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WASHINGTON – Fifteen years ago, a diabetic patient might have paid $ 175.57 for a 20-milliliter bottle of Humulin R U-500 long-acting insulin.
Today, it would pay $ 1,487 for the same small vial, based on data on the wholesale costs of the Elsevier Gold Standard drug database.
It's easy to blame drug manufacturers: three pharmaceutical companies, both gigantic and global, control the vast majority of the global insulin market, valued at $ 27 billion: Sanofi, Eli Lilly and Novo Nordisk. And they've always done it, almost since the discovery of the drug in 1921.
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But an in-depth look at the history of this drug, which goes back almost 100 years, reveals a much more complicated story: it clearly shows that drug manufacturers, their generic counterparts, their doctors and, increasingly, the Food and Drug Administration itself share the blame for the broken insulin market. And while many ideas are being proposed to address this problem, ranging from drug patent seizures to reducing the amount that diabetics can pay out of pocket for insulin, many policy experts have confided in STAT that creating a generic competition is probably the key to success. the costs for the more than 7.5 million Americans who rely on this drug.
As the Congress prepares to investigate the market – already, Sanofi will testify before the Senate Finance Committee next week and Representative Diana DeGette (D-Colo.) Is committed to bringing the big three companies ahead its sub-committee on energy and trade – it's worth asking if there is any reason to call others, like the generic manufacturers or FDA Commissioner Scott Gottlieb to testify as well.
"Everyone is at fault, which makes it difficult to find a solution," STAT's Dr. Walid Gellad, who heads the Center for Drug Policy and Prescription at the University of Pittsburgh, told STAT.
Modern insulins mimic insulin, a hormone normally produced by the pancreas, which regulates the amount of glucose in the user's blood. People with diabetes inject the product either because their pancreas does not create insulin on its own, or because the body has become resistant to the insulin produced by their body.
Knowing who discovered the drug first is controversial; even the Nobel Prize for his discovery was questioned. The honored researchers, Frederick Banting and John J.R. Macleod, were only two of a team of researchers at the University of Toronto who finally discovered how to use insulin to treat diabetes. And Banting publicly disliked that Macleod did not deserve this award from an assistant, Charles Best.
Banting sold the patent for the product at the University of Toronto for just $ 1, hoping the product would be readily available, given the vital importance of this discovery for treating a once-deadly disease.
Eli Lilly was the first drug manufacturer to produce the product on a large scale; Early versions used insulin from cattle, such as cattle and pigs. Since then, the three manufacturers have developed long-acting and slow-release variations, as well as many other products, some of which are now almost identical to what the body produces itself.
For most of its history, generic companies had little interest in entering the market. The insulin market was not as lucrative as it is today. In 1999, for example, Eli Lilly sold $ 701 million worth of insulin to the United States, according to documents filed by the SEC. In 2017, Lilly cashed $ 2.6 billion for just two of its insulin products.
"Twenty years ago, many of these products were so cheap that the value of the investment was not there for generics," said David Gaugh, senior vice president of science and technology. Regulatory Affairs of the Association for Accessible Medicines.
This has begun to change over the last decade, around the same time that drug manufacturers started raising their prices. In 2008, Humalog, Eli Lilly's top selling and most expensive insulin, generated sales of more than $ 1 billion in the United States, 12 years after it was released. In 2017, Lilly sold $ 1.7 billion worth of this drug. The increase in revenues in Lilly's coffers is largely due to higher prices, a fact Lilly repeatedly admits in its own annual reports to shareholders.
Today, there is more than one copy of insulin, made by Eli Lilly. The product, Basaglar, copies an expensive Sanofi product, Lantus, which is the world's best-selling insulin. It's about 15% cheaper than Lantus.
Other factors have also deterred generic companies from being interested in it.
According to the American Medical Association, doctors are reluctant to prescribe older insulin-based products, namely those that are eligible for generic competition. This is despite the fact that research shows that many people with diabetes respond as well to older insulins, according to a study published in the journal Diabetes Care. A 2014 study by the Institute for Clinical and Economic Review also found that there was sufficient evidence to suggest that older insulins were just as effective as new insulins for people with diabetes mellitus. type 2.
Dr. Kasia Lipska, an assistant professor of medicine at Yale, told STAT that prescribing insulin at a later age meant "going against the grain".
"This totally thwarts the competition of generic drugs because if the off-patent drug is considered already irrelevant, there is no impetus to invest in this drug," Lipska said.
Although even the American Medical Association has recently acknowledged in a policy statement that "guidance and education materials can help young physicians be more comfortable with prescribing alternatives. to insulin more affordable ", some doctors say that they should not be held responsible for the current crisis of insulin affordability.
"When we started using Humalog and Lantus, the cost difference was minimal, but the differences in hypoglycemia were modest," said Dr. Irl Hirsch, a professor of medicine at the University of Washington. "Since costs are not a big problem, how can we blame doctors?"
Brand-name manufacturers also deserve some responsibility for the concentrated market.
