Drawing the boundaries of data disclosure in clinical trials
In the context of clinical trial data disclosure, since 2010 the regulatory impetus has shifted towards enhanced disclosure obligations, culminating in the publication of a ‘pro-active’ policy on the publication of clinical trial data for medicinal products for human use1 (Policy 0070) by the European Medicines Agency (EMA) in October 20142.
In addition, legislative action has arrived in the form of the Clinical Trials Regulation 526/2014/EC, which is anticipated to enter into force in October 2018. These recent European Union legislative and policy developments are set to have a major impact on the continuing research and development cultures and practices adopted by the pharmaceutical industry. In particular, the scope of protection for legitimate commercial interests and, specifically, the redaction of commercially confidential information (“CCI”) remains legally uncertain. Indeed, at the time of writing the question remains subject to ongoing litigation before the European Courts.
With reference to pending cases before the European Court, this article shall explore the legal and ethical perspectives in the disclosure debate and will consider where the balance lies in setting the boundaries of commercially confidential information.
The legal basis for clinical data disclosure
It is an enshrined principle of EU constitutional law that all documents of EU institutions and agencies should be accessible to the public3 . With respect to pharmaceutical products, the EU regulatory framework contains prescribed rules requiring mandatory disclosure of both non-clinical and clinical information submitted in a marketing authorisation dossier4 . More generally, the Transparency Regulation 1049/ 2001/ EC (the ‘Transparency Regulation’) provides a public right of access to documents prepared by, or submitted to, EU institutions, including the EMA. However, Article 4(2) of the Transparency Regulation provides an important exception to this rule in cases where disclosure of information would “undermine the commercial interests of a natural or legal person, including intellectual property rights.” This exception is subject to a public interest requirement whereby disclosure may be justified if the public interest in disclosure outweighs the protection of commercial interests5.
The evolution of clinical trial data disclosure in the EU
Prior to 2010, the EMA applied a restrictive approach towards data disclosure on the basis that clinical study reports (“CSRs”) were considered to contain commercial information. This changed with the implementation of the EMA’s reactive policy on access to documents on written request (hereafter, referred to as “Policy 0043”)6 , which represented a significant change in approach by the EMA. The shift towards enhanced disclosure of clinical trial data has undergone a gradual change. following intense pressure from political, academic and medical lobbying groups. This resulted, on 2nd October 2014, with the EMA adopting Policy 0070, a ‘pro-active’ publication policy which reflected the culmination of years of consultation and stakeholder engagement by the EMA7 .
The legal significance of the Policy 0070 publication method
The burden of redactions
Under Policy 0070 the starting position is that clinical data is not confidential per se, although the EMA accepts that, in limited circumstances, study reports may contain CCI, which can be redacted. In recent guidance, the EMA has emphasised that it is the applicant’s responsibility to propose and justify redactions and to cite ‘specific, pertinent, relevant, not overstated, and appropriate justifications’ for each proposed redaction8 . However, the redaction process remains a major challenge as it is an extremely time consuming and resource intensive exercise, both for industry and the EMA. Companies must carefully consider what data in CSRs needs to be redacted and how the redactions can be properly justified. In doing so, companies must now commit appropriate resources and teams to review CSRs and adopt processes and systems to accurately and consistently redact CCI from CSRs.
Moving towards the Clinical Trials Regulation
The EMA has repeatedly emphasised that Policy 0070 was intended to be “a useful complementary tool” ahead of the implementation of the Clinical Trials Regulation 536/2014/EC (the “CT Regulation”), which provides the legal basis for the pro-active disclosure of clinical trial information9 . Between 2007 and 2011, the number of clinical trials conducted in the EU fell by 25% and one of the goals of the CT Regulation is to boost clinical research in Europe by simplifying the rules for conducting clinical trials10. Maintaining the significant number of clinical trials carried out in the EU provides a substantial economic and health benefit. However, if the regulatory landscape acts as a disincentive for innovative industries, this may defeat the key objective of the CT Regulation of stimulating more trials in the EU.
Are we any closer to understanding CCI?
Policy 0070 defines CCI as ‘any information contained in the clinical reports submitted to the Agency by the applicant/MAH that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant’. On first reading, this appears to be a sensible and logical approach. However, there remains a considerable lack of legal certainty as to the standard applied to CCI, especially since the only cases brought in the European Courts which would be able to clarify this standard have either been settled or not reached final determination. Nevertheless, it is helpful to consider the arguments raises by the parties and the Courts’ approach to them, so far, since it indicates the likely outcome of a final decision.
In the Abbvie11 and InterMune12 cases there was a challenge to the EMA’s decision to disclose parts of a CSR considered to contain CCI. It was argued that CSRs contain proprietary know-how and methodology such as trial design and complex statistical data analysis, which go well beyond the parameters required by the reporting of clinical trial results. It must be emphasised that these cases concern access to documents requests made pursuant to the Transparency Regulation and were ultimately meaning there was no final ruling of the merits. However, the general substance of the litigated issues remains the same, i.e., what is the scope of CCI with respect to the disclosure of clinical trial information?
