The Enigma of Thalidomide
Everything has an origin story. Thalidomide has two.
The second origin, the one most relevant to the myeloma community, was reported by the New York Times on November 18, 1999: Thalidomide, arguably the most notorious drug in history, was shown to have unprecedented success in a significant number of patients with an incurable cancer, multiple myeloma, in a University of Arkansas study.
No one had ever seen results like those in the 150-plus years since Sarah Newbury died of myeloma. In hindsight, this ushered in more than a quarter century of unprecedented progress in myeloma patient survival.
Thalidomide’s first origin story has two endings. Mounting news about thalidomide’s risk to pregnant women became unavoidable. Having begun in 1957, every nation withdrew all their approvals for thalidomide no later than early 1964.
The United States, so the myth goes, was spared. But, nothing could be further from the truth. The numbers of thalidomide victims in the U.S. will never be known, especially including miscarriages and children sent to adoption before their parents even saw them.
There is no doubt FDA staffer Frances Oldham Kelsey averted a catastrophe. It was not, however, due to any sexist rationalizations, it was because she was one of the few people in the world prepared for this task. She turned out to be the right person in the right place at the right time. Sometimes history does get it right.
Let’s begin with the myth…
Thalidomide is an oral drug designed to help sleep, reduce stress, and overcome nausea in adults. It was approved for use in some parts of Europe, mostly Germany, and was mostly used from 1957-1963. Birth defects and miscarriages would, over time, be linked to thalidomide taken by expectant mothers. Thankfully, use was limited outside of Germany.
In the United States, the agency responsible for approving drugs and medicines is the Food & Drug Administration (FDA). A new FDA staffer, Frances Oldham Kelsey, was given the thalidomide portfolio as her first assignment. Her obstinance and slow walking of the approval process came at the same time the linkage between thalidomide and birth defects was confirmed, so the drug was never approved, averting catastrophe.
To recognize and honor her work, Frances was presented an award of recognition and thanks by President Kennedy. The thalidomide episode, combined with the timing of Kennedy’s New Frontier policies, motivated congressional leaders to modernize the FDA’s drug approval process, a relic from the 1906 legislation that established it.
Thalidomide was mostly forgotten as a drug candidate. A small number of researchers dispersed around the world thought it still might have therapeutic applications. Some countries had large stockpiles of unused pills. By the 1990s, researchers found it was effective in treating Hansen’s Disease, better known as leprosy. Shortly thereafter began the myeloma chapter of thalidomide’s many lives.
In reality, the story, as told in a page-turner by Jennifer Vanderbes, Wonder Drug: The Secret History of Thalidomide in America and Its Hidden Victims, is not so tidy.
Although multiple myeloma is only mentioned in two of the book’s final three pages, any history of the disease would be incomplete without the thalidomide story. Vanderbes weaves together seemingly unconnected threads of events, politics, science, and anecdotes to explain one of the most sinister eras of medical history.
Frances faced intense pressure, resistance, and outright sexism. Underestimated by her rivals, she was anything but a wide-eyed novice or a bureaucrat who luckily parlayed timely obstinance into personal glory as myths would have us believe.
A tomboy upbringing near Vancouver, Canada nurtured Frances’ curiosity and independence, a prestigious prep school led to McGill university and dashed hopes to study endocrinology eventually led her to Chicago, becoming a research assistant – no men applied – to E.M.K. Geiling.
Geiling was “determined to find a methodical way to discuss how drugs behaved in the human body.” He arrived at the University of Chicago in 1936 to set up a lab to use animals to test drugs before they were tried in humans, quite a novel concept then.
Over time the “lab fed chemicals first to chickens and ducks, and anything promising was then given to rats, dogs, and monkeys.” Frances was given “a chance to probe the metabolic process of drugs.” clinical trials, they began using federal and state prisoners who could volunteer as subjects to test drugs. Frances coordinated studies to assess drug safety and efficacy, getting experience very few had at the time.
