Regulation on clinical trials on medicinal products for human use

April 2014

On 2 April 2014 the European Parliament finished the first reading and published its legislative resolution on the proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use; repealing Directive 2001/20/EC. Since a provisional agreement between the Parliament and the Council on the final act has already been achieved it can be expected that there will be few objections by the Council for the final version of the Regulation.

Background

The legislative procedure began with a proposal of the European Commission on 17 July 2012. According to the Commission, clinical trials are an indispensable part of clinical research which, in turn, is essential to develop medicinal products and improve medical treatment. money and medicineDirective 2001/20/EC aimed to simplify and harmonise the administrative provisions governing clinical trials in the European Union. However, experience shows that a harmonised approach to the Regulation of clinical trials has only been partly achieved. For pharmaceutical companies it is in particular difficult to perform a clinical trial in several Member States. Therefore, the number of applications for clinical trials has fallen whereas the costs for conducting clinical trials has increased in the last few years. The new Regulation is intended to solve these problems and set the global gold standard for transparency in clinical trials.

Proposal of the European Commission – new aspects

The scope of the proposed Regulation is essentially identical to that of Directive 2001/20/EC. The scope is limited to clinical research on medicinal products, but it is very wide in that it only excludes clinical studies that do not involve an intervention (e.g. surveys amongst medical practitioners without additional intervention). For non-interventional studies which are post-authorisation safety studies initiated, managed or financed by the marketing authorisation holder voluntarily or pursuant to obligations imposed by the competent authority for marketing authorisations, the rules are set out in Directive 2001/83/EC.

The proposal introduces a new authorisation procedure for clinical trials based on the following main concepts:

  • A harmonised authorisation dossier, partly codifying the existing Commission guidance contained in EudraLex, Volume 10;
  • A single portal to submit an application for conducting a clinical trial linked to an EU database. This portal is managed by the European Commission and is free of charge for sponsors;
  • A mechanism to appoint a reporting Member State and clear timelines with a concept of tacit approval in order to ensure compliance;
  • A coordination and advisory forum to address issues which may arise in the authorisation procedure. This forum is managed and chaired by the Commission;

caduceusRegarding clinical trials in emergency situations, Directive 2001/20/EC does so far not address the specific situation where, because of the urgency of the situation, it is impossible to obtain free and informed consent from the subject or the legal representative. To address this, specific provisions on clinical trials in emergency situations have been added in line with existing international guidance documents on this issue.

The rules on safety reporting follow the principles of the applicable international guidance documents. Compared to Directive 2001/20/EC, the rules have been streamlined, simplified and modernised. The option to exclude reporting by the investigator to the sponsor of adverse events, if this is provided for in the protocol is introduced as well as the direct reporting of suspected unexpected serious adverse reactions by the sponsor to the European database EudraVigilance. A simplified submission of the annual safety report by the sponsor is possible.

The proposed Regulation acknowledges that clinical trials do not in all cases pose an additional risk to subjects compared to treatment in normal clinical practice. Consequently, where there is no additional risk, or where that additional risk is negligible, it is not necessary to provide specific damages in compensation (be it an insurance or an indemnification) for the clinical trial. In these cases, the insurance coverage of the medical practitioner, the institution, or product liability insurance provides sufficient coverage. In cases where a clinical trial does pose an additional risk, the proposed Regulation obliges the sponsor to ensure compensation – be it through insurance, or through an indemnification mechanism.

European Parliament - what is new?

According to the European Parliament the Regulation must comprise more provisions in regard to the ethical aspects of clinical trials. A clinical trial should be subject to prior authorisation after having been examined by the ethics committee concerned in accordance with the World Medical Association’s Declaration of Helsinki. The Ethics committee shall be an independent body in a Member State, consisting of health-care professionals and non-medical members including at least one well-experienced, knowledgeable patient or patient representative. In cases of clinical trials involving minors, the ethics committee shall include at least one healthcare professional with paediatric expertise.