Following Abbvie and InterMune there are currently two cases pending before the Court of Justice13. In cases, T-718/15 R and Case T- 729/15, the General Court adopted a consistent approach by granting interim orders thus maintaining the practical effect of a future ruling on the merits. The EMA has previously stated its desire for a ruling on the merits in order to enable a workable approach by the EMA to the redaction and disclosure of clinical data. This author supports that position and, indeed, considers that a judgment from the Court of Justice would assist greatly in advancing legal certainty as to the likely judicial interpretation on the boundaries of CCI.
A major industry concern is that disclosure of this information can provide a road map for competitors to short-circuit the ‘full intellectual analysis and planning’14 that goes into the preparation of a regulatory dossier. This argument was also raised in the recent interim orders decision in PTC Therapeutics, which concerned the scope of permissible disclosures under an access to documents request for an orphan medicinal product15.
Why is transparency important to regulatory intellectual property rights?
The timeline to market launch of new medicinal products takes on average 12 years at an estimated cost of one billion Euros16. Furthermore, the attrition rate for novel compounds is huge. It is estimated that for every one approved compounds, up to 10,000 compounds are discarded17. In recognition of the significant time, resource and commercial risk invested in the research and development of pharmaceutical products, a unique suite of regulatory intellectual property rights apply to enable innovator companies to recoup the value of their investment. The maximisation of these rights are intended to incentivise further research and development18. Regulatory data protection (RDP) is a form of regulatory intellectual property right. It gives a period of protection during which the preclinical and clinical data generated by the originator company in support of its marketing authorisation application cannot be referred to by a generic applicant. Innovative companies have to be able to rely upon that protection in order to plan and execute their commercial activities not only with regard to earning back investments in already authorised medicinal products, but also to invest in the development of future medicinal products. The protection of innovative companies is therefore also in the interest of public health19.
Innovator companies have a major concern that RDP could be placed in jeopardy if appropriate mechanisms are not implemented to protect the value of proprietary data. For example, pharmaceutical companies could obtain proprietary data contained in a CSR in circumvention of the originator’s RDP in countries outside the EU/EEA. It is a very delicate balance to strike between the societal benefits of increased transparency against creating a culture of unbridled disclosure that could thwart further innovation. Ultimately, if companies are not able to protect the value of innovation, equitably and robustly, then further scientific advancement will stall.
In addition to the protection of RDP, there is a concern that the disclosure of information would affect the availability of patent protection and therefore significantly affect the interests of the innovative industry20. Companies may have to delay the filing of marketing authorisation applications to ensure that all relevant patent filings have been submitted so that they do not miss out on essential protection, which is the fuel to drive the further development of new medicines.
The patient’s perspective
From a patient’s perspective, the disclosure of excessive clinical information may lead to unauthorised or innacurate secondary data analyses. This, in turn, raises two key issues: (i) the re-evaluation of this data could violate individual patient privacy as those patients did not consent to such extensive use of their data; and (ii) there is the potential for reporting bias and flawed secondary data analyses, which if published, could confuse patients and create a public health risk due to widespread public alarm sparked by the dissemination of misleading data analyses.
Transparency is a fundamental requirement in order to maintain public trust and confidence in medical research as well as ensuring the accuracy of clinical trials. However, it is vital to have due recognition of the considerable investment that is made by pharmaceutical and academic organisations into the design and structure of clinical trials. It is critical that innovator companies are incentivised to continue to invest in potentially lifesaving and life-enhancing research and development. A disclosure platform that fails to acknowledge the significant resource and cost invested in clinical trials and corresponding intellectual property rights, know-how and CCI will affect the open dialogue with the authorities, potentially delay the introduction in the EU of innovative products and also serve as a disincentive for continued research and development. All these will be to the ultimate detriment of patient and public health in the EU.
About the authors
Maria Isabel Manley is a Partner and Head of the Regulatory Department at Bristows LLP. Maria Isabel specialises in IP matters with a particular focus on European and UK regulatory and competition law in the bio-pharmaceutical, chemical, medical devices, cosmetics and food sectors. She advises on a broad spectrum of matters, both contentious and non-contentious, that arise in the conduct of a pharmaceutical or a biotechnology business (in particular those arising in the context of the life cycle management of medicinal products, including advertising and product liability). Maria Isabel graduated with Bachelor of Law and Master of European Law degrees from Lausanne University. She also holds an LLM in International Law from Columbia University School of Law, New York, and a Postgraduate Diploma in EU Competition Law from King’s College, London. She qualified in 1998 in New York and 2003 in England and Wales, and was made Partner in 2005.
Grant Strachan, Senior Associate at Bristows, focuses on EU and UK regulatory law and has two years in-house experience in the corporate legal department of a leading global pharmaceutical company. Grant has experience of both contentious and non-contentious matters including: lifecycle management; due diligence; clinical trials; marketing authorisation procedures; pharmacovigilance; regulatory inspection processes; consumer products; product labelling legislation; and IP regulatory rights (i.e., regulatory data protection, paediatric research rewards and orphan market exclusivity). He holds a Bachelor of Law degree from the University of Glasgow, Scotland, and an LMM in Innovation Technology & Law (Medical Law, Intellectual Property and European Human Rights) from University of Edinburgh, Scotland. He qualified in 2009.