Last week, Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use was published in the Official Journal of the European Union. The Regulation establishes a single, EU-wide harmonised set of rules that will apply to all clinical trials conducted in the EU. Most notably, the Regulation streamlines the authorisation procedures, simplifies specific sponsor obligations, and ensures public access to clinical trial information. The Regulation will enter into force on 16 June 2014, but will not apply before six months have passed from the point at which the EU portal and database become fully operational, and in any event no earlier than 28 May 2016.
Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (“the Regulation”) will repeal the current regulatory regime for clinical trials laid down by Directive 2001/20/EC (“the current regime”). The current regime has been widely criticised by all stakeholders for having increased the regulatory burden and costs of conducting clinical trials in the EU, resulting in a significant decline in the number of trials since the adoption of the Directive.
With the objective of re-establishing the EU’s competitiveness in the field of clinical research, the Regulation introduces a single, harmonised regulatory regime that applies to all clinical trials conducted in the EU. The new system will operate through a single EU portal through which applications for clinical trials will be processed and through which the relevant information will be stored in a single EU database. The information in the database will be publicly accessible.
While the Regulation introduces simplified and more efficient procedures, at present it remains to be seen to what extent the new system will represent a true improvement for pharmaceutical companies in practice.
Main Changes Introduced by the Regulation
The Regulation introduces important changes, some of which concern (i) the scope of application; (ii) the ‘harmonised’ authorisation procedure; (iii) the streamlined reporting; and (iv) the public disclosure of clinical trial data.
1. SCOPE OF APPLICATION
The new clinical trials regime, just like its predecessor, will apply to all clinical trials conducted in the EU, apart from non-interventional studies. The Regulation clarifies certain definitions (e.g. clinical trial, non-intervention clinical trial) and introduces new ‘categories’ of clinical studies, actors involved, and medicinal products.
LESS BURDENSOME REQUIREMENTS FOR ‘LOW-INTERVENTION CLINICAL TRIALS’ – The Regulation adopts a risk-based approach (acknowledging that not all clinical trials carry the same level of risk) and introduces a new category of ‘low-intervention clinical trials’. Low-intervention clinical trials are trials that are conducted using authorised (instead of investigational) medicinal products and that do not pose a substantial additional risk compared to normal clinical practice (notably because quality, safety and efficacy would have already been assessed in the course of the marketing authorisation procedure). Low-intervention trials will be subject to less stringent rules, in particular with regard to insurance requirements, monitoring and reporting obligations, and traceability of investigational medicinal products.
NEW CONCEPT OF ‘CO-SPONSORS’ – The current regime requires that a single ‘sponsor’ be identified as the person or entity that takes responsibility for a clinical trial. In practice, this requirement has proved unfit for situations where multiple companies or scientific institutions act jointly in the organisation of a clinical trial. To solve this difficulty, the Regulation provides that a clinical trial may have one or several sponsors (defining the latter as ‘co-sponsors’). All co-sponsors in principle share the same responsibility, but they may provide otherwise through a written contract setting out their respective responsibilities.
NEW CATEGORIES OF MEDICINAL PRODUCTS – The Regulation introduces the concept of “auxiliary medicinal products” to refer to products that are used for the needs of a clinical trial as described in the protocol, but not as investigational products. Auxiliary medicinal products may or may not have been granted a marketing authorisation (in the former case they fall in the sub-category of “authorised auxiliary medicinal products”).
Moreover, the Regulation allows Member States to set specific requirements for special categories of medicinal products. In particular, the Regulation will not affect the application of national laws prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products containing, consisting of or derived from those cells, or products used as abortifacients, or containing narcotic substances. Also, no gene therapy clinical trials may be carried out which result in modifications to the subject’s germ line genetic identity.
2. A ‘HARMONISED’ AUTHORISATION PROCEDURE
The Regulation introduces a ‘harmonised’ procedure for the assessment and approval of clinical trial authorisation applications (as well as for applications for substantial modifications), operated through a single EU online portal. On the one hand, it allows companies to submit a single application dossier for all Member States where they intend to carry out the trial. On the other hand, most aspects of the trial, other than those of an intrinsically national nature, are subject to a single assessment valid for the entire EU territory. While the Regulation harmonises the authorisation procedure to a large extent, many aspects remain to be assessed at the national level, including by ethics committees. The extent of harmonisation that the Regulation will achieve in practice therefore remains to be seen.
