Suivre la trace de la distribution de l’insuline
By Christopher J. Rutty, Ph.D
Lead Historian, Defining Moments Canada, “Insulin 100”.
To mark the Insulin 100th, Canada Post issued a new stamp on April 15, 2021. It features a vial of “Insulin – Toronto,” which was produced by Connaught Laboratories of the University of Toronto. The vial’s label includes an important code — “Lot No. 292-19” — which reveals much about the history of not only this individual vial, and others from the same batch (or lot). The lot number also opens a window into how insulin produced by Connaught was distributed in Canada and spread around the world. Indeed, Connaught played a vital role in spearheading the global distribution of insulin. From the fall of 1923 and into 1925, Connaught became the first producer of insulin to provide it to many countries before domestic production could be established, or larger firms, based in the U.S., the U.K. and Denmark, were able to export insulin beyond their home country or region upon receipt of an export license from the University of Toronto Insulin Committee.
The story of “Insulin – Toronto,” Lot No. 292-19 can be told through several unique items in the Sanofi Pasteur Canada (Connaught Campus) Archives in Toronto. These include a large ledger book with hand-written records of every sale of insulin from January 2, 1924, through April 30, 1927. There are also two similar volumes that continued the insulin sales record from May 1927 through October 1931, and from November, 1931 through July, 1935. The Archive, moreover, holds filling records for each Lot, or “Lab No.” and “Package No.” The insulin sales volumes entries include details about the date of sale, order number, to whom it was sold and where, as well as details about the type/strength, amount and price of the insulin shipped.
A search through the first insulin sales book volume for Lot 292-19 shows that it was distributed during July and into early August, 1924. A check of the filling records for “Package Number” 292-19 indicates that this batch was filled on July 4th and included 379 vials. The vials, each containing 100 c.c. at 10 units/c.c. strength insulin, were most often packaged in a box of five vials. The 379 vials of Lot 292-19 were distributed to some 100 different individuals, physicians, hospitals, and provincial boards of health across Canada, as well as to Newfoundland (not yet a province), and to a doctor in Mexico as a free sample. Most notably, two packages from Lot 292-19 were also sent, on July 15th and August 1st, across the U.S. border to Dr. Herbert H. Best in West Pembroke, Maine. Dr. Best was the father of insulin co-discoverer, Charles H. Best, who, from May, 1922, through June, 1925, was director of Connaught’s Insulin Division. A special arrangement was made between Connaught and Dr. Best for bi-weekly shipments of 500 units (one package of 5 vials) of insulin, at no charge. Regular shipments from Toronto to West Pembroke continued from January 2, 1924, through to at least February 1927. It is uncertain when the shipments began since an insulin sales book has not been found for the period prior to January, 1924. Dr. H.H. Best was likely taking advantage of his personal link to his son to facilitate the provision of insulin to diabetics in the rural area around West Pembroke, who would otherwise be unable to access U.S.-produced insulin.
From the fall of 1922 through to the fall of 1923, the University of Toronto Insulin Committee focused on expediting the growth of insulin production in North America, at Connaught and Eli Lilly, as well as several small labs, hospitals and clinics. The goal was to meet a program of clinical evaluation through diabetic specialists, while also encouraging the establishment of local insulin production in other countries. The Insulin Committee transferred full insulin patent and licensing rights for the United Kingdom to the U.K. Medical Research Council in October, 1922.
In other countries, the Committee’s policy was to establish trustee-based arrangements with local committees or governments, which would be responsible for granting licenses to qualified labs or firms in order to facilitate the manufacture of insulin within those countries or defined regions. However, under these trustee arrangements, all proprietary rights (patent and trademarks) remained vested in the University of Toronto, although the Insulin Committee did not stipulate any specific requirements for the manufacture of insulin in a specific country. Trustees were given a free hand to oversee local insulin production and the University of Toronto Insulin Committee acted in an advisory capacity. But trustees could not profit from their trusteeship and the manufacturers they licensed could not distribute insulin outside of that country or defined region until the University of Toronto Insulin Committee granted an export licence. The initial trustee relationships were established in Denmark, Australia and Germany. However, setting up trusteeships and domestic insulin production outside of North America and the U.K. proved to be a slow and uneven process, leaving diabetics in much of the world with limited prospects for access to this vital treatment.
