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International Clinical Trials

Euro Vision

On 17th July 2012, the European Commission (EC) submitted proposals to replace the existing Clinical Trials Directive (Directive 2001/20) with a new Regulation (1-3). Given that the Directive only came into force fully in 2004, its reign looks set to be short-lived.

The Directive was originally introduced to harmonise the legislation governing clinical trials across the European Union (EU) and to facilitate cross-border studies. It also improved protection for trial participants and strengthened the role of ethics within the clinical trial process. However, although stakeholders agree with the Directive’s aims, it has been criticised for being heavy handed and inflexible. For example, it imposed the same requirements on clinical trials that use well-documented drugs (generally lower risk) as those that involve novel and untested ones (higher risk).

According to the Commission, EU clinical trial applications dropped by 25 per cent between 2007 and 2011. The apparent reasons for this are that:
● Each Member State has interpreted the Directive differently
● Administrative costs for conducting clinical trials have increased substantially (particularly for non-commercial sponsors, such as universities)
● The start of trials is now delayed for about a further 80 days

Clinical research contributes €20 billion of investment to the EU. The EC wants to cut red tape and eliminate obstacles to pan-European clinical trials. It claims that the proposed new Regulation will save the industry €800 million a year.

One key advantage of having a Regulation instead of a Directive is that it will be directly applicable. Member States will not have to enact the Regulation into their own legislation, which avoids the possibility of it being transposed differently in different Member States. While this does not guarantee that there will be no difference of interpretation of the Regulation at Member State level, it certainly reduces the chances.

Types of Trial

The draft Regulation starts by defining a ‘clinical study’, which is a broader term than ‘clinical trial’. Only non-interventional trials remain outside the regulatory framework of the proposals. The existing Directive places the same regulatory requirements on both high- and low-risk clinical trials. Lowrisk trials are therefore often overregulated and needlessly expensive. However, under the proposals, there will be lower levels of authorisation, monitoring, reporting, traceability and insurance obligations for low-intervention clinical trials.

These trials are those where the investigational medicinal product (IMP) already has a marketing authorisation; will be used in accordance with that marketing authorisation; or where the diagnostic or monitoring procedures do not increase the risk to the trial subjects more than minimally, compared to the authorised use of the IMP. This, for instance, will help with post-marketing studies to improve existing treatments. The costs for these trials should reduce significantly.

Simplified Authorisation Procedure

Currently, obtaining authorisation for a trial being run in more than one Member State can be a complex and burdensome process. Sponsors must obtain approval from both the competent authority and from an ethics committee in each Member State where the trial is held. To address this, the proposed Regulation will require sponsors to prepare a single clinical trial application to be submitted via a centralised EU portal. The application would list the Member States in which the trial will be held. The trial sponsor will propose one of those Member States to act as the Reporting Member State (RMS), to consider the application and take the opinions of the other relevant Member States into account before giving approval.

While this would be an improvement over the current system, there is no guarantee that other practical approvals will not be needed, such as NHS R&D approval in the UK. In addition, the assessment of the informed consent, compensation insurance and the suitability of both researchers and sites involved in the clinical trial will still be the preserve of individual Member States, although it should happen concurrently. The timelines imposed on the Member States are much shorter, which will place greater burdens on ethics committees and, if issues come back from several Member States, a shorter period of time for the sponsor to deal with them. While the specified timelines have to be complied with by Member States, they could, of course, come to different decisions.

Applications for modifications to trials are being similarly streamlined. Under the proposals, only a substantial modification will require further approval: this is one which is likely to have a substantial impact on a clinical trial subject’s safety or rights, or the reliability and robustness of the data generated. Minor modifi cations will only need to be recorded in the EU database if they are relevant to the supervision of the trial. There may yet be a push for more modifications to have to be notified, and further guidance on this issue is awaited.

Furthermore, the proposals could greatly reduce administration and costs for authorisation. The danger here is that if sponsors try and pick an RMS that gives them an easier ride, other Member States may invoke the ‘safety exemption’, which allows them to conduct their own authorisation process.

Sponsor Agreements

Currently, each clinical study must have a single trial sponsor, who is responsible for initiating and managing the trial across all relevant Member States. In reality, having a single sponsor in a multi-jurisdictional trial is rarely satisfactory. For this very reason, the proposed Regulation introduces the concept of co-sponsoring, whereby a sponsor could delegate all its roles and responsibilities to another party or split the sponsor responsibilities between a number of parties through contractual arrangements. For example, under the proposals, a UK sponsor of a pan-European study would be able to delegate all of its obligations relating to a French trial site to a French partner that ought to be better placed to manage this aspect of the study. While this should greatly improve trial management, it does require co-sponsors to have agreements in place which clearly state exactly who is responsible for what. Without such an agreement, co-sponsors will all have the sponsor’s responsibilities. For a sponsor based outside the European Economic Area, there will no longer be any need to have a legal representative in the EU. Instead, it will just need to have a contact person, with responsibility for the trial remaining with the sponsor.

Compensation Schemes and Insurance

Sponsors currently face insurance costs to cover their liability and that of the investigators. These costs are significant, and obtaining such insurance can be challenging, particularly for public bodies or small clinical trials organisations. In light of this, the draft Regulation proposes the following:
● For low-intervention trials, it would not be necessary to provide specific insurance or indemnity, on the basis that the insurance coverage of the medical practitioner, the institution, or product liability insurance will cover it
● For other trials, the sponsor would have to ensure there is insurance or an indemnity. Each Member State would be required to set up a not-for-profi t national indemnification scheme to compensate trial subjects for any injuries suffered because of the trial. The scheme would be free where the clinical trial was not intended, at the time of submission of the application for authorisation of the trial, to be used for obtaining a marketing authorisation for a medicinal product

This proposal will be greatly welcomed by smaller players in the industry and by public sector organisations, such as the NHS. Obtaining insurance for clinical trials – if it can be obtained at all – is currently very expensive. Any reduction in insurance payments will be welcomed, but the obvious question is how will these national compensation schemes will be funded by Member States in the current economic climate without asking for contributions from the industry.