SINGLE APPLICATION THROUGH A SINGLE EU PORTAL – Under the current regime, the sponsor of a multi-centre clinical trial to be conducted at sites that are located in different Member States must apply for an authorisation in each Member State. This means that a sponsor may be required to submit up to 28 dossiers to up to 28 national authorities, in up to 24 different languages.
The new regime will allow the sponsor to submit one application dossier to all Member States where it intends to conduct the study through a single online portal. Of note, the Regulation did not go as far as requiring Member States to accept submissions in English, though it recommends such practice (referring to the use of a “commonly understood language in the medical field”).
CENTRALISED ASSESSMENT BY A REPORTING MEMBER STATE – Under the current regime, each Member State is responsible for assessing the application for a clinical trial authorisation for its own territory. This exposes pharmaceutical companies to high costs and a significant administrative burden, as well as to a high level of (legal) uncertainty due to divergent positions among regulatory authorities in different Member States.
The Regulation now sets forth a twofold procedure for the assessment of clinical trial applications. All aspects covered in Part I of the dossier (namely those concerning the type of clinical trial, risk-benefit analysis, and compliance with technical requirements) are assessed by a so-called ‘reporting Member State’. The reporting Member State’s Part I assessment report is valid for the entire EU. All aspects covered in Part II of the dossier (i.e. those that have an intrinsically national nature such as informed consent and compensation of subjects), are assessed by the other ‘Member States concerned’, i.e. by each Member State individually for their own territory.
A Member State concerned may refuse to approve a clinical trial if: (i) it finds, on “duly justified grounds”, that the trial does not comply with the requirements covered by Part II of the assessment report; (ii) an ethics committee has issued a negative opinion that is valid for the entire Member State; or (iii) it disagrees with the reporting Member State’s Part I assessment report. A Member State concerned may only disagree in very limited cases, and namely if it can show that: (i) a subject would receive an inferior treatment than in “normal clinical practice” in that Member State; (ii) national law would be infringed; or (iii) subject safety or data reliability and robustness would be compromised.
SHORTER TIME FRAMES – The current regime provides for a harmonised time frame for the granting of a clinical trial authorisation that applies to all Member States. As a general rule, Member States have 60 days to reject a trial application from the receipt of the application.
Under the new regime, authorities’ time frame for approval will be (slightly) shorter. In particular, both the reporting Member State (for Part I of the dossier) and the Member States concerned (for Part II) must submit an assessment report within 45 days from the validation date. Validation of the application must take place within 10 days from the sponsor’s submission. Extensions of the time limits will be possible for certain categories of investigational medicinal products (e.g., biotechnology products) or if the reporting Member State requires additional information from the sponsor. If the Member State does not assess an application within the required deadline, the Regulation now explicitly provides for a system of tacit approval of the application.
REFERENCE TO OTHER CLINICAL TRIALS – If an applicant intends to refer in its application dossier to data generated in another clinical trial, it may only do so if the other clinical trial: (i) has been conducted in accordance with the Regulation, the current regime (for trials conducted before the Regulation becomes fully applicable), or equivalent principles (for trials conducted outside the EU); and (ii) has been registered prior to its start date in a public register which is a primary or partner register of, or data provider to, the WHO ICTRP (or alternatively, for trials started before the date of full application of the Regulation, if the results of the trial were published in an independent peer-reviewed scientific journal).
3. STREAMLINED REPORTING
The Regulation streamlines sponsors’ obligations to report adverse reactions and other events to the authorities of the relevant Member States. While the Regulation simplifies the current system, it overall appears to increase pharmaceutical companies’ reporting obligations.
SIMPLIFIED ADVERSE REACTION REPORTING – Under the current reporting system, the sponsor is required to report all suspected serious unexpected adverse reactions to the competent authorities and the ethics committees of the different Member States. The sponsor must do so within 7 days for all adverse reactions that are fatal or life-threatening, and within 15 days for all other adverse events.
