Dr Joseph Murray was impatient and frustrated. Fed up. As director of scientific relations for the drug company Merrell, it was Murray’s job to push and prod the FDA regulators into approving thalidomide for sale in the United States. But for more than six months Murray had fumed as Frances Oldham Kelsey, a novice FDA medical officer, raised a never-ending list of complaints and concerns about the safety of his pet German drug.
This was not the sort of treatment drug companies expected from the business-friendly FDA. But Kelsey was not the usual sort of FDA officer. For a start she was a woman, and a qualified pharmacologist as well as a medical doctor. Although she had recently arrived at the FDA, she was forty-six years old: experienced, confident and apparently immune to the pressure Merrell had been applying to her.
Kelsey was nursing her own good reasons to be irritated with Merrell and its chief lobbyist, Joseph Murray. Months earlier she had received the 31 December 1960 edition of the British Medical Journal. To her surprise she found Leslie Florence’s letter suggesting that thalidomide had caused nerve damage in four of his patients. This was a serious side effect and Kelsey was peeved Merrell had never mentioned it. She felt she had been misled.
It was now 11 May 1961 and Kelsey and Murray were meeting yet again: Kelsey annoyed and suspicious of the glowing claims for thalidomide; and Murray, angry that Merrell’s chosen date for the drug’s launch had come and gone, held up by a lone nitpicking FDA staffer.
Kelsey was accompanied by two other FDA officers at the meeting, but that didn’t daunt Murray. He again pressed the FDA to ‘expedite clearance’ of thalidomide and tried to explain away Merrell’s silence about nerve damage. Kelsey refused to be charmed or railroaded. She told Murray the FDA was unconvinced about thalidomide’s safety and gave him a list of issues on which more information was required. Most of the list was familiar to Murray: nerve damage, the need for long-term animal experiments, overdose information. But on Kelsey’s list was a new issue. What information was there, Kelsey demanded, to establish that thalidomide was safe for the foetus when used in pregnancy?
Later, when it emerged that thalidomide was responsible for the death and malformation of thousands of babies, Kelsey’s query assumed legendary status. But why did Kelsey raise the pregnancy question? What did she know that others did not? Was she, as many drug-company backers claimed, simply lucky? Or was there something about the drug that tipped her off? Some have even claimed that it was all an urban myth and that Kelsey never expressed concern about the foetus.
But Kelsey certainly did—for the first time at that meeting in May 1961 (more than six weeks before Wendy Rowe started taking thalidomide), and then repeatedly in the months that followed. Kelsey’s questions about thalidomide—including the concern that it might harm a foetus—blocked Merrell’s plan to make the drug a bestseller in the United States. Merrell was still struggling to satisfy Kelsey more than six months later in November 1961, when news about the malformations in Germany and Australia emerged, forcing Merrell to shelve its US thalidomide plans permanently.
Kelsey’s role in the saga soon became public and she vaulted to national prominence, feted by President Kennedy at the White House and celebrated as the woman who saved the United States from the scourge of thalidomide. She also very probably saved Merrell from lawsuit-driven bankruptcy. ‘If it hadn’t been for her, we’d be out of business,’ a Merrell lawyer noted. As it was, Merrell had irresponsibly spread millions of thalidomide sample pills across the US, causing at least ten recognised cases of birth damage (plus others never located and yet others who died at birth or shortly afterwards). But it could have been unimaginably worse.
Kelsey was and remains a hero to many—not least to the members of Lyn Rowe’s legal team. We asserted repeatedly in court documents that a careful and responsible pharmaceutical company would and should have worried that thalidomide might harm a foetus and done something about it: warned consumers, stopped or limited sale of the drug, surveyed pregnant women who had taken the drug, checked with doctors. Clearly, in our view, Kelsey took this assertion out of the realm of the hypothetical and made it real. Fact: a qualified, careful doctor at the FDA had questioned the effect of thalidomide on the foetus before its malforming effect had become known.
But how did Kelsey do it? The explanation for what led Kelsey to that moment in May 1961 is one of the keys to understanding exactly why so much of the thalidomide disaster was avoidable.
Frances Oldham (she added Kelsey after her marriage) was born in 1914 on Vancouver Island, Canada, into a family that encouraged women into higher education. Kelsey’s mother had two sisters: one a doctor, the other a lawyer.
After high school, Kelsey studied at Montreal’s McGill University, gaining a science degree and then a master’s degree in pharmacology in 1935. She then applied for a job at the University of Chicago’s pharmacology department. The acceptance letter from Professor Eugene Geiling started, ‘Dear Mr Oldham’. Kelsey agonised over whether to write back admitting to her gender, and offering Geiling the chance to reconsider. Undecided, she consulted her academic supervisor. ‘Don’t be ridiculous,’ he responded. ‘Accept the job, sign your name, put Miss in brackets afterwards, and go!’
Perhaps Kelsey was lucky: she later found Geiling very fair, but old-fashioned and conservative. ‘He did not really hold too much with women as scientists.’ And Geiling never revealed whether or not his offer would have held had he known Frances Oldham was a woman. In Chicago, Kelsey was awarded a PhD in 1938—her investigations concerned the posterior pituitary gland of the armadillo—and then did postdoctoral work and taught.
By this time, thanks to the most notorious drug disaster of that era, Kelsey had already learned something about the potential risks of new drugs. Sulfanilamide was developed in Germany in the early 1930s. The drug revolutionised the treatment of infection, though it was later partly superseded by penicillin. One US drug outfit in Tennessee, S. E. Massengill Company, decided in 1937 to mix sulfanilamide into a liquid solution to make it more easily ingested, especially by children. The company’s chief scientist, Harold Watkins, created ‘Elixir Sulfanilamide’ by combining sulfanilamide with a flavouring and the solvent diethylene glycol, also known as DEG. Diethylene glycol was chemically related to anti-freeze and, unknown to Watkins, very toxic.