Simplified Safety Reporting

Under the existing system, all suspected unexpected serious adverse events (SUSARs) relating to an investigational medicine must be reported to both the regulatory authority and ethics committees in each Member State. Each Member State must then report SUSARs to the EudraVigilance database, resulting in the duplication of work and costs.

The proposals simplify this procedure. The trial protocol will contain a list of adverse events or unexpected reactions to be reported to the sponsor in specified timeframes. The sponsor will then prepare a single SUSAR report to the database. Serious adverse events will have to be reported immediately, unless the protocol exempts the specific type of event. The sponsor will still be required to submit an annual safety report for each IMP used in the trial (other than placebos) and inform the marketing authorisation holder of any SUSARs that occur. It is not clear how situations where the IMP is identified by its generic name only will be dealt with.

In the event of any serious breach of either the proposed Regulation or the protocol, the sponsor will have to inform relevant Member States within seven days of the breach. A serious breach is one likely to significantly affect the safety and rights of the trial subject or the reliability and robustness of the safety data generated. The sponsor may also be required to submit any reports prepared by non-EU competent authorities about a clinical trial conducted by it.

Informed Consent

The proposals make it clear that the rights, safety and wellbeing of the subjects should prevail over the interests of science and society. They improve the protection for trial subjects and raise the bar on obtaining consent. There is more detail on what must happen, but who is a minor or an incapacitated subject still remains to be determined under the law of the Member State.

Under the proposals, trial subjects (or their legal representatives) must have the objectives, risks and inconveniences associated with the trial explained to them. They must also be told how the trial will be carried out and that they may withdraw from the trial at any time. The subject must be told that withdrawal will not result in the loss of a benefit associated with their participation. This information will have to be provided in an interview with a member of the clinical trial team. The consent of a trial subject will have to be written, dated and signed (with particular exceptions where the subject cannot write) after the interview. The trial subject will have to be given a copy of their written informed consent. In exceptional circumstances, oral consent may be given in the presence of a witness if the trial subject cannot write. In emergency situations, it may even be possible to obtain consent from a trial subject after the start of a clinical trial, subject to strict guidelines.

While undoubtedly improving the protection of trial subjects, much more thought will have to be given to obtaining informed consent. The fact that consent could be obtained orally or after the trial subject commences the trial will allow many more volunteers to be involved. Suitable safeguards will have to be carefully considered.

Conduct and Supervision

Moving forward under the proposed Regulation, clinical trials will need to be run in accordance with the protocol and ICH guidelines on good clinical practice (unless others are put forward). The sponsor will have to ensure the good conduct of the trial and the investigator, and others carrying out the trial will need specified qualifications, education or experience. The level of supervision required will depend on the nature of the trial. Regulatory authorities are likely to demand more detailed supervision protocols for complex trials.

All trial information will have to be archived in compliance with the relevant Member State legislation. A clinical trial master file will have to be maintained for a period of at least five years from the completion of the study, containing sufficient information to allow the competent authorities to be confident that the trial was run correctly. Any transfer of ownership of the master file to a new owner will require the new owner to maintain these responsibilities.

IMP Labelling

Under the proposals, there are reduced labelling requirements for IMPs and auxiliary medicinal products. Traceability and storage of them are key and there must be information about them in the application dossier. The requirements for the medicinal products used in a trial, but which are not an IMP, have been relaxed, but the ability to use unauthorised auxiliary medicinal products is very limited.

Conclusion

Many of the industry’s criticisms of the clinical trial regulatory regime are addressed by the proposed Regulation, although how effective the changes will be in dealing with all issues in practice remains to be seen.

Some Member States are likely to object to certain aspects About the authors of the Regulation, such as the proposed compensation mechanism, and the European Parliament may oppose what some see as a weakening of regulatory oversight. Even so, the final version of the Regulation that is introduced should simplify the management of cross-border clinical trials and place obligations on sponsors that are more proportionate to the risks of each individual trial.

The EC anticipates that the Regulation will come into effect in 2016. In order to allow for a smooth transition, the provisions of the Directive and the Regulation will apply in parallel for three years from the Regulation’s start date. Competent authorities are beginning to ask those involved in clinical trials to submit their views on the proposed Regulation ahead of a review by the European Council of Ministers. This should be used by those involved in clinical trials as an opportunity to shape the final Regulations ahead of the implementation.

References
1. Visit: http://eur-lex.europa.eu/LexUriServ/ LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF
2. Visit: http://ec.europa.eu/health/human-use/ clinical-trials/index_en.htm
3. Visit: http://ec.europa.eu/health/files/clinicaltrials/2012_07/ proposal/2012_07_proposal_en.pdf

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Janet Knowles leads Eversheds’ Life Sciences Group. She specialises in commercial life sciences transactions, including their regulatory and intellectual property implications. Her work ranges from early phase R&D and clinical trials to technology licensing, commercial manufacturing and supply and pharmacovigilance agreements. Janet deals with a variety of life sciences clients from start-ups to IPO and beyond. She is Company Secretary of Medilink and a lay member of a university ethics committee.

Dr Carl Fennessy is an Associate in the Eversheds’ Life Sciences Group and specialises in non-contentious intellectual property matters and general commercial contract work. Carl has a PhD in molecular biology and has written briefings on the regulation of medical devices, biosimilar medicinal products and importing active pharmaceutical ingredients into the EU.
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Janet Knowles
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Dr Carl Fennessy
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