The new Regulation takes a very similar approach and, in addition to providing a more detailed description of the events, confirms the 7-day and 15-day time limits for the reporting of adverse reactions. However, under the Regulation, the sponsor must no longer report the event to the individual Member States separately, but can do so through the newly established EU electronic database for safety reporting, i.e. a module of the Eudravigilance database that will be set up and maintained by the European Medicines Agency (EMA).
NOTIFICATION OF MILESTONE TRIAL EVENTS THROUGH EU PORTAL – The current regime requires limited notifications by sponsors to Member State authorities and ethics committees of events related to the lifecycle of a clinical trial. For example, sponsors are required to notify the end or early termination of the trial within 90 or 15 days respectively.
The Regulation puts in place a more systematic notification system whereby all milestone events concerning the life of the trial must be reported. In particular, the sponsor must notify the following events within 15 days and through the EU portal: the start of the clinical trial, the first visit of the first subject, the end of trial subject recruitment, any temporary halt of the trial, and the end or early termination of the trial.
4. PUBLIC DISCLOSURE OF CLINICAL TRIAL DATA
PUBLICLY ACCESSIBLE CLINICAL TRIAL DATA – Under the current regime, limited information on clinical trials is made publicly available through an EU Clinical Trials Register administered by the EMA. However, this database only publishes limited information, including the identification of the sponsor, information on investigational medicinal products, the design of the trial, and therapeutic areas. By contrast, the database does not provide public access to, for example, the full results of a clinical trial, authorisation documents from national regulators or ethics committee opinions.
The new Regulation creates an EU database that contains all information on clinical trials conducted in the EU. The database collects the data submitted through the EU portal in accordance with the Regulation. This includes a summary of the results of the clinical trial and a summary for laypersons, which the sponsor must submit within one year of the end of the trial (irrespective of the outcome of the trial), as well as the clinical study report, which must be submitted within 30 days after obtaining a marketing authorisation or withdrawing the application.
All information available through the EU database will be publicly accessible, excluding: (i) personal data; (ii) confidential commercial information (unless there is an overriding public interest in disclosure); (iii) confidential communication between Member States related to the assessment report; and (iv) information which disclosure would jeopardise effective supervision of the conduct of a trial by Member States.
5. OTHER CHANGES
In addition to the main changes outlined above, the Regulation also covers other aspects and revises the rules concerning, among other things, the subjects’ informed consent (especially for particularly vulnerable classes of subjects); indemnity and insurance obligations; manufacturing, import and labelling of investigational medicinal products; trials conducted outside the EU; and the supervision, inspection and control of trials by the Member States and the European Commission.
In sum, the Regulation represents a significant step forward with regard to the harmonisation of clinical trial regulations in the EU. However, whether the revised legislation will effectively lead to a harmonised and faster assessment of EU clinical trials and thus enhance the competitive position of the EU very much remains to be seen.
While the European Commission initially considered a centralised assessment of all non-ethical issues by a scientific committee within the EMA, in the final version of the Regulation the Member States nevertheless remain the central players of the new regime. Ethical (and therefore inherently national) aspects will be considered not only during Part II of the assessment, but also in Part I (e.g., the risks and inconveniences for the subjects taking into account the characteristics of the intervention compared to normal clinical practice). In addition, the Regulation often resorts to very vague concepts such as “normal clinical practice” or “duly justified grounds”, which leave ample room for interpretation and (therefore) Member State control, to the detriment of effective regulatory harmonisation.
Importantly, similarly to the current Directive, the Regulation does not set specific rules for non-commercial clinical trials (performed by academics, researchers, etc.), with the exception of certain fee reductions and waivers. However, in order to incentivise non-commercial trials, the Regulation (in the recitals) recommends Member States to adopt national measures to encourage these types of trials. Non-commercial clinical trials, which today amount to over 20% of all trials conducted in the EU, will thus remain subject to some differing national rules in areas not strictly harmonised by the Regulation. In addition, with regard to clinical trials involving human or animal cells, abortifacients, or narcotic substances, national laws prohibiting or restricting their use will continue to apply.
In conclusion, these elements could seriously jeopardise the practical ability of the Regulation to establish a truly harmonised clinical trial regime throughout the EU.