Regulatory Focus™ > News Articles > EU Regulators Claim Diabetes Medicines Clear of Safety Fears, but Data Key to Finding

EU Regulators Claim Diabetes Medicines Clear of Safety Fears, but Data Key to Finding

Posted 26 July 2013 | By Alexander Gaffney, RAC 

Diabetes drugs of the GLP-1 and DPP-4 class have recently come under intense scrutiny by regulators on both sides of the Atlantic Ocean, with both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) expressing strong concerns that the pancreatic risks associated with the drug might well outweigh their benefits. Now, however, EU regulators have reaffirmed their positive benefit-risk assessment, saying that no new concerns could be identified based on the currently available evidence.

Background

In October 2007, FDA approved Byetta (exanatide), the first of a new GLP-1 class of injection drugs intended to treat type-2 diabetes. By August 2008, however, it had received dozens of reports associating the drug with acute pancreatitis, and issued a warning to healthcare professionals saying some of these cases could potentially be severe. In particular, FDA said it had received six cases of hemorrhagic or necrotizing pancreatitis in patients taking Byetta, of which two were fatal.

By September 2009, FDA's concerns had spread to another class of drugs known as DPP-4 inhibitors, which include the diabetes drugs Januvia (sitagliptin) and Janumet (sitagliptin/metformin), which exhibited nearly identical trends to those seen in some Byetta patients.

In both cases (GLP-1 and DPP-4), FDA advised providers to be vigilant and aware of the signs and symptoms associated with pancreatitis, and to discontinue the drugs if pancreatitis is suspected.

In 2013, FDA once again issued a warning to healthcare providers, saying it had become aware of still more potential risks to patients taking GLP-1 and DPP-4 incretin mimetics, including a general increase in the risk of cancer.

While the risks of pancreatitis remained relatively stable, FDA said the list of drugs associated with those risks had grown to include exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto).

Based on what FDA called an "examination of a small number of pancreatic tissue specimens taken from patients after they died," it said it is concerned about "potential pancreatic toxicity" associated with the drugs.

While FDA said it continued to study the issue, EMA announced its own investigation into the issue shortly thereafter in March 2013. The investigation, which was being run by the agency's Committee for Medicinal Products for Human Use (CHMP) and Pharmacovigilance Risk Assessment Committee (PRAC), said any assessment would then be turned over to regulators for final analysis.

EMA: GLP and DPP are OK

The results of that assessment are now complete, and many drugmakers may be breathing a sigh of relief at its finding: GLP-1 agonists and DPP-4 inhibitors appear to be safe for use by patients.

"The [CHMP] concluded that presently available data do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines," EMA wrote in a statement. Regulators said the study on which the EMA's concerns were primarily based had been found to have "a number of methodological limitations and potential sources of bias, most importantly differences between the studied groups with respect to age, gender, disease duration and treatments, which preclude a meaningful interpretation of the results."

Even after reviewing other data, however, the CHMP was reportedly unable to find any data to support a need for a reevaluation of the overall risk of the medicines, EMA wrote. The trials "do not indicate an increased risk with these medicines" with respect to pancreatic cancer," the regulator added.

Is Data Quality the Biggest Factor?

The finding could portend a similar finding by FDA, though the quality data used by EMA seemed to play a significant role in its final decision not to require regulatory changes for the drug. A recent investigation published by the British Medical Journal said the manufacturers may be to blame for the paucity of data available to the public.

Writing in the June 2013 edition of the BMJ, Deborah Cohen, BMJ's investigations editor, said she had "reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to unwanted proliferative or inflammatory pancreatic effects."

Cohen also said she found no evidence that companies had conducted "critical safety studies" or released raw data that could have put some of the associated safety problems to rest, "posing serious questions about the safety of this class of drug."

And, as Cohen's piece explains, in case after case manufacturers have withheld certain data from regulators, raising questions about whether those data contain signals about pancreatic risks associated with the drug that would establish a more definitive causal link.

That leaves open the possibility that FDA's own investigation may well rely on different data than EMA's investigation, potentially leading to a different result.


EMA: Investigation into GLP-1 based diabetes therapies concluded


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