The European Commission (EC) has released a new proposal aimed at reforming Europe's pharmaceutical clinical trials regulations, dismantling an earlier attempt to modernize the rules and instead instituting an EU-wide harmonized approach.
The new rules, previewed by European Commissioner for Health John Dalli at a 27 June meeting in Washington DC, will replace the 2001 Clinical Trials Directive (CTD) (2001/20/EC) once-or if-they are enacted in 2016.
In a statement, the European Commission said they are proposing entirely scrapping the CTD in light of widespread criticism from "patients, researchers and industry alike." Of particular concern was the lack of harmonization between countries and the high costs of complying with the directive.
"This has contributed to a significant decline of clinical trials in the EU," wrote the commission. "Between 2007 and 2011 the number of clinical trials conducted in the EU fell by 25%. The number of clinical trials applied for in 2007 (5000) dropped to 3800 by 2011."
In an earlier statement to Reuters, Dalli said that while this was "not the only reason behind the decline in clinical research in the EU," regulators and public health officials had nevertheless taken the relenting criticism to heart and decided to start fresh. "[T]he Clinical Trials Directive is arguably the most heavily criticized piece of EU-legislation in the area of pharmaceuticals," conceded the Commission.
The new proposal would immediately affect an enormous amount of clinical research. EU regulators said approximately 4,400 clinical trials take place in the EU and European Economic Area (EEA) each year, with more than 60% being conducted by industry.
Twenty-four percent of the clinical trials conducted in the EU are part of multi-country trials. While the European Commission said this number could be construed as being insignificant, they noted the trials account for nearly 70% of all subjects covered by the legislation.
Proposal Emphasizes Speed, Ease-of-Use
While nearly identical in scope to the CTD-both proposals would cover clinical trials but pass over non-interventional studies-the clinical trials proposalwould approach the regulation of clinical trials in an entirely new way.
For instance, companies conducting clinical trials research would utilize a harmonized authorization dossier, a "single portal" to submit clinical trials applications regardless of country, and less onerous procedures to amend clinical trial procedures once the trial has been approved.
Applicants will also reportedly see faster assessment procedures, reporting mechanisms, timelines for approval, and trial extensions.
Despite the legislation's attempts at harmonization, differences will remain in the procedures used to authorize trials. "A crucial element of the rules for authorization of a clinical trial is the clear distinction between aspects where Member States shall cooperate in the assessment of the application for authorization of a clinical trial (Article 6 of the proposed Regulation) and those aspects where Member States conduct their assessment individually (Article 7 of the proposed Regulation)," wrote the Commission.
Unlike the CTD, the new proposal would not establish rules regarding which member states' entities may or may not authorize a clinical trial, allowing the members states to make that determination on their own. The legislation does mandate that states determine which bodies will conduct the assessments by the time the legislation comes into effect in 2016.
The legislation would also make an ethical carve-out for informed consent, allowing clinical trials to commence in "emergency situations" without the consent of an individual. "To address this, specific provisions on clinical trials in emergency situations have been added in line with existing international guidance documents on this issue," writes EC in the proposal. With the exception of the emergency situation provision, the remainder of the legislation only makes cosmetic changes to the informed consent sections "for the sake of clarity."
The rules would simplify safety reporting as well, explained the Commission, requiring fewer events to be reported to EU regulators. Unexpected serious adverse events, for instance, may be directly reported by the sponsor to the European EudraVigilance database and can bypass the sponsor entirely if the investigator is authorized to do so by the clinical trial protocol.
The proposal in several instances explains it will "bring together" currently disparate rules under the umbrella of the legislation. Rules for medicinal products intended for research and rules governing the conduct of trials, for example, will be "streamlined" with minor additions to both.
One of the most significant changes under the law applies to what EC refers to as "co-sponsorship"-the division of responsibilities among sponsors in a multi-center clinical trial, usually conducted in several countries.
"At the outset, all co-sponsors are responsible for the entire clinical trial," states the EC's proposal. "However, the proposed Regulation allows co-sponsors to 'split' the responsibility for the clinical trials amongst themselves," explains the proposal. "Even if co-sponsors split responsibilities, however, all co-sponsors remain responsible for establishing a sponsor who can take measures requested by a Member State, and who can give information on the clinical trial as a whole."
Sponsors will still be required to maintain an EU representative if the trial is conducted in a non-EU country to "ensure an effective supervision of a clinical trial." In addition, EU regulators will obtain the authority to perform inspections of all clinical trials registered in the EU whether they are conducted within the EU or in a "third country."
"In these cases, the proposal provides for compliance with regulatory requirements at least equivalent to those in the EU, including rules on transparency," wrote EC.
Costs of Trials to Decrease
The Commission acknowledged that the CTD's mandate that sponsors purchase insurance to cover compensation for damages suffered by patients in the course of a clinical trial had "substantially increased the costs and administrative burden of conducting clinical trials."
Under the new proposal, trials would not be required to maintain such insurance so long as they pose "no additional risk, or where that additional risk is negligible."
"In these cases, the insurance coverage of the medical practitioner, the institution, or product liability insurance provides sufficient coverage," EC noted. Clinical trials posing a more significant risk will still be required to obtain either insurance or put in place an indemnification mechanism.
The new regulations would also make the movements of medicines in the EU much easier by allowing investigational products to be approved only one time before being allowed to access the rest of the EU. This, as with the insurance provision, is expected to save industry both time and money by reducing the duplication of efforts needed to obtain approval for an investigation product across the EU.
The new legislation-which EC explains will take "the legal form of a Regulation"-must now clear both the European Commission and the European Parliament before becoming law. EC said this will ensure that all EU Member States "base their assessment of an application for authorization of a clinical trial on an identical text, rather than on diverging national transposition measures." The single regulatory framework will allow industry to avoid the current "patchwork" of national frameworks, EC added.
Upcoming Medical Device Legislation
While the proposal focused exclusively on medicinal products, the proposal foreshadows an upcoming expected revision to the Medical Devices Directive.
"Synergy expected with the revision of the legislation on 'medical devices'," writes EC. "[T]his legislation provides for a similar 'EU portal' for 'clinical investigations' (clinical research with medical devices) as is planned for clinical trials."