Case Study: Thalidomide
On Christmas Day, 1956, a little girl was born without ears in Germany. In the months prior to her birth, her father, an employee of Chemie Grünenthal, had given his wife samples of the “first safe sleeping pill” to help relieve morning sickness.¹⁰²  The bellwether birth signaled the beginning of what would become thousands of children congenitally malformed as a result of their mothers’ ingestion of thalidomide while pregnant.¹⁰³ The devastation and subsequent removal of thalidomide from the market prompted reforms in the way drugs are determined to be safe and effective, and approved for marketing in North America and elsewhere in the world.

The Impact of Thalidomide on Canadian and US Drug Regulation
Thalidomide received market approval in Canada in 1960 for sleeplessness and morning sickness. The greatest exposure to patients resulted from free (unsolicited) samples being resold by doctors to wholesalers, pharmacists, and others.¹⁰⁴ After evidence came to light of its teratogenic effects and the drug’s removal from the market, the Canadian government requested the Royal College of Physicians and Surgeons to appoint a special committee to review procedures for new drugs under the Food and Drugs Act.¹⁰⁵ As a result of the review, legislation was introduced that enabled Health Canada to make laws governing the distribution of drug samples, the prohibition of drug sales, the testing of new drugs, and the sales of new drugs.¹⁰⁶ Food and Drug Regulations were overhauled including¹⁰⁷:

• A mandate requiring manufacturers to produce substantial evidence of the clinical effectiveness of a drug (including case reports and in vitro studies)
• An amendment to discourage unsolicited sampling and track sample distribution

The aforementioned revisions to the Food and Drugs Act and the Food and Drug Regulations remain largely intact.

At approximately the same time, Dr. Frances Oldham Kelsey, a Canadian physician and pharmacologist trained at McGill and the University of Chicago, was beginning a new job at the US Food and Drug Administration (FDA) where she reviewed applications by companies seeking license to market new drugs.¹⁰⁸ She was not convinced by the safety data put forth in an application for the approval of a new sedative called Kevadon, also known as thalidomide. She did not approve the application. Her persistence for adequate safety data, and unwillingness to bend to corporate pressure, combined with the mounting evidence of the teratogenic effects of thalidomide on fetuses, prompted sweeping drug approval process revisions within the US FDA. Similar to the processes expanding the regulatory authority of Health Canada, legislation was introduced to expand the FDA. The 1962 Kefauver-Harris Amendments to the 1938 Food, Drug, and Cosmetic Act required more transparency in clinical trial design, continuous monitoring and reporting of ongoing clinical trials, and tighter tracking of drug distribution.¹⁰⁹ Additionally, the amendments required that manufacturers must prove the safety and efficacy of a new drug and an FDA approval was required before a drug could be marketed.¹¹⁰

A New Legacy
Although thalidomide was removed from the market worldwide, researchers continued to investigate its effects. It has subsequently been approved in the United States to treat inflammations associated with leprosy, AIDS-related wasting and throat ulcers, and multiple myeloma.

As a chemotherapeutic agent for multiple myeloma, thalidomide is marketed under the trade name Thalomid®. It was reintroduced to the US market with multiple layers of precautionary measures to prevent fetal exposure:

• It is available only through a Risk Evaluation and Mitigation Strategy (REMS) Program that requires patients to comply with guidelines and restricts distribution except through certified pharmacies
• Females of reproductive potential must commit to abstain from heterosexual sex, or use two forms of birth control 4 weeks before, during, and 4 weeks after treatment
• Females must take pregnancy tests before and during treatment
• Males must commit to condom use before, during, and after treatment, and are prohibited from donating sperm
• Anyone receiving treatment may not donate blood during, and within one month following, treatment¹¹¹

Summary
In the treatment of multiple myeloma, thalidomide, added to another chemotherapeutic agent, dexamethasone, significantly improved response rates and significantly delayed time to progression in patients.¹¹² The legacy of thalidomide is complicated. However, its failures in part, brought about safer drug approval processes in North America and in doing so, have paved the way for success when used in appropriate patients.

Thalomid® is a registered trademark of Celgene Corporation.