Chemical contraceptives as drugs

Efforts to control human fertility were probably among the earliest medical and pharmaceutical interventions.Footnote ¹ People attempted to avoid undesirable births – those outside accepted social arrangements, or those which represented an excessive economic burden. Some men used ‘coitus interruptus’ and mechanical devices which collected sperm, while some women ingested herbal decoctions in order to ‘bring their menses back’ (that is, to produce an early abortion), but also put substances such as honey, gum arabic and herbal preparations into their vaginas, which, they hoped, would make conception difficult. In the West, devices destined to dissociate sexuality from reproduction were condemned by religious authorities, but in all probability were nevertheless frequently used by women and men.Footnote ² Male condoms were widely diffused from the eighteenth century on, especially among the more educated and affluent social classes. In the nineteenth century, women could purchase female barrier methods – the diaphragm and the cervical cap – and in the second half of that century, people could also buy chemical preparations, such as jellies, suppositories and creams, which were expected to kill or incapacitate sperm cells when introduced into the vagina. These substances were either used alone, or together with a barrier method.Footnote ³ In the early twentieth century, a growing understanding of the physiology of reproduction opened the way to a search for scientific means to prevent conception. Studies on this topic were marginal, disreputable, suspicious, risky – but also interesting, challenging and at the cutting edge of scientific research.Footnote ⁴

Social historians extensively investigated contraception, an issue with broad social and cultural ramifications. Such historians were, however, mainly interested in the economic, cultural, juridical and religious aspects of efforts to control human fertility, in women's reproductive rights, and in the political consequences of debates on contraception. Only a few investigated the history of the production, testing, diffusion and use of modern contraceptive devices. In spite of important interest in efforts to control human fertility, the history of chemical contraceptives has been a relatively neglected topic.Footnote ⁵ Chemical contraceptives had a complex status. On the one hand, they were unmentionable products, hovering on the boundary of legitimacy and decency. On the other, some brands of chemical contraceptives were openly sold in pharmacies and advertised in newspapers and magazines. They were at the same time related to legal drugs – substances that belonged to the main circuit of the manufacture and distribution of pharmaceuticals – and to illicit or rather semi-licit drugs and patent medicines sold by disreputable peddlers. Furthermore, these chemical contraceptives came from a large variety of sources: small, semi-clandestine laboratories as well as big pharmaceutical plants, respectable and less respectable firms, companies linked with the birth control movement, and those in search of easy profit.Footnote ⁶

Advocates of contraception wished to put an end to the uncertain standing of chemical contraceptives to transform them into ‘ethical drugs’ – products of known chemical composition and physiological effects. They also aspired to disaggregate chemical products sold exclusively in pharmacies and often destined to be used with barrier methods, from less reputable products, sold in parallel circuits. One way to achieve this goal was to transform birth control into a legitimate subject of scientific inquiry. Another, complementary pathway was the stringent supervision of contraceptive products distributed in the legal circuit. The liminal status of chemical contraceptives and their close association with sexuality complicated both tasks.

Striving to dispel suspicions about contraceptive preparations, align them with bona fide drugs and legitimate their use favoured scientific innovation. It promoted the development of laboratory tests in which killing spermatozoids in a test tube became a surrogate marker of the capacity of a given product to prevent conception along with studies of long-term toxicity of chemical compounds. It also favoured the rise of new methods of investigation of the risk–benefit ratio of drugs and new patterns of regulation of therapeutic substances and other potentially toxic compounds. The history of chemical contraceptives displays not only the gradual refinement of methods employed to evaluate the efficacy and safety of pharmaceuticals, but also the limits of this enterprise. It was easier to standardize spermatozoids than to standardize sex.

Contraception in a test tube: laboratory studies of spermicides in Edinburgh and Oxford

Contraception was often coupled with protection against venereal diseases. Once scientists had shown that germs induce gonorrhea and syphilis, it was possible to present the male barrier method – condoms – as devices that offered protection from these pathologies, and to sell them openly in pharmacies for this indication.Footnote ⁷ Similarly, researchers noted that products that killed bacteria often killed sperm cells as well. Accordingly, some contraceptive preparations destined for women were also marketed as products destined to prevent sexually transmitted disease.Footnote ⁸ The British pharmacist Rendell was reported to be the first to produce, in 1885, a spermicidal suppository. German manufacturers quickly followed and proposed a wide range of suppositories, dry powders (the first was Dr Justus's ‘powder for the Malthusian’, manufactured in 1914), jellies (sometimes sold in tubes that were squeezed directly into the vagina), tablets, powders and creams. Similar preparations appeared in United States pharmacies in the 1880s.Footnote ⁹ Some preparations were presented as ‘disinfectants’ and as protection from venereal disease, marketed under the label ‘female hygiene’. Others, especially the popular quinine or chinosol-containing jellies, suppositories and creams, aimed exclusively to prevent conception.Footnote ¹⁰

The growing interest in scientific contraception was directly related to the professionalization of the birth control movement, and the transition from a radical movement of the early twentieth century, fuelled by feminist aspirations, to organizations of experts – doctors, academic scientists and social workers – lobbying for reforms. This shift was linked with the growing engagement of new professionals – often medical doctors or academic researchers – in the birth control movement. At that time, some militant feminists, such as the US pioneer of birth control, Margaret Sanger, increasingly favoured an alliance with professionals. Their abandonment of female contraceptive methods seen as unsafe, such as a vaginal douche, and the strong preference for a doctor-fitted diaphragm used together with a spermicidal cream or jelly were a part of this strategy.Footnote ¹¹ In the 1920s, the majority of birth control activists believed that that the most efficient way to prevent conception was the combined use of a female barrier method – a diaphragm or a cervical cap – and a spermicide.Footnote ¹² Birth control clinics, at that time small and marginal establishments, had strong preference for female-controlled devices, because their staff did not believe that women could rely on the goodwill of their male partners. The clinics therefore vigorously promoted the ‘diaphragm–jelly’ method and its variants. Their staff noted, however, that users' enthusiasm for their favoured contraceptive approach was moderate at best. More than half of women fitted with a diaphragm and advised to use it with a contraceptive jelly failed to show up to renew their jelly prescription; many others abandoned this method after a couple of months.Footnote ¹³ Activists explained these disappointing results by the (supposed) low intelligence and insufficient level of motivation of the clinics' clients (usually women who could not afford a visit to a private physician), by their difficult living conditions (crowded lodgings, the absence of bathrooms), and by the shortcomings of the existing contraceptive devices: difficult to apply, smelly, sticky, and interfering with the spontaneity of the sexual act.Footnote ¹⁴

The solution for all these problems, many birth control activists believed, would be the development of an efficient, easy-to-apply and pleasant chemical contraceptive which could be used by women from all social strata, including the poor and the uneducated. The latter aim resonated with the eugenic goal to reduce the birth rate among the poor, one of the central driving forces behind birth control activism in the United Kingdom and the United States in the first half of the twentieth century. The aspiration to make contraception scientific was closely intertwined with the larger goal of scientific steering of human reproduction, promoted by eugenicists.Footnote ¹⁵ The high fertility of the poor was attributed to their lack of sexual restraint, but also to their deplorable hygiene: dirt and a low consumption of soap favoured conception.Footnote ¹⁶ The only solution, some British eugenicists proposed, was the development of a simple, foolproof contraceptive that could be used by the ‘stupidest and therefore the most undesirable members of society’.Footnote ¹⁷ Robert Latou Dickinson, who after a long career as a mainstream gynaecologist became a leading advocate of contraception, and the director of the National Committee for Maternal Health (NCMH), a committee that fought for the incorporation of contraception into routine medical practices, similarly explained that ‘there is a great need of “applied science” directed to the problems of simplification and security and adaptation, not to cities and clinics, but to backwoods and slums and Oriental people. It must be done. It is not being done.’Footnote ¹⁸

