Bridget Henig: Hello, my name is Bridget Henig and I work in CDER's Office of Communications. I'm here today talking about the 50^th anniversary of the 1962 Kefauver-Harris Drug Amendments with FDA historian John Swann. 

 

The Kefauver-Harris Amendments to the Food, Drugs, and Cosmetic Act, also known as the Drug Efficacy Amendments of 1962, was signed by President John F. Kennedy and requires that all new drug applications demonstrate substantial evidence of the drug's efficacy for the marketed indication, in addition to the existing requirement of demonstrating the drug's safety and adequate labeling for safe use. 

 

John, can you walk us through some major issues in drug regulatory history prior to the 1962 Drug Amendments?

 

John Swann: Well, a number of factors contributed to the passage of the Drug Amendments in 1962, and I think in order to really appreciate it we have to go back to 1938 when the Food, Drug and Cosmetic Act was passed.

 

At that time the law in place, the 1906 Pure Food and Drugs Act, did provide for some protections for drugs. But in that case it was mainly just protections against adulteration and,  some core labeling restrictions. 

 

For example, drug ingredients generally didn't have to be labeled and there were standards identified for drugs. But essentially that was it as far as drugs were concerned. Some of the problems associated with that came out, of course, in the ensuing years. For example, prosecuting of false therapeutic claims became very problematic, and Congress tried to remedy that, but only in a limited way. 

 

So the agency had certainly pushed for revisions of the law and with the election of Franklin Roosevelt and the coming of the New Deal, there was a receptive political environment for change in the law, but that didn't in and of itself bring about change.

 

That certainly was on a large scale accomplished by the elixir sulfanilamide disaster of 1937, which basically was a case where a drug company put up a product in preparation of a useful drug, sulfanilamide—an anti-infective, a system anti-infective drug, on the market as a preparation that used a solvent diethylene glycol, which is a chemical analog of antifreeze. 

 

Now that product went on the market quite legally. There was no requirement for a drug to be tested before it went on the market, none whatsoever. So the company tested it for taste and for color and so on, but there were no tests. Had they even done a basic literature search they would have discovered some serious problems associated with this solvent. So the product went on the market in October of 1937 and within a number of days, the reports of deaths started to come in to the AMA first, but eventually to FDA as well. In response to that there were bills to improve the 1906 law—not with just respect to drugs, but with respect to other products as well. With foods for example, there were no, for the most part, no required standards for foods.

 

Cosmetics and medical devices had no protections whatsoever. Patients had no protections against problems with those, and there were a number of other issues that needed attention. So after the elixir sulfanilamide disasters, bills that had been floundering in Congress finally received serious attention, and eventually the president signed the Food, Drug and Cosmetic Act in 1938. That did require pre-market proof of safety before a drug could go on the market. That was the core change in the drug laws.  There also had to be adequate directions for safe use for drugs at that time.

 

Bridget Henig: Why did things begin to change in the development of drug regulations by the early 1960s?

 

John Swann: So there was a drastic improvement in the way the government oversaw drugs and with the provision of drugs to the public, but there were still a number of problems. One of which was that the drug didn't necessarily have to be effective in order to come on the market. 

 

Now in selected cases, FDA determined that a drug couldn't be safe without being effective. There were protections in place prior to 1962, but there was the lack of an explicit requirement for drug effectiveness. There was still a lot to be done.

 

Later in the 1950s there was a sort of a political change that's slowly evolving. That had a major impact on the way we regulate drugs and that emanated primarily from Senator Estes Kefauver, a Democrat from Tennessee. Kefauver had been a vice presidential running mate for Adlai Stevenson. He had also investigated organized crime. Now, he was the chair of the subcommittee on anti-trust and monopoly of the judiciary committee. 

 

He was quite interested in issues associated with drug pricing, and that's really what prompted his investigation of the pharmaceutical industry starting with hearings that started in 1959. Well, as these hearings evolved and certainly he heard stories of gigantic price markups of pharmaceuticals. 

 

This is not a story that is a contemporary one necessarily. It's just that this is one that certainly goes way back. But Kefauver had been focusing on issues such as modifications in patent law as a way to deal with elevated prices of drugs. 

 

But as the hearings unfolded, other issues came to light that caught a number of people by surprise. For example, there was one person, a former company executive who had remarked about the questionable advertising in the industry. So some companies were taking considerable liberties when it came to advertising their products, and he made the remark that that's bad but what's even worse about it is that some of these products just don't work. And that, of course, really attracted a great deal of attention. 

So the stories did come out about how some products, for example, were advertised in a deceptive way. For example, a, a nitroglycerin product that maybe cited an article in the Journal of the American Medical Association that lauded nitroglycerin—but that article that was cited in the ad would pertain to one dosage form and what the company was marketing was a completely different dosage form. So if you're talking about an oral dosage form versus a sublingual dosage form, those are quite different. 