Given that low-risk clinical trials have only a very limited and temporary adverse effect, they should be subject to less stringent rules, such as shorter deadlines for approval. Less stringent rules should not compromise scientific standards and should guarantee the safety of subjects at all times. Those low-risk trials should, however, be subject to the vigilance and traceability rules governing normal clinical practice.

The European Medicines Agency will set up and maintain an electronic database for the reporting in respect if clinical trials (Eudravigilance database). The Agency will also, in collaboration with Member States, develop a standard web-based structured form for the reporting by sponsors to the database of suspected unexpected serious adverse reactions. The reasons for early termination of a clinical trial will be published in the Eudravigilance database. This database will be publicly accessible unless confidentiality is justified on grounds of protecting personal data or protecting commercially confidential information. In particular, through taking into account the status of the marketing authorisation for the medicinal product, unless there is an overriding public interest in disclosure. Unless there is an overriding public interest in disclosure, data contained in the application dossier shall not be publicly accessible before the decision on the clinical trial has been made. Irrespective of the outcome of a clinical trial, within one year from the end of a clinical trial in all Member States concerned, the sponsor shall submit to the Eudravigilance database a summary of the results of the clinical trial. It shall be accompanied by a summary written in a manner that is understandable to laypersons. Participants shall be informed about the availability of this information in the Eudravigilance database.

An efficacy defect on an authorised medicinal product could represent a serious risk for patient safety and should, according to the European Parliament therefore be added as a reporting obligation under the new Regulation.

Although the Commission proposed that the sponsor shall archive the content of the clinical trial master file for at least five years, the Parliament is of the opinion that should a sponsor come under investigation for misconduct, the clinical trial master file would be vital. Therefore the master file should be archived at least 25 years after the end of the clinical trial. The clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of a clinical trial and the quality of the data generated, taking into account all characteristics of the clinical trial, including in particular whether the clinical trial is a low-intervention clinical trial.

Significance of the new Regulation and outlook

Directive 2001/20/EC has brought about important improvements in the safety and ethical soundness of clinical trials in the EU and in the reliability of clinical trials data. However, the Clinical Trials Directive is arguably the most heavily criticised piece of EU-legislation in the area of pharmaceuticals. The European Commission took up this criticism in the new proposal, in particular that the existing provisions of Directive 2001/20/EC have hampered the conduct of clinical trials in Europe.

four businessmen with jigsaw piecesThe proposed Regulation aims to harmonise the regulatory framework for clinical trials. In addition, the proposed Regulation aims to contribute to the harmonisation of the rules for pharmaceutical products placed on the market, including authorisation of their placing on the market and to harmonise the rules for medicines used in the context of a clinical trial, thus allowing for their free movement within the Union. Regarding the harmonisation of the rules on clinical trials, practically every larger clinical trial is conducted in more than one Member State. Moreover, the results generated in a clinical trial may be used as basis for other clinical trials. In this respect, it is critical to ensure that the rules for patient rights and safety and data reliability and robustness are harmonised in order for them to be recognised throughout the Union.

Already, one can expect that the Council will basically agree to the proposal. Companies shall become acquainted with the new Regulation in respect to future clinical trials that need to meet the requirements of the new legislation. Besides, the issue of transparency of information related to clinical trials is crucial. In this context the European Medicines Agency´s policy on the proactive publication of clinical-trial data need to be bear in mind. Whilst the pharmaceutical industry itself has most recently taken the initiative to give easier access to clinical trial data the data publishing policy of the EMA is still under review by the European Courts. A careful monitoring of the ongoing process on an EU-level by the concerned industry seems to be advisable.

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test tubes and pipette

Wolfgang Rehmann



Wolfgang is a partner in the Pharmaceutical & Patents group based in our Munich office.

Diana Heimhalt


Diana is a senior associate in the Patents group based in our Munich office.

"The new Regulation is intended to set the global gold standard for transparency in clinical trials."