Frances got an education few in her position would ever get, she became an expert in a nascent field, clinical pharmacology, internalizing its “key tenet…how drugs acted on the body.” Frances went on to earn her M.D. while working in Geiling’s lab, married another researcher, and gave birth to two girls. She took an offer to work in Washington, DC office of the FDA in 1960. The first drug approval file coming across her desk was thalidomide.
Approval seemed a routine matter. Glowing reports abounded about thalidomide’s ease of use and tolerability in the previous two years in Germany. Thalidomide’s German owner and manufacturer, Chemie Grünenthal, talked up its ease of use and effectiveness with no side effects. It was seemingly safe for all adults, induced sleep without next-day grogginess, pregnant women, elderly persons, anyone, really, all seemed to benefit. Contergan, the German brand name, became one of the most widely touted drugs of its time.
Investors around the world were attracted to thalidomide’s potential profitability. Marketing rights in the United States were sold to William S. Merrill Company (Merrill) and to Distillers in the U.K. and Commonwealth nations under the respective brand names Kevadon and Distaval. In all, the drug was distributed and used in forty-six countries between 1957-1963, the most in Germany.
As reports started to trickle in, Grünenthal did its best to minimize or even cover up bad news. For example, “a concerned Frankfurt doctor wrote to the firm: Contergan seemed to cause giddiness and balance disturbances in his elderly patients.”
Balance issues would come up again and again. “A pharmacist noted that patients on Contergan were losing warmth in their extremities. By July, another pharmacist, relating that his customers were suffering constipation and nerve damage, suggested Contergan might have ‘a negative effect on the circulation.’”
Moreover, a physician in Scotland had more worrying news: “Withdrawing the drug did not stop the pins and needles,” of peripheral neuropathy, a numbness of the hands and feet. This would become a telltale symptom myeloma patients would confirm again decades later.
Anecdotal evidence was mounting about a linkage between thalidomide and birth defects. A prominant American pediatric cardiologist became alarmed when a German dinner guest “spoke of an outbreak of birth defects in West Germany. A condition known as phocomelia – in which babies were born with flipper-like ‘seal limbs’ – was turning up in staggering numbers around the country, despite being previously so rare that most doctors would never encounter a single case.”
Was thalidomide teratogenic, meaning the drug could “cross the barrier” of the placenta to impact developing fetuses? A doctor in Australia and another in Germany, came to the same suspicion at roughly the same time. Widukind Lenz, the German, “explained how he had gone house to house in West Germany for months, surveying mothers of phocomelic babies, and had found one common link: thalidomide. Lenz knew that the crucial window for exposure was between thirty-four and forty-nine days after the last menstrual period, with even a single pill enough to harm a fetus.”
Marketing and legal tactics were trumping science and decency.
Grünenthal carefully orchestrated thalidomide’s marketing with Merrill and Distillers following suit. A May 1958 study observed no relationship between thalidomide and pregnancy, but “failed to share…specific data and omitted a crucial clarification: (it) never administered the drug to a single pregnant patient.” They did not disclose giving “Contergan to postpartum women only, and the nursing mothers – who accounted for more than half of his subjects – took the drug for approximately one week.”
In a drug toxicity study, mice were fed “five thousand milligrams per kilogram (one hundred times the human dose). The lack of a single fatality seemed strong confirmation of the drug’s safety.” But studies with opposite findings were suppressed, including one in which “more than half the rats were given a mere five hundred to one thousand milligrams per kilogram died.” In another, “All the experimental animals died, most within a day.”
Obfuscation and inconclusiveness became creative. “Within Distillers, objections now arose to using the phrase ‘no known toxicity’ in their thalidomide promotions, since the company’s own lab test hadn’t proven this.” Not knowing became a profitable virtue.
When asked by regulators around the world, “If thalidomide crossed the placenta, could it harm a child?” [Grünenthal’s] answer was ‘Improbable.’” Previewing Phillip Morris on smoking and Exxon on climate change in later years, Grünenthal had already “swiftly managed to prove by experiment that the drug did traverse the placenta” and sealed it internally.
