The European Medicines Agency (EMA or Agency) has decided to publish the clinical reports that underpin the decision-making on medicinal products. Following extensive consultations held by the Agency with patients, healthcare professionals, academics, industry and other European entities over the past 18 months, the EMA Management Board unanimously adopted the new policy1 at its meeting on 2 October 2014. The policy will enter into force on 1 January 2015; it will apply to clinical reports contained in all applications for centralised marketing authorisations submitted after that date. The reports will be released as soon as a decision on the application has been taken.
Main objectives of the policy
The EMA is committed to continuously extending its approach to transparency. A key goal for the EMA in this process is the proactive publication of clinical-trial data for medicines once the decision-making process on an application for a European Union (EU)-wide marketing authorisation is complete. The new EMA policy shall serve as a complementary tool ahead of the implementation of the new EU Clinical Trials Regulation ((EU) No. 536/2014) that will not come into force before May 2016.2 The EU Clinical Trials Regulation provides, for the first time, a direct legal basis for the release of clinical trial results. However, it does not provide a legal basis for proactively making clinical trial results available until such time as the Regulation enters into application. Furthermore, the Regulation does not encompass non–EU clinical reports and is limited to clinical trial results deriving from clinical trials conducted in the EU and authorised under the provisions of this Regulation. The EMA expects that under the Regulation the first clinical reports will not become publically available before 2019/2020.
Amendments compared to the first draft released in June 2013
The main concerns with regards to the first draft of the policy related to the concept of CCI and the protection from unfair commercial use, the protection of patient's confidentiality and to the concept of raw data.
According to the EMA, the main concerns regarding the concept of CCI and the protection from unfair commercial use have been addressed as follows:
- the use of redaction principles and a process for publication of clinical reports to manage CCI, meaning that downloadable clinical reports are only available to identified users.
After the revision, following the May 2014 targeted stakeholders consultation, the main concern expressed related to the view-on-screen access. This concept was criticised by academics, research bodies, medical journals, consumer organisations and healthcare professional organisations, as well as some EU institutions. To address this concern the EMA introduced "more user-friendly amendments", enabling the possibility to download, save, and print the trial data for academic and non-commercial research purposes.
Implementation of the raw data policy
The policy will be implemented in phases. The policy does not apply to clinical data held by the Agency for applications received under the centralised procedure before 1 January 2015.
The first phase starts on 1 January 2015. This means that the policy will apply from this date onwards to any new marketing authorisation applications and article 58 applications (medicines that are intended exclusively for markets outside the European Union) submitted after that date. Data will only start to become accessible once the final decision on a given procedure has been reached by the European Commission, which implies a timeframe of about 18 months. Then, the EMA will publish the clinical reports supporting applications for authorisation of medicines. The first phase concerns the publication of clinical reports only. The EMA has defined a process for publication of clinical reports whereby the data that will be accessible on the EMA website are:
- module 2.5 (clinical overview);
- module 2.7 (clinical summary);
- module 5 (clinical study reports (CSRs));
- appendices 16.1.1 (protocol and protocol amendments), 16.1.2 (sample case report form) and 16.1.9 (documentation of statistical methods).
In this first phase the clinical reports will be published excluding "raw data". In order to avoid confusion, the term "raw data" will no longer be maintained by the EMA, but instead the term "individual patient data" (IPD) will be used.
For post-authorisation procedures for existing centrally authorised medicinal products, the effective date will be 1 July 2015 for extension of indication and line extension applications submitted as of that date. The policy does not apply to clinical data held by the Agency for these applications received before 1 July 2015. For all other post-authorisation procedures the effective date still needs to be determined and will be communicated in due course.
In the second phase, the EMA will endeavour to find the most appropriate way to make individual patient data (IPD) available, in compliance with privacy and data protection laws. This will involve consultation with stakeholders on various aspects in relation to IPD.
Commercially confidential information and redaction principles
According to the EMA policy the overwhelming majority of data in clinical reports is not CCI. CCI is defined, for the purpose of the policy, as "any information contained in the clinical reports submitted to the Agency by the applicant/marketing authorisation holder (MAH) that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant/MAH".
Information contained in the clinical reports that may be considered CCI4 includes:
- elements relating to clinical trials and contained in "The common technical document for the registration of pharmaceuticals for human use" (from ICH harmonised tripartite guideline, Module 2 and 5), for example:
- the Product Development Rationale;
- the Overview of Biopharmaceutics; and
- the Overview of Clinical Pharmacology.
- the structure and content of clinical study reports (from ICH harmonised tripartite guideline, E3), for example:
- study Objectives (including Exploratory Endpoints and Efficacy and Safety Variables); and
- determination of Sample Size.
With the above in mind, the policy provides redaction principles. Under the policy, applicants will be asked to submit clinical reports in view of their publication. If they believe that some elements should be redacted, then the applicants may propose this together with the justifications for the redactions. According to the EMA, the starting point of the redaction principles is that clinical reports do not, in general, contain CCI. However, in a limited number of instances (see the examples above) there might be pieces of information that could be considered CCI; in such cases the Agency is prepared to consider the justifications for redactions.
Where redaction of CCI is proposed by the applicant/MAH, a consultation with the applicant/MAH will be undertaken following scrutiny by the Agency of the proposed redaction, including the justification provided by the applicant/MAH, as to whether the definition of CCI applies. Therefore, it is for the Agency to take the final decision on what is and is not to be redacted. The extent of what the Agency will redact will always be visible in the final documents that the Agency makes available. In case of disagreement with the Agency's final decision on the redaction, the applicant/MAH will be given a defined period prior to the publication to seek an interim injunction from the Court. In this case, the Agency will only publish the undisputed parts of the clinical reports.
Clinical trial data submitted under the centralised marketing authorisation procedure will be published by the EMA after the effective date of the policy. It remains to be seen whether or not the provisions of the EMA policy are sufficient to prevent the misuse of CCI. The assumption of the EMA, that, in general, clinical reports do not contain CCI, seems to be questionable. Clinical trial data contains information such as know-how and intellectual property regarding the manufacturing, technological approaches and development of innovative medicines and the innovator's clinical-trial design and product development strategy. This and other information are not in the public domain and, therefore, can amount to CCI. In any case, a proactive disclosure requires a clear legal basis and it is doubtful if Regulation (EC) 726/2004 provides such a basis at present. According to Regulation (EC) 1049/2001 regarding public access to European Parliament, Council and Commission documents, the institutions shall refuse access to a document where disclosure would undermine the protection of commercial interests of a natural or legal person, including intellectual property, unless there is an overriding public interest in disclosure. It is questionable whether there could be an assumption that publication of CCI contained in the marketing authorisation application is generally justified by an overriding public interest in disclosure because the publication as such does not lead to an improvement of public health. At the moment, it is not clear what the Court of Justice of the European Union in the caseInterMune UK and Others v EMA5 will decide about the publication of clinical trial data. Moreover, it needs to be kept in mind that in future the EMA also plans to make individual patient data available.