Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.

Rise of Cell Therapies Prompts Commission to Float Changes to Orphan Drug Rules

The European Commission has proposed changes to its orphan drug regulation. Officials want to make changes to the 17-year-old text to account for the rise of cell therapies and other advanced medicinal products, the nature of which are a poor fit for aspects of the existing regulation.

If the revisions come into force, the Commission will change some of the key definitions detailed in the regulation. The definition of “similar active substance” is among those set to be changed. As it stands, the regulation defines such a substance as being identical to or having “the same principal molecular structural features” as another substance with the same mechanism of action. This text fit the developmental candidates of 2000. That is no longer the case.

Researchers cannot fully identify the principal molecular structural features of advanced therapy medicinal products. This makes it impossible to tell if two substances are similar using the current definition. To address this shortcoming, the Commission wants to expand the definition to allow similarity to be assessed “on the basis of the biological and functional characteristics” if the principal molecular structural features are unknown.

This change is aimed squarely at advanced therapy medicinal products, such as cell-based and gene therapies. The Commission also wants to add text that unpacks how the change will apply to these two therapeutic modalities.

In the case of cell-based therapies, substances are not similar if there are differences in the starting materials, final product or manufacturing technology that affect its biological characteristics or “activity relevant for the intended therapeutic effect of the product.” Products can have different starting materials and still be similar, meaning it is possible to have similar autologous cell therapies.

The Commission has applied similar thinking to gene therapies. Differences in the therapeutic sequence, viral vector, transfer system or regulatory sequences can render two gene therapies not similar, provided these differences affect the biological characteristics and therapeutic effect of the product. Otherwise, the Commission will see the gene therapies as similar, regardless of underlying differences.

These definitions are important, as they dictate whether drugs can come to market in the 10-year window of therapeutic indication exclusivity enjoyed by orphan products in the European Union. Applicants facing such situations need to submit a similarity report to help the Committee for Medicinal Products for Human Use assess whether a potentially similar drug can come to market.

The Commission used the update process to make other changes to the content and format of the regulation, some of which were motivated by the experience it has gained since passing the original text. Changes made by the Commission include the removal of the definition of “active substance.”

The draft text is open for comment until 27 November.

Commission Proposal, Current Regulation

EMA Joins With Regulatory Peers to Create Antimicrobial Resistance Indicators

The European Medicines Agency (EMA) has published a set of indicators to assess the effect of efforts to curb the use of antimicrobials and the rise of drug-resistant strains. EMA joined with the European Food Safety Authority (EFSA) and European Centre for Disease Prevention and Control (ECDC) to create the indicators.

The indicators span antimicrobial use and resistance in humans and food-producing animals and are split up into primary and secondary measures. In each case, EMA, EFSA and ECDC have chosen the indicator on the basis of data already collected by member states. The Commission hopes the harmonized indicators will improve the region’s ability to establish measureable goals for cutting the rate of infection and encourage appropriate use of antimicrobials.

EMA and its collaborators have chosen the proportion of methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli as their primary indicator of resistance in humans. The agencies selected these bacteria after concluding MRSA is among the most important Gram-positive drug-resistant bacteria, and after identifying cephalosporin-resistant Escherichia coli as a fast-emerging problem in Europe.

Secondary indicators of resistance in humans include the proportions of resistant strains of  Klebsiella pneumoniae and Streptococcus pneumoniae. The agencies have also selected primary and secondary indicators for antimicrobial use and resistance in food-producing animals.

EMA thinks the indicators will be useful, but has warned against over-reliance on the measures. The agency and its collaborators think summarizing large data sets into indicators may oversimplify the true situation. As such, the agencies recommend the indicators are “interpreted with caution” and, in many cases, not used “to monitor the effects of targeted interventions in a specific sector.”

EMA Notice, Scientific Opinion

PRAC Calls for Further Restrictions on use of Biogen Multiple Sclerosis Drug

EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has called for further restrictions to be placed on the use of Biogen’s multiple sclerosis drug Zinbryta. PRAC recommended limiting the drug to third-line use after assessing its link to potentially fatal immune-mediated liver injury.

The latest call for restrictions comes four months after EMA placed provisional limitations on the use of the drug while PRAC was performing its safety review. PRAC wants to go further than those measures, notably by limiting use to patients who have unsuccessfully undergone two — not the earlier one — lines of treatment with a disease-modifying therapy (DMT). As before, PRAC wants use to be limited to patients for whom other DMTs are unsuitable.

PRAC is also proposing to toughen the patient monitoring requirements. Under its proposals, doctors will need to keep monitoring the liver function of patients for six months after the last dose. The earlier advice allowed doctors to stop monitoring patients after four months. The extension follows PRAC’s conclusion that patients are at risk of serious liver injury for six months after finishing treatment.

The EMA committee also used its recent meeting the initiate two new investigations. PRAC is reviewing the off-label use of products containing hydroxyethyl-starch and flupirtine-containing medicines. Both reviews were triggered by evidence the drugs are being used in ways prohibited under restrictions EMA implemented in 2013.

PRAC Recommendations, Meeting Summary

Looming Brexit Date is Limiting UK Role in Marketing Authorizations, EMA Says

EMA has said Brexit is already affecting the role the United Kingdom plays in EU-wide regulatory activities. The agency appoints rapporteurs using criteria to assess the best “available” expertise, a model that forces it to consider whether the UK will be in the EU for the whole regulatory process.

The UK is set to leave the EU on 30 March, 2019. Centralized evaluations of initial marketing authorization applications can take more than one year to complete. That means the UK may have left the EU by the time they are finished and, as such, rapporteurs from the country fail to meet EMA’s definition of “available” expertise.

In a report of an industry meeting on Brexit, EMA said these considerations are “already starting to take effect with regards to UK rapporteur appointments for new medicines.” The number of UK rapporteurs appointed to these assessments is likely to tail off long before the country leaves the EU.

EMA used the report to commit to holding industry Brexit meetings every two to three months. The agency is also planning regulator updates to its question and answer document — although it has delayed the first round of changes — and to publish procedural guidance to help the industry.

EMA Report