Tamoxifen Synthesis Essay

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  • Introduction

    Today, tamoxifen (brand name Nolvadex) is one of the world's best-selling hormonal breast cancer drugs. However, it was not always so. Compound ICI 46,474 (as it was first known) was synthesized in 1962, quite unusually for the time, by a female chemist: Dora Richardson, who was responsible for making triphenylethylene derivatives within a project to develop a contraceptive pill in the pharmaceutical laboratories of the British chemical group ICI (now part of AstraZeneca). Although designed to act as an anti-estrogen, the compound was found to stimulate, rather than suppress ovulation in women. This, and the fact that at first it could not be patented in the USA, its largest potential market, meant that ICI nearly stopped the project. If it was saved, it was partly because the team's leader, Arthur Walpole, threatened to resign, and pressed on with another project: to develop tamoxifen as a treatment for breast cancer. Even then, its market appeared small, because at first it was mainly used as a palliative treatment for advanced breast cancer. An important turning point in tamoxifen's journey from orphan drug to best-selling medicine occurred in the 1980s, when the results of clinical trials showed that it was also useful as an adjuvant to other forms of therapy in the early stages of the disease. Later, trials demonstrated that it could prevent its occurrence or re-occurrence in women at high risk of developing breast cancer. Thus, it became the first chemopreventative for any cancer, helping to establish the broader principles of chemoprevention, and extending the market for tamoxifen and similar drugs further still.

    Hailed as a pioneering medicine that has saved the lives of thousands of women, much has been written about tamoxifen, especially in recent years by Craig Jordan, the researcher who was influential in the latter part of its history (Maximov et al., 2016). However, as the public's and the medical profession's dependence on drugs not only to treat, but also to prevent an ever growing variety of conditions has come under increasing scrutiny (Greene, 2007), tamoxifen has also been investigated by sociologists as an example of what they describe as the “biomedicalization” of society, i.e., the shift in the use and meaning of drugs from treatment to prevention, involving a cost-benefit calculation that is seldom openly discussed (Fosket, 2010, pp. 341–348; Löwy, 2010, pp. 185–188; Löwy, 2012).

    There is another strand in the literature, which is somewhat less well-developed, and concerns tamoxifen at once as an emblematic and an idiosyncratic example of pharmaceutical innovation. For the history of tamoxifen suggests a model of pharmaceutical innovation that is far more complex than a linear model from bench to bedside (Schwartzman, 1976; Howells and Neary, 1988; Gambardella, 1995; Landau et al., 1999). Rather, it incorporates numerous dead ends, feedback loops, as well as serendipitous observations made by individual researchers (and associated with other discoveries, in this instance the isolation of the estrogen receptor). Hence, the scientists whose work has shaped pharmaceutical innovation are an important part of the story—in the case of tamoxifen, not only Richardson, but also Walpole, the biologist who led the research team at ICI and provided the link between the different projects within which tamoxifen was developed (Jordan, 1988), and, for the later stage in the drug's tortuous journey, Jordan.

    At a time when the drying up of old drug pipelines has led to anxieties about the end of the Therapeutic Revolution and the need to find new models of drug discovery to replace those which produced many of the blockbuster drugs we know today, tamoxifen therefore presents an opportunity to explore the historically contingent nature of pharmaceutical innovation, addressing several of the questions posed by the editors (see their introduction to this special issue). Using the research and development reports of the company that developed the drug (ICI), an unpublished history of tamoxifen, written by Richardson and accompanied by letters from patients, as well as some of the numerous publications on the topic, the paper will show how the early history of the drug shaped its fate in the medical marketplace, and therefore deserves to be better understood than it is at present. The paper argues that its origins as a contraceptive pill rather than a cancer remedy meant that concerns over side-effects, alongside its ability to counteract the action of estrogen, dominated the company's research and development agenda. Hence patients' voices, which provided indications the drug's safety and efficacy at once directly and indirectly, helped to define this agenda, and the absence of side-effects relative to its anti-estrogenic activity would become one of the key selling points of tamoxifen as an anti-cancer drug compared to alternative treatments.

