Perspective
History of Clinical Trials
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- Clinical trials are such an integral part of contemporary medicine that we tend to think of them as products of our own modern age. Yet more than 400 years ago, clinical trials already played a substantial role in mediating the relationships among the state, the drug market, and consumers. An examination of the use of clinical trials as a tool for the marketing and licensing of drugs in Europe from the 16th through the 18th centuries reveals a surprising history of governmental involvement in the certification of promising therapeutics.
Most drugs sold in early modern European pharmacies did not undergo rigorous testing. But medicaments sold outside of pharmacies by unlicensed “empirics” — who sometimes received official permission to sell a particular drug — required greater scrutiny. By the 1500s, Spain and Italy had well-established processes whereby empirics could obtain special drug licenses. Although other regions took longer to establish official practices, trials became an important tool in obtaining government support.
In 1580, for example, a miner named Andreas Berthold (d. 1610) traveled around Germany to advertise a wonder drug and poison antidote called Silesian terra sigillata, made from a special clay that was dug from hills outside the town of Striga (now Strzegom, Poland) and processed into small tablets (see imagesSilesian Terra Sigillata.). Like many antidotes, it was touted as a panacea, effective against every type of poison as well as several diseases, including plague. Striga’s town physician, Johannes Montanus (1531–1604), had allegedly discovered the drug, but Berthold became its main salesman and public spokesman. Rather than simply making claims regarding the drug’s efficacy, he invited authorities to test it themselves.
In three prominent cases, physicians, princes, and town leaders conducted trials involving poisoned test subjects. The mayor of Jülich, Germany, staged a small trial in which he gave one dog a strong dose of poison followed by the antidote and another dog the poison alone. The first dog lived; the second died. Wilhelm IV, prince of Hesse-Kassel (1532–1592), had his physicians conduct a similar trial of Berthold’s drug in eight dogs, using four different poisons. Only half the dogs received the antidote, and they all survived. The other dogs died in great agony — except for one, which recovered after the prince took pity on it and offered a half dose of the drug. After these resounding successes, another prince, Wolfgang II of Hohenlohe (1546–1610), had his physicians test Silesian terra sigillata on a condemned criminal in 1581, to see if it “works on humans as well as it works on animals.” The prisoner survived, providing further evidence of efficacy.
All three rulers provided Berthold with official testimonials about the trials, signed and sealed, confirming the drug’s success. Berthold appended these letters to a book he published on the virtues of the drug, which was translated into English in 1587.1,2
Although they were not licenses, the official approvals of these respected political leaders boosted Berthold’s fame and the reputation of Silesian terra sigillata, which was eventually sold in pharmacies from Nuremberg to London. Yet Berthold lost his ability to market the drug in the late 1580s, after Emperor Rudolf II gave the town of Striga exclusive license to sell it and Montanus discredited Berthold in published works. The trials had thus contributed to the creation of a monopoly, but not the one Berthold had intended.3
Poison-antidote trials provide some of the most dramatic examples of a broader trend in medical knowledge and the regulation of drug markets. Beginning in the late 1600s, the Bourbon kings of France regularly granted monopoly privileges to the inventors of new pharmaceutical preparations. Many applicants submitted their “secret remedies” to the king’s personal physician or other royal practitioners for approval, sometimes including evidence from hospital trials. If successful, the applicant could receive royal “letters patent” or “brevets” that provided for a legal monopoly throughout the kingdom of France and imposed substantial fines for counterfeiters. Good connections at Versailles were often a critical asset in securing a monopoly.
In a premodern parallel to concerns over collusion between political elites and today’s pharmaceutical industry, one royal physician, Claude Jean-Baptiste Dodart (1664–1730), felt pressured to recommend privileges for the medical favorites of powerful officials and members of the royal family. In 1728, Dodart decided to share the responsibility of evaluating new drugs with an expert committee of physicians, surgeons, and apothecaries. The committee was tasked with assessing whether drugs were truly novel, and it screened for thinly disguised variants of drugs already in the “public domain” of the pharmacopoeias (the “me-too” drugs of the 18th century). Dodart’s reforms did not last long, however. One of his successors, the royal physician Jean-Baptiste Sénac (1693–1770), was widely believed to approve drugs in exchange for money, regardless of the opinions of the commissioners.4
The testing of drugs to support the granting of monopoly privileges was sometimes closely linked to military procurement. State officials recognized that diseases — typhus, typhoid fever, malaria, and dysentery — often killed more soldiers and sailors than did actual combat, and they looked to civilian contractors to supply them with critical drugs.
Among the most famous drugs to be tested for both monopoly privilege and military use in 17th-century France was the dysentery remedy of the Dutch-born physician Adrien Helvétius (1662–1727). The drug’s principal ingredient was ground ipecacuanha root (ipecac) from Brazil. It was prepared using Helvétius’s secret technique to moderate its powerful emetic properties so that it would pass into the digestive tract, where its “specific virtue” could act against dysentery. To guarantee the efficacy of the drug, Louis XIV’s naval secretary ordered Helvétius to undertake trials in Parisian hospitals under the supervision of two practitioners from the royal household. The hospitals were not necessarily interested in cooperating with ambitious medical entrepreneurs, however, and Helvétius faced resistance from the spiritual director and nursing sisters when he tried to remove four men from the Hôtel-Dieu in order to isolate and better supervise the trial at a private residence. He turned to his royal patrons to expedite matters, and they ordered the hospital to accede to the king’s wishes and comply with Helvétius. The trial was successful, and in 1688 Helvétius was granted a legal monopoly over the production and sale of his drug.5 Similar military-led efforts were undertaken in the Holy Roman Empire, and the English navy famously tested remedies for scurvy in the 18th century.
Research has demonstrated that successful trials — supervised by practitioners close to the monarch and conducted in animals as well as in human patients — furnished critical evidence for officials who granted pharmaceutical monopolies between 1500 and 1800. The application and testing processes remained enmeshed, however, in the overarching structures of patronage and power that governed early modern states.
Today, our understanding of pharmaceutical intellectual property tends to start with the patent as conceived from the 1790s onward. Before that point, monopolies on a given drug’s sale were granted as a gift from the monarch rather than being a right of the entrepreneur. By the end of the Enlightenment, new liberal notions of intellectual property would redefine citizen-inventors’ ability to profit by their inventions as a right rather than a privilege. Such new beliefs would also demand public disclosure of knowledge, time limits on monopolies, and their management through government patent offices. But the older, absolutist form of intellectual property had already mobilized pharmaceutical trials in relation to state-sanctioned monopolies.Disclosure forms provided by the authors are available at NEJM.org.
Source Information
From the Department of History, Tufts University, Medford, MA (A.R.); and the Department of the History of Medicine, Johns Hopkins University School of Medicine, Baltimore (J.R.).
