The new European Clinical Trial Regulation536/2014 replaces the 2001 directive. Despite debates it remains a two-tier procedure and does not guarantee patient involvement. Using our experience in two European clinical projects, we provide support and recommendations to improve the new ethics assessment and monitoring procedure. The findings presented show that an integrated European-wide, multidisciplinary assessment from the ethical, safety, scientific and patients’ perspective is achievable.

Keywords: ethics, clinical trials, patient involvement, european regulation

The European Union (EU) Clinical Trials Directive 2001/20/EC regulated the administrative requirements and ethical and safety aspects of clinical trials on medicinal products for human use within the EU.¹ It was an assessment system with separate review procedures of clinical studies by national authorities on the one hand and a (medical) research ethics committee on the other. This double-review system is illogical, since performing research that is scientifically questionable is ethically not justified. The two-tier system is also time-consuming, bureaucratic, inefficient and increasingly expensive, as highlighted in reviews of the system and a survey by the European Commission (EC).^2-5 Moreover, the communication between the two review boards, their respective accountability and their capability of monitoring ethically approved studies is unclear and the role of the patient perspective is undervalued.

Integration of the ethical, scientific and patient perspective assessment seems better suited for most clinical studies.⁶ A review from the patient’s perspective is important as patients are affected by their own treatment and have the knowledge and experience of living with their disease every day. Having patients as partners in research ensures democratic decision making and the relevance of research, resulting in greater chances of societal implementation.^7-9 In 2014 the new clinical trial regulation was approved planning ethics review assessments for international clinical research at the European level and at the national level separately.¹⁰ However, patient involvement is still not explicitly warranted. Here we discuss a best practice from two European multidisciplinary research consortia where the scientific and ethical review assessments were combined and the patient perspective was integrated.

The Innovative Medicines Initiative (IMI), a joint undertaking between the EC and the European Federation of Pharmaceutical Industries and Associations, provides grants for collaborative research projects. IMI aims to improve healthcare, treatment, patient-doctor-scientist-industry relationships and patient information. Healthcare and patient-representing organisations are involved as partners and stakeholders.¹¹ This paper focuses on IMI funded projects U-BIOPRED¹² and PRO active.¹³ While both projects have medical objectives, U-BIOPRED had a strong life science focus towards an unbiased biomarker approach for severe asthma, whereas PRO active was looking at a clinically applicable, patient reported outcome measure capturing aspects of physical activity as experienced by patients. Both projects started in 2009 and ran initially for five years.

Within both projects, internal advisory boards dealt with ethical and patient safety issues from a patient, legal and scientific perspective (Table 1). The composition of the multidisciplinary boards is in line with European and national regulations, but include sup to 50% of patients from different European countries (Table 1). For patients, we developed membership criteria including higher education, interest in research, and ability to communicate in English with lay persons and scientists. This is in line with the proposed function and review role as described for professionals⁶ and patients.^14,15 These boards reviewed and advised on study protocols, patient information sheets and informed consent forms (PIS-ICFs), and monitor all ethical, scientific conduct or safety issues arising during the study. For patient perspective issues, the boards were assisted by patient advisory boards (Patient Input Platform, PIP). The assessment was done simultaneously from a scientific, as well as an ethical and safety perspective and it specifically addressed the patient perspective. The U-BIOPRED safety monitoring board (SMB) had decisive capacities related to safety issues that can affect the study or project progress. In PRO active, safety monitoring was integrated in the ethics board (EB).

In both projects, English-language PIS-ICF templates were developed. These templates were adapted by the clinical research centres to the local situation. We developed novel instruments for healthcare and research professionals, so that they could participate in the advisory boards and perform their tasks. These instruments included monitoring criteria, appropriate ways for communication and discussion (e-mail, secured web forum, face-to-face meetings), charters and standard operating procedures.¹⁶ The function of patients as lay persons was substantiated by the development of appraisal criteria that take different domains of the patient perspective into account.^8,17 The criteria included relevance for patients, improvement of quality of life, least burdening method for participants, compliance with regulations, clear lay and risk information to participants, and feedback of general results. One of the improvements was replacing the word “subject” in clinical studies with “person” or “participant”. The profits of patient engagement in U-BIOPRED have been described previously.¹⁸ We evaluated whether the boards contributed to the progress, quality and relevance of the projects. We studied the number of issues that the respective boards dealt with during the first 3.5 years, whether the advice was endorsed and implemented, and evaluated the process of interdisciplinary assessments and activities.

We examined the number and type of responses given by the boards that were implemented into the protocols, PIS-ICF, and other procedures (Table 2). Types of responses were: a) a review in which documents were commented upon; b) advice on a question or issue arising from the project; or c) an action referring to a request by board members to partner organisations, for example handing over approval from local ethics committees. Table 2 shows the percentage of the responses that were endorsed or acted upon by the study leaders. In U-BIOPRED, over 88% of the advice from the boards to the project partners was endorsed and implemented (EB: 22/25; SMB: 18/19). In PRO active, all advice was endorsed and implemented, resulting in adaptations of protocols and forms or texts.

Subsequently, we analysed the number and type of issues dealt with per advisory board (Table 3). Issues included: 1) recruitment rate; 2) lay language of the PIS-ICFs and brochures or web information texts; 3) methodological aspects in study protocols and PIS-ICFs (like safety and technical aspects of procedures, the need for nasal biopsies in U-BIOPRED, anonymisation procedure); 4) a better explanation of the study rationale, methods or rights of participants; and 5) feedback of results to participants. Differences between boards are related to ethical, safety or privacy issues regarding inclusion of participants (relatives, employees, patients already included in other studies), risk descriptions, such as radiation exposure and bronchoscopies or other methodologies, reporting of severe adverse events, and ensuring that the PIS-ICFs mention having an insurance for participants.

We also evaluated the process of interdisciplinary assessments and activities. All board members participated voluntarily. Upon a request for advice, the boards were informed within approximately two days. Reply time for the boards was set at 2-3 weeks. In U-BIOPRED the replies were given by 50.3%±22.3% (mean±SD) of the members in the boards with no differences between the boards. In PRO active 83%±13% of the EB members replied. All replies were given within the set time lines. Subsequently, the (co-) chair of the respective boards prepared a combined advice based on the replies within two working days. If needed, for example in case of further questions by board members, the advice was returned to the respective board. Where appropriate, the advice was adapted within one working day and sent to the study leaders. The total time for review or reply took 3-4 weeks. No differences in conduct or reply time were seen between the projects. The advice given contained elements related to ethics and/or patient safety, scientific and patient perspectives. Regular monitoring of the studies by the boards was based on newly developed criteria on ethics or safety aspects. This included safeguarding feedback of general results to study participants (done in year 4 of the studies).

This study was carried out on behalf of the U-BIOPRED consortium (www.europeanlung.org/en/projects-and-research/projects/u-biopred/who-is-involved/project-members) and the PRO active consortium (www.proactivecopd.com/about/advisory boards), including principal investigators, ethics boards, the safety monitoring board and patient input platforms as stated on these websites. We acknowledge review and type-editing by dr. P.D. Powell (European Lung Foundation, Sheffield, UK) and prof. dr. P.J. Sterk (Academic Medical Center, Amsterdam, NL). The U-BIOPRED study is funded by Innovative Medicines Initiative Joint Undertaking (IMI-JU) grant #115010 and the PRO active study is funded by IMI-JU grant #115011. The sponsor IMI has no role in this study or in study design, data collection, analysis or interpretation, the writing or submission of this paper.

Authors declare that there is no conflict of interest.

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