By the fall of 1923, however, there were significant improvements in access to insulin around the world. The completion of Connaught’s expanded facility in the refurbished YMCA Building led to increasing insulin production capacity. By the end of November, 1923, Connaught was producing 250,000 units of insulin per week, allowing it to meet not only Canadian demand, but also to ship insulin to many parts of the world. Eli Lilly did not receive an export license from the Insulin Committee until December, 1923. However, under the terms of that contract, the company could not export to Canada, Great Britain, Finland, Denmark, Norway, Sweden, Ceylon, Rhodesia, Newfoundland, Jamaica, India, Switzerland, New Zealand, South Africa, Australia, Austria, Spain, Japan, Egypt, Palestine, Belgium, Poland, Czechoslovakia, Hungary, Germany, and Holland. Starting in June, 1923, following the one-year University of Toronto-Eli Lilly insulin development agreement, other U.S. pharmaceutical firms were able to apply to the Insulin Committee for insulin production licenses. Three of these U.S. firms (H.K. Mulford, E.R. Squibbs & Sons, and Frederick Stearns & Co.) received export licenses between July, 1924, and April, 1925. In the United Kingdom, export licenses were granted to five British firms by July, 1924.
Connaught’s primary focus was to supply insulin to Canadian diabetics — individually or through physicians, hospitals, clinics, drug stores and provincial and local boards of health. But from the fall of 1923 to the summer of 1924, Connaught was in a unique position to also distribute insulin to diabetics in many other countries. The first volume of the Connaught Laboratories Insulin Sales book documents the spread of insulin around the world, often directly to individual diabetics, or through diabetic specialists, drug stores, or organizations in various countries, such as the Red Cross, or through intermediaries in Canada and the U.S., or their offices in other countries. Such intermediaries included the Royal Bank of Canada and its branch in Barcelona, Spain, and the Takamine Corp. of New York, established by Dr. Jokichi Takamine (1854-1922), a chemist, industrialist, philanthropist and “father of biotechnology” (in 1901 he isolated and purified the hormone adrenaline), who was dedicated to strengthening ties between America and Japan.[i] Connaught’s international distribution of insulin was an extension of its distribution of vaccines and antitoxins outside of Canada. An important purpose of much of Connaught’s international insulin distribution was to introduce it to physicians or diabetes specialists in various countries at no charge to enable local use, especially for severe diabetic cases, and to further support its clinical evaluation.
During early 1924, in addition to regular bi-weekly insulin shipments of 500 units to Dr. H.H. Best in West Pembroke, Connaught also filled several insulin orders from the U.S., including from drug stores in Niagara Falls and Boston, a physician in Omaha, Dr. V.E. Levine, and a few others. There were also several shipments sent at no charge to Professor Carl Voegtlin, Professor of Pharmacology at the U.S. Public Health Service in Washington, D.C., who was conducting a research project on the biological standardization of insulin.
The most notable U.S. customer of Connaught’s insulin was Elizabeth Hughes, who, when she was 15, had been treated by Banting in Toronto from mid-August through the end of November, 1922. She was the daughter of the U.S. Secretary of State, Charles Hughes, who made a special arrangement to have Connaught send regular monthly shipments of insulin to Elizabeth in Washington. She consistently expressed a preference for Connaught’s insulin over Eli Lilly’s and continued to use Connaught’s until at least the spring of 1927.
One of the first destinations outside of North America for insulin from Connaught was the Irish Free State, which, in 1922, became an independent Dominion of the British Commonwealth (like Canada) following the three-year Irish War of Independence. This conflict was fought between the Irish Republic, the Irish Republican Army and Britain, and resulted in much of the island seceding from the U.K. (Today, the Irish Free State is known as the Republic of Ireland.) During the first years after its establishment, the Free State experienced many challenges, some of which were eased by the efforts of the British Red Cross Society, which maintained a presence in the newly independent Ireland until 1930, when Irish Red Cross Society was formally established.
