The commercialisation of insulin

Cover photo. ‘Wellcome' Insulin: the insulin of outstanding purity, activity and reliability. Wellcome Collection, in copyright.

It is a failure of society and the global community that people who need insulin should encounter financial hardship to buy it or go without it and risk their life.

Dr Tedros Adhanom Ghebreyesus WHO Director General, September 2020 ¹

As the nineteenth century drew to a close, newly developed vaccines and antitoxins were promising to alter the course of several devastating infectious diseases, such as diphtheria, tetanus and smallpox. ² Countries then had to confront the costs involved in adopting these therapies, and decide whether these would be borne by individuals or the state. This was the beginning of public health medicine as a specialty, a time of great change in the management of infectious diseases.

In 1910, a young Canadian doctor, John Gerald (Gerry) Fitzgerald, abandoned his fledgling career in neurology and psychiatry, and spent 3 years travelling and studying the rapidly developing fields of bacteriology and preventative health. ³ He visited facilities in London and New York, and while at the Pasteur Institute in Paris and Brussels, learned to make diphtheria, rabies and smallpox vaccines and antitoxins. In every place he visited, diphtheria antitoxin was being made and distributed as a public health measure, whereas in Canada people were still dependent on expensive commercially marketed antitoxin. He returned to Canada in 1913 as an associate professor in the Department of Hygiene at the University of Toronto. Impatient and determined to improve the provision of preventive medicine in Canada, Fitzgerald established a small private laboratory at his own expense to make diphtheria antitoxin more widely available. His initial facility consisted of stabling for five horses, purchased from the glue factory for $3 each, and a small operating theatre. On 14 May 1914, just before the First World War broke out, the laboratory was officially taken over by the Department of Hygiene at the university.

It soon had to expand its operations. Once the war began, the terrible conditions in the trenches led to an escalating need for tetanus antitoxin. Colonel Albert Gooderman, whose own family distillery in Toronto, Gooderman and Worts Distillery, had already been handed over to the British government for war work, approached the university on behalf of the army to manufacture tetanus toxin at the facilities. ⁴ Gooderman then donated 75 acres of farm land to the university, where he built a modern laboratory complex. This facility, 12 miles north of the university, was opened in October 1917 and named Connaught Laboratories after HRH, the Duke of Connaught, then Governor General of Canada. It remained a non-commercial entity under the management of the University of Toronto, manufacturing vaccines and antitoxins.

On 25 January 1922, 2 days after Leonard Thompson became the first person to be successfully treated with insulin, the core University of Toronto research team of Frederick Banting, Charles Best, John Macleod and James Collip signed an agreement with Connaught Laboratories to continue their research and development, and to manufacture insulin for the Canadian market. ⁵ As part of this agreement, Best took up a new position as head of insulin production at the laboratory. This arrangement was a change in direction for Connaught Laboratories, who had previously only manufactured therapeutics for infectious diseases, but it was in line with their goal to improve public health initiatives. The insulin extraction technique was still far from perfect so the next few months were extremely stressful for the now expanded research team – and the few patients who had begun treatment with insulin. ^{6 , 7} Many patients had to return intermittently to their previous dietary restrictions and the researchers were acutely aware that some of these patients were dying due to inadequate insulin supplies.

Added to these problems was a growing concern that their work was gaining attention around the world and that another laboratory might develop and patent a different extraction technique. While the academic and medical world was fundamentally opposed to patents on medical discoveries, the university was anxious to retain control over the purity of the product. The researchers themselves were determined the product should be freely available to patients and were not interested in financial gain. A few months later, as production problems were finally being resolved, it was obvious Connaught Laboratories would be unable to supply the world demand for insulin. Other companies needed to be recruited to manufacture insulin, and the only way they could maintain control of the production process was to obtain a patent.

