How Were the First Licensed Medicines Developed? Early Clinical Trials

Clinical trials are an integral part of contemporary medicine, so we tend to think of them as products of the modern age. Yet clinical trials 400 years ago played an important mediating role in regulating relationships between governments, the pharmaceutical market, and consumers. Many will be surprised to learn that the use of clinical trials in drug marketing and licensing, and government involvement in regulating these processes, dates back to the 16th century.

Most medicines sold in European pharmacies in the early modern period did not undergo rigorous testing. Unlicensed medicines sold outside pharmacies by healers whom some called charlatans—people who sometimes obtained official permission to sell a particular remedy—required even closer scrutiny. By the 1500s, Spain and Italy had established procedures that healers had to complete to obtain special medicine licenses. In other regions, official procedures took longer to develop, making clinical trials an important tool for securing government support.

For example, in 1580 a miner named Andreas Berthold (d. 1610) traveled throughout Germany to promote Silesian terra sigillata as a miracle medicine and antidote. It was made from special clay from the hills of Striga (now Strzegom, Poland) and formed into small tablets. Like many antidotes, it was marketed as a “cure-all,” effective against every poison and several diseases, including plague. Although the town physician of Striga, Johannes Montanus (1531–1604), was said to have discovered it, Berthold became its principal seller and public spokesman. Instead of merely making claims about its effectiveness, Berthold invited authorities to test it themselves.

Physicians, princes, and town leaders conducted three important trials involving poisoned subjects. The mayor of Jülich, Germany, carried out a small experiment, giving a high dose of poison and the antidote to one dog and poison alone to another. The first dog lived; the second died. Prince Wilhelm IV of Hesse-Kassel (1532–1592) ordered his physicians to test Berthold’s medicine using eight dogs and 4 different poisons.

Only half the dogs received the antidote, and all those given it survived. The other half died in great suffering, apart from a dog that recovered after the prince took pity on it and gave it half a dose of the antidote. Following this resounding success, Prince Wolfgang II of Hohenlohe (1546–1610) ordered his physicians in 1581 to test Silesian terra sigillata on a convicted prisoner to see whether it was “as effective in humans as in animals.” The prisoner survived, providing further evidence of the medicine’s effectiveness.

The directors of these three trials supplied Berthold with signed, sealed official testimonials confirming the remedy’s effectiveness. He included these letters in his book describing its virtues, which was translated into English in 1587.

Although they were not licenses, endorsements from these respected political leaders enhanced the reputations of Berthold and Silesian terra sigillata, already sold in pharmacies from Nuremberg to London. However, after Emperor Rudolf II granted Striga an exclusive license to sell the remedy in the late 1580s, Berthold lost the right to market it, and Montanus undermined his credibility in published works. Although not as Berthold had intended, the trials helped establish a monopoly market.

Antidote trials are prominent examples of the growing trend toward regulating medical knowledge and pharmaceutical markets. In late-1600s France, the Bourbon royal family regularly granted monopoly privileges to inventors of new medicinal compounds. Many applicants submitted their “secret remedies,” sometimes accompanied by clinical trial evidence, to the king’s personal physician or other members of the royal household for approval. Successful applicants could receive royal “letters patent” or a “certificate of promotion,” providing a legal monopoly throughout the kingdom of France and imposing substantial penalties on counterfeiters. Good connections at Versailles were often essential to enforcing the monopoly.

Paralleling today’s concerns about collusion between premodern political elites and the pharmaceutical industry, a royal physician named Claude Jean-Baptiste Dodart (1664–1730) felt pressured to favor the medical favorites of powerful officials and royal family members. In 1728, Dodart decided to share responsibility for assessing new medicines with an expert committee of physicians, surgeons, and pharmacists. Its task was to determine whether medicines were genuinely new and identify disguised remedies already present in pharmacopoeias as “public property”—the generic medicines of the 18th century. Dodart’s reforms did not last long, however. One successor, the royal physician Jean-Baptiste Sénac (1693–1770), was believed to approve medicines for payment without considering the commissioners’ opinions.

Medicine testing carried out to support grants of monopoly privileges was sometimes closely connected with military procurement. State authorities recognized that diseases such as typhus, typhoid, malaria, and dysentery cost more soldiers and sailors their lives than actual fighting. They therefore needed contractors who could provide critical medicines.

The most famous medicine tested in 17th-century France for both monopoly privileges and military use was the dysentery remedy of the German-born physician Adrien Helvétius (1662–1727). Its main ingredient was ipecacuanha (ipecac) roots from Brazil. Helvétius’s secret preparation technique reduced the raw material’s powerful emetic properties, allowing the medicine to reach the digestive tract and exert its “specific effect” against dysentery there. To establish its effectiveness, Louis XIV’s secretary of the navy ordered Helvétius to test it in Paris hospitals under the supervision of two practitioners from the royal household. Hospitals, however, were reluctant to cooperate with ambitious medical entrepreneurs. When Helvétius tried to remove four men from the Hôtel-Dieu to conduct the trial more effectively on his private property and isolate the subjects, he met resistance from the hospital’s religious director and nursing staff. To avoid further delay, Helvétius appealed to his royal patrons, who ordered the hospital to submit to the king’s commands and comply with his wishes. The research succeeded, and in 1688 Helvétius obtained a legal monopoly on making and selling his medicine. British naval trials of remedies for scurvy in the 18th century were also among studies encouraged by the military.

Research has shown that successful animal and human trials conducted under practitioners close to the royal family provided important evidence for authorities granting pharmaceutical monopolies during 1500–1800. However, application and testing procedures in early modern towns governed by extensive patronage networks and power remain unclear.

Intellectual property rights in today’s pharmaceutical market began with patents continuing from 1790 onward. Before then, monopoly rights permitting the sale of a particular medicine were granted as gifts from royalty rather than as an entrepreneur’s right. Toward the end of the Enlightenment, new liberal ideas about intellectual property saw urban entrepreneurs’ ability to profit from their inventions as a right rather than a privilege. Such new beliefs required public disclosure of knowledge, time limits on monopolies, and administration by government patent offices. Yet the older absolutist form of intellectual property already had medicine trials mobilized around state-approved monopolies.