Public Health

Problems With Drug Potency
by Food and Drug Administration (FDA)

(Page 5 of 6)

But soon, it became clear that the new potency of drugs would bring unexpected problems. The central fact of the new drugs was that they were biologically active, inducing real changes inside the body: against the agents of illness, certainly, but also, unintentionally, against some healthy systems as well.

The trouble came with useful drugs like chloramphenicol, a powerful antibiotic, which in a small number of cases also caused a deadly blood disorder. That case highlighted the fact that overuse of a good drug could have some bad consequences. And, as in the previous two great crises, a public debate began with magazine and newspaper articles, soon followed by proposals to change food and drug laws. And once again, the reform law was essentially defeated and headed for the dustbin when a medical crisis intervened.

A company called Richardson-Merrell in Cincinnati, a subsidiary of the Vick Company, had bought from a German company the right to make and sell a drug it labeled "Mer-32." Its trade name was Kevadon; its laboratory name was thalidomide. It was, basically, a relaxant used as a sleeping pill.

When the application to market the drug came to the FDA, it was reviewed by FDA Medical Officer Frances O. Kelsey, M.D., Ph.D. The application contained many testimonials but scant scientific information, and Kelsey asked the company to produce better safety data. The company then began a fierce lobbying campaign to get the drug approved, including at least 50 recorded meetings with FDA officials and sending top company officials and hired physician-lobbyists to urge that thalidomide be put on the American market. But as the pressure was on, the first reports of nerve damage from the drug surfaced. Kelsey knew that nerve damage also meant the possibility of damage to fetuses, and she and a colleague, John Archer, began to raise the question whether it might cause birth defects. They recommended holding back on approval; after all, the drug was not life-saving and not much more useful than drugs already on the market.

Within months, the German company Grunenthal, which created the drug, began quietly dealing with the rising tide of complaints and lawsuits arising from the side effects of thalidomide. The drug did not reach the U.S. market, but Richardson-Merrell had sent it to 1,267 doctors to give to their patients as an "experiment." About 20,000 patients received the drug - it would have been the largest drug trial ever conducted in the United States, but data were not taken. It was largely an exercise in promotion to the doctors rather than testing on patients.

Hundreds of cases of nerve damage from the drug were reported before the first "thalidomide baby" was officially reported. The first case probably occurred in 1957 - four years before - but the news didn't break publicly in Germany until November 1961. Doctors began seeing a syndrome called phocomelia, or "seal limbs," in which babies were born with missing arms or legs. It took until July 1962 for the news to spread in the United States.

By conservative estimates, about 8,000 grossly deformed infants were born as a result of thalidomide use, almost all of them in Germany or in other European countries. Another several thousand, perhaps 5,000 to 7,000, died of their deformities before birth. In the United States, no accurate count is possible because of the lack of company records, but 17 cases of birth deformities are known and another nine are likely. If the drug had made it past FDA scrutiny to the American market, it is estimated that an additional 10,000 babies might have been born with the deformities.

The crisis came, once again, just as a new drug bill apparently had failed in Congress after years of hearings and debate. It was soon revived and brought forward. It was in October 1962, that the Kefauver-Harris Amendments to the food and drug law were passed and signed by President John F. Kennedy. The Secretary of Health, Education and Welfare wrote, in a letter to The New York Times, that "It is unfortunately true, as the thalidomide incident so well illustrates that the drug industry does not now always adhere to high standards, either in planning or in investigation, selecting the investigators, or providing the investigators with full information about the hazards ... the proposed regulations would change this. And they would have made it impossible for Richardson-Merrell to distribute millions of tablets to physicians who made no pretense of being investigators."

New System for Drug Testing

The law passed in 1962 laid out a rational system for drug testing. The previous law had said that companies could sell drugs at will unless the FDA objected, on the basis of data submitted by the sponsor, within 60 days of being notified that a drug was to be marketed. The power rested with the companies, and the burden with the FDA. The tests of safety for any drug were vague, and the standards generally quite low.

The new law reversed that. The new law put into writing that companies wanting to sell new drugs should show that they can be used safely and that they worked for the stated purposes. "Experiments" like the thalidomide distribution in America were prohibited; doctors and companies would now be required to keep records of what they gave to patients in experiments; and the patients must give their consent. The key result was that the FDA would be more closely involved in oversight.

The few words in Section 505 set the basic standards for evidence. The law said that safety and effectiveness should be shown by "adequate" investigations, meaning large and numerous enough studies. The studies had to be "well controlled," meaning testimonials and unverified results would no longer suffice. Controlled meant the studies should include comparisons of patients who took the treatment with those who did not.

It took some time for the full effect of this line in the law to be felt. Opinion was out; science was in; and companies and the FDA together would have to literally create a set of standards for what makes a good clinical experiment. It took more than a decade for the industry and the FDA to establish in discussion and in practice just what practical rules would fulfill the language: it was the birth of the modern clinical trial.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.