The tension between an aspiration to develop a cheap, simple, and user-friendly contraceptive, and the parallel pursuit to transform contraception into a regular medical practice privileging doctor-controlled devices, coloured much of the debates on birth control in the early twentieth century. For some birth control activists, a search for a safe and ethical chemical contraceptive was an attempt to reconcile both sides. The development of such a contraceptive was hampered by the difficulty of evaluating how well these products worked. The efficacy of a drug usually depends not only on its intrinsic properties but also on its correct and consistent use, and this was true for contraceptives, too. However, the dynamics of sexual intercourse were not well adapted to a careful observation of stringent rules. Moreover, people were unwilling and/or unable to accurately report their use of contraceptives.Footnote ¹⁹ Since a collection of reliable data on people's sex lives was difficult, scientists turned to a more easily controllable surrogate marker for sexual intercourse – the spermatozoid – and to studies of the rapidity of the killing of sperm cells in a test tube.

In the interwar era, laboratory studies of contraceptives were mainly promoted by two organizations: the North American NCMH and the British Birth Control Investigation Committee (BCIC). The NCMH's director, Dickinson, was an enthusiastic advocate of scientific studies of contraception: ‘the subject is susceptible of handling as clean science, with dignity, decency, and directness’.Footnote ²⁰ He tried accordingly to recruit scientists for studies of the efficacy of commercial preparations of spermicides.Footnote ²¹ Faced with difficulties in finding researchers interested in this topic in the United States, Dickinson and the NCMH's executive secretary, Louise Bryant, turned to British experts.Footnote ²² In 1926, they contacted Francis Albert Eley Crew, the director of the Centre for Animal Breeding at the University of Edinburgh, who recommended one of his students, the chemist and immunologist Cecil Voge. The NCMH applied to the Rockefeller-sponsored Bureau of Social Hygiene (BSH) for a joint Crew–Voge grant for scientific studies of contraceptives. The BSH provided a three-year grant, starting in 1929.

In 1932, Voge, who had become deeply involved in contraceptive studies, wished to renew his grant. Crew disagreed. He became persuaded that the development of effective contraceptives was not possible without a better understanding of the physiology of human reproduction. He also believed that Voge's studies took an excessively practical turn. If he persisted in his contraceptive studies, in three years he might not be able to find a research job. Crew also objected to Voge's zeal. Voge, Crew explained, started this work as a scientist; he was now becoming a propagandist.Footnote ²³ Louise Bryant, who thought highly of Voge's studies, attempted to find him alternative sources of funding. She tried at first to persuade the BSH to hire Voge for a major project on the standardization of contraceptives.Footnote ²⁴ When this project failed to materialize, Bryant was able to secure private funds for Voge's research. This was, however, only a temporary solution, and in the mid-1930s Voge was obliged to abandon his research on birth control.Footnote ²⁵

One of the main reasons for Voge's difficulties was the existence of a competing study conducted by John Randal Baker from the zoology department of Oxford University.Footnote ²⁶ In the autumn of 1928, the BCIC, an organization closely associated with the British Eugenic Society, attributed a grant to Baker for research on spermicides. At that time, many eminent, progressive British biologists, among them Lancelot Hogben, Julian Huxley and J.B.S. Haldane, were closely associated with the eugenic movement. John Randal Baker, one of Huxley's students, was a close friend of a fellow student of Huxley, the BCIC's secretary, and of the psychiatrist Carlos Paton Blacker (Blacker was also the general secretary of the Eugenic Society from 1931 to 1961). Baker's main area of specialization was cytology; his interest in the scientific study of contraception and energetic search for better chemical contraceptives stemmed from his strong eugenic convictions.Footnote ²⁷

The laboratory techniques used by Baker and Voge were quite similar. Both looked for the highest dilution of the tested substance still able to immobilize a fixed quantity of spermatozoids in a test tube, an approach directly inspired by studies of the antibacterial activity of disinfectants and antisera. The main difference was that Voge used exclusively human semen, while Baker worked mostly with guinea pig sperm. Baker claimed later that he was the first to develop an efficient method of testing the spermicidal activity of chemical compounds, and accused Voge of plagiarism. Voge energetically rejected these accusations.Footnote ²⁸ When Crew decided to withdraw his support for Voge's research on contraceptives, the BSH turned to Baker, and from 1932 on provided funding for his spermicide investigations. Baker's studies also continued to be supported by the BCIC and the British National Birth Control Association (NBCA).Footnote ²⁹

Voge summed up the results of his studies in his 1933 book The Chemistry and Physics of Contraceptives. Tests of commercial preparations of spermicides, Voge stated, had shown that the great majority of the approximately five hundred commercial contraceptive preparations marketed in the United Kingdom had a poor spermicidal capacity.Footnote ³⁰ Only less than two percent of these preparations were efficient, ‘the rest have only two places for them, either the incinerator or the museum of curiosities’.Footnote ³¹ In addition, many chemical contraceptives had an inappropriate consistency. They were either too viscous, failing to mix properly with the sperm, or too liquid, and therefore failing to adequately cover the cervix.Footnote ³² An ideal contraceptive, Voge explained, should be entirely dissociated from the sexual act itself, because one cannot ask people to behave rationally in emotionally loaded circumstances.Footnote ³³ Alas, such a contraceptive did not yet exist. In the meantime, it was important to improve the quality of the existing commercial contraceptive preparations through appropriate regulation: ‘I personally would plea for the definitive drive towards standardization, and standardization by people who do know what is being taught. Every product must be put through these tests and must be put through them before it comes to the clinics’.Footnote ³⁴

Voge wished to improve the existing chemical contraceptives. In contrast, Baker's main goal was to develop a more efficient product. He did not develop his test of comparative spermicidal activity in order to study preparations already on the market, but in order to compare the spermicidal capacity of pure chemical compounds. Baker elected to work mainly with guinea pig sperm cells because they were easier to standardize. He claimed that when guinea pig spermatozoids were suspended in a chemical solution that mimicked the characteristics of human sperm liquid, their behaviour and resistance to killing was similar to that of human sperm cells.Footnote ³⁵ Working with standardized and ‘humanized’ guinea pig spermatozoids, Baker had found that many presumably active components of popular commercial spermicides, such as chinosol and quinine, in fact had limited spermicidal capacity, vastly inferior to that of other substances, such as soaps.Footnote ³⁶ He had also shown that spermicidal and microbicidal properties are often dissociated: the best spermicides (substances that protect from unwanted pregnancy) were not the best microbicides (substances that protect from venereal disease), and vice versa.Footnote ³⁷

