Why ICH Exists – How Global Rules Changed Clinical Trials

In 1937, Frances Oldham Kelsey began her PhD in pharmacology at the University of Chicago, joining as the first student under Dr. Eugene Geiling, a new recruit from Johns Hopkins.

Soon after she arrived, a national health crisis unfolded. A medicine called Elixir Sulfanilamide, commonly used for infections, had caused over 100 deaths—including many children. The drug had been mixed with diethylene glycol, a toxic solvent that hadn’t been tested for safety.

Frances joined a research team led by Geiling to help investigate what had gone wrong. It was her first real exposure to the consequences of weak drug regulation, and it left a lasting impression. The case helped bring about a new U.S. law requiring drug safety testing before approval.

She stayed at the university during World War II to study antimalarials and later earned a medical degree. After a brief stint at the Journal of the American Medical Association, she was invited once again by Geiling—now at the FDA—to join a new pharmacology review team.

In 1960, just weeks into her role at the FDA, Dr. Frances Kelsey received a new drug application that, at first glance, looked like a simple review. The drug was already in use overseas promoted as a sleeping aid and widely praised for easing morning sickness in pregnant women. The company expected a swift approval. For many, it would have been a rubber stamp.

But for Kelsey, it felt too perfect. The submission was filled with glowing testimonials but lacked clear, clinical evidence. The praise seemed to outshine the science. With a PhD in pharmacology and a medical degree, Kelsey was trained to notice what others missed—and something about this application didn’t sit right.

To be sure, she asked her husband, Dr. Ellis Kelsey, a pharmacologist at the NIH, to take a look. His reaction reinforced her instinct. One testimonial stood out for all the wrong reasons: it claimed the drug had no known lethal dose. That alone was enough to raise serious doubts. Even food, when consumed in excess, can become toxic. A compound with zero toxicity at any dose? That wasn’t science—it was salesmanship.

And beneath that statement lay something bigger: the unsettling ease with which power, influence, and money can shape medical narratives. But Kelsey wasn’t moved by pressure. She was moved by evidence—and this application didn’t have it.

Not long after reviewing the application, a letter in the British Medical Journal caught Dr. Kelsey’s attention. It described cases of peripheral neuritis—nerve damage in the hands and feet—in patients who had taken the drug. The report was clinical, brief, but deeply concerning. And it wasn’t isolated. Other physicians in Europe and Australia had begun publishing similar warnings, pointing to subtle but consistent signs that something wasn’t right.

Kelsey reviewed the drug file again. Nowhere had the company mentioned this risk. She formally wrote to the manufacturer, stating what should have been obvious:

“The burden of proof that the drug is safe … lies with the applicant.”

Instead of answering her concerns, the company reached out to her supervisor, Dr. Ralph Smith, hoping to apply pressure from above. But Smith stood firmly behind her. He trusted her judgment.

Kelsey escalated the review. She asked for evidence of the drug’s effects on pregnancy—even though no birth defects had yet been reported in the U.S. Her questions were precise, professional, and inconvenient. The company responded by resubmitting the application again. And again. Four times in total, each without the answers she needed.

On the fifth attempt, as global concern grew louder, the application was withdrawn.

Within weeks, the headlines broke. Across Europe and Australia, infants were being born with severe birth deformities. The drug—now internationally suspended—was confirmed as the cause. Over 10,000 children had been affected worldwide.

In the United States, the damage was narrowly avoided. A few cases did occur—linked to early sample use—but widespread tragedy was prevented. The reason: one reviewer who refused to rush, overlook, or stay silent.

The drug’s name was thalidomide.

Frances O. Kelsey receives the President’s Award for Distinguished Federal Civilian Service from President John F. Kennedy, 1962.
*National Library of Medicine, Images from the History of Medicine, A018057.*

Her story didn’t just shape the thalidomide outcome—it helped define the very rules of drug approval in the U.S.

Back in 1937, as a graduate student, she had witnessed firsthand the tragedy of Elixir Sulfanilamide and contributed to the scientific investigation that pushed Congress to pass the 1938 Food, Drug, and Cosmetic Act—the first law requiring proof of safety before a drug could be sold.

Nearly 25 years later, she found herself on the front lines again. This time, her refusal to approve a poorly tested drug in 1961 directly influenced public and political pressure to strengthen oversight even further. Her determination and scientific integrity helped pave the way for the 1962 Kefauver-Harris Amendments, which added a critical new requirement: drug companies now had to prove that a drug not only was safe, but also worked.