At that time there was little government regulation of the drug industry, an open-slather approach that led to a marketplace full of quack remedies. It also meant that ‘Elixir Sulfanilamide’ was untested in animals or humans when it was shipped out of the Massengill factory. A slew of deaths quickly followed—more than one hundred in total. Many of the dead were children, victims of kidney failure. The drug was hastily withdrawn and the FDA turned to Frances Kelsey’s boss Professor Geiling at the University of Chicago for assistance in analysing the elixir. Geiling set up toxicity experiments in dogs, rabbits, rats and monkeys and enlisted his graduate students to help. The animals were given the different elements of the elixir and the effects were monitored. ‘My particular task was to watch the rats,’ Kelsey recalled. ‘In no time at all it was perfectly apparent that it was the diethylene glycol that was at fault…the rats soon died [of kidney failure] just as the kids did.’
The company owner, Dr Samuel Massengill, expressed sympathy but denied all responsibility for the deaths in a manner eerily similar to Grünenthal’s twenty-five years later. ‘My chemists and I deeply regret the fatal results, but there was no error in the manufacture of the product. We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results. I do not feel that there was any responsibility on our part.’ Watkins, the chemist who created the elixir, felt far worse than his employer: he reportedly took his own life.
Kelsey’s involvement in the sulfanilamide affair was the first in a remarkable series of events and circumstances which later made her among the most qualified and able people in the world to pick up the warning signs about thalidomide. The next critical experience—which gave Kelsey an insight into the vulnerability of foetuses—came when she and Dr Fremont Ellis Kelsey, a pharmacologist and fellow faculty member in Chicago she married in 1943, worked on a wartime hunt for a new antimalarial drug.
In 1942 Japanese forces invaded and occupied the Dutch East Indies (Indonesia), then home to the cinchona plantations that were the source of the majority of the world’s quinine (a product extracted from cinchona bark). Quinine was the key antimalarial drug, and the Japanese occupation cut off much of the United States’ supply. This was potentially disastrous at a time when a massive supply of the drug was needed for troops in malaria-affected war zones.
Part of the US Government’s response was to coordinate a research effort to find replacement drugs. The University of Chicago (and both Frances and Ellis Kelsey) played a role by running tests on some of the potential antimalarial compounds synthesised elsewhere. Rats, dogs, chicken, ducks and monkeys were infected with malaria and then treated with the test compounds. A limited supply of quinine was used to treat infected animals for comparison purposes.
Recounting this experience decades later, Kelsey recalled with amusement a veterinarian in Texas who had sent in a proposed malaria cure. He had tested it on his secretary and was planning to try it on his cattle. ‘When we read this, we said it shows the relative value placed on women and cattle in Texas.’
In addition to the hunt for new malarial drugs, the Chicago researchers were able to do some research on the side. Rabbits were known to break down quinine very quickly. Frances and Ellis Kelsey decided to see whether pregnant rabbits and rabbit embryos also possessed this ability. The result was interesting. The pregnant rabbit had a reduced ability to metabolise quinine, and the rabbit embryo no ability at all. That meant quinine in rabbit embryos was not removed from the (foetal) body and built up to toxic levels. This firsthand experience taught Kelsey, as she put it, that ‘the embryo or the young may handle a drug differently from the mother’. She also knew that a drug that did not harm the mother could severely harm a foetus. The doctors Kelsey and their co-workers authored several published articles on their quinine work in the 1940s.
At the end of the war Kelsey decided to study for a medical degree; she graduated in 1950, having given birth to daughters in 1947 and 1949. Kelsey was conscious of her health during pregnancy. She was, in any event, a non-smoker and drank very little. She was also ‘very cautious about using drugs during my own pregnancies’. After medical school Kelsey took a job with the Journal of the American Medical Association assessing articles submitted by doctors about new drugs. Kelsey observed that the science in the articles was frequently poor, and that certain authors’ names kept recurring. It was clear that some doctors had a sideline in talking up new drugs for the drug companies. ‘We would jot down, oh it’s Dr So-and-so again,’ Kelsey said.
In 1952 the Kelsey family moved to Vermillion, a small town in South Dakota, where Ellis Kelsey taught pharmacology and Frances Kelsey worked as a researcher, teacher and locum GP. By 1960 the couple wanted to move to a big city and both obtained job offers in Washington: Ellis Kelsey at the National Institutes of Health and Frances Kelsey at the FDA.
The FDA employed Kelsey as a medical officer. Her job was to assess NDAs, or new drug applications, submitted by drug companies seeking FDA sale approval. A team of three assessed each NDA: working alongside the medical officer, who was responsible for corresponding with the drug companies, were a chemist and a pharmacologist. Kelsey was in fact an exceptionally well qualified medical officer, with her PhD in pharmacology as well as her medical degree.
Kelsey spent her first few weeks familiarising herself with the FDA and its operations. Then, in early September 1960, she was assigned two NDAs at about the same time. One was for a rectal enema, Kelsey later remembered. The other was an apparently straightforward application for a sleeping pill. ‘I was the newest person there and pretty green, so my supervisors decided, “Well, this is a very easy one. There will be no problems with sleeping pills.”’ The drug was Kevadon, Merrell’s chosen brand name for its German drug, thalidomide.
