02 nd Oct Transparency of Clinical Trial Data
Clinical trials are conducted on humans; healthy volunteers and/or patients, to help determine if medicinal products are safe and effective for use. These can only take place once a clinical trial application (CTA) has been made to the relevant regulatory authority and an ethics committee. The CTA includes information on how the product has been manufactured and an overall risk-benefit assessment, as well as how the actual study will be carried out.
The transparency of data generated from clinical trials versus the protection of commercially confidential information (CCI) is a prime concern for the pharmaceutical industry. CCI is defined by the European Medicines Agency (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. This report will look at the specific policies being introduced in Europe for greater transparency of clinical trial information and reporting as well as the general trend for the legal and ethical move towards greater clinical trial transparency.
Accessing Clinical Trial Information
Publishing information about the development and authorisation of medicines in the public domain is important to generate trust and build confidence in the regulatory process and to provide the knowledge required for decision makers.
As described by the European Medicines Agency; it is important though to strike the right balance between “respecting patients’ and doctors’ needs and the publics’ 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.
There are currently two routes to obtain information regarding clinical trials. These are:
– the request of documents via Regulation 1049/2001/EC, and the EMA’s implementing Policy 0043 and
– the publication of clinical data as described in the EMA policy 0070
Regulation 1049/2001/EC, and the EMA’s implementing Policy 0043 allows any EU citizen or legal entity to request access to documents held by public authorities. Access will not be granted only in those cases where disclosure would undermine the commercial interests of a person or legal entity, including intellectual property rights, unless there is an overriding public interest in disclosure. Once released there is no restriction on how these documents may be used.
Policy 0070 is composed of two phases:
– Phase 1 of Policy 0070 entered into force on 1st 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 (IPD)
The EMA will only publish the clinical report once the procedure has been finalised. This will occur within 60 days following the European Commission (EC) 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 (EPAR) will be published ahead of publication of the clinical report in order to give prior notification of the rationale for the assessment decision.
The application of the EU clinical trial portal and database as provided for in the new EU Clinical Trial Regulation No 536/2014 will further change the process for gaining access to clinical trials information.
The table below, adapted from the EMA website compares EMA’s policy on the publication of clinical data with the Clinical Trial Regulation in terms of their scope and information published.
|Clinical data publication policy||Clinical Trial Regulation|
|Medicinal products covered||Centrally authorised products only||Investigational medicinal products regardless of whether they have a marketing authorisation|
|Clinical studies covered||Clinical studies submitted to the Agency in the context of a MAA, Art 58 procedure, line extension or new indication, regardless of where the study was conducted||Clinical trials conducted in the EU and paediatric trials conducted outside the EU that are part of paediatric investigation plans|
|Documents published||Clinical data (clinical overview, clinical summaries and clinical study reports) and the anonymisation report||All clinical trial-related information generated during the life cycle of a clinical trial (e.g. protocol, assessment and decision on trial conduct, summary of trial results including a lay summary, study reports, inspections, etc.)|
|Publication channel||EMA clinical data publication website||Future EU portal and database|
|Date it applies||January 2015 (MAA or Art 58 procedure) or 1 July 2015 (line extension or new indication)||Expected 2019|
|Publication from||October 2016||Expected 2019|
The aim of the new EU Clinical Trial Regulation No 536/2014 is to ensure that clinical trials conducted in the EU are done so to the highest standards of safety for participants. The regulation will come into application in 2019. Although the regulation was adopted and entered into force in 2014, the timing of its application depends on confirmation of full functionality of the EU portal and database through an independent audit. The regulation becomes applicable six months after the EC publishes notice of this confirmation. 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 harmonize the rules that govern clinical trials across the EU member states; simplifying the clinical trial application process.
EU Clinical Trial Portal
A key part of this simplification process is the introduction of a new portal and database system. These will be used for the single point of submission and maintenance of clinical trial applications within the EU, and serve as the source of the publicly available information.
Once the decision on a CTA has been made, the public will be able to access extensive details of the trial through the 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 Commission, draw up the functional specifications for the EU portal and the EU database, together with the time frame for their implementation. As stated previously, it is currently understood that the regulation will come into application in 2019 once the database and portal are independently audited and verified as fully functional.
