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In 2014, EU Regulation n.536/2014 represented a significant step toward transparency of clinical trials in Europe. However, despite the EMA’s policy 0070, which reinforced this concept, several aspects remain to be determined or evaluated, leaving room for additional requirements and local interpretation.
The European journey toward clinical trial transparency (see Figure 1) started in 2003 when the European Medicines Agency (EMA) first published the European public assessment reports. Since 2012, the EMA behavior on trial transparency was reactive, meaning that trial information was available upon request. In 2012, a more proactive measure was proposed for clinical trial transparency, and a long process of consultation with stakeholders, including clinicians, patients’ associations and pharmaceutical companies began.1 In 2014, a new regulation on clinical trials (EU Reg. n.536/2014)3 was published and in October 2014, the EMA policy 00704 reinforced the concept of clinical trial transparency. In addition, in 2012, the EU Pharmacovigilance Regulation was published.2
According to the European Treaty, a regulation shall have a general application and is directly applicable to all member states. Therefore, each of them should implement the EU Reg. n.536/2014 that applies to all clinical studies conducted in Europe, except for non-interventional studies. This new legislation replaces the EU Clinical Trials Directive (EUCTD), which was approved in 2001 and implemented in 2004.5 The EU reg. n.536/2014 established a novel definition of a clinical study. As stated in article 2 of the Regulation, a clinical study is any investigation about humans with the objective of ascertaining the safety and efficacy of those medicinal products, intended to:
To ensure a sufficient level of transparency in clinical trials, the EU reg. n. 536/2014 states that “the EU database should contain all relevant information as regards the clinical trial submitted through the EU portal. The EU database should be publicly accessible, and data should be in an easily searchable format, with related data and documents linked together by the EU trial number and with hyperlinks, e.g., linking together the summary, the layperson's summary, the protocol and the clinical study report of one clinical trial, as well as linking to data from other clinical trials which used the same investigational medicinal product. All clinical trials should be registered in the EU database before being started. As a rule, the start and end dates of the recruitment of subjects should also be published in the EU database.”
Based on this legal context, on Oct. 2, 2014, EMA released the policy 0070 on the publication of clinical data for medicinal products for human use,4 as a complementary tool ahead of the implementation of the EU Reg. n. 536/2014, effective since May 2016. In order to fully accomplish the EU reg n. 536/2014 requirements to guarantee clinical trial transparency, biopharmaceutical companies should start implementing an internal procedure to upload information of clinical trials to the EudraCT platform and provide the layperson summaries (see Figure 2).
Publication of clinical data
Policy 0070 on publication of clinical data for medicinal products for human use is the result of an extensive EMA initiative, which started in 2012 and involved more than 1,000 stakeholders among academic, industry representatives, patients’ associations, editors and lawyers. EMA was committed to continuously extending its approach to clinical trials data transparency, with the aim to make medicine development more efficient.
Moreover, EMA intended to foster public scrutiny to clinical study information by the scientific community and to develop knowledge in the interest of public health, protecting and nurturing the latter, while promoting a better-informed use of medicines. Indeed, the policy states “A high degree of transparency will take regulatory decision-making one step closer to EU citizens, and promote the better-informed use of medicines. (…) The access to clinical data will benefit public health in the future.”
The scope of the EMA Policy 0070 relates to proactively sharing study-level and patient–level clinical data, i.e., clinical reports (clinical overviews, clinical summaries, clinical study reports, protocol and protocol amendments, sample case report forms, documentation of statistical methods) and individual patient data (IPD), submitted under the centralized marketing authorization procedure after Jan. 1, 2015.4
The process included two sequential phases: in the first one, only the clinical reports supporting centralized marketing authorization application (MAA) submitted only after Jan. 1, 2015, and-starting from July 1, 2015-clinical reports supporting the request for line extensions followed the same rules. In the second phase, after finding the most appropriate way to make them available in compliance with privacy and data protection laws, the IPD will also be provided.4Anonymization of clinical report data
To protect the privacy of patients, EMA issued guidance6 to the pharmaceutical industry on anonymization procedures of clinical reports. The direction aims at assisting companies by recommending methods, techniques and processes that could be applied to clinical reports in order to achieve an adequate anonymization, while retaining a maximum of scientifically useful information on medicinal products for the benefit of the public. Indeed, the same data can be adequately anonymized in different ways, depending on the context of the data release.
In the case of public data release, the risk of re-identification should be slight, whereas, for non-public data sharing, a higher risk could be acceptable.
Due to an active and rapid IT research in this field, many anonymization techniques are currently available to marketing authorization holders (MAHs)/applicants. The legislation is not prescriptive about the techniques to be used by data controllers. According to the Article 29 Working Party Opinion, examples of techniques that could apply to clinical reports are masking, randomization and generalization.7
When anonymizing structured data, the main goal is preventing the linkage of sensitive datasets to an identified dataset (or similar background knowledge about individuals). While it is obvious to remove the so called “identifiers,” the attributes that may be used for linkage are defined as “quasi-identifiers,” which are not identifiers, per se, but may be combined to generate a linkage. In addition, these data cannot be removed because they may be required for the analysis. Assuming that directly identifying information has been already eliminated from the dataset, the k-anonymity privacy model should be implemented to enhance data protection. A dataset is k-anonymous if, regarding the quasi-identifiers, each data item cannot be distinguished from at least k-1 other data items. This property can be used to define equivalence classes of indistinguishable entries.8 To fully accomplish the generalization procedure, entries from equivalence classes that violate the privacy model (i.e., outliers) are automatically replaced with semantic-free placeholders, while the percentage of suppressed records is kept under a given threshold.8 Available IT tools can calculate utility measures to guarantee the minimal loss of information after k-anonymization and aggregation procedures.
