On 21 January 2015, the European Medicines Agency (EMA) ) launched a public consultation on the implementation of the transparency requirements of the new EU Clinical Trial Regulation No 536/2014 (CTR). The CTR requires the EMA to set up and maintain a single database where a large amount of information concerning clinical trials conducted in the EU will be publicly accessible. Among other exceptions, commercially confidential information (CCI) and information containing personal data should be treated as confidential and be excluded from publication.
The purpose of the EMA’s consultation is to determine exactly which information will remain confidential, and for how long. The consultation therefore represents a unique opportunity for industry to influence the practical interpretation of essential concepts such as CCI under the CTR but – indirectly – also under EMA’s Policy 0070 on proactive publication of clinical data, which entered into force on 1 January 2015. Life sciences companies should submit their comments by 18 February 2015.
Transparency Provisions in the New EU Clinical Trial Regulation
The new EU CTR introduces important modifications to the level of information that will be publicly available for each clinical trial carried out in the EU. It establishes a single EU portal for the submission of all applications and documents relating to clinical trials, and it requires the EMA to set up and maintain a single EU database where all information submitted through the portal will be publicly available. The CTR entered into force in June 2014 and is expected to apply by the end of 2016 at the earliest, six months after the EU portal and database are declared to be fully functional. [For a complete overview of the new CTR, see our e-alert of June 2014: New Clinical Trial Rules in the EU: A First Overview.]
The transparency requirements of the CTR will apply to all clinical trials conducted in the EU, independently of whether the results are included in an application for a marketing authorisation (MA). Publication will take place proactively and, depending on the type of information and on the type of trial, the information will become available in the database at the time of decision on the trial, during the course of the trial, or only (some time) after its conclusion. The exact timing for publication of certain trial information is one of the aspects under consultation.
All of the data and documents that are explicitly designated by the CTR will be listed in the EU database, including summary trial results and a summary in lay language (12 months after the end of the trial) and, for medicines for which a MA has been granted or the MA procedure has otherwise been completed, full clinical study reports (30 days after completion of the MA procedure). However, individual patient data listings (a.k.a. "raw data") included in the appendices to clinical study reports do not have to be recorded in the EU database.
In addition, the database will make publicly available the main characteristics of the trial (as set out in the clinical trial application form, comprising design, scientific and therapeutic intent, title, identification of the investigational medicinal product, treatment arms, treatment population and number of subjects, inclusion and exclusion criteria, main objectives and endpoints), protocol summary, conclusion on the assessment and decision on the trial (including reasons for refusal if any), start and end date of the trial, start and end of subject recruitment in each Member State concerned, substantial modifications of the trial, and notification of temporary halt or early termination of the trial.
The transparency regime introduced by the CTR substantially increases the amount of information that must presently be published in accordance with Directive 2001/20/EC on clinical trials. Under the current regime, only limited information is made publicly available through the EU Clinical Trial Register administered by the EMA, including in particular protocol related information and result related information in summary form, but not the full clinical study reports.
The CTR stipulates that any information submitted through the portal will be publicly accessible through the EU database, unless confidentiality is justified on the basis that it protects: (i) personal data; (ii) CCI, in particular taking into account the MA status of the medicine, unless there is an overriding public interest; (iii) confidential communications between Member States in preparation of their assessment; or (iv) effective supervision of clinical trials by Member States.
Importantly, the CTR contains no definition of what constitutes CCI. However, absent a legal definition, the consultation defines CCI as "any information contained in the data or documents submitted to the database that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the sponsor," thus adopting the same – rather vague – definition of CCI as set forth by EMA’s Policy 0070 on Publication of Clinical Data (see below).
The aim of the EMA’s consultation is to seek stakeholders’ views on the practical implementation of the transparency requirements under the CTR, and more particularly on the application of these exceptions and specifically the concept of CCI (under Section 4.4.). The consultation explicitly recognises that "a balanced approach is needed to protect public health and also foster the innovation capacity of European medical research, thus supporting the EU as a location for innovative, cutting edge research that results in development of novel products and research into new and better uses of existing products."