If not for a false start the thalidomide NDA might have landed at the FDA several years before Kelsey arrived. In 1956 another US drug company, Smith Kline & French (SKF), did a deal with Grünenthal to test and potentially market the drug. SKF did extensive animal and human testing with the drug—and, in the process, caused one known malformed birth. Careful monitoring and follow-up might have connected the baby to the test drug and raised concern. But, sadly, the testing was so poorly scrutinised that SKF said it did not become aware of the case until years later. In any event, by January 1958 SKF had gone completely cold on thalidomide. Its animal testing did not identify a significant sedative effect and, worryingly (and unlike Grünenthal), SKF was able to kill cats and stop dogs breathing using large doses of thalidomide. SKF concluded that thalidomide’s apparent harmlessness was not an inherent property, but rather a result of the drug being poorly absorbed.
SKF also found little clinical potential, in part because it believed the drug was not strong enough to remedy even moderate insomnia. In a carefully worded January 1958 letter, SKF told Grünenthal it was not interested in the drug. Grünenthal was not fazed. Almost immediately it did a deal with another US firm, Wm. S. Merrell, which, to its lasting regret, would prove far more enthusiastic than SKF.
Merrell was an old Cincinnati firm, established in 1828, which during the thalidomide era was a division of Richardson-Merrell. Merrell believed thalidomide to be a winner, and was desperate to get it to market. It reached an agreement with Grünenthal in 1958 and was hoping to get FDA approval the following year. In 1959 it estimated the total sedative market in the US was worth $20 million and, Merrell noted, thalidomide would have to be aggressively promoted as ‘highly effective’ yet ‘safe and comfortable’. Fortunately Frances Kelsey would reach her own view about the drug’s safety.
The FDA Kelsey joined in 1960 was in something of a crisis. A senior employee, Dr Barbara Moulton, had resigned in February 1960 and turned whistleblower. In June that year Moulton appeared in the caucus room of the Old Senate Office Building and gave incendiary evidence to a senate subcommittee. Moulton charged the FDA with ‘failing utterly’ to protect the public from unsafe drugs, and branded certain officials corrupt, stupid or misinformed. Fraternisation, she said, was rife between FDA officers and industry, and urgent action was needed to protect young FDA officers from ‘brainwashing’ by drug lobbyists. Even if a medical officer was able to resist industry pressure, he or she might still be overruled by an FDA superior anxious to appease the drug company. On one occasion, Moulton told the committee, her boss at the FDA had insisted she ease off on a drug company. ‘I will not have my policy of friendliness with industry interfered with,’ he told her.
Moulton called for urgent reform. FDA officials who had placed the ‘welfare of the [drug] industry above that of the consumer’ should be sacked. The FDA, Moulton said, should be given the power to judge a drug’s efficacy, not just its safety, because judging safety in the absence of efficacy was absurd. ‘No drug is safe if it fails to cure a serious disease for which a cure is available. No drug is too dangerous to use if it will cure a fatal disease for which no other cure is available.’
Moulton was right: existing drug laws were archaic. The 1937 sulfanilamide affair and the heavy death toll had led to important law reform in the guise of the Food, Drug, and Cosmetic Act of 1938—but it was far from adequate. Under the 1938 law—still in force when Moulton gave her evidence—drug manufacturers were obliged to supply the FDA with information on a drug’s chemistry, animal test results, and the outcome of (human) clinical trials. If the FDA judged the drug safe then the drug could be marketed. While a major step forward, there were big gaps. Under the 1938 law drug companies could conduct as many clinical trials as they pleased, without FDA approval or involvement and before even basic safety tests in animals. And they could also pick and choose their clinical investigators, with no regard to expertise or independence. This meant much of the drug company clinical trial work was deeply unscientific: one senior FDA officer described it as ‘all baloney’ and ‘essentially a bunch of testimonials’.
Another critical failing was that the question of whether or not a drug was actually effective was not within the FDA’s remit. This led to the continued criticism that an enterprising company could have bottled water and marketed it as a medicine. In fact some did—one cancer treatment was found on analysis to be almost pure distilled water.
The slack state of the law meant that to sell thalidomide, Merrell just had to persuade the FDA that it was safe. Effectiveness only entered the equation via the back door. FDA officers might be willing to tolerate more side effects (or a bit less safety) if a proposed new drug was critical or lifesaving. Conversely, if a drug was not critical an FDA officer might insist on strict safety. Frances Kelsey would make this point repeatedly in dealing with thalidomide. In her view an unimportant sleeping pill had to be genuinely safe.
Moulton’s whistleblowing—and her call for urgent reform—caused a sensation, especially within the drug companies and at the FDA, where she had labelled the Commissioner, George Larrick, as unqualified. Her evidence also came not long after a scandal in which Dr Henry Welch had been forced to resign as head of the FDA’s antibiotics division. Welch had been the editor of two drug journals focused on antibiotics, for which he told the FDA he was receiving a very modest ‘honorarium’. But to Welch’s disgrace it emerged that he had in fact enjoyed an ownership stake in the journals, collected a percentage of drug advertising, and had made about $250,000 over seven years from these and other extra-curricular activities.
Moulton’s scathing critique and Welch’s unmasking contributed to a groundswell of support for tougher drug laws and a regulatory authority with sharper teeth and a more industry-sceptic stance. Two years later that groundswell would be transformed into an irresistible force by Frances Kelsey and thalidomide, as the United States realised only Kelsey’s shrewdness and persistence—not the existing drug laws—had saved it from a German-style thalidomide disaster.
Once assigned the Kevadon NDA in September 1960, Kelsey had to act quickly because if there was no decision within sixty days the drug was automatically approved for sale. Kelsey and her team thought Merrell’s NDA was full of problems. Among her concerns was that doctors she had identified as hacks for hire (while working for the Journal of the American Medical Association) were involved in thalidomide studies. The claims made ‘were too glowing’ and many were ‘more testimonials than scientific studies’, she later said.
