Low-risk trials for children and pregnant women threatened by unnecessary strict regulations. Does the coming EU Clinical Trial Regulation offer a solution?

Evidence-based medicine has proven instrumental in improving healthcare, with the randomized clinical trial (RCT) regarded as the highest level of evidence. Since the introduction of the EU Clinical Trials Directive in 2001 [1], trials are subject to a regulatory system aimed at transparency and accountability, incorporated in the ‘International Council for Harmonization Guideline for Good Clinical Practice’ (ICH-GCP). Since then, the performance of clinical trials has become increasingly complex, time-consuming and expensive [2, 3]. The largest independent cancer research network in Europe (EORTC) reported that after the directive’s introduction, trial costs increased by 85% and the number of new trials fell by 63% [4]. Data from EU research institutes show a similar effect, as the percentage of investigator-initiated trials declined from 40 to 14% [5]. As a result, there is an increasing interest in nonrandomized (observational) studies to circumvent the administrative and financial hurdles that come with RCTs, though at the risk of biased results [6].

Commercial parties, such as pharmaceutical companies, are less inclined to invest in expensive research with little commercial value [7], such as research on children, pregnant women and other vulnerable groups. The latter results in a relative underrepresentation of these groups in clinical trials [8, 9]. To improve the quality of care and reduce healthcare expenses for these groups, academic researchers, working in a non-profit sector, need to perform their own studies [10]. However, the ‘administrative burden’ resulting from regulations and oversight procedures is becoming a critical obstacle in investigator-initiated research.

The principles that are at the core of our legislation for human subject research, such as that the health of my patient is my first consideration and that research must be conducted by qualified professionals, are beyond reproach. However, demanding full compliance with the ICH-GCP guidelines in studies with only minimal risks does not seem justified. By demonstrating some of the consequence experienced in current research practice, we hope to raise awareness of the effects the ensuing administrative burden has on research [11]. In this context, we will discuss the forthcoming EU Clinical Trial Regulation (No 536/2014) [12]. This new regulation has been adopted and entered into force in 2014, but has yet to come into application. This application will happen 6 months after the European Commission has published notice of a successful internal audit of a new EU portal that will ‘streamline and facilitate the flow of information between sponsors and Member States’. This audit is set to commence in December 2020 [13]. When the regulation becomes applicable, it will replace the current 2001 Clinical Trial Directive and the national legislation that was put in place to implement the 2001 Directive. Therefore, EU member countries and national regulatory authorities are now preparing for the introduction of the new Clinical Trial Regulation (CTR) in their countries. This article addresses and illustrates how the current legislation and the ensuing administrative burden disproportionally affects research practice and threatens the generation of necessary evidence in vulnerable populations [11]. Secondly, we discuss how the more ‘risk-based’ regulatory approach set out in the new EU CTR might offer a solution.

The ICH-GCP guidelines—on which the current oversight regulations are based—were predominantly developed to oversee high-risk commercial placebo-controlled trials evaluating new medical products pursuing market authorization [3, 14]. Unfortunately, these guidelines do not take into account the fact that the clinical trials they regulate can substantially differ in the extent to which they pose physical and/or mental risks to participants. The practical consequences of these regulations are especially evident in so called ‘pragmatic trials’—evaluating well-known, clinical strategies generally applied in present-day healthcare [15]. This type of trial generally causes no or very little additional risks for their participants, but still needs to comply with the same detailed rules as trials with new pharmaceutical compounds with unknown safety profiles.

To illustrate the far-reaching implications of the current regulatory system for research practice, two examples of pragmatic multicentre RCTs are presented here. Both are publicly funded and designed, initiated and carried out by academic researchers. The APAC trial compares initial antibiotic treatment to immediate appendectomy in children [16]. APOSTEL 8 is a placebo-controlled trial for the treatment of threatened preterm birth with the registered tocolytic drug, atosiban, which has been used for this indication since 2000.