Redaction of commercially confidential information
To allow pharmaceutical companies to protect any information contained in the clinical reports submitted to the EMA-which is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the applicant/MAH-EMA issued an External guidance on the identification and redaction of commercially confidential information (CCI) in clinical reports for the purpose of publication in accordance with EMA Policy 0070.6
For healthcare companies, the guidance is a working tool and a reference document that aims at supporting them in the procedure of redaction of CCIs and in the preparation of their justifications. EMA will scrutinize the justification for the redaction to assess whether the definition of CCI applies.
Since 2014, the delivery of the EMA Policy 0070 certifies on a publicly available website that established policies and procedures are available to implement data-sharing commitments.4 Currently, any users with a straightforward and limited registration process can access the clinical data of all trials submitted under the centralized MAA, irrespective of the outcome of the latter. However, it is reasonable to think that only qualified scientific and medical researchers would benefit from highly complex data, such as those reported in clinical trial documentations. Some pressure from patients’ associations and a novel patient-centered attitude led EMA to increase the ethical responsibility toward patients who actively participate in clinical studies and introduce a further document, the layperson’s summary, in the MAA procedure. The layperson summary should be posted on the EU database and linked to other documentations of the trial. Therefore, article n. 37 of the EU Reg. n. 536/2014 requires the sponsors to provide the summary results of clinical trials in a format understandable to laypersons. The Annex V of this regulation sets out the 10 elements that the document should include.3
The consistency in the way that trial results are presented will help participants, patients and other third parties improve familiarity and comprehension of the trial. Research participants and the general public are expected to be the primary audience of the lay summaries. Healthcare professionals and academics will also be able to access them. Given this broad audience, the summaries will need to take into account the literacy level of the general population, provide simple explanations and apply other measures to support health literacy. Indeed, the general principles of the layperson summary are not assuming any prior knowledge of the trial from the audience. The document should, therefore, be shaped in the most understandable way for people who have neither the level of competence nor the priority of interest of healthcare professionals. Conveniently, the Annex V does not provide any hierarchy of information but defines only the required contents (see Figure 3).
The author should keep in mind that the hierarchy of information is a discriminating criterion for the comprehensibility of the layperson summaries. For instance, common sense suggests that the clinical trial identification is not at the top of layperson priorities, with more interest in questions such as “what is this clinical study for?" and "does it demonstrate that this drug is safe and effective?” Furthermore, it is important that a professional writing team, which wrote the other clinical reports, also provides and/or reviews the layperson summary. This will guarantee the full consistency of the summary with other clinical data.
The trial sponsor should ensure that the layperson summary is developed and submitted to the EU database. The summaries are expected to be available in the local language of each European country where the trial took place. Where resources allow, sponsors should consider including an English version, as the use of a common language will allow greater accessibility across Europe; however, this is not mandatory.9
The debate on the best way to write a layperson summary is still open, and NHS is actively working on it. Although no official guidelines have been provided yet to write a fair layperson summary, the industry and patients’ associations have released some recommendations. The collaboration between sponsors and patients, patient representative, or advocated may be crucial to ensure that the layperson summary meets its expectation. This process won’t be feasible for some studies, but where it is a possibility, it may enhance the final version.
The document should be as short as possible (one or two pages at maximum, but no word number limitations have been established), focusing on unambiguous, factual information and void of any promotional content. The layout and content for each section should meet the needs of the general public regarding style, language and literacy level. Well-chosen and clearly designed visual aids can help enhance understanding of the text. Indeed, the combination of clear infographics with explanatory text can be a good way of presenting complex information.
Where used, visuals should offer one message per image and be clearly labelled with captions. Visuals should be near the text that they attempt to illustrate. On the other hand, very complex images, such as graphs showing several relationships, can be easily misinterpreted and should be avoided. Creative and interactive solutions to ensure understanding could include videos, cartoons and animation; these tools may be particularly appealing for younger patients.10, 11Conclusion
The EU Reg. n.536/2014 represents a significant step toward harmonization for the conduct of clinical trials in Europe. It sets up a common procedure for all types of clinical trial applications with a coordinated assessment by the reporting member state for the scientific documents. Furthermore, the provisions laid down in the Regulation also reflect societal demands for increased transparency on the clinical trial information both for healthcare professionals and for laypersons. Moreover, the Regulation also provides simplified and streamlined safety reporting requirements and establishes that the member states shall cooperate on safety information assessment.
However, despite the publication of Policy 0070, several aspects remain to be determined or evaluated at a national level, thus leaving room for additional requirements and local interpretation. To ensure a smooth transition to the new regulatory framework, MAH/sponsors should not only closely follow the development of the upcoming implementing measures but also start putting in place relevant measures to ensure compliance (e.g., adaptation of clinical trial application process, implementation of a suitable system for notifications).
A. Ferrari, MD, PhD, with Erydel S.p.A.; E. Sala, PhD, E. Ornago, MSc, and M. Zaninelli, MA, all with Maxer Consulting s.r.l.
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