13 th May Access Denied – Achieving Greater Transparency in Clinical Trial Information
The transparency of data generated from clinical trials versus the protection of commercially confidential information is a prime concern for the pharma industry. The latest policies to be introduced in Europe aim to achieve greater transparency of clinical trial information and reporting.
Commercially confidential information (CCI) is defined by the EMA as meaning any information which is not in the public domain or publicly available, and where disclosure may undermine the economic interest or competitive position of the owner of the information.
However, publishing information about the development and authorisation of medicines in the public domain is critical to generate trust and build confidence in the regulatory process, and to provide the knowledge required for decision-makers. As described by the EMA, it is important to strike the right balance between “respecting patients’ and doctors’ needs and the public’s entitlement to extensive and timely information about clinical trials, and developers’ and researchers’ need to protect their investments. A balanced approach is needed to protect public health and also foster the innovation capacity of European medical research”(1).
There are various ongoing regulatory procedures regarding clinical trial transparency, relating particularly to:
- The introduction of the EU clinical trial portal and database as provided for in the new EU Clinical Trial Regulation No 536/2014 (2)
- The publication of clinical data as described in the EMA policy 0070 (3)
Policy 0070 is composed of two phases:
- Phase 1 of Policy 0070 entered into force on 1 January 2015. This pertains to publication of clinical reports only
- Phase 2 will be implemented at a later stage, which pertains to the publishing of individual patient data (4)
With the aim of ensuring that clinical trials are conducted in the EU with the highest standards of safety for participants, the new EU Clinical Trial Regulation No 536/2014 will come into force in mid-2016. The regulation will substantially increase transparency of information, with details of the major characteristics of the trial and their results becoming publicly available. It will also harmonise the rules that govern clinical trials across the EU member states, thereby simplifying the clinical trial application process.
Clinical Trial Portal
A key part of this simplification process is the introduction of a new portal and database system that will be used as the single point of submission and maintenance of clinical trial applications within the EU, and also serve as the source of the publicly available information. Once the decision on a clinical trial application has been made, the public will be able to access extensive details of the study through this database.
In accordance with Article 82(1) of the new Clinical Trial Regulation (EU) No 536/2014, the Agency shall, in collaboration with the member states and the European Commission, draw up the functional specifications for the EU portal and the EU database, together with the timeframe for their implementation. The auditing of the database should be complete and endorsed by December 2017, with the production version scheduled to go live in September 2018 (5).
In March 2016, the EMA published detailed guidance for companies on the requirements to comply with policy 0070. The EMA expects to make continuing updates to this guidance (6).
It is currently proposed that the information to be made publicly available at the time of the decision on the trial will include: the start date; the main characteristics of the trial; the protocol summary; the conclusion on the assessment of part one of the trial; and the decision on the trial including reasons for refusal if the trial is not authorised (1).
Information released during the trial will include: the end date of the trial; the first visit of the first subject in the trial in each member state concerned; any substantial modification, temporary halt, or early termination of the trial; and notification on the end of recruitment in each member state (1).
Additionally, 12 months after the end of a trial, a summary of the results and a lay summary will be published. Then, 30 days after completion of the marketing authorisation process – regardless of whether this is an approval or rejection – the clinical study report for those trials authorised under the new regulation, and included thereafter in a marketing authorisation dossier, will also be published.
The Regulation requires that the information is made publicly available via the clinical trial database, unless one or more of the following exceptions apply:
- Protection of personal data
• Protection of CCI, in particular taking into account the marketing authorisation status of the medicine – unless there is an overriding public interest
• Protection of confidential communication between member states in the preparation of their assessment
• Protection of the supervision of clinical trials by member states
While the review and approval of clinical trials will remain within the individual EU member states, the portal and database will be the responsibility of the EMA.
Redaction of Clinical Reports
A recent EMA webinar explained how the Agency intends to implement policy 0070 on the proactive release of clinical trial data and the principles for the submission of redacted clinical reports (7). The EMA is looking at both a short-term and long-term solution, with the short-term option being the redacted clinical reports presented as read-through text, whereby the EMA can see what the proposed redactions are. The long-term option is to explore if a format change in the electronic common technical document (eCTD) could be achievable. An amendment to the eCTD would need to go through the ICH procedures – which would require international agreement.
Clinical reports are proposed to be provided between Day 181 and 220 of the marketing authorisation application (MAA) procedure, or within 30 calendar days post-receipt of the company’s letter notifying the withdrawal of the MAA. The organisation should certify that the only difference between the redacted clinical report and scientific review version are those proposed redactions. Companies will be required to make proposals to the EMA for redaction to protect both personal data and CCI. Businesses should, therefore, submit a justification table for CCI-proposed redactions (this will be based on the tool used in the EMA’s access to documents’ policy), and an anonymisation report explaining the company’s approach to the anonymization of clinical reports.
The organisation is free to choose the redaction software tool they like best, as long as it adheres to the technical requirements stipulated by the EMA. The Agency will support small- and medium-sized enterprises (companies with fewer than 250 employees and an annual turnover not exceeding €50 million) by obtaining a user’s licence for a redaction tool, and through provision of training and the creation of a helpdesk. This support will not be extended to large businesses due to financial constraints.
The EMA will provide guidance documents to assist with the anonymisation of clinical reports for the purpose of publication on their website, and the redaction of CCI in these reports. At the time of writing, these were still at a draft stage. The EMA will adopt a risk-based approach concentrating on the proposed CCI redactions, rather than reviewing personal data – it will be the applicant’s responsibility for submitting clinical reports that have been rendered anonymous. Redactions can be rejected if the information is already in the public domain, does not bear any innovative feature or does not, per se, constitute CCI.