At the same time, Baker devised a way to ‘humanize’ a bitch's vaginal epithelium (that is, make it more similar to women's tissue) through the application of sex hormones. He then used bitches to check if a candidate's spermicides irritated the vagina.Footnote ³⁸ Studies conducted in a test tube and in laboratory animals were more rapid, more reproducible and less expensive than clinical investigations. Baker was persuaded that they were also more reliable. As a rule, field studies of contraceptives, he argued, were experiments without controls. By contrast, well-controlled laboratory studies provided a good approximation of events in a woman's body. It is misleading to assume that ‘the vagina is a sort of chemical laboratory equipped to change the chemical constitution of every substance placed within it’.Footnote ³⁹ In 1935, when Baker described an ideal contraceptive in his book The Chemical Control of Conception, he probably believed that his confidence in laboratory studies of contraception had been vindicated: he was on the threshold of developing a near-perfect chemical contraceptive.Footnote ⁴⁰

Volpar: birth control, eugenics and commerce

From the very beginning, Baker's studies had an industrial orientation. In 1930, when he had found out that soaps were potent spermicides, he immediately considered the possibility of mass production of a cheap and efficient contraceptive based on soap. The BCIC's research subcommittee, informed about this possibility, recommended clinical tests of Dr Baker's new preparation in North Kensington, Cambridge and Birmingham birth control clinics.Footnote ⁴¹ However, hopes linked with a soap-based contraceptive were in all probability short-lived, since the subject did not appear in subsequent deliberations of the BCIC's research subcommittee. Baker continued his search for a potent spermicidal substance and in early 1933 he notified the BCIC that he was close to the discovery of a perfect compound, ‘substance A’: highly efficient, cheap, pleasant, and non-toxic.Footnote ⁴² Baker's original intention was to employ the non-profit networks of the BCIC and the NBCA to produce and market contraceptives containing ‘substance A’. The BCIC was interested in such a commercial venture, possibly in association with industrialists. Its report on 26 January 1933 included a resolution that stated,

Alas, in spite of the hopeful initial results, Baker rapidly found that substance A was spermicidal only in alkaline solutions (vaginal secretions are acid), and that it stained animal secretions. Baker was unable to solve these problems. The same year, 1933, chemists of a pharmaceutical company, British Drug Houses, who had patented a different substance with good spermicidal properties, contacted another researcher funded by the BCIC, the physiologist H.M. Carleton. They, too, found later (probably with Carleton's help) that this substance was toxic for laboratory animals, and could not be used as a contraceptive.Footnote ⁴⁴

At that point, Carleton and Baker became interested in collaborating with British Drug Houses, potential suppliers of promising molecules, manpower and funds. This was, however, problematic. Their research on contraceptives, funded by the BCIC and the NBCA, was perceived as ‘owned’ by the latter organization, hence the need to discuss the potential commercial outcomes of Baker and Carleton's research. In October 1933, the BCIC was informed about Blacker's informal contacts with representatives of British Drug Houses, and about a meeting, held on 18 May 1933, between British Drug Houses, Drs Carleton and Baker, the representative of the NBCA, Lady Derman and Blacker. The meeting did not produce a formal report, perhaps because at that point there was no marketable product in sight.Footnote ⁴⁵

In the autumn of 1935, Baker announced that his collaboration with British Drug Houses had led to the development of a truly promising contraceptive. The BCIC's secretary, Blacker and Mr Bennett, the representative of British Drug Houses, proposed that the NBCA's Medical Committee help Baker organize clinical trials of the new preparation. The BCIC's members were not sure at that point if investigators funded by the BCIC or the NBCA were entitled to royalties for a product which had been developed thanks to the support of non-profit organizations. They therefore proposed to interrogate external personalities (such as the eminent physiologists Henry Dale and Edward Mellanby – the latter was also the secretary of the Medical Research Council) on the ethical aspects of such an arrangement. Dr Jackson, of the NBCA's Medical Committee, also pointed to difficulties linked to industrial secrecy. It was difficult to ask the Committee to organize a clinical trial of Dr Baker's contraceptive without telling them what the ingredients of this product were. Blacker proposed a compromise to solve the latter dilemma. The Medical Committee members would be told what the principal spermicidal ingredient of this product (developed by Baker) was, but not what the accessory products – elaborated by British Drug Houses chemists – were.Footnote ⁴⁶

In December 1935, representatives of the BCIC, the NBCA and British Drug Houses discussed the details of marketing the new preparation. The first point was the ownership of the product's trade name: Volpar (for Voluntary Parenthood). Dr Carr, from British Drug Houses, argued that since the firm renounced the right to include their chemists in the publication of Baker's and Carleton's results in the scientific press, they should possess the rights for the trade name Volpar. It was finally agreed to explore the possibility that British Drug Houses and the NBCA would have joint ownership of the trade name Volpar, while British Drug Houses would be allowed to register it officially. The participants then discussed the distribution of royalties. British Drug Houses was willing to pay royalties to the NBCA, but the latter organization decided instead to be assured of the supply of a fixed quantity of Volpar for free distribution in birth control clinics. The next point was the objection of the NBCA's Medical Committee to organizing tests of a product of unknown composition. The participants adopted the compromise proposed by Blacker: the disclosure of the nature of Volpar's main spermicidal compound, but not its full formula. The final point discussed at the meeting was the endorsement of Volpar by the BCIC. Opinions on this topic were divided.Footnote ⁴⁷ The latter issue remained controversial, and was still being debated by the BCIC in 1938.Footnote ⁴⁸

In 1937 Baker and his collaborators officially announced the development of a new, particularly effective contraceptive, without first revealing its chemical composition.Footnote ⁴⁹ The main practical advantage of the new preparation was its ability to kill sperm cells rapidly: ‘there is no branch of pharmacology in which rapidity of actions is more important than in chemical contraception, since on each occasion in which a contraceptive is used, there is no intermediate condition between complete success and complete failure’.Footnote ⁵⁰ In 1939, Baker and his co-workers revealed Volpar's active compound – phenylmercuric acetate – and argued that their product was very close to the ideal of a perfect contraceptive. It was a powerful spermicide, non-irritating, inexpensive, small, solid (and therefore did not require a specific appliance for its insertion in the vagina), unaffected by the ordinary range of climates, and odourless. Moreover, it did not stain bedclothes or skin, and it was perfectly harmless.Footnote ⁵¹ The efficacy of Volpar was mainly deduced from laboratory studies. Only two groups of women tested the new preparation before its being marketed. In the first test, eleven women used the substance, for between one and twelve months. No pregnancy occurred in this group. In a second test, fifty-seven women used Volpar for one year or less. There was one pregnancy in this group.Footnote ⁵² Plans to provide a more thorough follow-up of Volpar's efficacy in real-life conditions were thwarted by the war. It is unclear, however, how keen managers at British Drug Houses were to conduct such tests.Footnote ⁵³

The BCIC and the NBCA did not object to Baker and Carleton's collaboration with British Drug Houses, and did not view their direct involvement in a commercial venture as problematic. Blacker was thus willing to use the BCIC's contacts with the NCMH to help British Drug Houses promote Volpar in North America.Footnote ⁵⁴ The NCMH, which co-founded Baker's studies of contraceptives, was less sure how to deal with their protégé's new role as an industrial researcher.Footnote ⁵⁵ The NCMH's executive secretary, Raymond Squier, explained that ‘certainly it has not been the policy of the National Committee on Maternal Health so far to supplement commercial subsidy or even finance research where there is a prospect of such financing being done in toto by a commercial organization’.Footnote ⁵⁶ The NCMH finally decided to continue its support of Baker's research, mainly as a sign of its goodwill towards their British colleagues. It stipulated, however, that Baker's grant could not be used for investigations made in collaboration with British Drug Houses.Footnote ⁵⁷

Volpar was a commercial success, but it did not become a ‘miracle drug’, able to provide highly efficient and trouble-free protection from unwanted pregnancies. It out-performed its competitors in the test tube, but was not found to be outstandingly efficient by its users. In the 1940s, Volpar became one among many ‘acceptable’ chemical contraceptives. Moreover, at that time, some researchers started to question the use of a potentially toxic substance, phenylmercuric acetate, as a drug. Baker's careful evaluation of the toxicity of his preparation in the laboratory was not sufficient to persuade other scientists that it was innocuous for women. Clinical trials of chemical contraceptives were perhaps, as Baker put it, ‘experiments without controls’, but in the 1950s they were increasingly perceived as the only reliable way to assess the long-term safety of these preparations.

