Clinical trials are studies conducted with human trial participants with the intention to increase knowledge about how well a diagnostic test or therapeutic intervention works in a particular population. Randomised clinical trials are the most stringent type of clinical research to determine efficacy and safety, only surpassed by systematic reviews of such trials 1234. However, most clinical trials are conducted using inadequate methodologies and involve too few participants 56789101112. This raises the risks of systematic errors and random errors. The tasks for clinical research are further challenged by the necessity to study the impact of different genetic subgroups on the intervention effect 1314. The summed consequences are that we need extensive research collaboration to secure adequate methodologies and sufficiently large participant numbers 1516. One way to attack these problems is to conduct multinational clinical trials.

Multinational clinical trials require the sponsor to navigate multiple legislative systems and regulatory environments. The objective of the Directive 2001/20/EC was to harmonise clinical trial regulations within the EU member states for investigational medicinal products 17. The opposite effect has been alluded to in a number of articles and reports, citing evidence that the implementation of the Directive 2001/20/EC resulted in divergences at the national level and increased complexity in conducting both national as well as multinational clinical trials 181920212223242526.

Knowledge of the different national regulatory requirements is an essential prerequisite for conducting multinational clinical research, and whereas the larger commercial companies have such provisions, the academic sector and small and medium sized companies are largely without this body of knowledge. The European Clinical Research Infrastructures Network (ECRIN) aims at integrating clinical research in Europe through connecting national networks of clinical research centres and clinical trial units. ECRIN helps investigators and sponsors navigate the minefield of regulatory issues which differ across boarders and provide information, consultation and access to services necessary to conduct multi-centre clinical studies for the benefit of patient and citizens 1516.

ECRIN's Working Group on regulatory requirements and interaction with competent authorities had the task to describe such regulatory requirements and delineate how to interact with competent authorities in the countries involved in ECRIN, covering approximately 70% of the EU population 27. We therefore conducted a survey to identify the national requirements for all categories of clinical research defined and agreed upon by the Working Group 27. The present article describes the results for regulatory requirements during the approval phase of clinical trials on typical investigational medicinal products, in the ten ECRIN countries.

In order to analyse the current situation regarding the regulatory environment during the approval phase of clinical research in Europe, we designed the survey as described in a previous publication 27. The full survey questionnaire is available as online supplementary material http://www.ecrin.org. For the purpose of the survey we identified seven common definitions for categories of clinical research, each split into sub-categories 27. One of the sub-categories was clinical research assessing typical investigational medicinal products (Table 1). Typical investigational medicinal products comprise in general chemically synthesised drugs, constituting the active substance within an investigational medicinal product. Such typical investigational medicinal products are used in phase I to IV clinical trials independently of the question, if they have been authorised before for the investigative or for any other use. Less typical investigational medicinal products, mainly biopharmaceutical investigational medicinal products and a variety of other less typical investigational medicinal products (Table 1) are also assessed in phase I to IV clinical trials, but are not dealt with in the results section of the present article. Our responses to the survey questionnaire on both typical investigational medicinal products and less typical investigational medicinal products have been reported to the European Commission in 2008 and are available at http://www.ecrin.org/index.php?id=101 28.

The ECRIN Working Group on regulatory requirements and interaction with competent authorities was composed of two chairpersons and at least two representatives from each national network from Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom: an expert in the field of regulations and regulatory requirements and the national ECRIN European Correspondent (ECRIN staff trained in clinical research and located in the national coordinating hubs) 27. For each of the categories of research, the following questions were asked to the Working Group members:

- what is the definition of an investigational product?

- what competent authorities exist in your country?

- is a submission to competent authority required (specify the name of the competent authority and who is responsible for the submission)?

- what are the timelines?