    However, because of its very ability to prolong life in women suffering from breast cancer, tamoxifen was later found to have a number of potentially serious long-term side-effects, which range from pulmonary thrombosis to endometrial cancer. Nevertheless, its usefulness in treating and preventing a major cause of death in women has meant that, to this day, it remains on the WHO's List of Essential Medicines (WHO, 2015). This paper will therefore also highlight the complex evaluation of risk that is involved in all therapies, but more especially perhaps in diseases as threatening and emotionally charged as cancer, not only at the regulatory and clinical levels, but also at the individual level of the patient.

    Results

    Before focusing on the development of tamoxifen, it is useful to describe the background for the different projects that led first to its synthesis, second to its early trajectory as an anticancer drug, for it illustrates not only the non-linear nature of pharmaceutical innovation, but also the lengthy accumulation of in-house scientific knowledge and technical know-how which underpins it, and yet is rarely brought to the fore in histories of drug discovery (Weatherall, 1990; Sneader, 2005; Ravina, 2011).

    The Use of Sex Hormones and Synthetic Analogues in Cancer

    The link between hormones and cancer has been known at least since 1916 (Lathrob and Loeb, 1916). However, their usage in the treatment of cancer depended on their isolation, purification and chemical determination, which was not achieved until the 1930s in the case of sex hormones. One such hormone was the follicular hormone (Follicle-Stimulating Hormone, FSH), which was prepared by the Roussel Laboratories, a French company specializing in biologicals, and supplied to Antoine Lacassagne at the Institut du Radium in Paris. Using this hormone, Lacassagne was able to show a direct link between estrogens and the appearance of breast cancer in mice (Lacassagne, 1932, 1936). But natural estrogens were difficult to obtain in the quantities required for large-scale experiments. A major turning point occurred when E.C. (later Sir Charles) Dodds, working at the Middlesex Hospital in London in collaboration with researchers at the Dyson Perrins Laboratory in Oxford, discovered that the synthetic compound stilboestrol had estrogenic properties (Dodds et al., 1938). Dorothy Crowfoot (later known by her married name, Hodgkin), who worked nearby at Oxford University's Inorganic Chemistry Department, established using X-ray crysallography that its chemical structure resembled estrogen (Carlisle and Crowfoot, 1941). Inexpensive to make and apparently well tolerated in patients, stilboestrol was therefore widely prescribed for cases of estrogen deficiency, especially in menopausal women (Sneader, 2005, p. 197). Although it would later be linked to cases of vaginal or cervical adenosarcomas in daughters of women who had been prescribed the drug in their first trimester of pregnancy (to avoid unwanted abortion; see Gaudillière, 2014), it was also the first synthetic drug to be used for treating cancer (Weatherall, 1990, pp. 217–218). Indeed, in 1939, Charles Huggins of the University of Chicago successfully treated cases of prostate cancer with stilboestrol (known as diethylstilbestrol in the US; Huggins and Hodges, 1941), and by 1950 a co-operative trial had shown that the synthetic estrogen was effective in delaying the progress of this type of malignant disease (Nesbitt and Baum, 1950). However, breast cancer proved more difficult to treat, as it could either be inhibited or stimulated by administration of estrogen.

    Following the publication of Dodds' findings, synthetic substances with a similar structure were examined for estrogenic activity, such as, triphenylethylene. These substances, which could not only be mass produced, but also be chemically modified to obtain derivatives with anti-estrogenic activity, therefore became compounds of choice for studies in Britain and elsewhere. One of the organizations that studied it was ICI, which I turn to now.

    ICI and Cancer Research

    The company's interest in cancer was a long-standing one. When triphenylethylene was found by Charles Scott, a researcher in Edinburgh, not only to be active by mouth, like stilboestrol, but to have a durable estrogenic action, and therefore to have potential as an alternative to stilboestrol, Arthur Walpole, a biologist who had joined ICI's Medicinal Section in 1938, began carrying out some exploratory work with the substance. This work led to the synthesis of various triphenylethylene derivatives, including triphenylmethylethylene (M 612) and triphenylchloroethylene (registered in 1940 under the name Gynosone). In 1942, these compounds were supplied by the company for trials in breast cancer to Alexander Haddow of the Chester Beatty Institute in London, Edith Patterson at the Christie Hospital in Manchester and their collaborators. Although improvements were only temporary, there was clear evidence that Gynosone in particular caused regression and therefore could be beneficial in the treatment of breast cancer (Haddow et al., 1944; Walpole and Paterson, 1949).

