The Clinical Trials Directive from 2001 (2001/20/EC) commissioned by the EU, and currently in force, seeks to regulate and streamline clinical research across Europe [
54‐
58]. Trial investigators and sponsors are required through this directive to ensure ethical review and authorisation by competent national authorities before enrolment into a trial, to manufacture drugs according to good manufacturing practice (GMP) principles, and to assure GCP standards during the conduct of a trial. Moreover, all trial-related changes are to be reported to the supervising authorities [
58]. The restrictive nature of the directive means that each EU member must stray from national legislation and form a legal framework that will meet the imposed requirements, which has caused regulatory approval for clinical trials across Europe to become exceptionally complex [
46,
55,
56,
58]. By increasing the administrative burden and time taken to launch new trials, the presently effective EU Clinical Trial Directive 2001/20/EC is believed to have contributed to the significant decrease in numbers of RCTs conducted in Europe, especially non-commercial RCTs [
6,
59]. The European Commission recently developed a new Clinical Trial Regulation (EU No 536/2014), which aims to simplify procedures and harmonise regulatory requirements across Europe. The new regulation is scheduled to come into force no earlier than 2019 [
60]. The ambition is to reverse the observed decline in RCTs, and to ensure that Europe remains an attractive site for clinical research [
61].
The arguments for applying a high degree of complexity to regulatory requirements are unclear, and in some cases, the regulation is inadequate. Issues include: (a) approval by multiple ethics committees with different sets of requirements leading to multiple trial contracts, and moreover, a lack of well-educated ethics committees that may delay approval and regulatory assessments, e.g., by requiring excessive, explanatory details in the protocol and during participant enrolment [
62,
63]; (b) multiple rules and different strategies for data management applied at different research sites or between countries that may lead to unnecessary costs and delays, and moreover, an increasing demand for reporting and storing information combined with inadequate data management systems, which could hamper data quality and thereby threaten the usefulness of results [
64]; (c) pharmaceutical companies are not required to deliver placebo free of charge, which may hinder non-commercial research as valid placebos are expensive and cumbersome to produce. Accordingly, international laws should demand from manufacturers of drugs, device components, food additives, colour additives, or dietary supplements that get access to a market, to provide valid placebos for independent investigations of the product on request; (d) lengthy informed consent forms that include complex legal language, which, first, raises doubt about whether patients are truly informed about the trial, and second, may intimidate eligible participants, leading to poor accrual, delays, and premature termination of trials [
58,
59]. It has even been claimed that requirements for consent forms focus on protecting the review board from risk rather than the participants [
65]; and (e) complex safety reporting, including detailed recording of minor events (e.g., known adverse effects), and over-reporting of all serious adverse events to all relevant regulatory authorities, ethics committees, and site investigators, which could lead to an overwhelming bulk of reports with rarely useful insights or improved safety [
58,
59,
66].