While Dr. Kelsey’s decisions shielded the U.S. from widespread harm, families elsewhere were living a different reality. In the United Kingdom, Mikey Argy was born in 1962 with limb differences caused by thalidomide—one of thousands affected. In the 1980s and 1990s, she became one of the most recognized voices for survivors. Through her advocacy, interviews, and public campaigns, she gave shape to stories that had been buried under decades of silence.

Her work brought long-overdue recognition and support to victims. In 2015, she was appointed a Member of the Order of the British Empire (MBE) for her services to thalidomide survivors—an acknowledgment of both her persistence and impact.

This wasn’t just a medical failure—it was a human one. And it forced regulators around the world to ask a question that still echoes today:

How do we make sure this never happens again—not just here, but anywhere?

The moral urgency of thalidomide sparked action—but not without consequences. Before nations came together in a coordinated effort, there was a long stretch of cautious and often fragmented responses. Countries began tightening their drug regulations, adding new requirements for toxicology, preclinical trials, and proof of both safety and efficacy before human use.

While these changes were necessary, they came with side effects of their own.

The cost of drug development soared. According to data compiled by William M. Wardell in Annals of Internal Medicine, the number of New Chemical Entities (NCEs) entering human testing in the U.S. dropped from an average of 89 per year between 1958–1962 to just 17 per year between 1975–1979—an 81% decline.¹ In the UK, new drug introductions fell threefold between 1960–61 and 1966–70. The U.S. Office of Technology Assessment later concluded that nearly half of the decline in new drug introductions was a direct result of the post-thalidomide regulatory tightening.²

These weren’t just bureaucratic delays—they affected access, pricing, and patient care. Pharmaceutical companies, faced with rising research costs, passed the burden on to health systems and patients alike.

Regulators around the world took notice and responded. In the UK, the Committee on Safety of Drugs was established in 1963, a body that would eventually evolve into today’s Medicines and Healthcare products Regulatory Agency (MHRA). In Europe, the European Economic Community (EEC) introduced Directive 65/65/EEC, laying the groundwork for what would become the European Medicines Agency (EMA). Japan overhauled its Pharmaceutical Affairs Law, and both Canada and Australia strengthened their review and approval processes.

Each country was acting with urgency, but often in isolation—crafting solutions tailored to their own national frameworks. These efforts, while well-intentioned, exposed a new challenge: global medicine needed global standards. Without them, drug development became fragmented, duplicative, and prohibitively expensive. The world was beginning to see that safety wasn’t just a national concern. It was international.

The turning point came in 1989. At the WHO’s International Conference of Drug Regulatory Authorities (ICDRA) in Paris, leaders from Europe, Japan, and the United States sat down with representatives from the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). The setting was formal—but the message was urgent. After decades of fragmented efforts, all parties acknowledged the same truth: the global system wasn’t working.³ Redundant studies, inconsistent standards, and rising costs were holding back innovation—and patient access.

It was at this meeting that the idea of a joint regulatory–industry platform truly took shape. While the meeting’s official minutes remain unavailable, the International Council for Harmonisation (ICH) confirms that what followed was historic: in April 1990, at a follow-up conference hosted by EFPIA in Brussels, the ICH was formally launched.⁴

The goal was bold but simple—to bring the scientific and technical requirements of drug approval into alignment across major markets. What began as a coordinated response to tragedy became one of the most important partnerships in public health history.

📘 Also Read: How ICH Was Formed (Blog 2) | Understanding the Purpose and Structure of ICH (Blog 3)

🧭 Coming Up Next: ICH: The People Behind the Process – Roles That Drive Harmonisation (Blog 4) – coming soon.

Wardell, William M. “New Drug Regulation: Cost and Benefit Tradeoffs.” Annals of Internal Medicine 84, no. 4 (1976): 534–538
U.S. Congress, Office of Technology Assessment. Pharmaceutical R&D: Costs, Risks and Rewards. OTA-H-522. Washington, DC: U.S. Government Printing Office, February 1993.
European Federation of Pharmaceutical Industries and Associations (EFPIA). The Pharmaceutical Industry in Figures. 2023.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). About ICH – History. Accessed May 7, 2025. https://www.ich.org/page/history

Why ICH Exists – The Story Behind Global Harmonization

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