Standardized spermatozoids: studies of the efficacy of chemical contraceptives in the United States

In the United States, laboratory tests of contraceptives were developed mainly thanks to the sustained efforts of a single semen activist scientist: Clarence Gamble. Gamble, an heir to the Procter & Gamble fortune, studied medicine and attempted at first to become an academic medical researcher. He was not happy, however, with his career choice. When, thanks to a chance encounter with the NCMH's director, Dickinson, he learned about the need to develop scientific research on contraception, he decided to dedicate all his efforts, and part of his personal fortune, to such research. Gamble was especially interested in ‘simple chemical contraceptives’ as his main hope was a massive diffusion of birth control.Footnote ⁵⁸ His family links with the pharmaceutical industry might have heightened his awareness of the need to test the quality of industrial products. Gamble's goal was to ensure that chemical contraceptives would adopt the same standards as did ‘ethical drugs’. In order to promote this goal, he systematically compared the spermicidal performance and physico-chemical properties of all the chemical contraceptives on the US market, and published the results of these investigations. Gamble's publications were directed above all to physicians. US doctors increasingly saw advice on contraception – given, they stressed, only to married couples wishing to space childbirths – as a legitimate part of their practice. Doctors, Gamble argued, need reliable information on the quality of products they prescribe. The second target of Gamble's annual publications on the quality of contraceptives was their manufacturers. Gamble hoped that manufacturers of contraceptives that performed poorly in laboratory tests would be persuaded – or forced by their commercial losses – to improve their products.Footnote ⁵⁹

In 1939, Gamble, with his collaborator, the zoology student Royal Brown, developed a test of spermicidal activity in vitro especially for comparative studies of performances of commercial compounds.Footnote ⁶⁰ Brown and Gamble's method was a variant of those of Voge and Baker. Brown and Gamble constructed an apparatus composed of a glass syringe, rubber tubing and a capillary tube screwed to a board with a ruler. The tested preparations were mixed with a fixed amount of human spermatozoids in a capillary tube, and the experimentation observed the rapidity of immobilization of all the sperm cells.Footnote ⁶¹ A capillary tube allowed Brown and Gamble to perform each test with a very small amount of semen, and to compare numerous substances using the same human ejaculate. They were therefore able to eliminate an important source of variability in comparative tests.Footnote ⁶² In their first study, in 1940, Brown and Gamble had found that the spermicidal power of commercial preparations varied greatly. Some products, such as Orthogynol and Cooper Crème, were very efficient, while one of the most popular preparations, Lanteen Blue Jelly, had a very low spermicidal activity.Footnote ⁶³ In 1941, they added Volpar Paste to their test, and confirmed its good spermicidal effects in the test tube.Footnote ⁶⁴

Spermicidal activity was but one element of the efficacy of chemical contraceptives. In 1936, the Birth Control Clinical Research Bureau, sponsored by Margaret Sanger and the NCMH, decided to fund jointly an investigation of the physico-chemical properties of contraceptive preparations. This was an important goal, because preliminary studies indicated that the efficacy of creams, jellies, suppositories and foams was at least as dependent on their physical properties as on their chemical composition. A young chemist, Leo Shedlovsky, hired by Sanger to perform these studies (and later co-funded by Gamble), devised a new method to measure the viscosity of chemical preparations.Footnote ⁶⁵ Data on the viscosity of products (satisfactory, too low or too high) were then added to Gamble's annual evaluation of contraceptive products. In the 1940s Gamble's comparative studies of laboratory performances of chemical spermicides were published in the journal Human Fertility, founded by Sanger in 1936 (its original title was Journal of Contraception).Footnote ⁶⁶ In 1952, Gamble's report on the spermicidal capacity of commercial jellies was published by the Journal of the American Medical Association, an indication of the growing respectability of this area.Footnote ⁶⁷

The aim of Gamble's and Shedlovsky's studies was to put pressure on commercial manufacturers of contraceptives to improve their products, not to develop alternative preparations. The NCMH was initially interested in sponsoring the manufacture of contraceptives. In 1923, Dickinson considered the possibility that the NCMH would manufacture and diffuse spermicidal suppositories developed by an ‘ethical druggist’, Mr Gehris. He abandoned this idea when he discovered that in order to put Gehris's formula on the market, the NCMH needed to secure a patent and a trade name, steps which, Dickinson believed, could not be taken by a non-incorporated organization.Footnote ⁶⁸ Gamble, unlike Dickinson, did not view the fact that the NCMH was a non-commercial organization as a major obstacle for the manufacture and marketing of contraceptives. The main difficulty, he argued, was not legal but psychological: the NCMH and the American Birth Control League (ABCL) were ‘dreadfully afraid of commercialism’.Footnote ⁶⁹ In May 1937, Gamble wrote a memorandum on the feasibility of the production of a cheap and more reliable (but not necessarily more efficient) chemical contraceptive by the NCMH. He first discussed this project with Randolph Cautley, a business consultant and NCMH's adviser. Cautley was interested, and approached two chemists who, he believed, could become leaders of this project.Footnote ⁷⁰ However, negotiations with these chemists failed. In the meantime, Gamble and Cautley came to the conclusion that their project was not commercially viable, and Gamble shifted his attention to the improvement of the products manufactured by pharmaceutical laboratories.Footnote ⁷¹

Gamble was persuaded that in order to make the manufacture of chemical contraceptives as close as possible to the production of ‘ethical drugs’, their producers needed to disclose the full formula of their products – not only their active elements, but also the inert compounds. Without such full disclosure, he argued, doctors could not make informed decisions, and could not be sure that the product they recommended was best suited for their patient.Footnote ⁷² Gamble's efforts to persuade industrialists to improve their products were at least partly successful. In the 1940s, manufacturers of contraceptives started to view good performance in standardized laboratory tests (spermicidal power, viscosity) as a major commercial asset.

Increasing attention of manufacturers to the results of laboratory tests was in all probability related to the growing recognition of spermicides as bona fide pharmaceuticals, and to their growing acceptability to physicians.Footnote ⁷³ In 1936, the American Medical Association (AMA) established its Advisory Committee on Contraceptives, a subdivision of the Council on Pharmacy and Chemistry. Gamble was elected chairman of this committee. In 1937, the AMA agreed – reluctantly at first – to approve the diffusion of contraceptive information by doctors.Footnote ⁷⁴ In the same year, the US Consumers' Union produced for the first time a list of ‘acceptable’ and ‘unacceptable’ contraceptive jellies.Footnote ⁷⁵ Brown and Gamble's systematic comparative studies of all the contraceptive preparations on the US market were a direct extension of these developments. The growing success of these studies may be contrasted with the quasi-indifference to Voge's earlier attempt to compare the efficacy of chemical contraceptives marketed in the United Kingdom. Standardization cannot thrive in the absence of institutional support.