Even dirty tricks, like “circulating news of [Lenz’s] Nazi father,” although true — his father was a bureaucrat with unclear duties and Lenz was a child — had nothing to do with Lenz. “A Canadian reporter had even been told that Lenz decided to vilify thalidomide because of psychic ‘visions.’”
All these efforts had some success. Even though all this information was becoming public, “the drug was still being sold over the counter throughout most [Germany]” and it was “not until August 1, 1961” that “three German states…finally place Contergan on prescription.” (Just twelve days before the Berlin Wall and partition between East and West Germany were created.)
Back in the U.S. media coverage including photo essays in Life “would solidify visuals for readers that thalidomide was a tragedy overseas…An exposé in the National Enquirer cemented this idea.” They did nothing to sway Frances’ views. Pressure to approve Kevadon continued, unrelenting. Even elements within the FDA were wary of her.
The FDA had, for decades, been something of an old boys’ club. “Questionable drug applications received friendly support. The agency essentially helped pharmaceutical firms circumvent its own regulatory hurdles.”
Frances knew she had little recourse if she succumbed to pressure to allow the approval process to begin formally because “the FDA lacked the legal power to recall a drug in the clinical trial phase.” Plus, Merrill’s tactics lined up with similar efforts worldwide.
Although thalidomide was not FDA-approved, on August 23, 1962, the agency reported “At least 19,822 Americans had been given” the drug, “roughly 25 percent more than its first estimate. Of those, 3,760 were women of childbearing age, and 624 were pregnant.” How could this be? Turns out “that over five years, five different drug firms had shipped the drug throughout the country, under different labels and trade names, in different countries.” Thalidomide was loose in the United States. No one knew where it was. The few clinical trials existing then had no consistent standards.
Furthermore, “no mention [was made] of the seven-hundred-plus doctors…dispensing the drug to more than twenty thousand Americans” Worse, it was being distributed haphazardly with no record keeping. “In Seattle, an obstetrician told (FDA inspectors) he had given several hundred pills to pregnant women at a charity (event) and destroyed the records.” One doctor later admitted that “he couldn’t explain what he’d done with the first seven hundred pills Merrill had shipped him” after denying having any thalidomide.
“In an act of stunning negligence (Merrill) wrote to thirty-seven doctors named in its New Drug Application (to the FDA)” about negative drug interactions but “it did not contact the one thousand additional doctors enlisted by its” sales forces. Soon after, Merrill reported 580 kilograms of thalidomide “had been distributed within the United States, but an additional 116 kilograms were entirely unaccounted for.” Further reports only added to public anxiety.
Upon learning this, Senator Jacob Javits (R-NY) posed the troubling question policymakers and the public were just beginning to understand at a Senate hearing, “Were doctors in the United States allowed to hand out experimental drugs without a patient’s knowledge?” The answer was yes. It was not comforting.
Frances’ suspicions endured. Her unique pharmacological training meant she was one of the few who understood thalidomide’s chemical structure was unstable and could cause unpredictable biological problems. Even the paperwork was shoddy. “The dates? The dosages? Frances bristled when she saw the animal data in the brochure for doctors.” Their “reports read, to Frances, like wildly enthusiastic testimonials from a bygone era, absent any scientific observation.”
In a fortunate turn, she met and became a close friend of Barbara Moulton, a former FDA inspector who resigned in 1960 in support of congressional testimony about agency corruption. An insider’s insider, she spent hours with Frances explaining the details of FDA’s policies and the thalidomide approval process, which was filled with absolute deadlines.
Moulton advised Frances to use “loopholes” in FDA regulations to “deem the Kevadon application ‘incomplete’ and ask Merrill for more data, restarting the sixty-day clock. It was a delay, not a denial, but it would keep the drug off the market while Frances gathered more information.”
