European Regulatory Roundup: Advances in Hepatitis C Care Prompt EMA to Revise Guidance (14 July 2016)

Regulatory NewsRegulatory News | 14 July 2016 |  By 

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

Fast Advance in Hepatitis C Care Prompts EMA to Revise Clinical Trial Guideline

EMA has proposed changes to its guideline on clinical trials of direct acting antiviral hepatitis C drugs. The revisions are intended to ensure the guideline reflects the dramatic changes that have happened in the hepatitis C sector since Gilead introduced its blockbuster Sovaldi (sofosbuvir).

When EMA adopted its current guideline in 2008, hepatitis C patients were still reliant on treatment regimens that featured interferon. That changed with the 2013 approval of Sovaldi, which offered the majority of hepatitis C patients a comparatively quick, safe way to treat their infections. With Sovaldi, its follow-up Harvoni (ledipasvir/sofosbuvir) and rival products from AbbVie and Merck having completely changed the face of hepatitis C care in Europe, EMA has decided that the guideline it wrote in the previous era of treatment is no longer fit for purpose.

In response, EMA has released a new, 19-page guideline for consultation. The guideline calls for trials designed to show viral clearance to use sustained virological response as the primary endpoint. EMA wants sponsors to measure hepatitis C RNA 12 weeks after the end of therapy, and conduct follow-up tests to confirm the durability of the response to a novel drug regimen. With Sovaldi and its rivals having reset expectations in hepatitis C care, new treatments will need to generate impressive safety and efficacy data.

The effectiveness of existing drugs is reflected in EMA’s expectation that clinical trials will feature an active comparator arm. EMA is open to dropping this requirement in some circumstances. If a drug delivers very high sustained virological response rates in Phase II, EMA may free sponsors of the obligation to run a randomized controlled study. In this situation, a safety trial comparing the drug to an active comparator or placebo, plus an uncontrolled efficacy study, could be sufficient. The flexibility is a reflection of the negligible rate of spontaneous resolutions in hepatitis C. 

EMA is accepting comments on the draft guideline until 31 December.

Draft Guideline

PRAC Softens Stance on Gilead’s Cancer Drug Following Safety Review

The Pharmacovigilance Risk Assessment Committee (PRAC) has dropped restrictions on the use of Gilead’s Zydelig (idelalisib) after completing its review into the safety of the blood cancer drug. PRAC originally advised against starting patients with previously untreated chronic lymphocytic leukemia (CLL) and certain genetic mutations on the drug, but has now softened its stance.

Having concluded its review, PRAC is now advising that patients with previously untreated CLL whose cancer cells have either the 17p deletion or TP53 mutation can start on Zydelig if there are no other therapeutic options and steps designed to cut the risk of infection are followed. When PRAC began its review in March, it took a more hardline stance. Under that original recommendation, physicians were advised against starting this subpopulation of CLL patients on Zydelig, a precaution that was underpinned by reports of serious adverse events in clinical trials of the drug.

The serious adverse events were seen in three clinical trials that administered Zydelig or a placebo alongside other cancer drugs. Most seriously, some subjects in the clinical trial died from infections including pneumonia. While the regimens used in the trial differed from those approved for use in Europe, EMA nonetheless felt the deaths had implications for the real-world use of Zydelig. As such, the regulator took immediate precautionary actions, including the moratorium on starting certain CLL patients on Zydelig, and began a detailed review of that situation.

Overall, the final recommendations represent a refinement, not a major overhaul, of the original advice. PRAC’s reservations about giving Zydelig to previously untreated CLL patients with the 17p deletion or TP53 mutation remain, although it is now advising that this subpopulation can start on the drug under certain circumstances. Similarly, the original recommendation that patients starting on Zydelig take antibiotics to prevent infection with Pneumocystis jirovecii is still in place. The latest advice adds that patients should stay on antibiotics for up to six months after stopping taking Zydelig.

PRAC has maintained its view that patients taking Zydelig need regular blood tests to take white cell counts, and that physicians should not start treatment if the individual is suffering from a generalized infection. The recommendations now pass to the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP), which has responsibility for adopting the regulator’s final position on the topic.

PRAC is now turning its attention to other matters. At the meeting to conclude the Zydelig probe, the committee started three new reviews and extended an ongoing investigation. The new reviews relate to the risks of modified-release paracetamol, retinoid medicines and factor VIII drugs. PRAC’s extension affects its review into SGLT-2 inhibitors. Initially, PRAC was only looking at Johnson & Johnson’s Invokana. Now, it has extended the scope to cover similar diabetes drugs from AstraZeneca and Boehringer Ingelheim.   

PRAC Statement, More

MHRA Starts Survey to Help Develop Side Effect Reporting Software

The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) has initiated a survey to inform the creation of online adverse event reporting software. MHRA is performing the work as the head of Web-RADR, a European project to overhaul pharmacovigilance.

Officials in charge of the scheme have designed two surveys, one for healthcare professionals and the other for the general public. The survey aimed at the public is designed to gauge to whom the respondent has reported adverse events in the past, what factors would prompt them to inform the national regulator of a side effect and what feedback they would like to receive after making a filing. MHRA also asks how likely people are to use paper, apps and web forms to report adverse events.

The survey targeting healthcare professionals is aimed more squarely at mobile apps. MHRA wants to know how interested people would be in having an app to submit and receive information, what functions they would like such an app to possess and what security system they would feel comfortable using. The regulator is also trying to gauge what proportion of healthcare professionals are aware of and use its existing YellowCard app.

MHRA plans to use the feedback to improve its YellowCard app. YellowCard is one of three apps set up by regulators involved in Web-RADR. The other apps were introduced by regulators in Croatia and the Netherlands earlier this year.

MHRA Statement

EMA Posts Draft Guideline on Quality Documents for Investigational Biologics

EMA has started a consultation on a draft guideline covering quality documents for investigational biologics. The draft is designed to replace a text adopted in 2012, since when Europe has revised its clinical trial legislation.

In response to the legislative changes, EMA has updated its guideline. The text is designed to establish harmonized requirements for documents submitted throughout the European Union, a model EMA thinks is needed given the prevalence of cross-border, multi-country studies.  

The bulk of the document deals with information on investigational biologics’ biological, chemical and pharmaceutical quality. EMA has also used the guideline to address documentation relating to active comparators and placebos used in clinical trials.

EMA is accepting feedback on the draft until the end of the year.

Draft Guideline

Other News:

EMA has released a draft strategy for the implementation of ICH Q3D. Draft Strategy


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