The Working Group members answered the questions by consulting national law documents, web-sites, conducting telephone interviews, etc. The responses to the questionnaire were circulated to the Working Group on regulation and interaction with competent authorities. The results were discussed during several teleconferences and in face-to-face meetings in Paris (19 and 20 May 2007) and Brussels (19 and 20 May, 2008). Moreover, additional teleconferences were held between one of the chairs (JD-M) and national representatives in order to discuss specific national aspects in depth 27. We also conducted a validation step with the national representatives from the competent authorities of the involved countries.

Our results show that clinical trials using typical investigational medicinal products require authorisation from a competent authority in each of the ten EU countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines in all ten countries surveyed. This is a clear indication that the requirements of the Directive 2001/20/EC 17 have been relatively uniformly adopted for this type of clinical research in these ten countries, and their application structure, that is the institutions one has to apply to, is comparable but not identical. The overall result of the implementation of the Directive 2001/20/EC is harmonisation of requirements for typical investigational medicinal products and a navigable landscape for the applicant.

In practice, this harmonisation of regulatory requirements is in fact specific to a certain type of investigational medicinal product, which we name 'typical investigational medicinal product'. In practice, the regulatory requirements are not harmonised for a number of other important investigational medicinal products, which we name 'less typical investigational medicinal products' 27, including different sub-categories of medicinal product as listed and described in the Directive 2003/63/EC 36:

○ Biological medicinal products, i.e., proteins preceded either from biological material by standardised purification techniques or by recombinant DNA technologies or hybridoma or monoclonal antibody methods.

○ Vaccines.

○ Advanced therapy medicinal products, consisting of

- gene therapy medicinal products (human or xenogeneic);

- somatic cell therapy medicinal products (human or xenogeneic);

- tissue engineered product, i.e., a product that contains or consists of engineered cells or tissues (human or xenogeneic).

○ Plasma-derived medicinal products.

○ Blood products.

○ Radio-pharmaceuticals and precursors.

○ Homeopathic medicinal products.

○ Herbal medicinal products.

The seemingly uniform definition of an investigational medicinal product from the Directive 2001/20/EC 17 did not prevent many sub-categories of medicinal products to be selected out across the EU. This gave rise to specific regulatory requirements across EU Members States. These specific regulatory requirements have increased the complexity of the national clinical trial regulation in the EU 28 and participated in the creation of a chaotic regulatory environment which threatens ethical and fairness considerations both to patients and researchers 1516181920212223242526. The chaotic regulatory environment, in which intervention decides regulation 28, alienate researchers from understanding the basis for implementing interventions into clinical practice and this puts patients at risk.

The definition of a 'medicinal product' in the Directive 65/65/EEC 29 and reiterated in the Directive 2001/20/EC 17 and the Directive 2001/83/EC 30 is much clearer, comprehensive, and fairer than the definition of an 'investigational medicinal product' in the Directive 2001/20/EC 17. The former Directives defines a medicinal product as: "a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis." However, the Directive 2001/20/EC 17 defines an investigational medicinal product as: "a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form".

We would very much have preferred that the definition of an 'investigational medicinal product' built upon the wording for the definition of a medicinal product used in the Directive 65/65/EEC 29, Directive 2001/20/EC 17, and Directive 2001/83/EC 30, e.g.,: a medicinal product (as defined by the three cited Directives) with potential beneficial properties being tested, or used as a comparator reference, in a clinical trial. Including products already with a marketing authorisation but used or assembled (formulated or packaged) in a way different from the authorised form, or when used for an unauthorised indication, or when used to gain further information about the authorised form.

There is a huge amount of legislation and guidance pertinent to clinical research in the EU as well as in the different member states; this makes it difficult to have an overall view of the full regulatory requirements 1730373839. An overview of the kind presented here is novel and provides a necessary overview of the regulatory framework within the ten EU countries participating in ECRIN during the 2006 to 2008 period regarding typical investigational medicinal products. To our knowledge this is the first time that a survey about the regulatory basis for typical investigational medicinal products has been conducted in such depth.