    Meanwhile, on the other side of the Atlantic, the compounds known as “nitrogen mustards,” which were being studied as part of a chemical warfare research programme, were shown to inhibit the growth of blood and lymph tumors by Goodman and Gilman at the University of Yale, a discovery often hailed as the beginning of cancer chemotherapy. Despite this wartime work being top-secret, Walpole and Haddow were also able to investigate these compounds, thanks to an Anglo-American agreement to exchange scientific information (Weatherall, 1990, p. 218). Another, parallel study relating to cancer at ICI involved anti-metabolites. Following the discovery that ICI's novel anti-malarial drug Paludrine was converted in the body to cycloguanine, an active metabolite which interferes with purine biosynthesis, and spurred by the announcement that Burroughs Wellcome's drug 6-MP was effective against leukemia, the search for anti-metabolites began at ICI under the leadership of Frank Rose, who had run their anti-malarial programme during the war. Rose became Research Manager of the Chemistry Department in 1954, whilst remaining involved in bench work. As well as the search for alkylating agents, synthetic estrogens, and anti-metabolites, Rose also encouraged investigations into carcinogenesis, which was a rare interest for researchers working on cancer chemotherapy at that time (Suckling and Langley, 1990, pp. 507–508).

    At first, ICI's approach to cancer was therefore largely empirical, involving the synthesis of derivatives of compounds that had known anti-tumor properties, without a formal cancer research programme. However, once plans had been made to build a pharmaceutical research center at Alderley Park near Manchester, and ICI started organizing its research in team projects, Cancer became such a project in 1955. The project was entitled “Cancer and Viruses: antibacterials,” and its team leader was the biologist E. Weston Hurst. Alderley Park opened in 1957, and between 1957 and 1960 Cancer and Viruses separated into two different projects.

    During that time Cancer was merged with a new project to find an oral contraceptive, led by Arthur Walpole. Then, in 1960, the discovery of the natural antiviral substance interferon, and ICI's involvement in its study in collaboration with the Medical Research Council (see Pieters, 2005, Chapters 5–6), led to Viruses and Cancer coming together again. Oral Contraception therefore split away from Cancer, with Walpole working in parallel on both projects. His involvement in the Oral Contraception project (which in 1963 was re-named “Endocrinology,” and later “Fertility,” reflecting a gradual change in the research emphasis) would ensure that breast cancer remained an important focus for both his teams. It was within this Oral Contraception project that tamoxifen (Nolvadex), a triphenylethylene derivative, was synthesized and subsequently developed, initially as a contraceptive pill.

    ICI, Oral Contraception, and the Origins of Tamoxifen

    The first contraceptive pill had been synthesized in the early 1950s, and in 1956 Walpole wrote a survey entitled “The technical possibility of oral contraception,” which—as had become customary within ICI by that time (see Quirke, 2005)—gave an overview of the field to enable ICI to decide whether or not it was worth entering.

    Walpole began by introducing the context in which such a pill would be developed. In doing so, he showed the extent to which contemporary concerns, which included anxiety over population growth, a decrease in death rates, food shortages, and an awareness of important differences between the developed and developing world, were internalized and acted upon by companies such as ICI. Then, in the main body of his report, Walpole enumerated the requirements for contraception:

    1. it should not “offend social or religious scruples” and as little as possible the “aesthetic feelings” of those who might wish to avail themselves of it (however, he added, such considerations remained outside the scope of experimental biology);

    2. it should be cheap enough to be readily available and simple enough to use by any people “intelligent enough to realize the possible consequence of coitus and to know whether or not they wished to conceive”;

    3. it should be effective over a known period of time with no prejudice to subsequent fertility;

    4. it should not depend on a local action contemporaneous with coitus or any form of treatment which must be timed in a complex or critical manner in relation to the menstrual cycle;

    5. it should involve only occasional dosage by mouth.

    After describing what at the time was understood about the physiology of reproduction, he went on to list the technical possibilities of contraception at different stages in the reproductive cycle, from (a) spermatogenesis and sperm, to (b) ovulation and ovum, (c) fertilization, (d) fertilized ovum, (e) implantation of embryo, and lastly (f) development of embryo.