They foresee only one consultation round between themselves and the company, ending with a definitive conclusion from the EMA rather than protracted rounds of discussions. If the Agency and the applicant do not agree on the confidential nature of parts of the reports, and the applicant has sought a court injunction to prevent the publication of certain information, then the published document will indicate that the redaction of these parts is under dispute.
The EMA will only publish the clinical report once the procedure has been finalised. This will occur within 60 days following the European Commission’s decision for approval/ refusal of the marketing authorisation or line extension, or within 150 days of the company’s withdrawal letter. The European public assessment report will be released ahead of clinical report publication in order to give prior notification of the rationale for the assessment decision
The Agency does acknowledge that redactions due to CCI will become less justified over the course of time, as what was previously recognised as being CCI gets into the public domain. A regular review of such published reports (14,000 per annum) would not be feasible. Therefore, the redacted reports will remain as such until, or unless, access is challenged under the access to documents scheme (8).
There has been much publicity and many calls for the publication of all raw clinical trial data. In May 2015, the British Medical Journal (BMJ) announced that they will only publish trials that commit to sharing data on request (9). This extension of the journal’s requirements applied to all submitted clinical trials from 1 July 2015. In doing so, the BMJ acknowledged that it was time for medical journals to play their part in the movement to make clinical trial data widely accessible.
In April 2015, the WHO and the Nordic Trial Alliance published declarations regarding clinical trial transparency (10,11). The WHO have reiterated their position that, before any clinical trial is initiated, the main details have to be registered in a publicly available, free-to-access website, which adheres to the WHO’s internationally agreed standards (12). The WHO position is also a condition of a favourable ethical opinion.
All studies need to be registered before the first patient is recruited. Examples of such websites available now are www.clinicaltrials.gov (13) or www.controlled-trials.com (14). The clinicaltrials.gov website is a service of the US National Institutes of Health and was made available to the public in February 2000. It now lists over 197,000 studies, with the number of studies listed increasing year on year.
The WHO statement notes that: “Concerns have been raised that there may be selective publication of trials dependent on their results, with particular concern that trial results which may be viewed as ‘negative’, are less likely to be submitted, or accepted, for publication in the scientific literature or made public in other ways.”
The WHO expects that:
- The main findings of clinical trials are to be submitted for publication in a peer-reviewed journal within 12 months of study completion, and are to be published through an open access mechanism – unless there is a specific reason why open access cannot be used, or otherwise made available publicly at most within 24 months of study completion
- In addition, the key outcomes are to be made publicly available within 12 months of study completion by posting to the results section of the primary clinical trial registry. Where a registry is used without a results database available, the results should be posted on a free-to-access, publicly available, searchable institutional website of the regulatory sponsor, funder or principal investigator.
Although these criteria are not mandatory, the WHO encourages reporting in shorter timelines. The new EU Clinical Trial Regulation and EMA policy 0070 go some way to addressing these calls in Europe.
Plan for the Future
In December 2015, when outlining his five-year EMA vision, Executive Director Guido Rasi highlighted transparency as a key aspect of the EMA’s approach moving forward (15): “We have a pioneering approach to transparency. We are the first regulator in the world to allow researchers and academics, and the public as a whole, access to the clinical data on which marketing authorisations are based.”
With these new policies, the EMA aims to build trust and confidence in the regulatory system, because it will allow the public to better understand the Agency’s decision-making. The public disclosure of clinical trial information will continue to be of major importance for the pharma and healthcare sectors. These new regulatory procedures will make Europe a leader in the publication of study data.
This article is taken from International Clinical Trials May 2016, pages 14-17. © Samedan Ltd
Regulatory Affairs Project Manager
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- EMA, Clinical Trials Regulation EU No 536/2014: Provisions on transparency, DIA 27th Annual EuroMeeting, Paris 2015
- Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Visit: www.eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32014R0536&qid=1430209172115&from=DE
- EMA policy on publication of clinical data for medicinal products for human use. Visit: www.ema.europa.eu/docs/en_GB/document_library/Other/2014/10/WC500174796.pdf
- EMA, External guidance on the implementation of the EMA policy on the publication of clinical data for medicinal products for human use. Visit: www.ema.europa.eu/docs/en_GB/document_library/Presentation/2015/09/WC500194090.pdf
- EMA, Delivery time frame for the EU portal and EU database. Visit: www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199078.pdf
- External guidance on the implementation of the EMA policy on the publication of clinical data for medicinal products for human use. Visit: www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/03/WC500202621.pdf
- EMA, Access to documents. Visit: www.ema.europa.eu/ema/index.jsp?curl=pages/document_library/document_listing/document_listing_000312.jsp&
- Current status of EMA policy on publication of clinical data, Stakeholder webinar. Visit: www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2015/06/event_detail_001163.jsp&mid=WC0b01ac058004d5c3
- The BMJ requires data sharing on request for all trials, British Medical Journal. Visit: www.bmj.com/content/350/bmj.h2373
- WHO statement on public disclosure of clinical trial results. Visit: www.who.int/ictrp/results/WHO_Statement_results_reporting_clinical_trials.pdf?ua=1
- Nordic Trial Alliance Working Group, Report on transparency and registration in clinical research in the Nordic Countries, 2015. Visit: www.nta.nordforsk.org/projects/nta_transparency_report.pdf
- WHO International Clinical Trials Registry Platform. Visit: www.who.int/ictrp/about/en
- Visit: www.clinicaltrials.gov
- Visit: www.controlled-trials.com
- EMA, Press release: EMA ready to address challenges ahead. Visit: www.ema.europa.eu/docs/en_GB/document_library/Press_release/2015/12/WC500198366.pdf