Their strategy to keep generic competition at bay? Patent filing – a lot of them. Each of the major manufacturers has hundreds of unexpired patents for their products, devices that provide the drugs, and methods of manufacture.
Sanofi, which manufactures Lantus, was particularly noted for allegedly repeatedly modifying its product to file new patents. According to I-MAK, he filed 74 patents on one version of this drug only.
Sanofi also fought against its Basaglar product, citing a patent infringement, which delayed the drug's launch in 2014 for nearly two and a half years, when the two men dodged it in court. And Mylan, who developed another copier for Lantus, has its own patent litigation with Sanofi, a dispute that began in 2017. (The Mylan product has not yet been approved by the FDA.)
"The inventions of our scientists are new and not obvious, as the patents we have received from the US Patent and Trademark Office recognize," Sanofi spokesman Ashleigh Koss told STAT. "By protecting our patented inventions, we are paving the way for the discovery of new medicines to address unmet medical needs."
Fear of similar patent conflicts may also discourage other generic drug companies from considering less lucrative imitators. Gaugh, from the generic lobby, told STAT.
"All types of patents are involved," Gaugh told AAM. "Whether process patents, manufacturing patents, device patents … packaging patents, labeling patents and trademarks, all these methods are different to prevent [competition]. "
At present, however, the main obstacle to generic insulin may actually be regulatory.
The regulation of insulin is more complicated than any other drug because of its unique science and history.
Insulins are technically biological products, a label used to describe drugs or therapies derived from living cells and organisms. But policymakers in Washington did not have a framework to regulate biopharmaceuticals and their imitating counterparts, biosimilars, until 2010, when Congress set the start in its competition and innovation law. price of organic products. As part of this law, Congress said that insulin – which was previously regulated like any other drug – would be regulated as an organic product by 2020.
Congress left the FDA with the logistics of this transition – and the agency's transition plan was not as flexible as generic drug companies expected, at least to encourage generic insulin.
The FDA's policy states that any insulin application pending before the agency on March 20, 2020 will be rejected. All applicants should then start over and submit a new application in a new biosimilar way.
Given the length of the drug development schedule – as well as the FDA's uncertain and often timely approval process – the sudden shutdown of 2020 made it difficult for drug manufacturers to submit a claim. potential for generic insulin for several years now.
Even companies that have insulins in development and are ready to apply to the FDA are now waiting to apply after 2020 because they want to avoid wasting time and money applying in 2019, to be rejected on March. 20 2020, date, AAM explained to the FDA in March 2016.
"[T]The policy is already having a devastating effect on the current development programs of many important protein products, including insulin, "AAM writes in its most recent letter to the FDA, adding that the policy" violates laws in force, is arbitrary and capricious, "words often used by companies to signal their intention to sue for a policy.
When proposed for the first time, generic drug manufacturers blew the blister of 2020, claiming that it "would hinder patients' access to affordable alternatives" to insulin and other drugs.
Gottlieb said at an industry conference in December that the FDA had "thoroughly reviewed all comments received on the previous draft directive," but rejected the major change desired by drug manufacturers Generic: Change the FDA policy regarding pending drug claims before the agency. March 20, 2020.
"We are cWe are seriously considering taking action for pending applications if they are on hold by March 20, 2020 to minimize disruptions to development programs, "FDA spokeswoman Lyndsay Meyer told STAT. "At the moment, the agency predicts that this will have an impact on few if any applications."
"The sponsors have been aware of this transition for a decade. They had time to get ready, "added Meyer.
Many lobbyists and consultants, including STAT, have agreed that the FDA has the ability to interpret the law so as not to delay generic insulins. AAM suggested that the FDA simply rely on the data included in any application already pending on March 20, 2020 and allow a sponsor to modify its application with any additional information that may be necessary, since the application will now be considered. by the FDA. to be a biological product, not a medicine.
"The opportunities for the FDA to actually accelerate the competition are huge, "said Gillian Woollett, Senior Vice President of Avalere Health. "The opportunities to encourage sponsors are all available now. So, what I do not understand is why the FDA and the HHS say everything they say. [about encouraging new generic competition] and they are not doing what they can do now to promote competition. "
While lawmakers on both sides see the price of drugs as an area for bipartite consensus and collaboration, it is clear that insulin is a top priority for Congress.
Three congressional committees held hearings over the past two months on the price of drugs and, to each, the issue of affordability of insulin was a major concern. Two committees have already started investigating insulin manufacturers and another is considering having an insulin manufacturer testify later this month.
Legislators, too, are already weighing on legislation to reduce insulin costs. The Congress Caucus on Diabetes has proposed a set of radical proposals aimed at increasing the affordability of insulin, including a legislative proposal to compel insulin manufacturers to disclose how they set their prices. price and another asking the FDA to speed up the examination of insulin at a lower cost.
"Who could believe that 100 years later, there are more than three manufacturers?" Said House Speaker Richard Neal (D-Mass.). "It's pretty crazy when you consider that."
Ike Swetlitz contributed to the reports.
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