By the late 1930s, the immobilization of spermatozoids in the test tube was seen by some specialists as a well-established method for testing the efficacy of chemical contraceptives. In 1937, Lewis Britt, a chemist with the Oregon State Board of Pharmacy, was asked to examine contraceptive products and to check if they were in agreement with Oregon law. Britt explained that he understood his task as testing contraceptives for safety and ‘global efficacy’. To evaluate the latter, he employed a variant of Baker's test. Contraceptive products which failed to kill all guinea pig spermatozoids after ten minutes were defined as inadequate. The method employed by Britt does not seem to be very stringent: four out of twenty-two examined brands of suppositories, capsules, tablets and powders, but only one of the thirty-seven examined jellies, failed this test.Footnote ⁷⁶

The Brown–Gamble test, and its simplified variant, the Sander–Cramer method (developed in 1941), were well adapted to compare performances of commercial contraceptives in a test tube.Footnote ⁷⁷ Researchers who worked in this area were, however, aware of their shortcomings in evaluating the ‘real-life’ efficacy of these compounds. Gamble developed in 1952 a test which put the tested substance directly in contact with non-diluted human spermatozoids. The elimination of the dilution and mixing stage, Gamble explained, more accurately reproduced the condition in the vagina during sexual intercourse. He was aware, however, of the fact that the mixing of spermicide and sperm had previously been presented as an attempt to reproduce events during the sexual act. Gamble therefore proposed to use the two versions of his test in parallel. The combination should provide a better ‘factor of safety’ than either one of these methods alone.Footnote ⁷⁸ Other investigators agreed. The parallel use of several variants of the spermatozoid immobilization test provided more reliable results.Footnote ⁷⁹

All laboratory tests of spermicides developed in the late 1930s and early 1940s were grounded in the same principle: immobilization of spermatozoids by the tested preparation. By contrast, the scientists who elaborated and used these tests were a very heterogeneous group. They had different affiliations, credentials and sources of funding. Some were academic researchers paid by their institutions, others were funded by non-profit organizations such as the National Committee on Maternal Health, the Birth Control Federation of America, the American Birth Control League, and the Clinical Research Bureau; some were scientists employed by the state, still others were industrial chemists who worked for manufacturers of contraceptives; finally, Gamble had a unique status since he funded, and therefore controlled, his own and others' research on birth control, and at the same time was the chairman of the AMA's Advisory Committee on Contraceptives. The efforts to regulate chemical contraceptives in the US through the use of standardized laboratory tests led to the emergence of a complex field, with numerous participants and multiple interests. After the Second World War, a new, powerful player entered this field: the Food and Drug Administration (FDA).

The efficacy of contraceptives: the FDA and the Lanteen Blue controversy

All the experts agreed that, ideally, contraceptives should be tested in field trials. One of Gamble's medical correspondents proposed testing contraceptives by using a post-coital test (a test which measures the quantity of viable spermatozoids in the vagina a short time after sexual intercourse).Footnote ⁸⁰ This was a logical proposition but, in all probability, it faced insurmountable practical obstacles. In order to test the various compounds on the market, one needed to mobilize hundreds of fertile women ready to undergo post-coital tests.Footnote ⁸¹ By contrast, laboratory tests were inexpensive, rapid, easy to standardize, and well adapted for the comparison of the performance of numerous products. Due to practical concerns, spermicidal time was accordingly often accepted as a valid surrogate marker of the real-life efficacy of chemical contraceptives, and Gamble's extensive correspondence with manufacturers of spermicides insisted above all on the need to improve the spermicidal times of their preparations.

From the 1930s on, the FDA took an increasingly active role in tracing ‘unethical’ drugs (for example ‘gland extracts’ without active components), and fined manufacturers for marketing faulty products and inaccurate advertising.Footnote ⁸² The Federal Food, Drug and Cosmetic Act of 1938 authorized the FDA to extend its power to the regulation of medical devices, a definition which included condoms, officially sold as protection from venereal disease. From 1938 on, the agency systematically destroyed batches of defective condoms, an action which started even before ratification of the 1938 act.Footnote ⁸³ The right to control the quality of medical devices was later extended to diaphragms; that is, products employed exclusively as contraceptives. Finally, the FDA attempted to assess the efficacy of spermicidal jelly. However, this was a more complex issue. When testing the quality of condoms or diaphragms, FDA inspectors assumed that if a barrier device had no mechanical defects and did not deteriorate rapidly when stored, it would correctly fulfil its function. The case of spermicides was different. In the absence of reliable clinical tests, there was no way to know if a given chemical product could prevent conception. The FDA therefore elected to use a surrogate marker – the killing of spermatozoids in a test tube – to argue that a contraceptive jelly, Lanteen Blue, had a poor spermicidal capacity, and should therefore be banned from interstate commerce.

Lanteen Laboratories of Chicago, manufacturers of Lanteen Blue Jelly, were a major player on the US contraceptive market. Producers of diaphragms, jellies, suppositories and powders, Lanteen Laboratories combined an aggressive advertisement campaign of their products in journals and magazines and on the radio with direct marketing to consumers. It also opened a ‘Medical Bureau of Birth Control Information’ in Chicago (similar agencies were later also opened in Detroit and Milwaukee). In this commercial venture, medically trained personnel provided contraceptive advice, fitted women with diaphragms, and sold Lanteen products. The services offered by Lanteen-sponsored centres were similar to those provided by clinics sponsored by the American Birth Control League (ABCL), with one important difference. Lanteen-sponsored centres were willing to provide contraceptives to all women able to afford their fees. By contrast, the ABCL's clinics wished to make contraception respectable, affirming that their clinics provided services to married women only.Footnote ⁸⁴ The ‘moral laxity’ of commercial clinics was strongly condemned by the non-profit birth control establishment. Dickinson (head of the ABCL-affiliated NCMH) visited the Lanteen-sponsored Medical Bureau in Chicago in 1930, reporting with dismay open discussions of sexual practices, even suspecting that a pregnant woman could obtain information there about doctors willing to perform an abortion.Footnote ⁸⁵ The animosity between the birth control establishment and Lanteen Laboratories was exacerbated in 1937 by Lanteen's attempt to produce a ‘one-size-fits-all’ diaphragm, sold over the counter. The possible success of such a device was a major threat to the ABCL's strategy of using the diaphragm – defined by them as a device fitted only by a doctor – as a way to enroll AMA's support for contraception.Footnote ⁸⁶ The aggressive commercial strategy of Lanteen Laboratories was probably one of the reasons why the FDA became especially interested in this enterprise.

