How and when will they affect you?
Two things. The most substantial change to international guidelines in 20 years occurred earlier this year when the ICH* issued a draft addendum to its GCP guidelines, ICH E6(R2). At about the same time the guidelines go into effect, new Clinical Trial Regulation (CTR) 563/2014 will replace the current, decade-old EU Directive 2001/20.
Rationale: Although the intent of the original version of ICH E6 was to provide sponsors flexibility to innovate, it is sometimes misinterpreted in ways that impede innovation. So says the ICH business plan. The new addendum attempts to rectify this by encouraging “improved and more efficient approaches to clinical trial design, conduct, oversight, recording and reporting.” Dr. Colin Wilsher of RQA (formerly BARQA) wrote a superb analysis of the draft addendum, correlating changes in the guidance to “hot topics,” areas in clinical research that continue to account for more than their fair share of investigational findings.
ICH E6(R2) includes:
ICH is encouraging stakeholders from EU, USA, Japan, Canada and Switzerland to submit their comments to their respective Regulatory Authorities. Publication of the final guideline is slated for November 2016
Rationale: The EU member states are experiencing a significant drop in clinical trial applications. The new directive implements efficiencies designed to make the EU an attractive place to conduct clinical research while maintaining a high standard of patient safety.
In her 60-minute webinar, Dr. Martine Dehlinger-Kremer, Global VP, Medical and Regulatory Affairs for SynteractHCR, provides a very thorough overview of the new EU regulation. Harmonization. Dr. Dehlinger-Kremer explains that the 28 EU member states interpreted the current Directive (2001/20/EC) into local law differently from one another. Different submission requirements, timelines, and safety reporting has made it difficult and expensive for sponsors who want to conduct trials across Europe. (The RQA GCP Committee refers to the member state practice of imposing additional requirements as “gold-plating.”) The proposed regulation requires no national interpretation.
Under the new process, a sponsor will be able to submit a single clinical trial application that covers all EU countries involved in the study. All Concerned Member States (CMSs) will review the application, but an appointed Reporting Member State (RMS) will coordinate the reviews and provide the sponsor a single outcome, a single assessment report that will be valid for all CMSs. The regulation provides some limited provisions for CMS disagreement and procedures for country and site-specific documents/processes. Even so, the single application EU portal will dramatically reduce current-day CMS-specific application procedures. Similar to clinical trial applications, safety reports (SUSAR) will also be coordinated across EU member states.
Application Timelines. Timelines for application review will be quite predictable, meaning sponsors will have a dependable schedule on which to plan. However, the timelines are tight, meaning sponsors will have to plan. In the (otherwise) 60-day application process, there are two points at which sponsors may have to respond to requests for more information. They will have at most 30 days to comply, so they must be sure to have the correct resources on hand.
Transparency. The regulation also dictates clinical trial reporting to support industry trends in research transparency and knowledge sharing. Sponsors must provide study summaries which are “that is understandable to a layperson,” and must submit clinical study reports (CSRs) that accompany Marketing Authorization applications, even if the application is withdrawn or ultimately not approved. These data will be made publicly available via a new EU database.
Flexibility. The new regulation includes provisions that support flexibility in TMF content and in monitoring (think RBM), which dovetail with the ICH E6(R2) changes. Important differences with FDA: Under the new EU regulation, a trial must be registered in the EU database before it begins; trials in the US can be registered as late as 21 days after enrollment of the first participant. Also, the EU will require registration of Phase I studies in the EU database, while Phase I trials in the US are exempt from Clinicaltrials.gov registration requirements. If a sponsor wants to use data collected in US trials to support a Marketing Authorization in the EU, the US studies must adhere to the registration requirements in the new EU regulation.
Though the regulation could potentially become effective as early as May 2016, a precondition must first be met: both the Operational Database for clinical trial transparency and the submission portal for clinical trial applications must be functional for 6 months.