Dr. Frances Kelsey, Who Protected Americans from Thalidomide, Turns 100

By: John Swann, Ph.D.

Today marks the 100th birthday of one of America’s most celebrated public servants. Frances Oldham Kelsey, Ph.D., M.D., was born in Cobble Hill, Vancouver Island, British Columbia, and earned her Ph.D. in pharmacology and her M.D. at the University of Chicago. She was on the faculty of the University of South Dakota and practicing medicine when, in 1960, she accepted the offer to become a medical officer at FDA.

John SwannA month after assuming her position she was assigned the review of a new drug application for thalidomide, a sedative that had been used by expectant mothers and many others in dozens of countries since the late 1950s. U.S. law at the time required a firm to provide evidence of a drug’s safety as a requirement for sale. Despite the global popularity of this drug, and despite a constant and increasing pressure from the firm to approve the application, Dr. Kelsey refused to do that without adequate evidence that the drug was safe, a decision that was supported by her colleagues and superiors.

By late 1961 scientists discovered that thalidomide was responsible for crippling birth defects in thousands of babies in many parts of the world. Thanks to Dr. Kelsey’s “exceptional judgment in evaluating a new drug” — as her firm stand was described in the President’s Award for Distinguished Federal Civilian Service she received from President John Kennedy — the U.S. was mostly spared the tragedies. But the close encounter with a public health catastrophe convinced Congress and the White House to resuscitate proposals to revitalize the regulation of pharmaceuticals. The result was the 1962 enactment of the Kefauver-Harris Drug Amendments that mandated “substantial evidence” of a drug’s effectiveness as developed by “experts qualified by scientific training,” in addition to evidence of a drug’s safety, and provided for greater oversight of drug investigations. These and other requirements in the new law established a global standard for the evaluation of drugs.

Frances Kelsey

Dr. Kelsey today, pausing between crossword puzzles.

After 1962, Dr. Kelsey oversaw the evaluation of investigational drugs and, later, of oncologic drugs and radioisotopes. Concerns in the agency with problematical clinical investigations continued in the early 1960s, such that FDA created the Division of Scientific Investigations in 1967 and placed Dr. Kelsey in charge. She remained in this position until 1995. The division engaged in inspections of clinical investigators, animal studies, and institutional review boards involved in drug trials. Thus, Dr. Kelsey helped ensure the reliability of data vital to FDA’s evaluation of therapeutic products over a span of four decades.

Frances Kelsey, the recipient of the highest honor that can be bestowed on a federal civil servant, officially retired from FDA in 2005, but her commitment to the integrity of science in service to the public health continues to inspire those in the FDA and beyond.

To learn more about the life and work of Dr. Kelsey, see her “Autobiographical Reflections.”

More about thalidomide and the 1962 Kefauver-Harris Drug Amendments that came out of this crisis can be seen at http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm.

John Swann, Ph.D., is an Historian at FDA

Artifacts Tell the Story of Our Culture and FDA’s History

By: John Swann, Ph.D.

Looming sentry-likJohn Swann_0254e over the collection of artifacts that document FDA’s  history, the products  we regulate, and our interactions with the public is a rather large and curious figure. It is a green velvet head with bulbous, languid eyes and two upper teeth in an otherwise large and empty mouth. It doesn’t have ears or hair, but is marked by a few bright green pustules.  This is part of a life-size costume, an element of a public education campaign called Fight Bac! in which FDA was a major participant. It began in the 1990s to alert the public, young and adult alike, to the dangers of food-borne diseases and how to avoid them.

Countless objects in our collection tell the decades-long tale of FDA’s educational activities. For example, the agency still has a cabinet and some of its contents from the “Chamber of Horrors” exhibit that traveled around the country in the early 1930s to alert citizens, legislators, the press and others of the need for a stronger consumer protection law, drawn from egregious examples of how the law then in place fell short.  FDA officials also communicated through a variety of other displays for Congressional testimony and other purposes.

Much of the collection captures the problems that gave rise to the laws and regulations we have today, a regulatory arc often originating with a problem product—sometimes of disastrous proportions. Thus one can find specimens of:

  • Elixir Sulfanilamide, a poisonous preparation of a wonder drug in 1937;
  • thalidomide,  the globally marketed sedative that caused thousands of grave birth defects in the 1950s and 1960s;
  • Bon Vivant vichyssoise, a botulism threat in the early 1970s;
  • the ill-designed Dalkon Shield intrauterine device that caused thousands of pelvic infections; and
  • ephedra-containing dietary supplements from the 1990s that killed several users.

These are among the objects that eerily illustrate why we have the laws and regulations we do.

Decision-making in the agency depends to a considerable extent on investigations and analyses, some of the tools of which are documented here. These artifacts of the growth of regulatory science include:

  • balances and early calculating devices used in the laboratories of the Bureau of Chemistry from the 1900s to 1920s to analyze questionable foods and drugs;
  • triers, tools used for routine sampling of various foods to ensure compliance with the law, from the mid-20th century; and
  • advanced analytical devices from the 2000s to detect sophisticated counterfeiting of medicinal products.

Thatcher_CalculatorTreatments of dubious value for both serious and non-serious diseases make up a significant part of the collection as well. There are hundreds of fraudulent medications, primarily up to about World War II, as well as hundreds of medical devices from the 1950s and 1960s that offered hope with no scientific underpinning.

