The debate about data transparency has returned to the spotlight following an investigation into the safety of new diabetes drugs by the BMJ and the Channel 4 programme Dispatches which found that evidence suggesting potential harm from certain therapies, the incretin mimetics, has not been published.
The probe, published on bmj.com and broadcast in Diets, Drugs and Diabetes on Channel 4 in the UK, centred around glucagon-like peptide-1 (GLP-1) agonists such as Byetta (exenatide), now owned by Bristol-Myers Squibb and AstraZeneca, and Novo Nordisk's Victoza (liraglutide), but also dipeptidylpeptidase-4 (DPP-4) inhibitors, a class led by Merck & Co's Januvia (sitagliptin). Deborah Cohen, the BMJ's investigations editor, noted that this drugs were seen as "the 'new darlings of diabetes treatment, the biggest breakthrough since the discovery of insulin nearly a hundred years before".
The investigation cites critics who say drug regulators in Europe and the USA have been slow to pursue concerns about the potential adverse effects of these new diabetes drugs, "despite the emerging warning signs in the medical literature, regulatory documents and adverse event databases". The BMJ has reviewed thousands of pages of regulatory documents obtained under freedom of information and found unpublished data pointing to "unwanted proliferative or inflammatory pancreatic effects".
The BMJ also found that, despite published reports that indicated safety concerns, "companies have not done certain critical safety studies; nor have regulators requested them yet". It argues that "access to raw data that might help resolve doubts about the safety of these drugs has been denied".
'Worrying picture emerges'
Ms Cohen says that "on their own, the individual pieces of unpublished evidence may seem inconclusive, but when considered alongside other emerging and long-standing evidence, a worrying picture emerges, posing serious questions about the safety of this class of drug". The investigation refers to three publications this year which have raised concerns about the potential side effects of GLP-1 based drugs, prompting both the US Food and Drug Administration and the European Medicines Agency to launch a review into whether the drugs may cause or contribute to the development of pancreatic cancer. Across the pond, hundreds of people are suing manufacturers alleging that the drugs caused pancreatitis and in some cases cancer.
The BMJ and Dispatches cite research by Peter Butler at the University of California Los Angeles which "found worrying changes" in the pancreases of animals that received a GLP-1 based drug. He has also found abnormal changes, including pre-cancerous lesions, in the pancreases of eight organ donors taking these drugs compared with patients taking other anti-diabetic therapies.
Still the BMJ says "the evidence is fiercely contested amongst scientists and manufacturers stoutly defending the safety of their products". Both the EMA and the FDA have confirmed to the journal that they have "signal" for pancreatic cancer - but this does not mean there is a causal link.
In statements to Dispatches, the drug companies all maintain their commitment to patient safety and on monitoring say they have regular, close and vigorous safety processes in place, including large-scale, long-term trials. The results are routinely submitted to the regulatory authorities.
Writing in the BMJ, editor-in-chief Fiona Godlee said: "All drug licensing is about balancing benefits and risks. But instead of engaging in open debate about legitimate and important scientific questions, the manufacturers have been unwilling to share their data. Meanwhile patients and doctors have not been kept properly informed about the uncertainties surrounding these drugs."
She added that the debate "would be much easier to resolve if all the information was placed in the public domain so scientists, doctors and ultimately patients could make up their own minds".
ADA calls for independent review
As the programme was being transmitted in the UK, across the Atlantic, the American Diabetes Association issued a statement asking all pharmaceutical companies involved with incretin-based medications "to make patient-level data on their products available for an independent review that could help settle the question of whether such therapies contribute to the development of pancreatitis or pancreatic cancer".
Robert Ratner, its chief scientific and medical officer, said patients "should have the benefit of all that is currently known about their risks and advantages in order to make the best possible decisions about their treatment". The ADA is calling for applications from "academic and research organisations capable of integrating large experimental databases to illuminate the potential role of incretin therapy in pancreatic pathology".