European Regulatory Roundup: Sandoz, Sanofi and Teva Drugs Face Suspension After EMA Faults Bioequivalence Tests (28 July 2016)

Regulatory NewsRegulatory News | 28 July 2016 |  By 

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

Sandoz, Sanofi and Teva Drugs Face Suspension After EMA Faults Bioequivalence Tests

The European Medicines Agency (EMA) has recommended the suspension of drugs from Sandoz, Sanofi, Teva and other companies following an investigation into a bioequivalence testing site. EMA found the testing company, India’s Semler Research Centre, had substituted and manipulated clinical samples, prompting the regulator to recommend the suspension of drugs assessed at the site.

Sandoz, Sanofi and Teva are among the biggest companies to be affected by the recommendation, which could see more than 250 products pulled from the market or stopped from receiving approval on the basis of the available data. EMA is refusing to grant approval to drugs that rely on data from Semler. Many of the affected products are formulations of the same active ingredient sold at different dosages and in different countries — generic versions of cancer treatment Tarceva feature prominently — but even so the suspension recommendation has a broad reach.

EMA felt compelled to make the recommendation after conducting a review of Semler. The review was prompted by failings raised by inspectors from the United States Food and Drug Administration (FDA) and World Health Organization (WHO). In separate reports published in April, FDA and WHO took Semler to task for manipulating study samples and data integrity failings. FDA responded by telling sponsors that are seeking approval on the basis of data from Semler that they must repeat the study at another, non-Semler site.

European regulators have taken a similar approach to the problem. Firms that are seeking approval must provide new, non-Semler data if they are to receive a positive decision from EMA. Similarly, the companies affected by the suspension recommendation can keep their drugs on the market if they provide data from another source to demonstrate bioequivalence. Some companies, notably Lupin, have already presented such data, resulting in EMA allowing an HIV combination treatment to stay on the market.  

The actions against Semler and the drugs it tested are reminiscent of EMA’s handling of GVK Bioscience. Last year, EMA recommended the suspension of the marketing authorizations of 700 products after an inspection uncovered evidence of electrocardiogram data manipulation. The EMA suspension had far-reaching implications, most notably because the Indian government canceled trade talks with the European Union in protest.  

Press Release, Suspension List

EMA Targets 65% Drop in Colistin Sales to Stem Rise of Antimicrobial Resistance

EMA has committed to cutting sales of colistin by 65% after releasing new advice intended to curb the rise of antimicrobial resistance. The publication of final advice on the use of colistin concludes a rapid regulatory rethink over the role of the antibiotic, which was triggered by the discovery of the MCR-1 gene in November.

Having recognized that MCR-1 represented a previously unknown mechanism of resistance to colistin and seen the gene being found around the world, EMA published a draft revision to its advice on the use of the antibiotic in May. Following a comment period in which some organizations called for an outright ban on the use of colistin, EMA has released final advice that limits the antibiotic to a second-line role. EMA is also asking member states to cut their use of colistin to 5 mg per population correction unit over the next three to four years.

If member states comply with this request, EMA forecasts sales of colistin will fall by 65%. Europe has already lowered its use of colistin in recent years. EMA would like to see member states go further still. The regulator sees colistin use of below 1 mg per population correction unit as ideal, but has put 5 mg as the target for “high and moderate” consumers. The decision not to ban colistin completely, as some respondents to the draft advice requested, was underpinned by concerns that a withdrawal would lead to increases in the use of fluoroquinolones and other critically important antimicrobials.

The restrictions on the use of colistin, which is one of the five most used antibiotics in animals in the European Union, mark the beginning of the end for the brief resurgence of the 50-year-old product. Colistin’s reemergence after decades in which toxicity concerns limited its use was prompted by the rise of resistance to other products. Now, with colistin running into resistance issues of its own, the drug is set to fade away once again.                

Press Release, EMA Advice

CVMP Expands Scope of Stem Cell-Based Veterinary Medicine Debate

The Committee for Medicinal Products for Veterinary Use (CVMP) has posted two more sets of draft questions intended to guide the focus of regulatory discussions regarding the use of stem cell-based products. CVMP addresses target animal safety and risk of tumor development in the questions.

Officials have the most questions about tumorigenicity. While the use of mesenchymal stem cells in humans is yet to result in reports of tumor formation, CVMP views it as a valid concern. The question for CVMP is the extent to which these concerns are applicable to veterinary uses of stem cells. In an attempt to gauge the risk of tumorigenicity and what it can do to minimize the threat, CVMP has released nine questions intended to start a discussion on the topic.

The questions address how the veterinary sector can implement biodistribution assays, which in vitro controls could detect tumorigenic cells and whether the pharmaceutical formulation of products can minimize the risk of tumor formation. CVMP is accepting feedback on the text until 30 September. The committee has set the same deadline for comments on its other draft document, a list of four questions on how to assess the safety of stem cell-based products.

Members of EMA’s Ad Hoc Expert Group on Veterinary Novel Therapies (ADVENT) have released the questions for consultation to start a process that could lead to the creation of question and answer guidance documents. ADVENT released another set of questions regarding stem cell-based products last month with the same objective in mind. Those earlier questions covered how to ensure stem cell products are free from extraneous agents such as viruses, bacteria and protozoa.

Draft Questions, More

MHRA Releases Data Integrity Guidance for Consultation

The UK's Medicines and Healthcare Products Regulatory Agency (MHRA) has published draft data integrity definitions and guidance for consultation to inform the pharma industry of its data integrity expectations across the drug development lifecycle. 

In the draft, MHRA calls for companies to adopt a working environment and organizational culture that ensure the completeness, consistency and accuracy of data, regardless of whether it is kept on paper or electronically. MHRA is advocating for a risk-based approach. As such, firms should commit more time and resources to ensuring the validity of data if an integrity failure could detrimentally affect patients or the environment.

“Organizations are not expected to implement a forensic approach to data checking on a routine basis, but instead design and operate a fully documented system that provides an acceptable state of control based on the data integrity risk with supporting rationale,” MHRA wrote. This entails carrying out routine data reviews to assess the integrity of individual datasets, while also performing periodic audits to ensure the effectiveness of existing control measures.

The draft guidance applies to both paper and electronic data.  

MHRA Guidance


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