In June 1946, the FDA seized a batch of Lanteen Blue contraceptive jelly in San Francisco, charging the company with misbranding, Section 502(a): ‘the labelling of the articles was false and misleading since it represented and suggested that the rubber diaphragm and jelly were effective in preventing conception when used as directed, whereas they were not effective for such purpose’.Footnote ⁸⁷ Gamble learned that the FDA officers declared legitimate the misbranding accusation by the jelly's low ratings on the Brown–Gamble test, an accusation he had found exaggerated and unfair. While an earlier version of Lanteen Blue jelly indeed performed poorly on the Brown–Gamble test, this was no longer true in 1946. The new variant of this jelly had an excellent spermicidal action.Footnote ⁸⁸ Moreover, Gamble believed that the formula of Lanteen Blue jelly was modified as a result of his efforts. He wrote earlier to Royal Brown:

At that time, Gamble developed a friendly relationship with the chemist who tested Lanteen products, C.C. Fowler. Fowler reported to Lanteen Laboratories that in his test – a variant of the Brown–Gamble test that used guinea pig spermatozoids – new batches of Lanteen Blue jelly had excellent spermicidal time.Footnote ⁹⁰ Lowry, the director of Lanteen Laboratory, learned, however, from Dr Granger, the FDA expert responsible for the capture of a Lanteen Blue shipment in San Francisco, that the Food and Drug Administration had no confidence in Fowler's tests because the manufacturer of the suspect product employed him. FDA officials explained that they would believe that Lanteen had improved the spermicidal time of its jelly only if either Gamble or Brown would perform the test. Fowler immediately contacted Gamble, asking him to test the incriminated samples.Footnote ⁹¹ Gamble, who at that time was suffering from a duodenal ulcer, asked Brown to do these tests for a fee.Footnote ⁹² Brown declined this offer. He reported to Gamble,

In the meantime, Gamble, displeased with the FDA's action, decided to react to it. He prepared a first draft of a paper, ‘Spermicidal times and the law’, and asked Brown to co-sign it.Footnote ⁹⁴ In this text, Gamble explained that the Brown–Gamble test evaluated only the relative efficacy of the materials tested, not their capacity to prevent an unwanted pregnancy. He also stated that the manufacturer of the seized preparation had modified its composition, and the new jelly had a much better spermicidal time.Footnote ⁹⁵ Gamble submitted the draft of his paper to Fowler, asking the opinion of the Lanteen Laboratories directors.Footnote ⁹⁶ The Lanteen executives were pleased with text, and did not suggest any changes.Footnote ⁹⁷ Brown was decidedly less enthusiastic. He wrote to Gamble that he did not wish to co-sign his text:

Gamble might have been comforted by the fact that Dickinson, unlike Brown, found that his article was useful.Footnote ⁹⁹ In the spring of 1947, the FDA dropped its charges against Lanteen Blue Jelly, but maintained its claims against Lanteen's cap diaphragm.Footnote ¹⁰⁰

Gamble's defense of Lanteen Blue reflected his conviction that the FDA action was unfair.Footnote ¹⁰¹ In ‘Spermicidal times and the law’, he also forcefully stated that the spermicidal power of a preparation such as it is measured in a test tube does not adequately reflect its effectiveness in real-life use. However, on other occasions, Gamble sent more ambivalent messages. He affirmed that ‘spermicidal times of contraceptives cannot duplicate conditions present in the post-coital vagina’ and that his test provided ‘the only information available regarding the possible clinical effectiveness of chemical contraceptives’.Footnote ¹⁰² He explained that ‘the post-coital vagina contains semen and jelly in concentrations varying from 0 to 100%’, but claimed nevertheless that laboratory tests ‘appear to be of value to clinicians’.Footnote ¹⁰³ Brown was equally ambivalent on this topic. He and his collaborators acknowledged that there were no data whatsoever on the correlation between spermicidal times and a capacity to prevent pregnancy, affirming that ‘spermicidal activity appears to be the only quality measurable in the laboratory from which it is reasonable to predict the relative clinical performance of contraceptive materials’.Footnote ¹⁰⁴ It is not surprising that FDA officers, perhaps irritated by the aggressive promotion of Lanteen products, elected to listen to Gamble and Brown when they defended the practical value of their test, not when they discussed its limitations.Footnote ¹⁰⁵

Toxicity of contraceptives: the AMA and the phenylmercuric acetate debate

The Lanteen Blue controversy illustrates the difficulty of evaluating the efficacy of chemical contraceptives. The evaluation of the safety of these products was seen as somewhat simpler. It was not too difficult to dismiss obviously toxic products, or those which produced an irritation of the vaginal mucosa. The evaluation of the long-term effect of topical applications of a chemically active substance was, however, a more difficult task. This difficulty is visible in the controversy on the use of phenylmercuric acetate – the active component of Volpar – as a spermicide. Mercury is a highly toxic element. Baker and his collaborators from British Drug Houses claimed, however, that Volpar contained a very low concentration of mercury, well below the threshold of toxicity for humans. Moreover, it was applied locally and never entered the blood stream. Volpar was sold mainly in the UK, but two US manufacturers commercialized spermicidal compounds that employed phenylmercuric acetate as their main active ingredient: Lorophyn Suppository and Jelly, produced by Eaton Laboratories, and Koromex Cream and Jelly, produced by Holland Rantos Laboratories (a company linked with Sanger's Birth Control Clinical Research Bureau). In the 1940s, US scientists started to question the safety of these preparations.

In 1944, two researchers, Nicholson Eastman from the department of obstetrics of Johns Hopkins University and A.B. Scott from the department of organic research of the Norwich Pharmaceutical Company, investigated the toxicity of phenylmercuric acetate in rats. They found that this compound was not very toxic when applied to the vagina of female rats. They also installed this substance deep in the vagina of six women admitted to Johns Hopkins Hospital, massaged it vigorously for a full minute (the latter manipulation was probably designed to mimic the conditions of sexual intercourse), and left it there for 24 hours. During this time, urine specimens of these women were collected through a catheter and analysed for their mercury content.Footnote ¹⁰⁶ Eastman and Scott found that only 3–4 per cent of the mercury installed in the vagina was recovered in the 24-hour urine specimen. They did not entirely rule out the possibility that more frequent use of this substance would lead to the accumulation of mercury in the organism, but argued that this was unlikely, because women who used Volpar for six consecutive months did not have a high concentration of mercury in their urine.Footnote ¹⁰⁷

A 1949, study made by Edwin Laug and Frieda Kunze of the FDA was less reassuring. Laug and Kunze claimed that Eastman and Scott focused exclusively on the secretion of mercury in urine. They therefore failed to address the most important question: the risk that mercury was trapped in tissues. Laug and Kunze found that the livers and kidneys of female rats having received vaginal suppositories of phenylmercuric acetate contained significant amounts of mercury. Moreover, 60–80 per cent of the mercury stored in the kidney was still present in this organ one week after the installation of a single dose of phenylmercuric acetate in the vagina. Laug and Kunze concluded that urinary excretion of mercury did not provide an adequate measure of absorption and retention of this heavy metal, and recommended paying attention to the danger of cumulative effects of systematic use of phenylmercuric acetate-based contraceptives.Footnote ¹⁰⁸

Dr Kautz, of the AMA's Council on Pharmacy and Chemistry, wrote in 1949 to Gamble (then the secretary of the Council's Advisory Committee on Contraceptives), questioning him about the safety of the Lorophyn Suppository in the light of Laug and Kunze's study. Gamble answered that in his opinion Laug and Kunze's data were an invitation to be vigilant, but not a sufficient indication to recall the marketing permit for contraceptives containing phenylmercuric acetate. Eastman did not observe health problems in women who used contraceptives containing mercury. Moreover, he stated, ‘rats are of course different from humans and the absorbing power of the vagina may be very different’. Gamble nevertheless wrote to Eaton Laboratories, the producers of Lorophyn, asking their opinion about Laug and Kunze's study.Footnote ¹⁰⁹