Frances Kelsey also had the benefit of a memo from her husband about Merrell’s pharmacology. ‘An interesting collection of meaningless pseudo-scientific jargon, apparently intended to impress chemically unsophisticated readers,’ is how Ellis Kelsey described one section of the work. He reserved great scorn for the claim that thalidomide was so atoxic that no LD50 (the dose of thalidomide required to kill fifty per cent of test animals) could be found. ‘No other substance can make that claim!’ In fact part of Merrell’s submission was so absurd that Ellis Kelsey concluded: ‘I cannot believe this to be honest incompetence.’
Frances Kelsey and her team also wondered why the drug was effective as a sedative in humans and not in rats. Was the weak sedative effect and low toxicity in test animals because the drug was not being absorbed? If that was the case, it might be far more toxic than it appeared.
Merrell could have shed some light on these concerns. James Knox Smith, who did some animal testing for Merrell, told a later legal hearing that Merrell had been able to kill mice with large doses of the drug. But Merrell did not report this to the FDA, an omission Knox Smith criticised. Further, Merrell was able to kill twenty-two out of thirty rats with large doses of thalidomide mixed into a syrup. Again, the FDA was not told of these experiments. Instead Merrell told the FDA about separate tests in which all rats survived.
There were no tests on pregnant animals in the Merrell submission to the FDA. Like Grünenthal in Germany and Distillers in the UK, Merrell had not done this testing. Dr Carl Bunde, Merrell’s director of medical research in 1960–61, told a later court hearing that ‘at that time’ testing drugs on pregnant animals ‘was not routine. It was not usual. It was not part of the ordinary operation’. Instead, Bunde said, the ‘universal’ practice was to ‘simply look for [deformities] when it was used in a human. The use of animals was not considered a method of solving this problem’.
Bunde was being loose with the truth. In 1959, at exactly the time it was working on thalidomide, Merrell did reproductive testing on another substance it had under investigation—the notorious anti-cholesterol drug MER-29 that, once released in 1961, caused a spate of severe injuries including skin damage and cataracts. The MER-29 reproductive testing was performed both in-house and at an external consultancy. Even earlier, in 1956 and 1957, Merrell had performed reproductive testing on another drug under development and found it damaged rat foetuses. So, contrary to Bunde’s assertions, Merrell knew about reproductive testing, appreciated the need for it, and tested drugs on pregnant animals in its own laboratories and at external consultancies.
Merrell has never satisfactorily explained why no reproductive testing was done for thalidomide. But a big part of the explanation is that it was seduced by Grünenthal’s false and meaningless assurances that there were no side effects of any consequence despite massive sales across Europe.
But while the lack of safety information about pregnancy did not yet worry Frances Kelsey, she had seen enough in the Merrell material to be concerned. On 10 November 1960, she marked the Kevadon (thalidomide) NDA incomplete and told the company to submit further information. The sixty-day clock started again. It was a brave move by Kelsey. Drug companies were not accustomed to being treated in this fashion and Merrell executives poured the pressure on. They telephoned and visited Kelsey and complained to her superiors, all the while stressing the need for a swift approval.
By now, though, Merrell had taken steps that ensured that no matter what Kelsey ultimately decided, millions of thalidomide pills would reach US consumers. That came about because Merrell was determined to familiarise doctors with Kevadon in advance of the FDA’s green light. But how to do that when sale of the drug was still prohibited? The solution was simple. Under the still-in-force 1938 laws, a drug company could conduct as many clinical trials as it wanted prior to sale approval. This was a loophole Merrell exploited ruthlessly.
In October 1960 Merrell conducted a two-day thalidomide seminar for its salesmen. A manual distributed at the seminar—Kevadon Hospital Clinical Program—made clear this was a promotional campaign masquerading as a clinical investigation. Salesmen were to contact ‘the most influential’ doctors ‘for the purpose of selling them on Kevadon and providing them with a clinical supply’ and ‘to perfect and develop the best possible [sales] story for the national introduction of Kevadon’.
Sales reps were told that the importance and safety of thalidomide had already been firmly established. What Merrell wanted was ‘widespread confirmation of its usefulness’—good news which would be ‘spread among hospital staff members’. And in case any sales reps were tempted to take the research part too seriously, there was this caution:
You can assure your doctors that they need not report results if they don’t want to…
Let them know the basic clinical research on Kevadon has been done. Don’t get involved [in] selling a basic clinical research program instead of Kevadon. Appeal to the doctor’s ego—we think he is important enough to be selected as one of the first to use Kevadon in that section of the country.
Naturally, salesmen were also encouraged to approach doctors with the Grünenthal-inspired safety mantra. ‘It is perfectly safe to state that every known hypnotic agent, except Kevadon, is capable of causing death by respiratory failure.’
Merrell’s overblown claims were not limited to safety. It produced a brochure for doctors claiming that Kevadon was useful in treating ‘anxiety and apprehension’ arising from no less than twenty-four different conditions including bed-wetting, marital discord, nightmares, poor schoolwork, premature ejaculation and, tellingly, nausea and vomiting.
Clearly the Merrell ‘clinical program’ was about sales, not research. Under its guise, Merrell supplied 2,528,412 thalidomide pills to more than 1200 doctors. About 20,000 patients, including more than 3000 women of child-bearing age, received a drug that had never been approved for sale and which was appallingly dangerous. Later, when it uncovered what had gone on, the FDA argued for Merrell and its executives to face criminal charges over what the FDA believed was a blatant and illegal sales push.