There were precedents for biological patents as both adrenaline (1900) and thyroxine (1914) had been patented by their discoverers. The final decision around patenting insulin seems to have been heavily influenced by a letter John Macleod received from Edward Kendall, who had isolated thyroxine in 1913.^8,9 Kendall considered patenting of his manufacturing process a ‘… valuable safeguard to physiological and biochemical preparations …’. ⁸ After obtaining a patent for the thyroxine extraction technique, he had given it to the University of Minnesota with the understanding that they ‘use all proper means for its presentation in the commercial field in order that it may be made useful to the medical profession’. The university had then appointed a committee to oversee the negotiations with the pharmaceutical companies, with Kendall as secretary; Kendall also retained a share of the profits.

In Toronto, the insulin research team took out a patent which they sold to the university for one dollar.^7,10 The university then appointed a committee, initially consisting of three members of the board of governors of the university, an advisory committee composed of the four discoverers, Banting, Best, Macleod and Collip, and the director of Connaught Laboratories. It soon expanded to include industry representatives, academics, researchers, and a patent attorney. The committee, later known as the Insulin Committee, was responsible for managing the manufacturing rights and ensuring the purity of manufactured products. To facilitate the latter objective, they established a small laboratory to test the purity of samples from the manufacturing companies they subsequently appointed. This overall approach, including the application for patents, was generally favourably received. One publication even went so far as to consider it an ethical advance, stating that patients with diabetes could be assured they were ‘obtaining the real thing and will not be overcharged … all profits from the monopoly will be devoted to medical research …. It represents “medical ethics” in a really modern aspect’. ¹¹

The first US manufacturing and export rights were awarded to Eli Lilly in May 1922 in a carefully worded, one-year exclusive rights, experimental contract. ¹⁰ One year later, the Insulin Committee began the complex process of awarding non-exclusive contracts to pharmaceutical companies in the UK and Europe, as well as more distant places such as Australia. It is important to realise that at this time there was effectively no regulation of drug efficacy anywhere in the world. These patents gave the University of Toronto, and subsequently bodies such as the Medical Research Council in the UK, power over drug manufacture and commercialisation that was unprecedented. ¹⁰ Although federal drug regulation in the US officially began with the passage of the 1906 Pure Food and Drug Act, the now Federal Drug Administration (FDA) had no direct control over drug efficacy and purity until a series of regulations beginning with the 1938 Drug, Food and Cosmetic Act. ¹²

Throughout the 1920s and 1930s, Connaught Laboratories retained effective control over further patent developments, ¹⁰ but eventually others began to modify the product to change it from a simple insulin extract. ¹³ Hans Christian Hagedorn and colleagues at Nordisk added protamine, and later zinc, to prolong the action and absorption of insulin, patenting a protamine–zinc formulation in 1946. The lente insulins, longer acting but without protamine, appeared in the 1950s, extending new patents into the 1970s. Eli Lilly then re-entered the patent field with ‘single-peak’ insulins in the 1970s and the first recombinant human insulins in the early 1980s. These incremental changes in insulin manufacture have been fundamentally positive—improving the safety, efficacy or convenience of the product—but they have also extended patents and increased the cost, often making insulin less accessible, particularly in low and middle income countries and those without a robust public health system. ¹³ Most patents are now reaching their expiry date and the introduction of new biosimilar insulins does offer some hope that costs may fall slightly in the future.

In April 2021, the World Health Organization (WHO) launched the Global Diabetes Compact at the 2021 Global Diabetes Summit. This event was hosted by the WHO and the government of Canada, to commemorate the 100th anniversary of the discovery of insulin. ¹⁴ A year later, several targets for 2030 were announced by the WHO, one being that ‘100% of people with type 1 diabetes have access to affordable insulin and blood glucose self-monitoring’. ¹⁵ There is also evidence that the three major global pharmaceutical companies currently dominating the insulin manufacturing market—Sanofi (which now owns Connaught Laboratories), Novo Nordisk and Eli Lilly—are working with organisations like the Access to Medicine Foundation to ensure more equitable access to their products. ¹⁶