Among those challenges was the availability of insulin at an affordable price to diabetics with limited incomes. As reported in the British Medical Journal on December, 22, 1923, members of the Joint Committee of the British Red Cross Society and the Order of St. John of Jerusalem discussed the issue “of providing insulin for the treatment of poor persons suffering from diabetes.” It was clear the Irish Free State government “could not see its way to contribute towards the expense,” with it estimated that “about £1,000 would purchase a sufficient supply of insulin to meet the needs of urgent cases for the present.”[ii] Thus, after consultation with physicians, the Joint Committee decided to set up an insulin fund to which it allocated £500, and then launched a public appeal for additional funds. At the same time, contact was made by the Joint Committee with Connaught Laboratories. As was noted in the British Medical Journal, “it is hoped to obtain a considerable reduction in the cost price for poor patients, and that a phial [vial], sufficient for four or five days’ treatment, which in the ordinary way costs 17s. 6d., will be supplied at 7s. 6d.”[iii] Connaught was well known to the British Red Cross due to the Labs’ extensive work during World War I, supplying tetanus antitoxin and smallpox vaccine to the British military.
However, Connaught’s shipments of insulin to the Irish Free State created a conflict with the U.K. Medical Research Council (MRC), to which the University of Toronto Insulin Committee had transferred full insulin patent and licensing rights. This arrangement enabled British producers to supply insulin to the entire British Isles, which at the time of the agreement (October 1922) included all of Ireland. The Irish Free State had not been formally established. And as of late 1923, the MRC assumed it still controlled the distribution of insulin there and had the right to prevent imports from foreign producers, such as Connaught, especially when sold at a lower price than British insulin.
Connaught’s insulin order book documents shipments to the Irish Free State from the beginning of January 1924 until July, 1924, although shipments likely began in late 1923. There were six to Mrs. J.G. Douglas, of Dublin, between January 3 and June 18. Most were shipments of 1,000 units, each at a price of $20 as of January 5, but by the last shipment, on June 18, the price had fallen to $10, reflecting the downward trend in Connaught’s insulin costs as production scale and efficiency increased. There were a similar series of shipments to Mrs. E. Kelly in Dublin, two orders to Mr. Hannigan in Rothbritt, and two to James G. Douglas, Esq. in Dublin. The largest shipments to the Irish Free State were to the Irish Red Cross Society in Dublin, totalling eight shipments of 20,000 units each between January 5 and June 2. The price of each shipment fell from $300 on January 5 to $150 on June 2. There was also a series of eight large orders sent to a drug store known as Fannim & Co., ranging from 5,000 to 40,000 units; one order for 8,550 units was sent at no charge.
The MRC’s concerns about Connaught’s insulin sales in the Irish Free State prompted correspondence with, and ultimately visits to London and Dublin by, the Secretary of the Insulin Committee, F.L. Hutchinson, as part of a European tour to investigate the status of insulin production and distribution. From the perspective of the Insulin Committee and Connaught, the Irish Free State was considered a Dominion of the British Commonwealth, not unlike Canada, and thus should be treated as an independent political entity, separate from Great Britain, the same way as it dealt with Australia and New Zealand. As such, the University of Toronto retained the “prerogative of licencing the sale of insulin imported into the Irish Free State by manufacturers other than Great Britain.” For the MRC, there were concerns about the lower price of Connaught’s insulin, the associated publicity and the potential for imports or smuggling from the Irish Free State into Northern Ireland, which remained part of the U.K. Hutchinson felt the MRC was being overly bureaucratic. As he reported to the Insulin Committee, “Mr. Fannin of Fannin & Co. Ltd. and Dr. Henry F. Moore have promised to do everything in their power to ensure that Insulin-Toronto be not shipped from the Irish Free State into Great Britain or Northern Ireland.” In addition, he added, the “President of the Irish Red Cross Society expressed to me the most sincere and warm appreciation of the Connaught Laboratories’ dealings in their supply of Insulin-Toronto to his Society for distribution in the Free State.”[iv]
During the first half of 1924, Connaught’s insulin was distributed to individuals, physicians and medical clinics in several countries, often through organizations with international links. For example, the Royal Bank of Canada, through its office in Barcelona, Spain, facilitated several shipments of insulin to Mr. Juan Salas Yolez in Barcelona. In response to a major earthquake in Japan, Connaught sent a series of large shipments of insulin (50,000 to 100,000 units) through the Takamine Corporation of New York City. The earthquake occurred on September 1, 1923. At a meeting of the Insulin Committee on September 11th, the members “felt that some consideration might be shown in Japan in view of the recent catastrophe there.” Best, Hutchinson, and Connaught’s Director, J.G. FitzGerald, agreed to “consider any action that might appear to be advisable with respect to providing for a year, probably, free Insulin to those in Japan who need it and had been deprived of the means of providing it for themselves.”
