Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
Boom in Hemophilia R&D Prompts EMA to act to Prevent Enrollment Bottleneck
The European Medicines Agency (EMA) is planning to revise its guideline on development of drugs to treat hemophilia to cut the risk of patient enrollment bottlenecks slowing progress. EMA began the process after becoming concerned that the minimum data requirements of its current guideline are incompatible with the “historically unique” pace of progress in hemophilia R&D.
In the current guideline on the clinical development of factor VIII products, EMA calls for companies to provide clinical data on at least 100 patients in their marketing submissions. Manufacturers are then expected to collect post-authorization data on at least 200 patients within a defined time frame. EMA implemented the 100-patient requirement in 2012, and saw no reason to change it in the most recent set of revisions. The guideline resulting from those revisions came into force in May.
Now, months after adopting the guideline, EMA has released a draft concept paper proposing further changes. EMA has framed the move to revise the guideline again as a consequence of the fast pace of change in hemophilia R&D. “The development of new therapy options in hemophilia is increasing dramatically,” EMA wrote. “Because hemophilia A is a rare disease, the recruitment of suitable clinical trial patients might be a bottleneck.”
Faced with what it sees as a “historically unique” surge in the pace and breadth of development of hemophilia products, EMA is proposing to reconsider its requirements on patient number. Officials will establish exactly how this will work through regulatory and public discussions between now and the planned release of a revised draft guideline early next year. One option is to shift the burden of evidence generation away from clinical trials and toward registries.
EMA Pitches Changes to Crohn’s, Ulcerative Colitis Clinical Trial Guidelines
EMA has proposed changes to its guidelines on the clinical development of products to treat Crohn’s disease and ulcerative colitis, the two main forms of inflammatory bowel disease. The changes are focused on the potential claims, endpoints and comparators associated with clinical trials in adults.
While EMA has separate guidelines for Crohn’s disease and ulcerative colitis, its explanations for why it is revising the documents now are identical. Regarding claims, the revised guidelines state drug developers must demonstrate efficacy in terms of inducing and maintaining remission for their product to be approved as a treatment for active forms of either condition. In some circumstances, EMA is open to approving drugs as either inducing or maintaining remission.
EMA has also used the update to revise its advice on endpoints. Both texts now address the need to define and justify remission according to the instrument used to assess patients, a subject that is absent in the current guidelines. The revised guidelines state new drugs must provide symptomatic relief, but diverge somewhat in terms of how to assess this in a trial. Patient reported outcomes are part of the picture in both indications.
The other major topic addressed in the revisions is the choice of comparator. In keeping with its current guidelines, EMA wants to see an active comparator used, although there are still situations in which it thinks a placebo is the best option. Any company seeking to win approval for a first-line therapy in either Crohn’s or ulcerative colitis will have to show their candidate can match up to the standard of care. EMA is accepting comments on the drafts until the end of January.
UC Guideline, Crohn’s Draft
Diabetes and Bipolar Disorder Trial Guidelines in Line for Revision at EMA
EMA has released draft concept papers on its plans for guidelines covering diabetes and bipolar disorder clinical trials. The publication of separate papers mark the start of move to update the diabetes and bipolar disorder guidelines, which EMA sees as being rendered out of date by new thinking about cardiovascular safety and the publication of DSM-5, respectively.
In the bipolar disorder concept paper, EMA details the implications of the publication of DSM-5, the manual of mental disorders. The latest version of the book changes the symptoms associated with bipolar disorder, a revision that has implications for the selection of clinical trial participants. Other changes include the separation of bipolar disorders from depressive conditions, and a revision to the relationship between the I and II forms of the condition.
When paired to a movement toward early treatment and recognition that bipolar disorder targets may overlap with schizophrenia and depression, the changes to DSM-5 have prompted EMA to take a fresh look at its guideline. Harmonization with guidelines covering schizophrenia and depression is one of the topics up for discussion. EMA is accepting comments on the draft until the end of October.
The regulator has set the same deadline for feedback on its diabetes concept paper. EMA created the paper to start the process of bringing its advice in line with the reflection paper on cardiovascular safety it adopted earlier this year. The regulator will also use the revision process as an opportunity to look at the deployment of different outcome measures to assess efficacy and other topics raised by the industry since it last updated the text.
Diabetes Paper, Bipolar Paper
EMA Revises Layout of 2,000 Scientific Guideline Documents
EMA has revised the layout of more than 2,000 documents to improve the presentation of its human and veterinary scientific guidelines. The reorganized display uses a single pageto show the current version of each guideline alongside the drafts, reflection papers and concept papers that went into its development.
The page on the guideline on clinical development of products to treat HIV infection, for example, features details of the currently active text at the top of the page. Beneath this area is a document history section featuring links to each of the texts that went into the second and third revisions of the guideline. In the case of the third revision, there are links to the guideline that is due to come into force in January, the concept paper and draft that preceded it and feedback received by EMA.
Putting links to all of this information on a single page means it would be trivial to review the thinking behind a current guideline, should someone want to perform such an exercise. Prior to the reorganization, only some documents were collected and there were not individual pages for each guideline. Under this earlier approach, the full context of revision two of the HIV guideline was easy to access, but the site did not collate the documents generated in the third revision process.
Italy and Spain are reportedly leading the race to host EMA if, as expected post-Brexit, it leaves its current home in London, UK. Both countries have backed up their calls to be considered by setting up groups focused on laying the groundwork for their candidacies. Spain is putting Barcelona forward as its choice for the new home of EMA and is preparing a report to outline its case. EurActiv
EMA has reported a sharp increase in the number of good clinical practice (GCP) inspections it conducted in the Middle East and Asia Pacific region. The area, which EMA classes as a single region for its reporting, was the focus of 20 GCP inspections in 2015. In contrast, 2013 and 2014 saw EMA conduct, respectively, 10 and 11 GCP inspections. EMA Report