How an 18th century instrument maker may have inspired the first clinical trial of the modern age

CNN — The first controlled clinical trial recorded in the modern age, carried out in 1747 to test treatments for scurvy, may have drawn inspiration from the nephew of Sir Isaac Newton's laboratory assistant, according to new research.

Today, clinical trials are an essential part of medical research that can lead to crucial advances, but this type of systematic study comparing treatments to assess which is most effective hasn't always been standard scientific protocol.

Things changed when Royal Navy surgeon James Lind set out to see what could be used to treat scurvy, the scourge of sailors for thousands of years.

But a new analysis of an 18th century study by Francis Hauksbee the Younger, just four years before Lind's controlled trial, suggests that Hauksbee laid out an approach to how one should execute a controlled trial. The design of his study likely sparked Lind's pivotal research that identified oranges and lemons (and ultimately, vitamin C) as a cure for scurvy.

The new paper, published Jan. 7 in "Notes and Records: The Royal Society Journal of the History of Science," sheds light on early clinical trials that pushed for a more critical, open-minded approach to testing medicine, as well as how such trials have evolved over time.

"When one examines old medical books it is common to read claims from doctors that their own treatments can cure every disease under the sun and without any side effects, despite often using chemicals like mercury," said lead study author Dr. Max Cooper, senior lecturer in primary care and public health at England's Brighton and Sussex Medical School, in an email.

"When stumbling upon Hauksbee's writing, I was immediately struck by his scientific open-mindedness in calling for evidence both 'for and against' his drug. To say that about one's own medication was very unusual."

Designing a 'decisive experiment'

Hauksbee isn't a well-known figure from history, and even when he was alive, he was confused with his namesake and uncle, Francis Hauksbee the Elder, who served as an inventive lab assistant for Newton, the polymath and pioneering scientist, at the Royal Society, the United Kingdom's national academy of sciences.

Hauksbee the Younger was an instrument maker and science lecturer who became the society's housekeeper and clerk. And while he was never a physician himself, he created a new medicine for genital discharge, referred to in his study as venereal disease.

The London medical community wouldn't consider Hauksbee's treatment, or support the prescription of his treatment, largely because he wasn't a physician, Cooper said. Instead, Hauksbee was hit with allegations of "quackery."

In the 18th century, for many physicians who typically formulated their own medicines, it would have been highly unusual to prescribe someone else's treatment, Cooper said.

"Because patients were paying physicians directly for their services, treatment choice was (personalized) to the individual," Cooper said in an email. "Professional reputation was key for sustaining physicians' livelihood. In essence, money and reputation came ahead of making a fair comparison of different treatments."

Hauksbee set out to compare different drug treatments for venereal disease, including his own medication, in a proposal he called "Experimentum Crucis," which is Latin for "decisive experiment." Hauksbee wrote that he himself had been inspired by the methods of English physician James Jurin, who in the 1720s published outcomes of inoculating people against smallpox, a precursor to smallpox vaccination.

Jurin compiled reports from those who were inoculated, then calculated the risk of dying from the practice, said Dr. Andrea Rusnock, a professor in the department of history at the University of Rhode Island. Rusnock was not involved in the new research. Jurin then compared the level of risk with the larger risk of dying from contracting actual smallpox and found that inoculation was safer.

Hauksbee laid out a practical 10-step approach to the research. The study proposal called for 12 patients. Half of the participants would receive Hauksbee's medication, while the others would receive treatments from other doctors, Cooper said.

Hauksbee wanted to record the outcomes of the patients and have them independently assessed, and then share the findings for all 12 patients with the public. He also believed it was important to focus on a "lasting cure" by following the patients' long-term clinical outcomes, Cooper said. Additionally, Hauksbee's proposal considers the patients' diets and accommodations throughout the study.

"The key similarity with modern drug trials lies in the fundamental importance of comparing one treatment against another," Cooper said. "Before people like Hauksbee and Lind, most drug 'trials' simply involved giving the treatment to as many patients as possible and seeing what happened. The lesson of Hauksbee and Lind is the need for a comparison of treatments that is as fair as possible."

Seeking a solution to scurvy

There is no evidence to suggest that Hauksbee's study ever took place, according to the new research.

The London medical faculty had no interest in pursuing such a study from a nonphysician, and at the time, it was thought best that patients with venereal disease "should refrain from public inspection," Cooper said.

But Hauksbee's study proposal was published in 1743, and it happened to be on a topic of Lind's interest: venereal disease. Lind wrote his doctor of medicine thesis in 1747 on the same topic, according to the new research. To do so, Lind must have read extensively on the subject, Cooper said.

Then, Lind pursued his trial of scurvy treatments. On May 20, 1747, Lind assessed a dozen patients with scurvy aboard the Royal Navy ship HMS Salisbury while at sea. All 12 patients were in the same part of the ship and shared a common diet. He divided the patients up into six pairs and gave each a different treatment to see if "cyder," vinegar, seawater, oranges and lemons, or an electuary (a medicine mixed with honey or syrup) could be effective against scurvy.

After six days, Lind observed that the "most sudden and visible good effects were perceived from the use of the oranges and lemons."

Both Hauksbee's and Lind's studies included 12 participants and considered the patients' diet and accommodation, Cooper said.

Alisha Rankin, department chair and professor of history at Tufts University, believes the new study "adds to the substantial body of research conducted over the last decade revealing that healers were thinking about how to test drugs long before the modern period." Rankin was not involved in the new study.

"What I found particularly interesting in this article was the convincing theory that Hauksbee's trials served as a model for Lind," said Rankin. "It shows that Lind's experiments were part of a broader conversation about testing medicines at the time, and it adds to the evidence that practitioners derided as 'quacks' actually had an enormous role in shaping experimental thinking in (those times)."

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