 

Anyway, issues like that started coming up. Kefauver and his staff were still very interested in the pricing issues, but eventually by 1961, he did introduce a bill—a bill that was opposed quite stridently by the industry, and also by professional associations like the AMA, and by many in the medical research community.

 

This was because included in the bill that Kefauver had proposed were controls, enhanced controls by FDA over drug investigations. Enhanced investigations would help this problem of having ineffective or only partially effective drugs on the market. So certainly there was considerable opposition to Kefauver's proposal, even by members of his own party. The White House certainly was not on board with this early on in the process.

 

Bridget Henig: Can you tell us a little bit about the discovery of the marketing and production of thalidomide in the mid 1950s?

 

John Swann: In September 1960, FDA received the drug application required under the 1938 law for a drug called Kevadon; the brand name was Kevadon. It was thalidomide, a drug that had been introduced in 1956 as a sedative by a German company called Chemie Grunenthal. And as a sedative, it appeared to offer a great many, uh, advantages over other sedatives that were on the market. 

 

For example, unlike phenobarbital which certainly was subject to over-dosage and many problems, thalidomide seemed to be a drug that could be almost taken without any concern with over-dosage and it seemed to be an effective sedative. It also seemed to be useful for women who suffered from morning sickness during pregnancy. 

 

This was a drug that was marketed starting in 1956 in Germany. It was marketed in over 40 countries around the world. Of course, in the U.S., the law did require a new drug application and so that application was handed over to a new medical officer, someone who'd just arrived to FDA around August or so of 1960. Her name was Frances Kelsey.

 

Bridget Henig: What was Dr. Kelsey's role at the FDA at the time?

 

John Swann: Dr. Kelsey was a medical officer and she had been trained originally as a pharmacologist under EMK Geiling, a renowned pharmacologist at the University of Chicago. She had also worked at the American Medical Association helping to review articles, particularly articles on new drugs that came in to the journal. She also had some medical practice experience in South Dakota. So when she came to FDA in 1960, she had a pretty extensive background both in drug investigations and in medical practice as well.

 

Bridget Henig: What were her thoughts about the drug?

 

John Swann: Well, Dr. Kelsey saw the application and was not very impressed to say the least by the nature of the evidence that was included. It was almost more testimonial as she said than actual rigorous clinical evidence. 

 

So she turned it back to the company within the 60-day framework required under the law because under the 1938 law, if the agency did not act on an application within 60 days, the application would become effective automatically. That was another issue with the 1938 act that would eventually need some attention. 

 

But Dr. Kelsey was also concerned that a sedative based on the way it would be used really needed to have chronic toxicity data to help establish its safety and this application certainly lacked that. So she turned it back. She said this application is incomplete in its present form and that it needs more data. 

 

Bridget Henig: What sort of pressures was she up against when she refused to approve its use in the U.S.?

 

John Swann: Eventually the company got quite frustrated. They started putting considerable pressure on her to get the application approved. It wasn't unusual to have some interactions between a pharmaceutical company and the medical officer. This approached a new level of pressure. 

 

In fact, the company that had submitted the new drug application, the William S. Merrill Company of Cincinnati, had actually gone to Kelsey's superior in the Bureau of Medicine to see if he could loosen this from her hands. They also threatened to go to the Commissioner eventually. But Kelsey really had the full support of her colleagues and her superiors in the agency, so this was really going nowhere.

 

Bridget Henig: When did people start to realize the dangerous side effects?

 

John Swann: There are clusters of very rare and severe birth defects that are starting to form around the world now. No one really understands where this is coming from, but this is a rare, very severe form of birth defect called phocomelia. And in that case, it's a result of either stunted or absent long-bone formation, so you would see, for example, hands that emanate directly from the shoulders or feet that come directly out of the hips. So it's a severe birth defect and no one can really account for where this is coming from yet.

 

Bridget Henig: And what problems were associated with the drug?

 

John Swann: In early 1961, a report becomes known to Dr. Kelsey that those taking thalidomide have been linked to cases of peripheral neuritis, which is a very different sort of adverse reaction. Peripheral neuritis is a neurological condition that affects the extremities. It can be quite painful and it can vary, but it is a serious side effect of a drug. 

Well, presented with this new information, not necessarily from the company, but from a report in a British medical journal, Dr. Kelsey requests safety evidence that shows the drug can be used safely in pregnancy. This is based in large part on work she had done when she was at the University of Chicago that related to the ability of a drug to cross the placental barrier and have an impact on the fetus. She had done work during World War II that connected those two, and certainly others in the bureau shared those concerns as well.

 

Bridget Henig: When did Dr. Kelsey and other medical officers make the connection that the use of thalidomide during pregnancy was causing birth defects?

 

John Swann: The occurrence of these clusters of severe birth defects continue, but there's really no clear relationship to where these are coming from, not until later in 1961. So the company continues to pressure FDA to get thalidomide approved. 

