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Did a red herring over drug safety put paid to India's first new drug?

Global drug development history has its examples of instances where red flags were raised, which later turned out to be red herrings.

twitter-logo E Kumar Sharma        Last Updated: January 18, 2016  | 14:49 IST

E Kumar Sharma, Associate Editor, Business Today
On December 16, 2015, the US Food and Drug Administration (USFDA) removed the final restrictions on the use of rosiglitazone, an anti-diabetes medicine. While it was an important development that came as a relief to pharma companies, it also raises a nostalgic point around the efforts of those engaged in drug development using this class of compound.

For, here is a red flag raised on the safety of the drug that, in a sense, turns out to be a red herring. What the drug regulator has now said is this: "FDA is eliminating the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing type 2 diabetes medicines, which are approved as Avandia, Avandamet, Avandaryl, and generics. The REMS is no longer necessary to ensure that the benefits of rosiglitazone medicines outweigh their risks."

It goes on to say: "In 2013, FDA required removal of the prescribing and dispensing restrictions for rosiglitazone medicines after determining that data did not demonstrate an increased risk of heart attack with rosiglitazone medicines compared to the standard type 2 diabetes medicines metformin and sulfonylurea."

The restrictions imposed on rosiglitazone followed a study in 2007 that linked use of rosiglitazone to possible increase in risk for cardiovascular death.

This drug had been of great interest to Kallam Anji Reddy, the founder of Dr Reddy's Laboratories, as he was steering efforts on these within his company. Before his death in 2013, he would often talk of his two lead drug development candidates - ragaglitazar and balaglitazone. In fact, in his autobiography released after his death, there is a whole chapter on it titled 'Graveyard of Glitazars'.

Here, he says: "There is little hope that the FDA of the European Medicines Agency will consider approval of a new glitazone or glitazar (another class of compounds) without evidence of cardiovascular safety and the absence of carcinogenicity. Such evidence can be generated only through clinical trials that are so large and of such long duration that it is commercially infeasible to do so."

While efforts to develop 'ragaglitazar' were given up after adverse impact on mice, 'balaglitazone' progressed through trials without any hitch. But today, it has gone into oblivion with its patent also expired. All of it only raise the point that what if the 2007 meta analysis had not thrown up a red flag, maybe history could have been different and perhaps there would be potentially a new drug in the works from India.

As Reddy says later in the book: "The many glitazones - over fifty of them - that followed balaglitazone and the glitazars that followed 'ragaglitazar' have all fallen by the wayside." And, he further goes on to add: "Some of the largest pharmaceutical companies in the world pursued the glitazars after us - Bristol-Myers Squibb with muraglitazar, Hoffmann La-Roche with aleglitazar and AstraZeneca with tesaglitazar. All these molecules had entered Phase III but were eventually buried in the graveyard of glitazars."

This is not new. Global drug development history has its examples of instances where red flags were raised, which later turned out to be red herrings.

Consider the saccharine story, where based on a study, this artificial sweetener was banned (in the 1970s) and later allowed. On its website, here is what the FDA says: "Saccharin remains on the market today. The basis for the proposed ban was a study that documented an increase in cancer in rats being fed saccharin. The "Delaney clause" of the Food Additive Amendments to the Federal Food, Drug, and Cosmetic Act states that no substance can be deemed safe if it causes cancer in humans or animals. In suspending the proposed saccharin ban, Congress ordered that products containing the popular sweetener must carry a warning about its potential to cause cancer. The FDA formally lifted its proposal to ban the sweetener in 1991 based on new studies, and the requirement for a label warning was eliminated by the Saccharin Notice Repeal Act in 1996."

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