Why Are There No Generic Insulins?

Miriam E Tucker

March 18, 2015

Why, nearly 100 years after the discovery of insulin, are no low-priced generic versions available?

The complicated answer to that question is explored in a special article published in the March 19 issue of the New England Journal of Medicine by Jeremy A Greene, MD, PhD, and Kevin R Riggs, MD, MPH, from Johns Hopkins University School of Medicine, Baltimore, Maryland.

Generic drugs account for more than 80% of prescriptions filled today, saving the healthcare system billions of dollars a year. In contrast to about a $4/month out-of-pocket cost for some generic pills, monthly costs for brand-name insulins range from $120 to $400.

The case of insulin — used by approximately six million people with type 1 and type 2 diabetes in America — differs from other drugs for a number of reasons, Drs Greene and Riggs explain.

Insulin's Canadian discoverers sold the patent to their university for $1, stating that profit was not their goal. Since then, a series of incremental technological advances have maintained the patents, while older formulations have been pulled from the market.

The recent move toward "biosimilars" — so-called because the properties of large molecules don't allow for exact copies as do generic small-molecule drugs — isn't likely to dramatically affect the cost equation either, the authors assert.

"The drugs that ultimately see extensive generic competition differ from those that attract few, if any, manufacturers. The history of insulin highlights the limits of generic competition as a public-health framework. Nearly a century after its discovery, there is still no inexpensive supply of insulin for people living with diabetes in North America, and Americans are paying a steep price for the continued rejuvenation of this oldest of modern medicines," the doctors write.

"Discoverers Didn't Intend Insulin to Become a Profitable Monopoly"

After identifying the glucose-lowering substance later known as insulin at the University of Toronto in 1921, Dr Frederick Banting and medical student Charles Best waited 2 years before seeking a patent and then only with the intent of publishing the extraction method, writing: "When the details of the method of preparation are published, anyone would be free to prepare the extract, but no one could secure a profitable monopoly."

In 1923, they teamed up with Eli Lilly, already an established pharmaceutical company, to produce the extract on a larger scale. They also licensed the rights to produce insulin to several other companies, including Denmark's Nordisk Insulinlaboratorium (which later merged with Novo Terapeutisk Laboratorium to form Novo Nordisk).

The next several decades brought successive improvements: adding protamine prolonged insulin's action, while zinc allowed it to be combined with short-acting insulin in a form patented in 1946 under the name "neutral protamine Hagedorn (NPH)," after its Danish founder. Lente, a slower version without protamine, came along in the mid-1950s.

These advances allowed for more dose-adjustment options and also extended the patents into the 1970s. Further innovations that improved purity pushed the patents ahead another decade, Drs Greene and Riggs say.

Recombinant Technology

Recombinant technology came along first from Genentech and Lilly in 1978, when they inserted cloned insulin genes into bacteria and created Humulin R (rapid) and Humulin N (NPH) in 1982. Novo Nordisk's chemical conversion of bovine into human insulin to create its own recombinant insulin reached the United States by 1988.

Thus, "A new web of insulin patents, held by Lilly, Novo Nordisk, and Genentech, promised to stretch into the 21st century," the authors write.

Next, scientists began moving around amino acids to create new insulin analogs with different properties: In 1996, lispro became the first fast-acting insulin analog to be approved, with the aim of better minimizing postprandial glucose excursions, followed by aspart in 2000 and glulisine in 2004.

Long-acting synthetic analogs were also developed to reduce hypoglycemia and improve overall diabetes control. Glargine was first of these, on the US market in 2000, followed by detemir in 2005. The first patents on these products expired in June 2014.

Biosimilar, but Cheaper?

Now with those patents expired, "biosimilars" have entered the picture. Lilly and Boehringer Ingelheim's biosimilar version of glargine was recently approved in the European Union.

In the United States, the same product received tentative approval from the Food and Drug Administration, but final approval is being held up for 30 months, until mid-2016, because Sanofi has filed a lawsuit claiming patent infringement.

Meanwhile, unregulated biosimilar insulins have appeared in countries with less strict regulatory policies, including China, India, and Mexico.

Even if biosimilar insulins do take hold in North America, they're not likely to produce the same cost saving as do generic drugs, given the additional data that will be required to prove their safety and efficacy, including immunogenicity studies.

Economists estimate that the price reduction for biosimilar insulins might not exceed 20% to 40%, in contrast to the 80% or greater cost savings from most other generic drugs, the authors point out.

A Series of Incremental Improvements

Moreover, biosimilars aren't going to change the fundamental difference between insulin and many other types of drugs that have been copied to various degrees, the authors say.

"The incremental innovation has repeatedly precluded the formation of a generic insulin industry in North America when earlier patents expired. The history of insulin hasn't followed the standard chronology of pharmaceutical innovation, in which patent monopolies predictably give way to generic competition."

Indeed, "insulin is not a single entity but a family of related products that has evolved through incremental improvements. Subsequent iterations of insulin represented actual innovations, each one being safer, more effective, or more convenient than its predecessor."

Because of that, "generic drug manufacturers are unlikely to invest in producing older versions of insulin that may already be obsolete," Drs Greene and Riggs observe.

And this is the case despite the fact that studies don't consistently show that analogs produce better outcomes than do the older NPH and regular insulins, and the advantages should be weighed against the costs, particularly for patients without adequate health insurance.

"On the whole, it's hard to say that contemporary patients who cannot afford their insulin (let alone the patent-protected glucometers and test strips required to adjust the dose) are well served by having as their only option an agent that is marginally more effective than those that could have been generically available 50 or 30 or 10 years ago, had generics manufacturers introduced cheaper versions when patents expired."

The upshot, they say, is that "after generations of incremental innovation, insulin may be no more affordable than it was when the original patent holders sold their stake for $1 to ensure access to this essential medicine."

Dr Greene reports grant support from the National Science Foundation, the National Library of Medicine, and the National Institutes of Health. Dr Riggs reports grant support from the National Institutes of Health and nonfinancial support from the Johns Hopkins Berman Institute of Bioethics.

N Engl J Med. 2015;372:1171-1175. Available at: www.nejm.org.


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