One of the doctors Merrell supplied with thalidomide was Ray Nulsen, a Cincinnati GP then in his late forties, who had devoted himself to obstetrics and who enjoyed the good fortune of being Don Merrell’s fraternity brother. Nulsen had been happy to oblige when Merrell, a descendant of the founding Merrell family, kicked off Nulsen’s career as a drug tester by asking him to test a varicose veins treatment in about 1940.
Merrell’s enthusiasm for Nulsen as a tester continued for twenty years, right up until the thalidomide disaster in 1961. He was ‘very cooperative, he was competent and he was geographically convenient,’ the company’s medical director Dr Raymond Pogge later said, in perhaps a case of damning Nulsen with faint praise.
Indeed, Nulsen’s testing had multiple shortcomings: he employed slack investigative methods, ignored and denied horrible side effects, and abdicated much of the science to his friends at Merrell. In subsequent court hearings Nulsen presented an easy target. For a start, his clinical trials were farcical. As he told it, ‘one of the girls in the office keeps a running record of the patients who take the medication’. Relevant patient comments or observations were jotted down. Then—perhaps at lunch, he told a court hearing—Nulsen would hand the results to Merrell’s medical director, Raymond Pogge.
It was Pogge who broached the subject of thalidomide testing with Nulsen—perhaps during a game of golf, Nulsen later ventured. Pogge told Nulsen he didn’t know how thalidomide worked but that it was ‘absolutely harmless’. And would Nulsen please trial the drug on women suffering insomnia in late pregnancy? As usual, Nulsen was happy to get started. He found thalidomide ‘acted beautifully’ and he and his family helped themselves to free samples, of which there was no shortage: Merrell sent Nulsen about 100,000 thalidomide tablets over two years. Soon Nulsen expanded the ‘trial’ to at least seven hundred patients. At the explicit request of Merrell he began including pregnant women suffering nausea.
One noteworthy feature of the long-running Nulsen–Merrell partnership was that Nulsen would occasionally burst into print to extol the virtues of a Merrell drug. In June 1961, an article about the use of thalidomide in the third trimester of pregnancy was published under Ray Nulsen’s name in the American Journal of Obstetrics & Gynecology. But Ray Nulsen, as it happened, was not the author.
‘Now, sir, did you physically write the article?’ a lawyer for one of the United States victims asked Nulsen at a 1966 deposition.
‘No,’ Nulsen responded.
Who wrote it?
Dr Pogge or someone at the Merrell company.
Did you supply for this article any of the information with respect to the chemical facts contained in this article?
No.
Did you supply any of the footnotes for this article?
No.
Who made the original drafts?
Dr Pogge.
…
Were you [shown] a draft of the article?
Yes.
Did you make any additions to it?
I don’t remember.
Did you make any changes to it?
I don’t remember.
…
Who submitted the article for publication?
Merrell.
Nulsen’s sloppy testing and cosy relationship with Merrell led to tragedy. The thalidomide article that appeared under Nulsen’s name included this line: ‘There is no danger to the baby if some of it appears in the milk or passes the placental barrier.’ Under questioning, Nulsen conceded he did not write that and had no idea whether or not thalidomide passed the placenta and reached the foetus.
Merrell’s Raymond Pogge had written the whole article, including the foetus line: he admitted as much under oath, adding that he had written articles for doctors up to thirty times in the past. He too admitted he had not known whether or not thalidomide passed the placenta and reached the foetus.
Nulsen’s ‘tests’ and his ghosted article were used by Merrell to vouchsafe the effectiveness and safety of thalidomide in pregnancy. In one letter to doctors Merrell reported that ‘Nulsen administered Kevadon to expectant mothers with a sleep problem without effect on the newborn infants’. This was a very misleading précis—it carried the false implication that Nulsen had checked on the capacity of the drug to damage a foetus. On other occasions Merrell resorted to variations of these false assurances. In December 1960 it wrote to a US doctor in response to a question on the possible effect of Kevadon on the foetus. Merrell replied that it was not known ‘whether or not there is any transfer of Kevadon across the placental barrier’ but that even if there is ‘it would be completely safe’.
Far worse was to come. During the first five months of 1961 Nulsen delivered five severely damaged children, two of whom were stillborn. Did alarm bells ring for Nulsen? Why were his patients’ babies suddenly afflicted in this manner? Could it have something to do with the new pills he was using? If these thoughts ever occurred to Nulsen he never admitted it, and apparently he did not report the malformed births to Merrell. Shortly after the last of these births, Merrell wrote to Nulsen asking for his assistance in satisfying Kelsey’s queries about the foetus. Had he seen any foetal abnormalities during his ‘trial’? Nulsen responded that he had not.
Perhaps Merrell might have pursued Nulsen with a little more vigour. But it is also possible that Merrell could never have extracted the truth from its ‘geographically convenient’ pregnancy tester. After the danger of thalidomide was publicly revealed in late 1961 and the FDA and others began trying to find babies damaged by thalidomide, Ray Nulsen denied having given thalidomide to the mothers of any of the five malformed infants. FDA documents show that both it and Merrell thought Nulsen was lying. Even when the mothers swore that Nulsen had given them Kevadon, Nulsen denied it. ‘Merrell does not believe him,’ a 1962 FDA memo read. ‘Merrell is quite sure he did dispense the drug to her throughout the period of pregnancy.’ The FDA’s investigation of Ray Nulsen continued for months. At one point the FDA discovered that Nulsen had made about forty donations to an orphanage in the name of children he delivered stillborn or who had died shortly after birth between 1959 and 1962. The FDA briefly believed it had discovered a secret list of Nulsen’s thalidomide victims. This theory was later discounted, though the exact number of deaths and injuries caused by thalidomide in Nulsen’s practice was never ascertained.
