapy in question obvious (e.g. T 108/21, T 799/16 and T 1806/18). Overall, these decisions mean that clinical trial disclosures may represent a significant obstacle for patents and patent applications, depending on the facts of the case.
Accordingly, even under the old EU-CTD, it was advisable to file patent applications before starting clinical trials to avoid the applicant’s own clinical trial disclosures being citeable as prior art. The EU-CTR does not change this advice, but makes the potential ramifications of not doing so much more severe due to the increased amount of information that can be made available to the public.
On the other hand, for third parties looking to invalidate a competitor’s patent, the new CTIS may be a valuable resource for finding useful prior art. Even outside of oppositions or other post-grant proceedings, the increased transparency in European clinical trials (such as the publication of interim results) could be extremely useful for parties who have an interest in monitoring the progress of competitors’ trials.
Key points for applicants and sponsors to consider
- The new EU-CTR affects the way that clinical trials will be run in all EU Member States.
- By default, almost all documents that a sponsor submits during the clinical trial process might be immediately published on the publicly accessible database, CTIS.
- Publication of commercially confidential information may be deferred for a certain amount of time depending on the category of trial, but deferral is not guaranteed and will be monitored by the EMA and/or Competent Authorities. Deferral must be requested separately for each new document that is submitted.
- Applicants should file patent applications relating to, for example, any new drug products, drug combinations, formulations, dosage regimens, or new medical uses as early as possible, and preferably before any new clinical trial applications are made, to avoid any information relating to the clinical trial becoming citeable as prior art.
- Trial sponsors should consider whether in-house counsel and/or external European counsel should review any new documents or data before they are submitted to the CTIS, to ensure that the appropriate patent applications have already been filed before any new disclosure.