European Regulatory Roundup: EMA’s PRAC Seeks to Suspend Four Imaging Agents (16 March 2017)

Regulatory News

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PRAC Asks to Suspend Authorizations of Four Imaging Agents After Reviewing Safety

The Pharmacovigilance and Risk Assessment Committee (PRAC) has recommended the suspension of the marketing authorizations for four linear gadolinium contrast agents. PRAC put forward the proposal after finding “convincing evidence” accumulations of gadolinium are present in the brain many months after the contrast agent is last injected.

Officials at the European Medicines Agency’s (EMA) risk assessment committee want to see the marketing authorizations of gadobenic acid, gadodiamide, gadopentetic acid and gadoversetamide suspended following their review of the evidence. PRAC found no evidence the small amounts of gadolinium deposited in the brain cause harm, but is advocating for a precautionary suspension on the grounds there is a lack of data on the long-term effects of the chemical element on the brain.

More evidence is available for other organs and from preclinical studies. Researchers have linked deposits of gadolinium to skin plaques and nephrogenic systemic fibrosis (NSF). NSF, which was first identified in 1997, is thought to occur when patients with severe kidney failure are exposed to gadolinium-based MRI contrast agents. PRAC also pointed to preclinical studies suggesting gadolinium can harm tissues to justify its precautionary approach. 

In reviewing the safety of imaging agents, PRAC looked at both linear and macrocyclic agents. The former are less stable and, as such, are more likely to release gadolinium. That said, PRAC is planning to keep two linear agents on the market.

PRAC is proposing gadoxetic acid stay on the market because there are few alternatives for the important liver scans it enables. Gadopentetic acid is also set to stay on the market provided it is injected directly into joints. The concentrations of gadolinium used in this application are very low compared to those used when the imaging agent is administered intravenously. For both linear agents, PRAC is advising the lowest possible doses are used, and only in cases where unenhanced scans are unsuitable.

The risk committee wants to see the same precautions applied to the use of macrocyclic agents.

Companies affected by PRAC’s suspension recommendations can ask the committee to reassess its advice. Also, suspensions can be lifted if marketing authorization holders provide evidence the benefits outweigh the risks in a certain population, or that their product does not release significant levels of gadolinium or lead to accumulation of the chemical in tissues.

PRAC Notice

EMA Establishes Data Protection Position on Comments Filed in Public Consultation

EMA has released a data protection statement covering information submitted as part of its public consultation on access to documents. The statement details what information EMA will collect, who will have access to it and how long it will be kept when people submit feedback on planned changes to a regulatory text on document access.

That document access consultation, which EMA began last month, is subject to European Union legislation on data protection because it will further process the personal data it collects. As such, EMA has released a data protection statement outlining what will happen to the personal data of people who take part in the consultation.

The statement says EMA will only collect the information needed to manage and review people’s contributions to the consultation, such as professional contact details and the views expressed. EMA will publish people’s personal data unless they provide “valid justification” doing so would harm their “legitimate interests.” If EMA receives a justified request for anonymity, it will publish the feedback anonymously.

EMA will store submissions and data on a database accessible only by people within the organization who have a relevant user ID and password. Contributors can contact the data controller to verify what personal data is stored or ask for records to be changed or deleted. EMA will delete data from its internal records two years after the public consultation ends.

EMA Statement

PRAC Starts Review of Docetaxel Following Reports of Neutropenic Enterocolitis

PRAC has begun a review into the safety of cancer medicine docetaxel. The initiation of the review follows reports of cases of the serious inflammatory condition neutropenic enterocolitis in patients in France.

Neutropenic enterocolitis is a known but rare side effect of docetaxel. In up to one in 1,000 people, the now-generic chemotherapy is linked to inflammation of part of the large intestine known as the cecum. The condition is also associated with low levels of a type of white blood cell. In France, the side effect has affected enough patients recently, particularly those being treated for operable breast cancer, to raise safety concerns.

PRAC has performed an initial assessment of the frequency of reports of neutropenic enterocolitis over the past two years. That assessment found no evidence that incidence of the side effect is on the rise, but PRAC is now thoroughly reviewing the data to confirm the safety signal detected in France is a blip rather than an underlying trend.

While PRAC performs that review, EMA is advising doctors to continue to prescribe docetaxel in accordance with the recommendations made in the current product information. The recommendations include guidance on how to prevent and manage low levels of white blood cells in patients taking the drug. 

Docetaxel was introduced in Europe in 1995 and was sold under the brand name Taxotere. Last year, Sanofi, which makes Taxotere, recalled vials of the chemotherapy following a manufacturing failure, prompting EMA to warn of a supply disruption. The situation was resolved by September.

PRAC Notice

Swissmedic Tightens Ties to Austrian Regulator, Furthering Bilateral Cooperation Agenda

The Swiss Agency for Therapeutic Products (Swissmedic) has formed a bilateral collaboration with the Austrian health regulatory agency. By signing the memorandum of understanding, Swissmedic furthered its push to tighten its ties to other agencies, particularly in German-speaking countries.

Swissmedic signed the agreement with the managing director of the Austrian Agency for Health and Food Safety (AGES) this week. The agreement lays the groundwork for closer collaboration between Swissmedic and AGES. Exact details of how the regulators plan to work together are yet to emerge. 

Having signed the pact, Swissmedic now has cooperation agreements with drug product regulatory authorities in all German-speaking countries. This follows a concerted effort by Swissmedic dating back several years to improve cooperation with regulators in the European Union and in other countries of strategic interest to Switzerland.

Swissmedic, which is outside EMA, sees the collaborations as helping it to make the best use of its resources. The agency views this as particularly important given the rising complexity of the products and processes regulated by drug authorities.

Swissmedic Notice

Other News:

EMA has updated its pre- and post-authorization procedural advice question and answer documents. The pre-authorization text features a new section on what additional information companies can include on the outer packing of their products. EMA also revised a section on how centrally authorized products are handled in Norway, Iceland and Liechtenstein. The document of post-authorization advice features multiple changes about periodic safety update reports. Pre-Authorization, Post-Authorization

Regulators from the EU have met with their African counterparts to discuss opportunities for collaboration. The meeting looked at how EMA, the World Health Organization and countries that access medicines through Article 58 — a procedure that approves products for use outside the EU — can better communicate. One idea is to involve experts from target country regulators more in the Article 58 process. EMA Notice