Ray Nulsen ended up as one of the villains of the thalidomide story. But it could have been so different. He was testing thalidomide in pregnancy at the request of the drug company. He was in a prime position to connect the drug to the malformations and halt the disaster. But he didn’t make the connection—or if he did, he said nothing. Had he raised the alarm, Ray Nulsen would be remembered very differently.
In February 1961, with Merrell pressuring her to approve thalidomide in time for a March 1961 launch, Frances Kelsey received some recent copies of the British Medical Journal. In the 31 December 1960 edition she read Leslie Florence’s letter suggesting thalidomide was responsible for peripheral neuritis in his patients. The report disturbed Kelsey. First, Merrell had never told her about this side effect. Second, thalidomide was just a sleeping pill, not a lifesaving drug, and it would be widely used. Any significant nerve damage was an unacceptable side effect. In her polite but firm manner Kelsey asked Merrell why she had not been told about this side effect.
Merrell claimed it had known nothing about nerve damage and immediately dispatched a team to the UK and then on to Germany for discussions with Distillers and Grünenthal. The American team was roundly assured of the drug’s safety. Grünenthal, for example, declared the condition was rare and played down its seriousness. The Merrell men appeared to swallow the Grünenthal line willingly. They returned to the US and Merrell told Kelsey that thalidomide nerve damage was very rare and ‘rapidly reversible’.
Kelsey was not taken in. ‘I had the feeling throughout that they were at no time being wholly frank with me and this attitude has obtained in all our conferences etc regarding this drug,’ she wrote in a memo on 30 March 1961. She suspected that the frequency of nerve damage was ‘very much greater’ than Merrell wanted her to believe.
Merrell followed up with intense lobbying and complaints to Kelsey’s bosses. Undaunted, Kelsey wrote to Merrell on 5 May 1961 and again reset the sixty-day clock on the thalidomide application. She accused Merrell of failing to be frank about the nerve-damage side effect and warned the company it had an obligation to prove the drug was safe. Within days senior Merrell management had accused Kelsey of libel, and visited her bosses to complain.
But Kelsey, not to be browbeaten, was ready to raise another—crucial—concern about thalidomide’s safety. Thanks to the 1937 sulfanilamide disaster and her peripheral role in it, Kelsey knew that drug companies were capable of selling untested (or poorly tested) drugs with catastrophic results. Thanks to her World War II quinine experiments, Kelsey knew that a drug could be safe for the mother and still devastate her foetus. Thanks to her work at the AMA journal, Kelsey knew that some doctors were willing to make absurd claims for a new drug. And, obvious though it is, Kelsey was not just a doctor but a woman who had had two children of her own. She had been careful not to take drugs during her pregnancies. She regarded the health of the foetus as important, a consideration that clearly did not preoccupy the men in charge at Grünenthal and Distillers. Kelsey also had the advantage of colleagues who shared her concern about the health of the foetus. She talked with two of them, and they encouraged her to pursue this line of questioning.
So at that famous 11 May 1961 meeting, Kelsey told Merrell she wanted to know whether the drug was safe in pregnancy. Merrell subsequently tried to satisfy Kelsey with some information about late pregnancy from its soon-to-be-disgraced investigator Ray Nulsen. Kelsey rejected it. She wanted to know about early pregnancy and continued to raise the issue. At one point she said that if the drug was approved it would need to carry a warning about the ‘possible hazard to the fetus if the drug is given during pregnancy’.
In the aftermath of the thalidomide scandal, Kelsey was asked to explain why she had worried about thalidomide’s effect on the foetus. Her reasoning was straightforward. If the drug could damage the nervous systems of adults, what might it do to a vulnerable, growing foetus? ‘We felt that the fetus might be particularly susceptible to such toxicity inasmuch as it might be exposed to a drug for as long as nine months,’ and this was especially so in light of the ‘rapid growth and imperfect enzyme systems of the developing [fetus]’.
Merrell saw Kelsey’s complaints and queries as uninformed pig-headedness. Not content with repeatedly lobbying her directly, Merrell went behind Kelsey’s back to her bosses. In total Merrell contacted the FDA fifty times between September 1960 and November 1961.
In September 1961, Merrell, in desperation, organised a meeting at the FDA of some of its medical investigators to deal with Kelsey’s concerns. Kelsey asked the assembled doctors if any of them could assure the drug’s safety for the foetus. None could, and one backed Kelsey, agreeing that it would be ‘highly desirable’ to check for a possible effect.
During this period the FDA started keeping a list of doctors submitting ‘incredible’ reports on behalf of drug companies. This was not for those who were ‘substandard, poor reporters [or] overly enthusiastic’, an FDA memo informed Kelsey and her fellow medical officers. Rather, the list was for doctors suspected of ‘untruthfulness, psychosis, or dangerous incompetence and irresponsibility’. It is not known if Kelsey submitted the names of any of Merrell’s investigators, but Merrell was now despairing of ever persuading Kelsey that thalidomide was safe. ‘We live in hope,’ a Merrell vice-president advised Grünenthal.
But events overseas were about to intervene. Kelsey had time to restart the sixty-day clock one final time on Merrell’s application before the company’s chief lobbyist Joseph Murray telephoned her on 30 November 1961. Thalidomide, Murray told Kelsey, had been linked to birth malformations in Germany.
Merrell executives must have been shocked by the news from Germany. But it appears not shocked enough, or not sufficiently convinced that the threat was real, to adequately warn doctors or the public.
