Suspend Dozens of Drugs Based on Flawed Studies, EMA Says

A committee of the European Medicines Agency (EMA) has recommended suspending the sale of roughly four dozen generics for conditions such as diabetes, depression, and hypertension because their approvals were based on flawed clinical studies conducted in India, the agency announced today. The US Food and Drug Administration (FDA) has not yet taken action on the issue.

Familiar names on the list include candesartan, donepezil, escitalopram, esomeprazole, and metformin. The list extends more than 120 pages because the drugs are marketed individually in multiple European Union (EU) nations in various dosages, and therefore appear over and over.

Abbott Laboratories, Actavis, Dr Reddy’s Laboratories, Mylan Pharmaceuticals, Sandoz, and Takeda Pharmaceuticals are some of the many manufacturers involved.

The EMA recommendation to suspend the drugs would apply across the entire EU. Drug regulators in France, Germany, Belgium, and Luxembourg have already acted to stop the sales of 25 drugs.

The clinical studies in question were conducted by GVK Biosciences, a contract research organization in Hyderabad, India.

The recommendation of the EMA’s Committee for Medicinal Products for Human Use to suspend the drugs was based on a French inspection of GVK Biosciences that revealed “data manipulations of electrocardiograms during the conduct of some studies of generic medicines,” apparently over the course of at least 5 years. The systematic and prolonged nature of these manipulations and the number of staff involved “cast doubt” on the integrity of the trial methodology and the reliability of the data generated, said the EMA.

However, “there is no evidence of harm or lack of effectiveness linked to the conduct of studies by GVK Biosciences.”

In a statement posted on its website, GVK Biosciences called the EMA recommendation “unprecedented and highly disproportional.” It said that the EU agency had extrapolated findings about the suspect electrocardiograms in nine studies to all studies conducted at its Hyderabad facility. The company quoted French inspectors who said that the electrocardiograms “are not essential given the demonstration of bioequivalence,” and that their observations should not be extrapolated to the bioanalytic, pharmacokinetic, and statistical aspects of its research.

GVK [Biosciences] is working closely with its customers to ensure an appropriate and quick resolution to these issues,” the company said.

FDA Has Taken No Action After Its Own GVK Inspection

Medscape Medical News asked the FDA to comment on the EMA recommendation. It received a statement that the agency had released last month after the decision of several EU nations to suspend sales of various generics. In it, the FDA said that some 40 drug applications received from 2007 to March 2012 contained GVK clinical data, and that some of these applications were approved.

The FDA declined to identify the drugs in question or indicate those that had been approved.

According to the FDA statement, the agency inspected GVK Biosciences in September 2014 on the heels of the French inspection in May 2014 and failed to find any evidence “that affects the safety or efficacy of drug products subject to pending applications or products approved in the US.”

The agency promised to take “swift and appropriate action” to protect American consumers if it “identifies issues concerning GVK Biosciences that relate to products approved by the FDA.”

Exceptions Can Be Made

The EMA investigation of drugs studied at GVK Biosciences encompassed more than 1000 individual generics in various forms and strengths as individually approved in 29 EU nations. Of this group, 300 generics had enough supporting clinical data from other sources to warrant staying on the market, according to the EMA.

That left roughly 700 generics — reiterations of the core four dozen or so drugs — that should be suspended, the EMA said. However, individual countries can make an exception for drugs that are critically important because there are no alternatives to meet patients’ needs.

The EMA recommendation goes to the European Commission, the EU’s executive agency, for a legally binding decision that will apply to all EU nations, including those that already have suspended the generics in question.