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

NICE Takes Sides in Fight for PCSK9 Market, Recommending Amgen While Rejecting Sanofi

The National Institute of Health and Care Excellence (NICE) has recommended using Amgen’s PCSK9 inhibitor Repatha in certain indications, while rejecting the use of Sanofi and Regeneron’s rival drug Praluent. While both manufacturers offered discounts of undisclosed magnitudes, only Amgen met the value criteria used to decide which drugs are reimbursed in England.

In its initial ruling in November, NICE knocked back both drugs, only to reverse its decision regarding Repatha in an update to its draft recommendation this week. If the recommendation is finalized, a subsection of patients with primary hypercholesterolaemia or mixed dyslipidemia will be given the Amgen drug. Only patients who have persistently high levels of low-density lipoprotein cholesterol (LDL-c) despite prior therapy and are contraindicated or intolerant of statin therapy are eligible. Such patients can get Repatha if Amgen supplies it at a discount agreed in the patient access scheme.

Sanofi and Regeneron offered a discount, too, but it has failed to convince NICE of the cost-effectiveness of its drug. The decision appears to be at least partly motivated by the relative costs of the rival drugs.

“Both [Praluent] and [Repatha] appeared to have similar efficacy in terms of LDL-c reduction,” the NICE committee wrote. “Therefore, their relative drug acquisition costs would be a likely key driver of their cost-effectiveness. Both the high [incremental cost-effectiveness ratios] and key uncertainties meant that [Praluent] was not a cost-effective use of [National Health Service] resources.”

The ruling gives Amgen an edge in England in a class of drugs widely predicted to generate blockbuster sales, although the terms of NICE’s draft recommendation mean Repatha is unlikely to immediately start generating major revenues in the country. With Amgen yet to generate data showing the reductions in LDL-c achieved by Repatha correlate strongly to improved cardiovascular outcomes, NICE is unsure of the value of the product. Once Amgen has such data, which it is working to generate now, NICE plans to review its guidance. 

Repatha Guidance, Praluent Guidance, Reuters

EMA Backs use of Xarelto After Analyzing Impact of Defective Device on Trial Data

The European Medicines Agency (EMA) has maintained its stance on the safety of the anti-clotting drug Xarelto after reviewing the impact of the use of a defective device in clinical trials. EMA ruled potentially flawed readings taken by the device used in the trial would have had a “marginal” effect on the data, leading it to judge that safety and risk-benefit conclusions from the study are valid.

Officials at EMA began investigating the issue after Bayer, which markets Xarelto in Europe, told it about a defect in the international normalised ratio (INR) device used in the ROCKET trial. In the trial, researchers gave 14,000 people with nonvalvular atrial fibrillation either Xarelto or the anticoagulant warfarin. US Food and Drug Administration (FDA) reviewers brought up concerns about the warfarin control arm when assessing Xarelto in 2011, only for the agency to go on to approve the drug. Late in 2014, fresh fears surfaced when the Alere device used to oversee warfarin usage in the ROCKET trial was subject to a Class I FDA recall.

The recall was prompted by a realization that the device could deliver INR results that were lower than those that would be yielded from a laboratory test. If the device had delivered such inaccurate data in the ROCKET trial, it may have affected the quality of the results generated in the control arm, a situation that would call into question the validity of the conclusions reached in the study. EMA has spent the past five months probing this question, culminating this week in it stating its confidence in the validity of the overall safety and benefit-risk balance picture that emerged from ROCKET.

“Any incorrect measurements obtained with the defective device would have had only a marginal effect on the study results, and the safety of Xarelto remains unchanged,” EMA wrote. “In addition, data from other large studies confirmed the comparative safety of the medicine and showed similar rates of bleeding in their warfarin groups.” A separate analysis performed by researchers involved with the original ROCKET study reached a similar conclusion to EMA, as did a review performed by Bayer and Johnson & Johnson, which markets Xarelto in the United States.

However, as Cardiobrief notes, the series of analyses ruling in favor of the safety of Xarelto has failed to quell concerns completely. A paper published in BMJ summarizes the lingering worries, which are unlikely to be dispelled unless the trial data are made available for independent analyses. Reportedly, J&J is willing to make the trial data available but Bayer has refused.

EMA Statement, Cardiobrief, BMJ

EU Committee to Vote on Harmonization of Period of Protection for Antimicrobial Animal Drugs

The Environment, Public Health and Food Safety Committee (ENVI) is to vote next week on proposed changes to regulations covering veterinary medicines. Members of the European Parliament committee have spent the past year looking at the draft legislation, which includes a section that could result in the harmonization of the length of time technical documents for veterinary antimicrobials are protected.

Under the original document put forward in 2014, technical documents covering novel antimicrobial veterinary medicinal products for cattle, sheep, pigs, chickens, dogs and cats would be protected for 14 years. When Françoise Grossetête, the ENVI member in charge of drafting changes to the text, reviewed the document, she proposed increasing the period of protection to 18 years and tweaking the list of species protected. The proposal called for salmon to be added to the list and to limit the period of protection for sheep to animals raised for meat.

Grossetête presented the changes as a way to encourage antimicrobial research. “The period of the protection of technical documentation on antimicrobial veterinary medicinal products should be increased in order to encourage research and innovation in the field of antibiotics,” she wrote. Other members of ENVI have a different stance, with some arguing the period of protection should be cut to 10 years. Having gone through this process, ENVI is set to vote on a set of amendments, which include proposals to harmonize — and potentially prolong — protection, on 17 February.

ENVI Agenda

MHRA Creates Toolkit on the Risks of Taking Valproate During Pregnancy

The Medicines and Healthcare Products Regulatory Agency (MHRA) has released a toolkit to support decisions about using valproate during pregnancy. MHRA has created the toolkit to address concerns that healthcare professionals were failing to adequately explain the links between the drug and birth defects.

For the toolkit, the United Kingdom drug regulator has created separate brochures for healthcare professionals and patients, plus a checklist both parties must fill in and sign to show they understand the risks posed by valproate. The release of the documents comes 12 months after MHRA revised its warnings about the drug to reflect growing awareness of its links to birth defects and developmental disorders.

When valproate is taken during pregnancy, up to 40% of babies may have developmental disorders, while MHRA puts the proportion who have birth defects at 10%. “MHRA has worked with a number of stakeholders to create detailed guidance for healthcare professionals and their patients, while confirming that valproate remains a very effective medication for a number of people with epilepsy,” Matthew Sowemimo, director of external affairs at the Epilepsy Society, said.

MHRA Release, More