On 1 December 1961 executives from Merrell and from Horner, a Canadian firm that had been selling thalidomide for a few months, flew to Germany. The subsequent account of a Horner executive suggests Grünenthal played down the concerns expressed by Widukind Lenz, who had finally connected thalidomide to the rocketing number of dead and malformed babies. Grünenthal treated the American visitors to a critique of Lenz’s arguments and claimed that Lenz was refusing to reveal his data. ‘[Lenz] is supposed to have told Grünenthal that he had a “vision” indicating Contergan as the cause of all these deformities,’ the Horner executive wrote. Grünenthal also appears to have engaged in a familiar dose of character assassination. ‘[Lenz’s] father was a famous and popular geneticist in Nazi times since he had “proven” the validity of the master-race concept on genetic grounds,’ the same Horner executive reported.
On 5 December 1961 Merrell wrote to US doctors advising them of the reports of malformations overseas and suggesting that thalidomide not be given to pregnant women. A further letter was sent in February 1962. Both emphasised that the link to birth malformations was uncertain. The FDA appears to have believed that this was adequate warning. What the FDA did not know was that Merrell had given thalidomide samples to more than 1200 doctors across the United States—but had sent the half-hearted warning letters to only about 150 of them. Merrell had simply left 1100 doctors in the dark, many of them armed with deadly thalidomide tablets that Merrell had previously assured them were outstandingly safe.
Merrell knew very well that the media had not alerted the doctors to the danger. On 22 December 1961 a Merrell vice-president wrote to Grünenthal mentioning there had been ‘no publicity in the lay press in either the United States or Canada’. It was not until 20 March 1962, almost four months after learning of the danger, that Merrell wrote to all of its 1200-plus ‘investigators’ asking for the thalidomide ‘research’ to stop and requesting the return of all stocks. The FDA did not discover Merrell’s monumental failure to warn doctors until the following month, April 1962. Up until then the FDA believed that only about 150 doctors had been given the drug and all had been warned in December 1961. This was a gross error of judgment; the FDA should never have trusted Merrell.
Bruised—and embarrassed at having been duped—the FDA began an intense investigation of Merrell’s thalidomide conduct, featuring raids on Merrell offices and interviews with current and former employees. FDA staff were also sent to retrieve the drug from doctors’ offices. By questioning doctors the FDA quickly discovered ten babies whose malformations had been caused by Merrell’s thalidomide and another seven caused by thalidomide obtained overseas. (This search for affected babies was far from exhaustive.)
At a conference in November 1962, senior FDA officers and lawyers discussed their findings and possible action against Merrell. The FDA believed Merrell had made false and misleading claims to investigators, run a marketing program for thalidomide before getting sales approval, withheld adverse drug data, submitted false data, and misled the FDA about the drug recall.
The FDA then pushed for charges against Merrell and some of its key staff, the central issue being Merrell’s thinly disguised marketing campaign for a drug it was not allowed to sell. Disappointingly for the FDA, and surprisingly given the evidence, the US Department of Justice decided not to prosecute.
The decision was based partly on ignorance of the devastation thalidomide had wrought. ‘It would be difficult to prove that Kevadon’s distribution in the United States resulted in grave harm,’ the Department of Justice decided in 1964. ‘As far as is known, only one malformed baby has been born in the United States as a result of its mother’s use of Kevadon.’ This was wrong—the FDA itself knew of ten cases at the time, and more would have been found with a thorough investigation.
Merrell’s handling of thalidomide in the United States was shameful but it was not a one-off. At almost exactly the same time as its thalidomide fiasco, it was running an even more disgraceful campaign for an anti-cholesterol drug that would ultimately lead to criminal convictions for the company and three of its senior employees. The drug was MER-29, touted as lowering cholesterol and thus a weapon in the battle against stroke and heart attack.
In MER-29 material submitted to the FDA in 1959 (the year before its thalidomide NDA was submitted), Merrell extensively falsified animal test data and hid other crucial information. Unaware of this, in April 1960 the FDA allowed the drug’s sale under the brand name Triparanol.
Once on sale, MER-29 caused a massive spate of injuries, including severe skin damage and cataracts which sometimes resulted in permanent eye damage and even blindness. An estimated 5000-plus people were injured during the two years the drug was on sale. Merrell pushed the drug hard and responded to reports of side effects with a grab bag of tricks: falsely denying any knowledge of similar cases; suggesting other drugs must be to blame for MER-29 damage; and keeping the FDA in the dark. In a Grünenthalesque fashion, Merrell promoted its dangerous drug as ‘virtually nontoxic and remarkably free from side effects even on prolonged clinical use’. In November 1961 the FDA finally asked Merrell to withdraw MER-29 from sale. Merrell refused, saying it would defend MER-29 at ‘every step’. The serious injuries continued to pile up until in April 1962, acting on a tip-off, the FDA raided Merrell’s offices and found damning documents. Finally Merrell withdrew MER-29 from sale—this was only a few months after thalidomide had been exposed. Little wonder that soon afterwards the FDA raised the red flag over all Merrell applications. ‘In view of [recent events] we cannot consider the information submitted by this firm as reliable without thorough verification,’ a May 1962 FDA memo read.
In 1963 the company and three senior scientists pleaded no contest to criminal charges over MER-29: the company was fined $80,000 and the scientists each received six months’ probation. More than 1500 victims of the drug eventually brought legal claims, and the company paid out tens of millions of dollars in jury verdicts and settlements, and millions more to its lawyers.
As for Frances Kelsey, she became a legend. In July 1962 a young Washington Post reporter, Morton Mintz, wrote an article which ran on the front page. It began:
This is the story of how the skepticism and stubbornness of a government physician prevented what could have been an appalling American tragedy, the birth of hundreds or indeed thousands of armless and legless children.