It should be noted that the new EU portal and database will operate in an automatic way, through a software enabling to determine if, and for how long, a particular data element or document should be made public, requiring only minimum human interpretation (e.g., for situations where there is an overriding public interest in publication). It is therefore absolutely crucial for life sciences companies that – by means of this public consultation – the EMA obtains a good understanding regarding the specific data which should be considered CCI and therefore be excluded from publication.
EMA Policy 0070 on Publication of Clinical Data
The EMA currently also has its hands full with an even more comprehensive revision of the transparency rules relating to clinical trial data, which goes beyond the CTR. In October 2014, the EMA adopted Policy 0070 on publication of clinical data for medicinal products for human use (the Policy), which entered into force on 1 January 2015. The CTR and the Policy are two separate initiatives and have a different scope, though (amongst other things) "share" essential concepts such as CCI and personal data.
The Policy regulates how the EMA will proactively publish clinical trial data submitted to the EMA under EU centralised MA application procedures. This means that the policy applies to studies that are beyond the scope of the CTR as, for example, it also covers clinical trials conducted outside the EU but submitted to the EMA in support of a MA application in the European Union. The Policy further complements EMA’s Policy 0043 on access to documents (dated November 2010), which deals with reactive disclosure of a more extensive set of information – including clinical trial data – in response to requests for information in the framework of the Transparency Regulation (EC) No 1049/2001.
The Policy requires the EMA to proactively disclose both clinical reports (which include clinical overviews, clinical summaries, clinical study reports, protocol and protocol amendments, sample case report forms, and documentation on statistical methods) and – in contrast with the CTR – individual patient data (IPD or "raw data"). However, the Policy is subject to a "stepwise" implementation, whereby only clinical reports will be published during the first implementation phase. The EMA still has to determine an appropriate approach to make IPD available while ensuring compliance with personal data protection legislation, and is expected to launch a public consultation seeking the views of the industry in the near future.
In addition to the protection of personal data, the most important challenge of the Policy concerns the management of CCI in clinical reports. The EMA explicitly acknowledges that clinical reports could contain CCI, which should be subject to redaction prior to publication. Similarly to the consultation, the EMA Policy defines CCI as "any information contained in the clinical reports submitted to the EMA that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant or MA holder."
In order to provide guidance on how to interpret this broad definition, Annex 3 to the Policy contains examples of information that "may" be considered CCI (e.g., information describing "the clinical development programme of the medicinal product, including on-going and planned clinical studies and the basis for the decision to submit the application at this point in the programme"). However, this guidance only describes what information may be considered CCI, which falls far short of giving life sciences companies clear and predictable rules.
Moreover, unlike the CTR transparency rules, the EMA does not intend to adopt an automated process to protect CCI in clinical trial data under the Policy. Rather, the applicant/MA holder and the EMA will play an important role in proposing and reviewing ad hoc redactions of CCI in clinical reports. However, it goes without saying that both the EMA and industry would greatly benefit from a harmonised approach under the CTR and EMA’s Policy 0070 (as well as EMA’s Policy 0043) in this respect.
Why Companies Should Respond to the Consultation
Life sciences companies have until 18 February 2015 to respond to the EMA’s public consultation. Companies are strongly encouraged to submit their comments, as this consultation provides a unique opportunity to influence the practical implementation of the transparency requirements of the CTR.
Moreover, even though the consultation focuses on the CTR specifically, it is likely that the outcome of this consultation will have a much broader impact on the EMA’s general approach to transparency of clinical trial data, in particular with respect to the definition of CCI (as included in the different EMA policies as well). In their responses to the consultation, life sciences companies should therefore stress the importance of a harmonised approach towards CCI under both the CTR and the EMA Transparency Policies. In addition, companies should aim at providing concrete and practical examples of potentially harmful situations "where disclosure may undermine their legitimate economic interest."
Indeed, the EMA has demonstrated to be keen on taking into consideration industry’s input as far as the implementation of pharmaceutical regulatory policy is concerned. This recently became very clear with regard to the adoption of its Policy 0070 (for which it received an enormous amount of input from stakeholders) as the final – "compromise" – policy effectively reflected some serious concerns raised by industry. In this respect, life sciences companies should also be on the lookout for, and begin preparing for, upcoming EMA consultations on transparency of IPD concerning the second implementation phase of Policy 0070 on Publication of Clinical Data.