Moulton became Frances’ secret weapon in congressional hearing, bolstering her credibility. Members of Congress and the public were soothed by Frances’ matter-of-factness and enthralled with her command of the facts ranging from scientific to bureaucratic detail. She turned out to be politically successful by consciously being non-political.
As a myeloma advocate since 1998, when the use of thalidomide in myeloma became known to most in the field, I was bewildered upon learning that the second ending of the first origin is ongoing. While it may be the most important issue Vanderbes raises, I will discuss it least today.
This story is still being lived by surviving children born with thalidomide-caused disabilities. Although news of the drug’s use in myeloma was public in 1998-9, it seems to have gone unnoticed by those who survived thalidomide-induced disabilities. All of them understood the unique obstacles thalidomide caused for each, few knew about others like them, and still fewer knew about the positive revolution thalidomide was unleashing in myeloma.
Today they are adults in their early-to-mid sixties. Although late and, in most cases, too meager, every nation in the world with thalidomide-affected citizens provides them with various types of support. On the other hand, “To this day, the United States remains the world’s sole developed nation to refuse support to a single thalidomide victim” despite documented proof of government negligence.
In the United States, Merrill and other companies mostly escaped accountability. Their consistent tactics of sowing doubt and uncertainty were aided by time: legal statutes of limitations. As a result, many have lived their lives in isolated poverty facing difficult physical and social barriers. Others have been fortunate to be among loving, nurturing families and communities.
Just prior to the pandemic, American thalidomide survivors held their first national meeting in San Diego. Social media helped in bringing together more than one hundred attendees. Vanderbes attended, as did Frances’s surviving children. For many, it was the first time they met someone else “like them.” (Newly diagnosed patients and caregivers attending a support group meeting for the first time can relate!)
One can’t help but ask why governments and societies haven’t done more to make the consequences of the thalidomide tragedy more tolerable for its victims. Especially when considering how much profit was made from the second origin story of thalidomide and its consequences.
Thalidomide’s patent was bought and sold a few times until a mid-1990s acquisition by Celgene. When asked by the University of Arkansas to try the drug on myeloma, the disease was not part of their business plan, which would never be the same once the news success in myeloma came out.
Celgene created a safety protocol for use of thalidomide that became the source of most of its profits, not the drug itself. Each prescription had to start from scratch, refills were not automatic. Since it was approved for use in leprosy, doctors could start to use it “off-label,” allowing it to be used for disease for which it was not specifically approved. At least ninety percent of thalidomide was off-label. The FDC did not make it on-label for myeloma until 2006.
Celgene earned billions of dollars. Lenalidomide, thalidomide’s successor, would become a backbone drug for myeloma therapy soon after, making myeloma among the most profitable cancers to treat. Questions about how Celgene made its pricing and compensation decisions even drew the ire of members of Congress in hearings.
Thalidomide is still used in most part of the world, rarely in the United States. That’s a topic worthy of discussion in the future as well.
Barbara Moultrie summed up the point of it all at a congressional hearing: “No drug is ‘safe,’” she argued, “if it fails to cure a serious disease for which a cure is available.”
This echoed a standard line of Robert Kyle’s warning to patients: “There is no such thing as a safe drug.” He would point out that even aspirin, arguably the safest and most used drug in history, was responsible for a handful of deaths due to allergic reactions every year.
Thalidomide isn’t the only drug with safety issues. But like a cat, it has many lives. Still.
My goal in writing occasional reviews like this one is a bit different than regular newspaper or magazine reviews. I’m reading them through the lenses of a myeloma advocate, looking for the relevant lessons and connections for its community. It is not to provide a comprehensive overview, but instead, how it fits into the history and future of myeloma.
Although this tragedy occurred more than a half century ago, Vanderbes makes it seem current.
Wonder Drug: The Secret History of Thalidomide in America and Its Hidden Victims, by Jennifer Vanderbes, Random House, 400 pp., $28.99 (Hardcover)