Soon tales of Kelsey’s grit and savvy were a staple of news reports across the country. On 1 August 1962 Kelsey testified before a senate subcommittee; at a press conference on the same day President Kennedy singled her out for praise, urged tougher drug laws and called for vigilance about thalidomide. A week later, Kennedy presented Kelsey with the Distinguished Federal Civilian Service medal at the White House.
By this time another American woman had received a less welcome share of the thalidomide spotlight. Sherri Finkbine was a mother of four in Arizona and the presenter of a children’s television program, Romper Room. While pregnant with her fifth child and nervous about the pregnancy, Finkbine took some sleeping pills her husband had bought on a trip to England. Shortly afterwards, Finkbine read about thalidomide and asked her doctor to check whether Distaval was safe. ‘You’ve been taking pure thalidomide,’ was the response. Her doctor recommended an abortion. Finkbine agreed, but then gave an anonymous interview to a newspaper in order to spread a warning about thalidomide. Her identity leaked, and a brief legal skirmish ensued, during which the local county attorney, a father of nine, declared he would prosecute if the abortion took place. With time running out, Finkbine felt she had no choice but to fly to Sweden for the procedure. All of this occurred amid a blaze of publicity that caused enormous stress for a family in the midst of a crisis. Even the Swedish doctor’s confirmation in August 1962 that the terminated foetus had been badly malformed was reported on front pages in the United States.
The critical and immediate result of America’s brush with thalidomide was more stringent drug laws and new powers for the FDA. On 10 October 1962, President Kennedy signed into law the Kefauver Harris amendment to the 1938 Food, Drug, and Cosmetic Act. Named for its proponents, Senator Estes Kefauver and Representative Oren Harris, the law finally obliged drug manufacturers to prove their products were effective as well as safe. Kefauver had been campaigning for tougher drug laws for years and the country’s thalidomide near-miss gave him valuable ammunition. Over industry protest, the new laws obliged pharmaceutical companies to report adverse drug reactions to the FDA, give consumers accurate information about drug side effects and obtain informed consent from patients participating in clinical trials. The FDA also issued regulations mandating preclinical trials to establish basic safety for new drugs before broader and better regulated clinical trials.
Thalidomide forced many other countries to take drug regulation far more seriously: Germany, the UK and Australia were among many to introduce a drug regulating authority with substantial powers. Over the years the testing of drugs for an effect on the foetus has become increasingly stringent. Repeat animal tests, carefully observed small-scale clinical trials, ongoing doctor reporting and an elaborate risk grading system for drugs to provide information to doctors and consumers are all part of the arsenal aimed at preventing another thalidomide. Pregnant women, too, are generally far more cautious than they were fifty years ago about what they ingest. Yet not all risks can be eliminated completely and constant vigilance is necessary. Because as Frances Kelsey realised, and even with all the animal testing in the world, the first time a pregnant women is given a new drug there is always a degree of uncertainty.
Frances Kelsey worked at the FDA for the rest of her long and distinguished career—even in her eighties she was still a part-time employee. She remains a hero there. The annual Kelsey Award recognises excellence and courage in protecting public health. Among other honours is a school named after her on Vancouver Island, her birthplace in Canada. Yet she was not without her critics. James Goddard, a highly regarded FDA commissioner from 1966 to 1968, clashed with Kelsey over organisational reform. In a 1969 interview he praised her as ‘a lovely woman, a kind person’—then bent to the task of dismantling her reputation.
In retrospect one would have to say that Frances became a Presidential gold medal award winner and heroine because she procrastinated. There had been an [application] pending on thalidomide and Frances couldn’t make up her mind and just sat on the material…President Kennedy wanted to pin a medal on somebody and that somebody happened to be Frances Kelsey. So that was basically how Frances came to become a sacred cow in the FDA. You couldn’t do anything about Frances…Frances couldn’t make a decision. My appraisal of her is that if it were raining, she’d drown before she could make her mind up that she ought to go indoors. Indecisive.
Goddard’s analysis of why Kelsey blocked thalidomide is nonsense. But it underlines the degree of resentment Kelsey aroused, not just in industry, but even in her own workplace.
Kelsey, who turned one hundred in July 2014, was in her late nineties when Lyn Rowe’s case began in Australia. We hired a former US government historian who knew Kelsey to speak to her on our behalf, but we knew we would not have to trouble her as a witness. The historical documents recording Kelsey’s resistance to Merrell and thalidomide—the wisdom and tenacity that had saved the US from a full-blown disaster—would be more than enough. Kelsey’s caution also proved that some doctors and scientists were capable of greater insight than the complacent drudgery on offer at Grünenthal and Distillers. In fact, Distillers appeared to acknowledge as much.
On 3 August 1962 Dr Denis Burley, Distillers’ medical director, wrote to his counterpart at Merrell. Burley had just read a newspaper article which mentioned that in 1961 Kelsey had told Merrell she was concerned about thalidomide’s effect on the foetus. Burley was agitated. If the newspaper was correct, Kelsey had worried about the foetus months before the drug was withdrawn. He wanted his Merrell counterpart to tell him if that was true. The letter, from Grünenthal’s UK thalidomide licensee to its US licensee, can be seen as both a concession of failure by the thalidomide companies and a bouquet for Kelsey.
‘You can readily appreciate,’ Burley wrote, ‘that we are likely now to be faced with the question, “If Dr Kelsey suspected ill effects on the unborn babies on reasonable grounds why didn’t the Distillers Co. similarly suspect?”’