 

Dr. Kelsey in particular is strongly standing her ground that the clinical evidence required under the law still does not exist and they're still waiting on that. So this is early 1961 when the connection with peripheral neuritis becomes apparent to FDA. By late in that year, there finally is evidence put together by two workers, a pediatrician in Germany and a gynecologist in Australia named. 

 

Both of these workers independently are able to make the connection that these clusters of severe birth defects are indeed linked to thalidomide. Well, the news is announced in Germany at a press conference and immediately the drug in Germany is taken off the market. 

 

The new drug application (NDA) remains open in the U.S. In fact, it wasn't until March of the following year that the company withdrew the NDA officially. But press attention to this connection is still something waiting to be seen and in the meantime there's another person who enters this story, a pediatric cardiologist named Helen Taussig at Johns Hopkins. 

 

She's in Europe and she's seeing for herself tremendously severe birth defects that are caused by this drug. She comes back to the U.S. in 1962, and in April contacts a colleague of hers in the Bureau of Medicine, John Nestor. And both Nestor and Frances Kelsey sit down and talk with Tausig to find out what's going there. 

 

Taussig subsequently goes on to Congress and informs congress about this horrible drug that's causing these terrible birth defects. There were a couple of reports by the New York Times and the AP wire press about this, but it basically ended there. The press just isn't getting it really, the global tragedy that's unfolding. 

 

In the meantime, there's something else going on that would have a clear impact on the law itself, and that was the bill that Kefauver introduced earlier in the year that's struggling for support. Well, Kefauver finally decides that Kefauver and his staff are going to leak the information about what happened and they know about Kelsey's role in this as the medical officer and they decide to leave this information to the Washington Post. 

 

And so in July the Washington Post publishes an article on the front page, top fold if I remember right, about America's near tragedy and Frances Kelsey's role and so at that point, the floodgates open. The story is all over the press nationally and internationally.

 

Bridget Henig: How did the, Kefauver's efforts and the thalidomide tragedy affect drug regulation?

 

John Swann: In August of 1962, President Kennedy has a press conference and announces to the country that there's this dangerous drug, thalidomide, that may well still be in the medicine cabinets of many Americans because remember—this drug was investigated and FDA thought it was a typical drug investigation of a few dozen clinicians, turns out to be apparently much more widely distributed. 

 

There were over 1,000 doctors who received the drug who were giving it to their patients--almost 15 to 20,000 patients as we later found out and over 600 pregnant women. As it turns out, there were about 17 cases of thalidomide-induced phocomelia among newborns in the U.S., about 7 or so of those were instances where the parents brought the drug in from abroad. But about 10 of those were from the so-called investigation. 

 

The bill that Kefauver had proposed was finally signed into law in October of 1962, and that law completely changed the face of drug regulation in the U.S. and globally. Of course, the most important provision of the law was the requirement for drug effectiveness as well as safety. But it was the nature of the evidence, too, that was key.

 

As the law's understanding unfolded, what would be required would be randomized double-blinded controlled clinical trials, essentially the gold standard for what we still rely on for drug investigations. For a drug to be shown to be effective and safe, it had to have good, solid, robust clinical evidence by experts. 

 

The law also required enhanced monitoring of clinical investigations by FDA that were shown to be lacking with this wide distribution of thalidomide. Now, patients also under the new law would have to show that they have informed consent to any investigation they're a part of. 

 

Remember, one of the issues that came out in Kefauver's hearings was advertising. Well, under the law FDA would be assigned control over prescription drug advertising, which had been the responsibility of the Federal Trade Commission. So it was only prescription drugs, but FDA would now be in charge of that. 

 

FDA would also have enhanced inspectional authority. FDA would have more access to drug records, quality control records, for example, and good manufacturing practices systematically would be the rule of law as well.

 

Bridget Henig: Why are the 1962 amendments so significant to FDA and the general public today?

 

John Swann: The law changed so many things in the way we regulate drugs and certainly established in its interpretation the gold standard for drug approval. The system of using advisory committees in the drug evaluation process really started after 1962. 

 

Originally there was a committee formed to help investigators understand how the requirements of the law would need to be applied, and then there were specific advisory committees for different product areas that were formed. 

 

That happened after 1962 and, of course, that brings the role of outside experts into decisions FDA makes. We've certainly been in touch with clinical experts before 1962, but this truly systematizes the way we do this after 1962. 

 

One of the things also is that we see much broader press attention on the Agency after 1962. And I think finally with the passage of the 1962 amendments, there's an elevated public expectation for FDA to ensure confidence in and reliability for pharmaceuticals, particularly when we see what happened around the world because thalidomide caused 8 to 10,000 cases of birth defects and an untold number of stillbirths. Because this did affect the developing fetus and so there were untold number of lives lost because of thalidomide.

 

But the U.S. was essentially spared, but only because the Agency and its medical officers stood their ground. It's a story that continues to resonate on its 50^th anniversary and it will continue to resonate.

 

Bridget Henig: Thank you, John. For more information on the FDA 50^th anniversary celebration of the 1962 drug amendments, visit www.fda.gov.