Hopefully, the above illustrates how the ‘one-size-fits-all’ approach of the current regulatory system makes the performance of low-risk research very time-consuming and costly without serving its primary goal: ensuring medical progress by carrying out research, while protecting research subjects against risks and burden. Therefore, the medical community has—more than once—called for a more proportionate and appropriate set of rules warranting accountability and transparency [3, 4, 14, 19, 20]. The forthcoming 2014 EU CTR might offer a solution as it introduces a new ‘low-intervention clinical trial’ regulatory framework [12]. It states (recital 11): ‘[m] any clinical trials pose only a minimal additional risk to subject safety compared to normal clinical practice. Particularly when the IMP is covered by a marketing authorization [ …] Those low-intervention clinical trials are often of crucial importance for assessing standard treatments and diagnoses […] contributing to a high level of public health. Those clinical trials should be subject to less stringent rules, as regards monitoring, requirements for the contents of the master file and traceability of IMPs’. The areas that will be positively affected by the new regulation and the probable practical consequences are summarized in Table 2, based on the regulation [12], question and answer draft [21] and the expert group recommendation [22]. All the conditions to classify as a ‘low-interventional clinical trial’ and thus will be subject to less stringent rules are stated in the CTR. article 2. par 3 and are the following:

The exact definition of low-risk trials that can be subjected to this less stringent regulatory regime will determine to what extent the new CTR will bring about less administrative burden. This will depend on how national regulatory authorities interpret the conditions set out in the CTR article 2. par 3. The most important decision will be whether a treatment is considered to be ‘supported by published scientific evidence’ and to what extent additional risks and burden will be regarded as ‘minimal compared to normal clinical practice’. This could be a threat to paediatric and obstetric research as many medical products have not been specifically tested in children or pregnant women and many risk classification tools consider research with these populations to be high risk by default. If this strict interpretation is maintained, it is unlikely that low-risk paediatric and obstetric research can benefit from the less stringent regulatory regime laid out in the CTR.

As for the condition ‘minimal additional risks or burden’, some guidance is provided by the EU commission’s expert group on clinical trials [22]. They specify the following examples of diagnostic/monitoring procedures that can be considered as a minimal additional burden: ‘weighing, height measuring, questionnaires, analysis of saliva, urine, stool samples, EEG and ECG measurements, blood withdrawal through a pre-existent catheter or with minimal additional venepuncture’. Unfortunately, the expert group recommendations are accompanied by a warning that the document does not necessarily reflect the views of the European Commission and should not be interpreted as a commitment to any official initiative. Therefore, it remains unclear to what extent they can be regarded as an official explanation of the terminology of article 2. How this condition is eventually implemented will again depend on the interpretation by the national regulatory authorities. Strict interpretation of the conditions for low-risk clinical trials would mean that the generation of essential evidence for the treatment of vulnerable populations is made almost impossible.

We hope that our experiences with the two trials presented in this paper offer compelling evidence that it is time for a paradigm shift. Such a shift implies that the current one-size-fits-all approach, which dominates current clinical trial oversight, is replaced by a risk-based approach. We expect that this could give a substantial impulse to low-risk investigator-initiated trials, which are currently more and more discouraged by unnecessarily time-consuming and expensive ICH-GCP guideline recruitments. These trials are indispensable for obtaining evidence on optimal and safe treatments for patients, specifically groups that are underrepresented in current medical research, such as children and pregnant women. We hope that both the clinical research community and the European and national regulatory authorities see the urgency of this problem and provide clarity about the room for less stringent monitoring and safety regulations for low-risk trials, as provided in the forthcoming EU Clinical Trial Regulation. We urge regulatory authorities to handle these conditions, needed to classify as low-risk, in such a way that it does not excluded research with children and pregnant women. We also ask for a ‘task-tailored’ approach towards (GCP) training requirements as the current one-size-fits-all approach. The current requirements makes research with extensive teams that perform only limited study tasks alongside their regular clinical work almost impossible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research.