Work on insulin production in Australia was initiated in the fall of 1922 at the University of Adelaide’s Darling laboratories and at the Commonwealth Serum Laboratories (CSL) in Melbourne. CSL was established in 1916 and operated in Australia similarly to Connaught, but it was a government agency and began to distribute insulin in March, 1923. The first insulin used in Australia, administered to a gravely ill 9-year-old diabetic on January 7, 1923, was produced at the University of Adelaide. However, in April 1924, when the production limits at the Darling labs were reached, CSL took on full responsibility for insulin production in Australia.
By January, 1924, CSL could meet the immediate needs of diabetics in New Zealand, although the high price of the imported supply remained a challenge. However, as was noted in the Auckland Star, on January 5, 1924, “The time must come very shortly when the health authorities of this Dominion will have to consider very seriously the question of manufacturing insulin in this country.” CSL’s supply, the article observed, “is about sufficient for our needs here, but this state of affairs cannot continue indefinitely.” By early January 1924, Connaught was able to provide some relief to New Zealand’s insulin challenges with seven direct shipments to Wellington Hospital through early July, of 5,000 to 10,000 units each.
During early 1924, the insulin supply situation in Finland was similar to New Zealand’s. Nordisk Insulinlaboratorium in Copenhagen had partnered with the Løven Chemical Company to produce insulin for Scandinavia, including Finland. But supplies remained limited, meaning prices were high. As was recorded in the Connaught Laboratories insulin sales book, the Labs filled eight orders from the First Medical Clinic in Helsinki for insulin between January 8 and July 2, 1924. The orders were for 1,600 to 4,000 units. There were also two orders received from the Second Medical Clinic in January and February.
From February 5 though May 15, 1924, a series of insulin orders were sent to a “Samen Klenganstall” in the city of Brunn, although in the Connaught Labs Insulin order book Brunn was referred to as being in Austria-Hungary or in Czechoslovakia. The uncertainty reflected the re-drawn map of Central Europe after World War I. “Samen Klenganstall” was likely a hospital or a medical clinic, from which Dr. Jakob or Dr. Schon placed seven orders of insulin over a three-month period, with the first five orders for 500 units and the last two for 750 units.
By the summer of 1924, local production of insulin in Central Europe was of quite limited scope, scale and quality. In Austria, there were two types being produced, but only one, “Insulin-Chemosan,” was “a sincere and serious endeavor,” according to Hutchinson. In Hungary, there was an active Insulin Committee with 22 professors drawn from the country’s four universities, as well as two insulin producers. But both remained at an elementary stage of development. They were, however, eager to learn, and sent a representative to Connaught for a month. In Czechoslovakia, the Ministry of Health had proposed that insulin should be produced by a new State Institute of Hygiene that was nearing completion, with funding from the Rockefeller Foundation. This project included support for a Rockefeller Fellow to spend two months at Connaught learning about insulin production. There was also insulin being produced in Czechoslovakia by Professor Dr. Wilhelm Wiechowski of the German University in Prague. He claimed to have an entirely unique insulin production process, although Hutchinson felt the quality was poor.
The Connaught Labs Insulin Sales Volume also records several sales of insulin into Eastern Europe from early January to late March 1924, including four shipments to a doctor in Latvia, and to a doctor and a drug store in Bucharest, Romania (at no charge). In April and May, Connaught sent several packages of insulin to the Soviet Union, at no charge to a diabetic in Moscow, and to doctor in Pirson. In February and March, there were insulin shipments (often at no charge) to Manchuria, to Korea, and to several doctors in what was then known as the East Indies (Singapore, Penang and Java), to West Burma, and to doctors in various parts of China. There were also small shipments to Jerusalem (then in Palestine) and Cairo, Egypt. Shipments of Connaught’s insulin were also sent to a doctor in Colombo, Ceylon (now Sri Lanka), and there were several individual shipments to South Africa, including to the South African Institute for Medical Research, to a doctor in Johannesburg, and three shipments to G.E. Linney & Co. in Capetown.