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 commercially confidential information, in particular taking into account the marketing authorisation status of the medicine, unless there is an overriding public interest in disclosure;
– protection of confidential communication between Member States in relation to the preparation of their assessment;
– protection of the supervision of the conduct of clinical trials by Member States.
Whilst 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.
Policy 0070 and the Redaction of Clinical Reports
Policy 0070 on the proactive release of clinical trial data, is implemented by the EMA through the submission of redacted clinical reports.
Companies are required to make proposals to the EMA for redaction for both protection of personal data and protection of commercially confidential information (CCI). Companies should submit a justification table for CCI proposed redactions (this will be based on the tool used in the EMA ‘access to documents’ policy) and an anonymisation report explaining the company’ approach to the anonymisation of clinical reports.
The company is free to choose the redaction software tool they like, as long as it adheres to the technical requirements stipulated by the EMA. The EMA will support small and medium sized enterprises (SMEs) (companies with fewer than 250 employees and an annual turnover not exceeding EUR 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 other companies due to financial constraints.
The EMA has provided a guidance document to assist with the anonymisation of clinical reports for the purpose of publication on the EMA 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 the personal data– it will be the applicants’ responsibility for submitting clinical reports that have been rendered anonymous. Redactions can be rejected if the information already in the public domain, does not bear any innovative feature or does per se not constitute CCI.
The proposed redacted clinical reports must be provided by the applicant 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 company should certify that the only difference between the redacted clinical report and scientific review version are those proposed redactions.
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 EMA 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, the published document will indicate that the redaction of these parts is under dispute.
The agency acknowledges 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.
The current guidance issued by the EMA relates to the redaction of documents submitted in-line with policy 0070. Presumably a similar if not identical procedure will also be adopted for redaction of documentation submitted under the clinical trial regulation.
The Call for Release of Clinical Trial Data
There has been much publicity and many calls for the publication of all raw clinical trial data.
In an article for the Buzzfeed news pages Ben Goldacre – a champion for the use of rigorous scientific evaluation and one of the founders of the alltrials.net website– highlighted the importance of publishing all clinical trial data. AllTrials is a campaign which calls for all past and present clinical trials to be registered and their full methods and summary results published. It does not call for individual patient data to be publicly available. The principle behind the campaign is that it is only through the scrutiny and re-evaluation of the data, that the original conclusions of a clinical trial can be validated.
In May 2015, the British Medical Journal (BMJ) announced that they will only publish trials that commit to sharing data on request. This extension of the journal’s requirements applied to all submitted clinical trials from 1st 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. The journal only previously applied these criteria to those trials that test drugs or devices, a policy that came into effect in January 2013. This policy specifies that trials would only be considered for publication if the authors agreed to make the relevant anonymised patient level data available upon request. As of May 2015, all authors had agreed to this stipulation and the BMJ have not had to reject a paper for non-compliance of this policy.
The WHO reiterated their position that before any clinical trial is initiated the main details should be registered in a publicly available, free to access, website, which adheres to the WHO’s internationally agreed standards. 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 or www.controlled-trials.com. 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.
The Nordic Trial Alliance (NTA) was a pilot project that ran from 2013 to 2016, with the aim of enhancing Nordic cooperation in clinical multicentre trials. The NTA acknowledged that in the past decade there had been a significant decrease in clinical trials in the Nordic Countries (Denmark, Finland, Iceland, Norway, and Sweden). This negative impact on those countries health sector may have the consequences of; delaying new methods and treatment, having clinical trials that cannot deliver conclusive data and therefore must be repeated and the having multinational trial proposals redirected to other areas of the world.
As part of the pilot project, in 2014 a sub-project was run examining clinical trial transparency. The resulting NTA report on transparency and registration in clinical research goes further than the WHO’s statement in a comprehensive review of the current position of the Nordic countries data transparency. The recommendations were as follows:
– registration of all clinical trials irrespective of type of intervention, phase, or disease or condition before inclusion of the first participant, including the full protocol, in one of the primary registries approved by the WHO or in the ClinicalTrials.gov registry.
– expansion of the current WHO-defined 20 items of registration to include a monitoring plan, a statistical analysis plan, a data management plan, safety reporting procedures, and conflicts of interest.