In addition, how the public came to engage FDA and its work, especially from the 1970s forward, can be seen in a number of objects, including protest buttons and placards from the past two decades.

Artifacts like these tell the story of how our many laws and regulations came to be, how FDA has carried them out, and how the public and FDA have engaged each other in the interest of the public health.

John Swann, Ph.D., is an Historian at FDA

Celebrating a Public Health Milestone: The Kefauver-Harris Drug Amendments

By: Margaret Hamburg, M.D.

Margaret Hamburg, M.D.My predecessor, FDA Commissioner George Larrick, once said that, with the exception of 1906 and 1938, no date had more significance in the agency’s history than October 10, 1962, when President Kennedy signed into law the Kefauver-Harris Drug Amendments.  Commissioner Larrick stood behind the President at that momentous event.

The amendments were the response by Congress to the birth of thousands of malformed children, in Europe and elsewhere, whose mothers had used thalidomide during pregnancy.  The U.S. was spared that tragedy, thanks to the vigilance of FDA’s Dr. Frances Kelsey.

Fountain pen enscribed "The President - The White House"

With this pen, which he presented to Dr. Frances Kelsey, President John Kennedy signed into law the 1962 Kefauver-Harris Drug Amendments.

The time was therefore ripe for reform to protect and to promote public health, and it came in the form of legislation proposed by Sen. Estes Kefauver.  The Drug Amendments of 1962 strengthened the Federal Food, Drug and Cosmetic Act by requiring solid and rigorous science-based evidence that drugs are both effective and safe and in doing so the law laid the foundation for today’s modern pharmaceutical industry. 

To comply with the new amendments, manufacturers were now required to test their drugs in a truly scientific manner — typically, by conducting two well-designed and controlled clinical trials.  Companies also had to adhere to good manufacturing practices and monitor safety reports after the drugs reached the market.

With the benefit of hindsight, we can now see that the Drug Amendments of 1962 did much more than strengthen FDA’s authorities to ensure that our medications are safe and effective. The requirements of this law have since then been adopted world-wide, and became the “gold standard” for science-based decisions involving drugs.

In short, the Drug Amendments of 1962 merit our great praise on their fiftieth anniversary: they have saved countless lives around the world.

Margaret Hamburg, M.D., is Commissioner of the U. S. Food and Drug Administration

50 Years after Thalidomide: Why Regulation Matters

By: Margaret Hamburg, M.D. 

Fifty years ago, the vigilance of FDA medical officer Dr. Frances Kelsey prevented a public health tragedy of enormous proportion by ensuring that the sedative thalidomide was never approved in the United States.  As many remember, in the early 1960’s, reports were coming in from around the world of countless women who were giving birth to children with extremely deformed limbs and other severe birth defects.  They had taken thalidomide. Although it was being used in many countries, Dr. Kelsey discovered that it hadn’t even been tested on pregnant animals.

Dr. Kelsey’s reaction to thalidomide exemplifies the FDA’s mission: protecting and promoting the health of the American people, using science for regulatory decision-making.
Margaret Hamburg, M.D.Now I know that in some circles regulation is viewed as a roadblock to innovation and economic growth. But in actuality, when done right, regulation isn’t a roadblock; it’s the actual pathway to achieving real and lasting innovation.

Smart, science-based regulation instills consumer confidence in products and treatments. It levels the playing field for businesses. It decreases the threat of litigation. It prevents recalls that threaten industry reputation and consumer trust, not to mention levying huge preventable costs on individual companies and entire industries. And it spurs industry to excellence.

The tragedy of thalidomide led to changes that strengthened both the regulatory and scientific environment for medical product development and review.

In response to the public uproar, in 1962 Congress enacted the Kefauver-Harris amendments to the Federal Food, Drug and Cosmetic Act. Thanks to these new amendments, manufacturers had to prove that a drug was not only safe, but also effective. Approvals had to be based on sound science. Companies had to monitor safety reports that emerged postmarket and adhere to good manufacturing practices that would lead to consistently safe products. And there were new protections for patients.

The amendments not only benefited patients, they helped industry, raising scientific standards that eventually ushered in today’s sophisticated, science-based life sciences industry.

For the very first time, many companies put in place research and development programs, including the design and implementation of controlled clinical trials. Major therapeutic breakthroughs resulted, including the use of beta blockers in patients after a heart attack and angiotensin-converting enzyme inhibiters to improve survival in patients with heart failure. All of these were good news for public health and for corporate bottom lines. The best drugs and treatments rose to the top, not simply those that were most heavily marketed.

The Harris-Kefauver Amendments created a culture of quality and innovation that laid the foundation for our current regulatory environment which fosters a domestic pharmaceutical industry that is second to none.

Going forward, smart regulation requires regulatory flexibility that responds to changing situations, new information and new challenges. It also demands that we advance regulatory science: the knowledge and tools necessary for the meaningful and timely review of products for safety, efficacy, quality and performance.

Thalidomide, once again, is a good example. It came back on the U.S. market in 1998 after data showed it was safe and effective to treat a complication of leprosy. In an appropriate balancing of benefit and risk, FDA required strong safety monitoring and a strict dispensing plan before approving the drug.

Regulation such as this requires a strong, robust FDA, one endowed with the necessary resources to ensure smart, sound, science-based regulation.

Margaret Hamburg, M.D., is Commissioner of the U. S. Food and Drug Administration.