Producers of mercury-free contraceptives attempted to capitalize on the controversy of the potential toxicity of their competitors' products. In 1952, Kautz consulted Gamble about a new publicity campaign of Whittaker Laboratories, which advertised their contraceptive jelly as being ‘without mercury’. Gamble this time adopted Laug and Kunze's argument, answering that Whittaker Laboratories' claim was not unfounded: mercury did accumulate in the liver and kidneys.Footnote ¹¹⁰ In his subsequent letters, Kautz agreed with Gamble that the implicit critique of Whittaker Laboratories seemed to be justified, and the producers of contraceptives containing mercury should be advised to study the long-term effects of their products, especially on the kidney.Footnote ¹¹¹ Kautz stressed, however, the difficulty of conducting such studies. Eastman, Kautz reported, initially planned a joint research with Laug and Kunze, using moribund women at Johns Hopkins Hospital. The aim of this study was to examine the possibility of damage to tissues following a vaginal application of phenylmercuric acetate. Eastman abandoned this project, however, when he found that it was very difficult to find ‘normal’ values of mercury in the tissues. He made a preliminary investigation of a patient who had had phenylmercuric acetate jelly instilled in the vagina a few weeks prior to death. When the patient died, Eastman compared her tissues to those of three normal controls (that is, other cadavers). He found that both the controls and the experimental subject had high levels of mercury in their kidneys. Eastman speculated that perhaps the mercury found in the controls came from fillings in their teeth. Eastman was aware of the fact that his sample was much too small to draw definitive conclusions, but he and Dr Lange were worried that they would be unable to find mercury-free controls, and decided to abandon their project.Footnote ¹¹²

The AMA's Advisory Committee on Contraceptives continued to ponder the Whittaker publicity case. Sollman, from the Committee on Pharmaceutical and Chemicals, argued that contraceptives containing mercury should be retired from the market until proven safe. Gamble disagreed. The concentration of mercury in the urine of women who used a contraceptive containing mercury, as Eastman and Scott had found in 1944, was only a fraction of the amount considered to be within the safe limits for industrial workers exposed to mercury. Gamble added that nobody had observed damage to the kidneys or liver in women who used phenylmercuric acetate-based contraceptives.Footnote ¹¹³ Finally, he mentioned the high doses of mercury compounds used, in pre-penicillin days, to treat syphilitic patients. At that time, doctors did not hesitate to inject people weekly with the equivalent of the total absorption of all the mercury found in sixty-five doses of contraceptives containing phenylmercuric acetate.Footnote ¹¹⁴

The Council on Pharmacy and Chemistry remained divided on this issue. Some of its members believed that phenylmercuric acetate might produce long-term risks, others that it was innocuous in the concentrations in which it was used as a contraceptive. The council finally informed Whittaker Laboratories that it considered the advertisement of their product as ‘mercury-free’ to be unfair and unethical and a violation of the council's rules. The council added, however, that the safety of contraceptive products containing mercury was still debatable, and should be settled through a study of the physiological effects of products containing mercury, especially in the kidneys. At the same time, it informed manufacturers of contraceptives containing mercury that it wished to examine the acceptability of phenylmercuric acetate preparations. The council then contacted Eastman, and asked him to investigate the secretory functions of the kidney in at least six women who used contraceptives containing mercury for six to nine months.Footnote ¹¹⁵ Under these conditions, the Eastman study did not find any impairment of kidney functions. Kautz then wrote to Holland Rantos Laboratories, Easton Laboratories and Whittaker Laboratories to inform them that an investigation initiated by the council had shown that contraceptives containing phenylmercuric acetate did not harm the kidney.Footnote ¹¹⁶ In the 1960s, contraceptive preparations containing mercury were, however, gradually phased out. Their abandonment probably reflected a greater awareness of the risks of long-term exposure to low doses of toxic substances, and increased concerns about the safety of pharmaceutical preparations (vaccines, contraceptives) used by healthy people.

‘Real-life contraception’: clinical tests of spermicides

Scientists who studied contraceptives aspired to conduct trials with humans. As one author of a review of laboratory investigations of chemical contraceptives explained, ‘the final test is always made with the anatomy and the secretions present in the vagina’.Footnote ¹¹⁷ The relative abundance of laboratory studies of contraceptive creams and jellies in the interwar era contrasts, however, with the paucity of clinical studies of these compounds. One reason for this might be the birth control activists' strong attachment to the diaphragm-and-jelly method, and their unwillingness to experiment with approaches seen as decidedly inferior.Footnote ¹¹⁸ This strong preference for the diaphragm-and-jelly method persisted even when empirical studies failed to display its decisive advantage.Footnote ¹¹⁹ Another, and probably more important, reason was the practical difficulty of studying the effects of contraceptives in humans. The main source of information on the efficacy of contraceptive methods was retrospective data collected by birth control clinics. However, important differences in the organization of these clinics, their recruitment of users, the information they provided and client turnover produced, unsurprisingly, highly variable results.Footnote ¹²⁰

Prospective clinical studies of contraceptives focused initially on limited, ‘doable’ goals. Some researchers investigated the acceptability of contraceptive preparations by users, as measured for example by the rate of renewal of prescriptions.Footnote ¹²¹ Others observed the behaviour of a chemical contraceptive shortly after the installation of a dose of the tested substance in a women's vagina.Footnote ¹²² Others still were interested in the fate of sperm during sexual intercourse. In the early 1930s, BCIC experts were preoccupied by the possibility that spermatozoids might be sucked very rapidly into the uterine cavity. If this were the case, only a barrier method could prevent conception, and the search for an efficient chemical contraceptive was a wild goose chase. Preliminary studies conducted by Howard Florey and H.M. Carleton in dogs did not show a rapid passage of sperm into the uterus.Footnote ¹²³ Florey and Carleton nevertheless stressed that observations made in an animal model needed to be confirmed in a clinical experiment.Footnote ¹²⁴ In 1932, the BCIC outlined a project for such an experiment. In the proposed schema, a woman would be asked to introduce barium (a radio-opaque substance) into her vagina just before an ‘experimental coitus’ – a sexual relation with her husband – and then visit a radiology clinic for a rapid radiography of the uterus. The husband would be asked to make a special effort to produce an orgasm, because it might favour the suction of sperm into the uterine cavity. The document added that volunteers for this experiment should be recruited among people personally known to the committee members, and should be carefully selected and instructed.Footnote ¹²⁵

It is not clear whether the planned experiment ever took place, but in 1935, when the BCIC enthusiastically supported Volpar, its members did not any longer seem to be concerned by possible physiological obstacles to the use of chemical contraceptives. At that time, some birth control activists were, however, preoccupied by the possibility that chemical contraceptives induced cancer. The North Kensington Birth Control Clinics proposed a case control study on the frequency of cervical malignancies in women who used chemical contraceptives, and a systematic interrogation of women treated for cervical cancer at the Marie Curie Clinic and at London Hospital about their contraceptive practices.Footnote ¹²⁶