    On the basis of substances already known to act as contraceptives, he concluded that it “would seem possible to produce temporary infertility in men by giving androgens, and of these methylsterone is active by mouth.” He added that it was also possible “either to prevent conception or interrupt pregnancy at a very early stage in women by giving estrogens by mouth,” but that such treatments must be free from undesirable side-effects. Among the newer partly synthesized steroids now becoming available, he believed that substances might be found that were be more specifically antagonistic toward progesterone (anti-progestins), and he argued that these would seem more suitable for continued use. Other substances from natural sources, such as, the Lithospermum ruderale, a North American plant with a small white flower that could also be found in English hedgerows and was being investigated at the time by the Medical Research Council (Marks, 2001, pp. 49–50), appeared to him as “rather more suspect,” and he acknowledged that clinical evidence was lacking, not only concerning these natural compounds, but also human contraception more generally.

    As to the other substances that might be considered for contraception, toxicity was a major problem, such as the anti-folic drug aminopterin, for not only did it act as an early abortifacient, but it carried serious toxic hazards, like some of the other anti-metabolites. Similar concerns were associated with biological alkylating agents, which were potentially mutagenic and carcinogenic. Hence, taking into account both the requirements for contraception and the need to avoid toxic effects, especially since contraceptive substances were intended for use in normally young and healthy adults (Oudshoorn, 2002, pp. 123–157), the search for triphenylethylene derivatives, alongside investigations of natural and part-synthesized steroids, became the preferred course of action, as evidenced by ICI's research reports.

    ICI were not alone in pursuing the triphenylethylene route. Indeed, when Leonard Lerner, a researcher working on a cardiovascular research program at the American drug company Merrell, reported in 1958 that a newly synthesized compound, MER 25 (ethamoxytriphetol), not only resembled structurally triphenylethylene, but had anti-estrogenic activity on both spayed and intact female rats, his discovery stimulated laboratory research and clinical investigation of other potential anti-fertility agents among triphenylethylene derivatives. ICI considered acquiring the drug under license from Merrell in order to study and potentially exploit it as a contraceptive, but interest in it waned, for in the meantime ICI had found that another compound, ICI 22,365 [N:N-bis (allylthiocarbamyl) hydrazine], which they employed in analytical chemistry and were currently investigating as an anti-parasitic for use in the poultry industry, prevented the development of sex organs and secondary characteristics such as the emergence of combs in chicks. This finding led Walpole's team, which at that stage included G. E. Paget and J. K. Walley working on the biological side (while Dora Richardson and G. A. Snow worked on the chemistry), to test the compound in male and female rats, producing evidence that it caused a selective and reversible inhibition of the gonadotrophic functions of the pituitary in rats, and prevented pregnancy either by inhibiting ovulation, or by preventing implantation (the precise mechanism of action was yet unclear). In a report written in September 1960, Walpole wrote that the compound not only provided an interesting lead in oral contraception, but also in hormone-dependent cancers of the prostate and breast, and it was decided that “if an alternative patentable compound were found which, in laboratory tests, proved superior (or even equivalent to it), then this compound should replace 22,365 in clinical studies.”

    The most promising compound to come out of this programme, ICI 33,828 (which had a similar structure to 22,365), was therefore tested in pre-menopausal patients with mammary carcinoma, which was justified on the grounds that it might have a therapeutic as well as an anti-fertility effect. It was also tried in prostatic cancer, however the clinicians involved in these trials at the MRC Clinical Endocrinology Unit in Edinburgh received complaints from patients about nausea, anorexia, and occasional vomiting. Walpole also discovered that, before trials with 33,828 could begin, 22,365 had been given in November 1960 to a psychotic patient who was 15 weeks pregnant in order to induce abortion. However, the drug had failed to terminate the pregnancy, and estrogen excretion had remained unaffected by the treatment. The fetus, which had therefore had to be removed surgically, appeared normal. At the same time as plans for more extensive clinical studies, preferably closer to home so that his team could be more directly involved in the trials, Walpole therefore also made plans to develop more sensitive assay methods for gonatrophins in urine, blood, and pituitary, to better assess the clinical effects of their lead compound, and obtain more reliable measures of activity in animal experiments. Shortly afterwards, in 1962, Mike Harper, a young endocrinologist who would play a significant part in the tamoxifen story, was invited to join the team.