The present study has a number of weaknesses. First, we only assessed ten countries. Although we covered the majority of the EU population (70%) there are still 17 EU countries not considered. ECRIN is in the process of linking to the national clinical trial networks in these countries and ECRIN will assess their regulatory environment regarding typical investigational medicinal products 30. Second, we only assessed the regulatory authority structure during the approval phase of the trial in the surveyed countries, not how the regulatory process was working during the conduct and termination of the trial. Third, we did not go into details about how other aspects of the Directive 2001/20/EC, e.g., good clinical practice were implemented and functioned. Fourth, we only concentrated on how the typical investigational medicinal product was handled in the national laws and regulations. The latter also explains why the present study observes relative harmonisation compared to other assessments of the implementation of the Directive 2001/20/EC, which found divergences at the national level and increased complexity in conducting multinational clinical trials 181920212223242526. In our assessments of less typical investigational medicinal products we observed substantial heterogeneity 28.

Compared to typical investigational medicinal products, the regulatory landscape is not so navigable for other categories of clinical research 2728. Although, strictly speaking, all investigational medicinal products are legislated for under the 2001/20/EC Directive and the definitions therein, less typical investigational medicinal products such as biopharmaceutical investigational medicinal products or other less typical investigational medicinal products investigating gene therapy, tissue engineering, cell therapy, blood-derived products, monoclonal antibodies, recombinant proteins, vaccines trials, etc 27 all necessitate additional regulatory requirements, which vary across Europe 28. In short, the regulatory environment is much more heterogeneous and thereby problematic for academic trialists and small and medium sized companies regarding other medical interventions 28. This puts at stake the interests of patients 2526.

Regulatory requirements should be in place with the principal objective of protecting the participants and ensuring their safety, and that regulatory requirements can be adjusted according to the risk of the trial 28. However, it appears that regulatory requirements in different Member States are driven trivially by the category of the intervention and not on the overall risk of the trial 2728. An innovative biopharmaceutical product could be equally as high risk as an innovative surgery. Risk is a complex and multi-faceted concept and can be influenced by, among other things, vested interests (sponsorship), the size of the trial (feasibility), the number of centres (feasibility and quality assurance), and crucially, and the nature of the experimental and control interventions 40. Therefore, a risk based approach rather than an approach depending on type of investigational medicinal product seems a better way to determine the need for security and monitoring in a given clinical trial 2441. Interestingly a pilot initiative steered by the MHRA, the MRC, and the Department of Health started in April 2011 the UK, defining risk assessment and risk-adapted supervision in the framework of the Directive 2001/20/EC 33.

The Voluntary Harmonisation Procedure implemented since 2010 represents a substantial progress for the regulatory supervision, allowing coordinated review for multinational trials 34. We ought to go further and implement a single application and authorisation process for all clinical trials, by which the sponsor submits one electronic application which is accessible by the competent authorities, the ethics committees, and the public, with harmonised definitions of the roles of the ethics committees (protection of the trial participants) and of the competent authorities (assessment of the health product) 2835.

The Directive 2001/20/EC seems to have delivered on its harmonisation objective regarding typical investigational medicinal products during the application phase; we commend this achievement. However, it only benefits sponsors and investigators conducting clinical trials on typical investigational medicinal products. We cannot have a hierarchical system where the regulatory requirements are relatively harmonised and navigable for one set of clinical interventions and a minefield of country-specific barriers for other clinical interventions 28. Our results show that the harmonisation is limited to the field of typical investigational medicinal products 28; this harmonisation does not even encompass all investigational medicinal products that Directive 2001/20/EC itself defined. Only a European regulation, binding in their entirety to and immediately applicable in all EU member states, can truly harmonize the rules for clinical research in Europe. De-fragmentation of the authorisation procedure as well as risk-based clinical trial supervision and monitoring processes should be key elements in such new legislation.

None of the authors have financial or non-financial competing interests.

CK, JDM, and CG drafted the survey and conducted the analyses of the results. All the authors participated in the development of the survey and discussion of the results. JDM, CK, KW, and CG drafted the manuscript. All the authors have read and corrected draft versions of the manuscript and approved the final version.