Connaught also shipped insulin to parts of Central and South America, including to Costa Rica and San Salvador. There were also six shipments to a Dr. F. Schuldt in Mexico City, two of which were sent at no charge. In April and June, the Canadian Agencies Ltd. assisted with distributing two shipments to Kingston, Jamaica; reflecting the declining price of Connaught’s insulin, the April 24 price was $33.45 for 3,000 units, but then $22.00 for the same amount on June 13.
Connaught’s insulin also made its way to doctors Porto Rico, the Dutch West Indies, and to individuals in El Salvador and Trinidad. In addition to a shipment to a hospital in Bolivia, the Connaught Insulin Sales Volume records general shipments to South America sent through the Canadian Government Commission. From April 24 through July 25, Connaught’s most consistent shipments of insulin to South America were sent through Crocker & Co. of Montevideo, Uruguay, which was a large import/export firm. During this period there were 15 shipments of mostly 2,000 units each, plus one of 4,000 units and one of 5,000 units, which was sent at no charge.
Through the first half of 1924, Connaught total insulin production varied between 804,850 units during January, to 707,300 units in February, 778,400 units in March, and peaks of 1,043,800 units in April and 1,016,200 units in May, and a slight reduction to 938,000 units in July 1924. Reflecting the declining price of insulin during this period, total insulin sales income fell from $14,308.62 in January to $7,869.86 in July.
Connaught’s international insulin distribution was declining by mid-1924 as more export licenses were approved by the University of Toronto Insulin Committee. Eli Lilly’s export license had been approved in December, 1923, but was initially quite restrictive. Another U.S. firm, Stearns, was granted its export license on July 3, 1924, with fellow U.S. producers, Squibb and Mulford, receiving their licenses in April and June 1925, respectively. Insulin producers based in the United Kingdom received their first export license on May 15, 1924 (Evans Sons), followed by Boots Pure Drugs on July 1, and Allen & Hanbury’s, British Drug Houses, and Wellcome Foundation, following on July 15. On May 15, 1924, an export license was also approved by the Insulin Committee for Løven Chemical Company of Copenhagen, Denmark, which distributed insulin produced by Nordisk. Despite the increased global distribution of insulin by the large producers, domestic insulin production remained important in many countries as Connaught continued to fill an important gap in many parts of the world that lacked domestic production infrastructure and/or were more sensitive to the higher prices charged by larger firms.
By the mid-1920s, as the world’s first producer of insulin, Connaught had built a strong reputation for the quality and low price of its insulin. An article in the June 8, 1925, edition of the Toronto Star, “Is Wide Demand for Connaught Products,” concisely summarized Connaught’s international position: “The rapid development of insulin was made possible by teamwork of the different departments of the university.” Research into the chemical properties of insulin led by Dr. Peter Moloney had been critical, as well as extensive research into methods of preparation under the direction of Charles Best, along with work led by Dr. Donald Fraser in developing a better method for determining the strength of insulin. And as the article emphasized, “Insulin prepared in the University of Toronto is distributed not only in Canada but also in the following other countries: Ireland, Newfoundland, New Zealand, Japan, British West Indies, Venezuela, South Africa, Finland, Spain and Russia.”
As the Connaught Labs Insulin Sales Volume, now kept in the Sanofi Pasteur Canada (Connaught Campus) Archives, reveals, during the first half of 1924, Connaught played a vital vanguard role in the international distribution of insulin. Such a role was made possible through a wide range of channels and networks originally built to expedite international distribution of its other biological public health products during and after World War I. The Connaught Labs “Insulin-Toronto’ vial on the new Insulin 100th Canada Post stamp is thus symbolic of the essential part Canada played in not only the discovery of insulin, but also in bringing it to the world.
[ii] Accounting for inflation, £1,000 would convert to about $108,000 (CAN$) in 2020; https://www.bankofengland.co.uk/monetary-policy/inflation/inflation-calculator; https://www.xe.com/currencyconverter/