    Meanwhile, at Merrell, researchers had pressed on with the search for novel triphenylethylenes and in 1961 discovered that MRL 41 (also known as clomiphene, or chloramiphene, brand name Clomid), which was in fact an ether derivative of Gynosone, also inhibited pituitary gonadotrophins although it showed weak estrogenic activity. Remembering the earlier trials with Gynosone and M 612, Walpole therefore suggested to his team that they develop and examine an ether derivative of M 612. The compounds they prepared in 1961 not only inhibited implantation of the fertilized ovum in the rat at a low dose (below that at which they would show estrogenic activity), but with the addition of a methoxy group they also had a greater duration of action. After the arrival of Harper, whose new series of biological tests helped to produce a clearer picture of the structure–activity relationships of triphenylethylenes, the programme of chemical synthesis was therefore stepped up. The team had grown, and as well as Walpole, Walley, and Richardson, it now included several members of the Biology Group: A. M. Barrett, M. J. K. Harper, G. E. Paget, Miss J. M. Peters, and J. M. Thorp, of the Chemistry Group: R. Clarkson, E. R. H. Jones, J. K. Landquist, B. W. Langley, W. S. Waring, and of the Biochemistry Group: W. A. M. Duncan. It was hoped that, with such increased resources, ICI could improve upon both clomiphene and a new Upjohn product with similar activity, U 11,555, by finding alternatives with less estrogenic and pituitary-inhibitory activity relative to their anti-fertility activity. For, by then, clinical studies of ICI 33,828 had produced disappointing results: not only did it have unpleasant and worrying side effects (nausea, drowsiness, a fall in thyroid function measured by thyroidal I132 uptake, and a rise in serum cholesterol), but the inhibition of ovulation could not be achieved without suppressing menstruation, which made it undesirable as an oral contraceptive in women.

    Among the newly synthesized triphenylethylenes, Harper drew up a short list for further study, primarily as potential anti-fertility agents. These included the dimethylamino ethoxy compound ICI 46,474 (later known as tamoxifen, brand name Nolvadex). It had been synthesized in 1962 by Richardson, and Harper selected it for additional tests and for preliminary toxicity studies. At the same time, the company lodged patent applications to protect ICI 46,474 and related compounds from competitors. As well as providing basic data on these compounds, Patent GB1013907 covered a number of potential therapeutic uses, including cancer. It read:

    The alkene derivatives of the invention are useful for the modification of the endocrine status in man and animals and they may be useful for the control of hormone-dependent tumors or for the management of the sexual cycle and aberrations thereof. They will also have useful hypocholesteraemic activity.

    ICI 46,474 (1962–67)

    Although marred by a number of dead ends, which were partly due to ICI's strategy of closely following their competitor's activities and using their compounds as leads in the search for new, patentable products, the early phase of the Oral Contraception programme shaped tamoxifen and determined its future in many ways. The compounds developed within this programme were designed to act as contraceptive pills, yet from the beginning their usefulness in breast cancer was explored in close parallel. This dual objective was pursued as a result of Walpole's own research interests, and thanks to the fruitful collaborations he established both with endocrinologists and with clinicians working in cancer. The feedback loops between bench and bedside which this relationship created, and which led to a series of twists and turns that would become the hallmark of the tamoxifen story, meant that the compounds functioned both as research tools to study hormone function and metabolism in the laboratory, and as experimental treatments in the clinic. Importantly, the dual objective of developing a contraceptive pill whilst assessing the usefulness of compounds in breast cancer (even if as we have seen this was also a means of testing drugs before administering them to healthy women), also meant a constant preoccupation with side effects, and the low toxicity of tamoxifen relative to its potency would turn out to be one of its crucial advantages over its competitors.

