Martyn Ward – Update on proposed EU Clinical Trials Regulation

ICR Ethics & GCP Forum – Part 1 of 5

Speaking at the ICR Ethics & GCP Forum today, Martyn Ward of the MHRA Clinical Trials Unit gave an update on the proposed EU Clinical Trials Regulation and the MHRA’s views on the ongoing negotiations. As the discussions are still in progress, there were limits to what he was able to say, and positions could still change before the regulation completes its passage through the European Parliament and the Council of Ministers.

Martyn covered the background behind the proposed Regulation, covering the criticisms of the current Clinical Trials Directive, particularly around divergent implementation between MemberStates, and the lack of proportionality around post-registration studies particularly conducted by academics.

He then recapped the proposed Regulation itself. Key points include that there is no longer specific reference to tasks performed by Competent Authorities and Research Ethics Committees, and also the concept of tacit approval if regulators do not reach a conclusion in the required timeframe.

Harmonised authorisation process

The Regulation includes a new authorisation procedure, using a single harmonised dossier, submitted through a single portal. This submission is divided into aspects where member states co-operate in the assessment (Part I) in a manner similar to the current Voluntary Harmonisation Procedure, and aspects where each member state should consider local issues independently (Part II). This makes the sponsor’s interaction with the process much simpler.

When a research proposal is submitted, the sponsor can nominate a “reporting member state”, although that state can choose to decline and seek an alternative. The reporting member state validates the submitted dossier and then serves as secretariat for the multi-state discussions over Part I. In parallel, individual member states will consider Part II issues. For both parts, it is possible to request additional information from sponsors, with clock-stops until responses are supplied.

Ultimately, each member state makes a single decision based on Part I and Part II.

Timelines would generally be:

  • 6 days for validation
  • 25 days for assessment of both Parts in parallel (10 days for low intervention studies, 30 days for Advanced Therapy studies)
  • 10 days for a final decision to be communicated to the sponsor

If further information is required, a clock-stop of 20 days can be made for standard studies (10 days for low-intervention studies), with a further period of 5 days for this information

Interestingly, Martyn highlighted that it is possible to submit a Part I application but defer Part II application. This could be useful, for example, if a sponsor has not yet finalised the countries in which they wish to conduct the study. This mechanism also makes it easier to add additional member states to an already authorised study.

Transparency & reporting

This whole system can only function if the portal and its underlying database, which is an area of concern for many. The system will be built and managed by the European Commission rather than the EMA, and will need to have its budget revalidated after 5 years. The Commission has already put together a project team to handle this development. Ultimately, the database will also replace EudraCT. Crucially, the database will also be publicly accessible except to protect personal data and for issues of commercial confidentiality. This ties the discussions in with the ongoing transparency initiative (see other articles for further discussion of these points).

Once a trial is approved, the sponsor will notify start and end dates for the trial, and for the recruitment phase, using the portal. This will be useful for potential participants seeking active studies in their disease area.

SUSARs will be reported via EudraVigilance, either directly by sponsors or via Competent Authorities. The protocol may specify adverse events that are not required to be reported. Other rules are as per CT3 guidance. Annual reporting will be to a new database at the EMA, based on ICH E2F guidance. DSURs will not be required for products within their licensed indications.

The current proposal includes a public database providing a register of all EU trials, and will provide access to summary results within one year or the end of the trial. Martyn also mentioned the potential for this to tie in with other discussions around transparency of clinical trial data, pending other workstreams within the EMA.

Risk-adaptation & other topics

Martyn went on to discuss risk-adaptation around clinical trial regulation. This is covered by the concept of low-intervention studies, but also includes simplified safety reporting, risk-adaptation of monitoring and simplified labelling for already authorised medicines.

The regulation also proposes a national indemnification mechanism to be developed by each member state. It will not be compulsory for sponsors to join (and MS may impose fees for commercial sponsors to use the mechanism) by academic studies not linked to marketing authorisations should be free.

Other changes that Martyn highlighted but did not discuss in great detail included:

  • Emergency research
  • Co-sponsorship
  • Clinical trials conducted in third countries
  • Cooperation between MS
  • Inspections

UK involvement & negotiating position

Martyn went on to explain the process by which the proposed Regulation is being considered. The EU Council working party and the European Parliament both consider the Commission’s proposal. If the groups can agree a final text on either its first or second reading, then a conciliation committee will attempt to resolve any differences. However, now that the proposal is in the political process, there is less scope for regulators to influence the text directly. However, Martyn highlighted that several areas in the current proposal stemmed from UK influence:

  • Risk-adaptation
  • Reporting of serious breaches of GCP
  • Co-sponsorship
  • IMP provided free to participant (NOT necessarily paid by the sponsor, which has been a barrier to academic sponsorship)
  • Emergency research

The UK adopted an agreed negotiating position in October 2012, and Martyn described the early and deep engagement with UK stakeholders. This is broadly supportive of the proposal, but has concerns:

  • Some of the wording and definitions
  • The transparency of the authorisation process
  • The availability and functionality of the portal
  • The national indemnification scheme
  • The Commission’s potential to inspect MS’ implementation of the process

Timelines to implementation

A public consultation was held late in 2012, and responses should be published by the end of March 2013. These are generally supportive, but highlight some of the same areas of concern. A working party of the European Council has already held nine meetings, with three more planned. They hope to complete the first reading in the first half of 2013 (under the Eire Presidency of the EU) with the Lithuanian Presidency hoped to complete the consolidation, with the Council of Health Ministers hoped to agree the text in December 2013 (Martyn said that the June 2013 meeting would be unlikely). This working party has discussed concerns including the lack of mention of ethics committees in the text, the timelines and issues around the database.

The proposals have also been discussed within the European Parliament, with a consolidated draft report published on March 1st, which included 731 proposed amendments. A vote by the ENVI committee should be held on April 24th, with a plenary vote in the European Parliament planned for June 10th, which should be way ahead of the Council. These discussions have also highlighted issues around the lack of mention of ethics committees and the need for greater coordination of the work of ethics committees through the EU. The timelines and the database have also been raised as concerns.

Martyn then explained the phasing of implementation, which is expected to start in 2016 and conclude in 2019 when the current Directive will be repealed.

Responding to questions, Martyn suggested that comments about ethics committees are likely to become more explicit in the final text of the regulation. He also differentiated between the “register”-type transparency included within these negotiations and the wider EMA initiative around transparency of raw data.

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