– making trial registration a condition for ethical approval.
– better compliance with study reporting practices according to the CONSORT statement.
– making full clinical trial reports and the analysed data sets supporting the results available at the same time.
– public upload of depersonalised (or in exceptional cases anonymised) individual participant data (i.e., the analysed data set as well as essential source or raw data) after publication of the full report of the trial.
– setting up a Nordic transparency council to become a central, trusted public party for keeping the identification key for depersonalised data sets as well as to grant waivers to the general requirement to upload trial results within 12 months as well as the requirement to upload depersonalised individual participant data.
– creation of harmonised legislation in the Nordic countries requiring the posting of a summary of the study results at the site of registration. The legislation should be developed in close collaboration with all stakeholders.
– introduction of harmonised legislation in the Nordic countries in collaboration or as individual nations to govern the suggested steps of trial registration and increased transparency for both investigator-initiated and industry-initiated clinical research.
– legal definition of attempts to re-identify depersonalised or anonymised data as an unlawful act.
How are Pharmaceutical Companies addressing these transparency calls?
As discussed by Ben Goldacre, there is a problem with clinical trial results being routinely and legally withheld. Around half of all clinical trials fail to report their results, the same being the case for industry trials and academic trials. There is also a bias in the literature, with trials producing positive results being about twice as likely to post results.
The pharmaceutical industry is increasingly heeding these calls for more transparency, as noted by the increase in submissions to publicly available websites.
GlaxoSmithKline (GSK) is one of the companies taking the lead in the transparency of their clinical data. In January 2014, their clinicalstudydatarequest.com website was launched in conjunction with a number of other trial sponsors. This site allows researchers to request access to anonymised patient-level data and/or supporting documents from clinical trials in order to conduct further research. This request is then reviewed by an independent review panel, managed by the Wellcome Trust. Consistent with continued transparency, this new study protocol should provide a commitment for the researchers to publish their findings.
This progressive move to further transparency was challenged in the UK by judicial review. The National Health Service Health Research Authority (HRA) has a role to promote transparency in health research, including making the registration of clinical trials a condition of an NHS Research Ethics Committee favourable opinion. The HRA were challenged in its steps taken to monitor the registration of clinical trials.
With effect from 30th September 2013, the HRA made the registration of a clinical trial, and publication on a publicly available website, a condition of approval to run that trial. From 1st April 2015, the HRA has asked researchers applying to run a clinical trial to declare that all past trials have been registered, including those approved before 30th September 2013. This retrospective change was challenged as being unlawful. The judgement found that there were parts of the HRA material that were ambiguous about the nature of the obligations on researchers. The ruling means that companies sponsoring phase I clinical trials in the UK retain control over whether and when they make public the registration of previously conducted trials. The material was found to be unlawful because it was not clear enough about the source of obligations – whether these were legal or ethical.
The outcome of the aforementioned judicial review goes to the heart of the future steps for further transparency – are these steps to be taken from a legal or ethical standpoint?
As addressed in the judicial review, and assessed by Ben Goldacre for AllTrials:
“The judge has stated clearly that people conducting trials have ethical obligations, as well as legal ones, and that research regulators are entitled to hold companies to those ethical standards.”
Those ethical considerations would include the registration of all clinical trial data. If there is a bias toward trials being in the public domain which have a positive outcome, it does not give the research community, healthcare professionals or the general public a clearer idea about the wider picture of trials which have been stopped, drawn inconclusive results or not published.
The public disclosure of clinical trial data will continue to be of major importance for the pharmaceutical and healthcare sectors. Following both regulatory stipulations and public awareness campaigns more companies will follow suit in publishing the outcomes of their clinical research. Further advocacy groups and charities will pledge support for transparency, and professional bodies will continue to encourage the next generations of clinicians and researchers to adhere to reporting principles.
As summarised by Professor David Henry of the University of Toronto, in an editorial for the BMJ, after the re-evaluation of study data for GSK’s antidepressant drug paroxetine:
“Liberated trial data have enduring potential to benefit patients, prevent harm, and correct misleading research.”
References not online:
 European Medicines Agency. The Clinical Trials Regulation EU No 536/2014: provisions on transparency. DIA 27th Annual EuroMeeting, Paris 2015.