    A triphenylethylene derivative, with groups and side chains to enhance its anti-estrogenic and pituitary-inhibitory effect and prolong its duration of action, without interfering with its anti-fertility activity, ICI 46,474 had been demonstrated as the most potent and least toxic of all the compounds tested by June 1964. But what exactly was it? In the process of gathering data for patent applications, scaling up production and preparing a submission to the newly formed Committee on Safety of Medicines (CSD), uncertainty arose as to the precise structure of the compound. Using an NMR spectrometer recently acquired by the company, in 1964 G. R. Bedford, a spectroscopist who had joined ICI's Pharmaceutical Division in 1963, showed that many of the active compounds synthesized so far were a mixture of isomers. However, it was unclear in which isomer the anti-estrogenic activity resided (did it reside in the cis, or the trans isomer?). The isomers were separated by fractional crystallization by Richardson. This represented quite a feat at the time, and revealed ICI 46,474 to be more active as an anti-implantation agent than its cis isomer ICI 47,699, which was more estrogenic (Bedford and Richardson, 1966; Harper and Walpole, 1966). In the meantime, Merrell had carried out a spectroscopic analysis of their own drug clomiphene, and disagreed with ICI's interpretation of the spectroscopic data, attributing the anti-estrogenic activity to the cis, not the trans isomer. The controversy led to some confusion among researchers, and eventually the matter was settled by X-ray analysis, which confirmed ICI's findings that the anti-estrogenic activity did indeed reside in ICI 46,474, that is to say in the trans isomer of the compound (Kilbourn et al., 1968).

    So how did tamoxifen work? Before making a submission to the CSD, which in the wake of the thalidomide disaster had been set up to review all laboratory data on potential drugs in advance of their introduction into human patients, a basic understanding of their mechanism of action, as well as knowledge about any toxic effects, had to be achieved (see Quirke, 2012a). Therefore, unsurprisingly perhaps since it was intended for use in contraception, the first teratogenic test ever to be performed by ICI was carried out with tamoxifen. At the very low doses necessary to allow implantation of the fertilized ovum, rat offspring developed a deformity called “kinky ribs.” However no such effects could be seen in rabbits or in primates, and it was later concluded that since ICI 46,474 restricts uterine growth, the deformity was caused by mechanical contraction and therefore could not considered a true teratogenic effect.

    Tamoxifen was most effective in preventing implantation in rats when given on day 4 of the pregnancy, and virtually inactive on day 5. This suggested that it acted by interfering with a crucial event that had already occurred by the 5th day. It was suspected that ICI 46,474 prevented implantation by interfering with the critical estrogen release on the uterus that occurs between 12 and 20–21 h on the 4th day. However, it was unclear whether the estrogen released at this time acted directly on the uterus or whether its action was mediated by vasodilating amines such as histamine. As there was evidence to support the latter hypothesis, ICI 46,474 was thought to act either as a direct estrogen antagonist, or by preventing the release of histamine, or as an antagonist of the amine. To explore this hypothesis, whilst carrying out further toxicity tests, experiments were devised in additional animal species (as well as rats, in mice, rabbits, dogs, monkeys, and sheep, for by then the compound was also being considered for use in veterinary medicine). These experiments revealed considerable species specificity, and by 1965 doubts had arisen whether an “estrogen surge” was necessary for ovo-implantation in humans, as it was in rats, and whether at the dosage required to oppose estrogen sufficiently to inhibit implantation ICI 46,474 would cause menstrual irregularities, therefore whether the compound would prove effective and be acceptable as an oral contraceptive. Although it was still hoped that ICI 46.474 would provide a welcome alternative to the now familiar method of using mixtures of orally active estrogens and gestagens (also known as progestogens) to inhibit ovulation while at the same time producing withdrawal bleeding to replace spontaneous menstruation, a method which was considered too costly and too complicated for use in underdeveloped communities, it was felt that such doubts could only be “settled in the clinic.” However, first, the team needed to ascertain whether or not ICI 46,474 would produce irreversible damage to the ovaries or uterus, and for this studies in monkeys, particularly pig-tail monkeys in which changes in the reproductive cycle were found to most closely resemble those in man, were deemed to be the most helpful.