Investigations of the acceptability, safety and short-term behaviour of contraceptives, however important, could not replace prospective studies of their capacity to prevent unwanted pregnancy. This was, however, a difficult task. It was necessary to recruit a large number of participants, follow them for several years, and collect reliable data on the way they used the tested method. The latter point was seen as especially problematic because, as John Baker put it, ‘one can never be certain that a product is used in the right way’.Footnote ¹²⁷ An additional obstacle was the users' tendency to abandon rapidly contraceptive methods they did not like.Footnote ¹²⁸ The statistician Raymond Pearl proposed overcoming this difficulty by calculating the number of ‘months of successful use’, an approach which allowed taking into account not only ‘faithful contraceptors’ but also women who switched to a different method after several months.Footnote ¹²⁹ Hannah Stone, of Sander's Birth Control Clinical Research Bureau, applied Pearl's method in her pioneering study of foam powders, which showed that when used regularly this contraceptive method was reasonably efficient.Footnote ¹³⁰

All the clinical investigations of chemical contraceptives conducted in the 1940s adopted a calculus of ‘months of successful use’. These studies confirmed that a regular use of chemical contraceptives reduced fertility. They also indicated that the theoretical advantages of the combination of diaphragm and spermicide were often nullified in practice by the difficulty of correctly applying this method of birth control.Footnote ¹³¹ The latter conclusion needed, however, to be verified in large-scale clinical trials. Participants in such trials were as a rule recruited among clients of birth control clinics, thus among poorer and less-educated women, seen by the researchers as less trustworthy and less apt to use contraceptives correctly.Footnote ¹³²

A study of the clinical efficacy of contraceptive suppositories, conducted by Gamble and the NCMH's statistician, Christopher Tietze, illustrates the latter point. This investigation recruited women from impoverished rural areas in Alabama. The decision to carry out an investigation in this setting, Gamble and Tietze explained later, was a mistake. It was impossible to trust information supplied by women who participated in this trial. They provided inaccurate data about their sexual history, sex life and use of contraceptives. Women who did not get pregnant claimed that they used the contraceptive suppositories as instructed, but, after pregnancy occurred, admitted irregular use in two cases out of three. The trial was condemned to failure, Gamble and Tietze concluded, because the population they studied was ‘backward, poorly educated, shiftless, and irresponsible’.Footnote ¹³³

The most ambitious large-scale clinical trial of chemical contraceptives was organized in the late 1950s and early 1960s by Mary Steichen Calderone, the medical director of the Planned Parenthood Federation of America (PPFA).Footnote ¹³⁴ Claderone wished to show that ‘simple contraceptives’ could be efficient, and that women of all social strata could learn how to control their fertility. The Clinical Investigation Program (CIP), coordinated by Calderone, was conducted in numerous PPFA-affiliated clinics. Its goal, Calderone explained, was to rate methods and not products.Footnote ¹³⁵ The CIP – planned and supervised by the NCMH's statisticians Christopher Tietze and Sarah Levitt – put a strong accent on the correct methodology of clinical trials, especially on randomization, an element entirely absent from earlier clinical trials of contraceptives.Footnote ¹³⁶ Another important innovation was direct collaboration with pharmaceutical laboratories that supplied the tested products. In spite of the careful preparation of this clinical trial, birth control centres which participated in the CIP systematically reported difficulties in ascertaining that women who participated in this trial used the prescribed method in a consistent way and provided accurate data on protected and unprotected sexual intercourse.Footnote ¹³⁷ Calderone's conclusion was that the CIP did confirm that a chemical contraceptive alone ranked just below the barrier method plus spermicide, and that ‘the best method for the patients is the one the patient will use consistently’.Footnote ¹³⁸ The CIP's results were, however, imperfect. It was difficult to align the criteria of recruitment and follow up on participants and obtain statistically valid data. Another major obstacle was the unfortunate timing of this clinical experiment. In the late 1950s and early 1960s patients enrolled in the CIP became increasingly tempted by a new, simple and efficient birth control method – the Pill.Footnote ¹³⁹

The results of Tietze and Calderone's trial of chemical contraceptives illustrate the major difficulty of clinical trials of contraceptives generally: the ultimate impossibility of dissociating failure due to insufficient protection provided by a given contraceptive product from that due to its inappropriate use. With the advent of highly efficient contraceptives – the Pill and intrauterine devices (the IUD was developed in the early twentieth century but was adapted to general use only in the 1960s) – researchers who studied contraception were able to focus on a single group of variables: those related to imperfect use of contraceptive methods.Footnote ¹⁴⁰

Conclusion: innovation at the margins

The history of non-hormonal contraceptive preparations did not end in the 1960s. Some women were unable to use hormonal contraception or the IUD for medical reasons, others were dissatisfied with these methods, still others resisted the perceived over-medicalization of reproduction and the exclusive focus on physician-controlled contraceptives.Footnote ¹⁴¹ Earlier contraceptive methods, such as spermicides, continue to coexist with newer approaches, but are often perceived as inefficient, clumsy, bothersome and old-fashioned. The introduction of a more efficient family of spermicides, the surfactants, in the 1970s failed to improve the status of these preparations in Western countries.Footnote ¹⁴²

Nevertheless, the AIDS epidemic led to a renewal of interest in spermicides. In the absence of an anti-HIV vaccine, the prevention of AIDS was mainly based on the diffusion of condoms. Exclusive reliance on a male-controlled device might, however, be dangerous for many women. From the early 1990s on, groups affiliated with the US Women's Health Movement promoted the search for a ‘simple microbicide’ – a substance which, when applied to the vagina before sexual intercourse, will reduce rates of HIV infection in women. At first, activists and scientists hoped that spermicides already in use would also prevent the transmission of AIDS. These hopes were disappointed. Today, the search for an efficient microbicide is hampered by obstacles akin to those encountered by scientists who attempted to develop chemical contraceptives in the first half of the twentieth century: insufficient understanding of the physiology of female reproductive organs, discrepancies between results obtained in test tube and field trials, and the difficulty of standardizing human sexual practices.Footnote ¹⁴³ On the other hand, studies of microbicides are radically different from those of spermicides. In the twenty-first century, a drug can obtain a marketing permit only if its manufacturer proves its safety and efficacy in laboratory studies and clinical trials. This paper displays the links between this (today self-evident) rule and efforts to transform chemical contraceptives into respectable mainstream drugs.

As Trevor Pinch, Harry Collins and Ian Hacking have proposed, methodological innovations may stem from an aspiration to legitimate science at the margins.Footnote ¹⁴⁴ Standardized tests of spermicidal activity of contraceptive preparations were among the first efforts to control the efficacy of pharmaceuticals; negotiations between the BCIC, the NBCA and British Drug Houses were an early attempt to lay down rules of collaboration between non-profit organizations and the pharmaceutical industry; and interrogations about the safety of contraceptives containing mercury were among the first attempts to study the long-term toxicity of low doses of dangerous chemical products. The ‘smelly and sticky’ decoctions of the contraceptionist, initially associated with quack medicine and lax sexual mores, helped to shape the present-day manufacture and regulation of pharmaceuticals. These substances brought with them a complex legacy: of doubtful products and rigorous scientific investigations, shady commercial strategies and progressive aspirations, a striving for purification and simplification and the unavoidable messiness of real-life sexuality, science and politics.