    The First Collaborative Trials (1967–71)

    While these further studies were being carried out, ICI began planning a trial with Dr. Klopper at Aberdeen, for the induction of ovulation in amenorrheic women rather than contraception. Indeed, by then, clomiphene had been found to stimulate ovulation and prolong luteal function in amenorrheic women, and in 1967 was approved for the treatment of infertility in the US. Moreover, obtaining approval to evaluate ICI 46,474 in oral contraception was problematic, not only because it involved long-term administration, but because of persisting fears among British gynecologists that it might lead to fetal malformation. In their eyes, unlike the conventional pill which contained familiar ingredients such as estrogens and progestins that had traditionally been given to pregnant women without harm to the fetus, evidence of a lack of teratogenic effect in animal experiments with an unknown compound like ICI 46,474 did not constitute an adequate safeguard. Therefore, they believed that the first women to receive ICI 46,474 as a contraceptive must be offered an abortion, but under the terms of the 1967 Abortion Act this could only be offered to a very limited number of women. Two solutions to this conundrum were envisaged: (1) to arrange a consortium of gynecologists to contribute such patients to a central unit in the hope of collecting a reasonable number fairly quickly; (2) to go abroad to a country, such as Hungary, where abortion was accepted as a means of population control. Meanwhile, therapeutic studies would be conducted to provide the sort of doses to be used in contraceptive trials, and approval to carry these out was obtained from the CSM in 1969. These studies included ICI 46,474 (now also referred to by its brand name Nolvadex) for the treatment of anovulation or menorrhagia associated with high levels of endogenous estrogen (to be carried out at Aberdeen, Manchester and the Women's Hospital in Chelsea), and of breast carcinoma in 30 menopausal and post-menopausal women (at the Christie Hospital in Manchester).

    The preliminary reports received from Dr. Klopper in Aberdeen and Drs. Murray and Osmond-Clarke in London helped to cast further light on the drug's mechanism of action, showing that that tamoxifen was capable of inducing ovulation at higher dose levels, while at lower doses it tended to have an anti-estrogenic effect. As to the Christie breast cancer trial, although two of the women complained about hot flushes (which was taken as evidence of its anti-estrogen effect), no toxicity was observed and the drug appeared to be well tolerated, even at the highest dose of 10 mg by mouth.

    In her unpublished history of tamoxifen, Dora Richardson wrote of the team's excitement as the first trial results arrived. She described the news of the birth of a child to a woman who had been infertile for 12 years and had failed to respond to treatment with clomiphene as a “boost to morale.” She also described how the team were encouraged by the results of the breast cancer trial, even though these results were not received with universal enthusiasm at ICI: Walpole and his colleagues were told that they were supposed to be looking for a contraceptive pill, not an anti-cancer agent! At a Development meeting on 28th August 1970, sales estimates and quantities of bulk drug were set at 2 kg for initial stocks. Richardson concluded from these figures that the Development Department obviously envisaged treating only “dead people,” an indication of the hopelessness of the condition as it was viewed at that time (as well as lack of faith or ignorance on the part of the Development team). However, fortunately, on the basis of the positive clinical results, the CSM granted the company permission to prolong the trials as well as extend them to other centers. By the end of 1970, 60 patients had been admitted to the Christie breast cancer trial, and of the 40 women who had been on the trial for more than 10 weeks, all had shown measurable and marked tumor regression. Although these results were comparable to those achieved with the established synthetic hormone diethylstilboestrol, the clinicians carrying out the trial, Drs. Todd and Cole, reported how impressed they were with the absence of toxicity and the low incidence as well as trivial nature of any side-effects (Cole et al., 1971), especially compared with other agents used in cancer at the time, which were often either toxic, or—in the case of breast cancer—tended to have androgenic effects, and in some instances were so intolerable that patients had been withdrawn from treatment.

    In return, the trials provided clinical material for laboratory studies of tamoxifen. By then, the estrogen receptor had been isolated and identified by Gorski (Gorski et al., 1968), and Walpole and his team developed a receptor protein-binding assay method. However, in a clinical setting, it was felt that a radio-immunoassay was more specific for measuring blood-estradiol levels in patients given tamoxifen. The receptor-protein binding assay was therefore mainly used for experiments in laboratory animals, and showed tamoxifen to be a competitive inhibitor of estradiol binding to the uterine receptor protein in rabbits and in mice. Receptors sensitive to anti-estrogen were also found in various parts of rats' brains, including the hypothalamus and the pituitary. The results of the receptor-protein binding experiments in both these test systems suggested that, like other anti-estrogens, the action of tamoxifen was due to a high association constant but low effectiveness of the complex it formed with estrogen receptors (i.e., it was a partial agonist, with high affinity but low intrinsic activity). This was a pharmacological action with which ICI researchers had become familiar in their work on the beta-blockers (Quirke, 2006). It helped to cast further light on the physiological processes at a molecular level, and made tamoxifen a particularly useful research tool for investigations of hormone-dependent tumors (Jordan et al., 1972).

    Rendered confident by the clinical and laboratory studies carried out so far, Walpole's team began planning trials in contraception, and the Nolvadex Development Programme was drawn up. This would play an important part in the drug's transformation from quasi-orphan to blockbuster drug (Quirke, 2012b).

    The Nolvadex Development Programme (1971)

    The “Development Programme” was an organizational innovation which standardized and codified the R&D process at ICI. It marked the transition from the “Proving Trial” to the “Development Trial Stage,” thus helping to bring together the “R” and the “D” in R&D. ICI's first Development Programme had been written up in 1964 for the beta-blocker propranolol (Inderal). It followed a series of quarterly development reports, and coincided with the hitherto separate Research and Development Departments coming together under the responsibility of a single Director, the Technical Director, as well as with the creation of the CSD in 1963. It therefore was a response to both internal and external factors and stimuli.

    The Nolvadex Development Programme, which came 7 years after the Inderal Development Programme, included 16 rubrics, describing the work done up to June 1971 (the date of the start of the Programme), making an assessment of the drug's potential market, and plans for future work:

    1. Clinical trials

    2. Further laboratory work

    3. Analysis

    4. Sales formulation

    5. Packaging

    6. Process development and manufacturing of bulk drug

    7. Manufacture and packing of tablets

    8. Position in North America

    9. Launch dates

    10. Registration

    11. Competitive situation

    12. Sales estimates

    13. Trade Mark and approved name

    14. Patents

    15. Publications

    16. R&D costs

    Three important considerations were taken into account when planning future work. First and foremost were tamoxifen's possible clinical uses, based on the results of trials received to date. These included: treatment of estrogen-dependent mammary carcinoma; induction of ovulation on women suffering from infertility due to failure to ovulate; menstrual disorders associated with abnormal levels of endogenous estrogen; oral contraceptive (a) for women, (b) for men; treatment for oligospermia; test for pituitary function; others. Secondly, the drug's position in North America was under question, following Ayerst's rejection of ICI's offer of Nolvadex for the American market, and the FDA's likely negative attitude toward its use in breast cancer. This attitude may have been due to a 1971 report in JAMA which had suggested that there was a link between diethylstilbestrol and a rare form of vaginal cancer, and was promptly followed by an FDA bulletin warning against the use of DES (FDA, 1971). Thirdly, the commercial situation, shown in Table 1, indicated that a number of therapeutic treatments of hormone-dependent breast cancers were already in existence, each of which commanded almost equal shares of the market.

    Table 1. UK major branded products.

    Despite such competition from rival firms in America and Europe, tamoxifen had two advantages on which its market position would ultimately depend in relation to breast cancer: (1) its unique mode of action in being an estrogen-antagonist without androgenic properties, and since at the time it was the only product of its type its use should be larger; (2) it possessed very low incidence of side-effects compared with other forms of treatment. Another important consideration was that of past R&D costs (shown in Table 2), which had a bearing on budgeting and planning for future expenditure.

    Table 2. Nolvadex R&D costs (£'000).

    The gaps in particular columns and rows in Table 2 exemplify the non-linear nature of pharmaceutical R&D, with bottle necks and feedback loops when advances in one area are held up by, and then develop in response to those in another. They also illustrate the pivotal part played by drug regulation in shaping the research and development activities of pharmaceutical firms. The trials that followed the CSM's approval for Nolvadex in 1969 not only led to an increase in existing expenditure in areas such as biochemistry, but to new expenditure in areas such as formulation (shown in bold).

    As well as further trials in anovulatory infertility (in Abderdeen, Oxford, London, and Dublin), and in breast cancer (Manchester, Glasgow, and London), the Nolvadex Development Programme included plans for trials in contraception. “In view of the reluctance of British gynecologists” to become involved in such trials, in 1971 ICI contacted Professor Egon R. Diczfalusy, co-founder and Director of the WHO Research and Training Centre on Human Reproduction at the Karolinska Institute in Stockholm

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