Dr. Edward Lammer, a geneticist who devoted his career to studying the causes of birth defects, died on February 20, 2016. He was 62, according to the New York Times.
Lammer’s most visible work, though far from his only important contribution to the field of birth defects research, was the identification of a link between the acne drug Accutane and what came to be known as “Accutane syndrome,” a host of craniofacial, nervous system and cardiovascular abnormalities.
How Do You Get Doctors To Stop Prescribing A Dangerous Drug? It’s Hard. Really, Really Hard.
Accutane’s risks were so high that the US Food & Drug Administration took the unprecedented step of requiring women use two forms of contraception while taking the drug.
Ensuring compliance with the System to Manage Accutane Related Teratogenicity (SMART), instituted between 2001 and 2002, required pregnancy testing every month, and detailed counseling on birth control methods. The drug’s manufacturer, Hoffman-La Roche, who developed SMART in line with FDA guidance, established an entirely new, albeit rudimentary, scheme to coordinate the efforts of physicians and pharmacists. After a female patient had satisfied the requirements of SMART, her dermatologist would affix a small yellow sticker to her prescription for Accutane. Pharmacists would only fill prescriptions with a yellow sticker, and would refuse to fill prescriptions more than 7 days after they were written.
It was a groundbreaking effort, and one, as we’ll see, that has been characterized as a “total failure.” But SMART itself was only one iteration in a long line of regulatory programs intended to reduce the number of women taking Accutane during pregnancy. In hindsight, it’s astonishing how long it took to get Accutane-related birth defects under control, especially when you consider that medical researchers have known about the drug’s dangers for more than 40 years.
Extraordinary Benefits, Extraordinary Risks
Many experts, including Dr. Lammer, noted well before the drug was recalled in 2009 that Accutane was one of the most dangerous products ever released onto the US market. It was also, however, “one of the most effective prescription drugs available,” wrote Julia Green in 2002, then a student at Harvard Law School. After taking Accutane for five months, Green noted, 85% of patients with severe recalcitrant cystic acne, the specific condition the drug was approved to treat, “achieve full remission.”
That extraordinary effectiveness certainly explained Accutane’s success, pulling in sales of almost $800 million per year for its manufacturer. Before the company lost its patent on the drug’s active ingredient, retinoic acid or isotretinoin, in 2002, sales for brand name Accutane accounted for a remarkable 8% of all the prescriptions sold in America.
Challenging The FDA’s Power To Protect
To the FDA, Accutane represented a unique challenge, a drug that was both radically effective and radically dangerous in equal measure. Mitigating the drug’s risks demanded an entirely new bureaucracy, a considerable expansion of the Food & Drug Administration’s power to regulate the pharmaceutical market and, ultimately, a manufacturer’s decision to stop making it.
But in 2001, when Hoffman-La Roche established the SMART program, Accutane’s risks would not have been unforeseen. Its devastating effect on fetal development did not come out of the blue, and its dangers were not simply missed by a generation of medical researchers. Long before the drug’s approval, the company’s own researchers were well-aware of Accutane’s teratogenic (causing birth defects) potential.
What Happens In Switzerland, Stays In Switzerland
Accutane’s active ingredient, a synthetic derivative of vitamin A called 13-cis retinoic acid, was generating buzz throughout Hoffman-La Roche’s laboratory as early as the 1960s. In those years, a doctor named Werner Bollag, employed at the company’s Switzerland headquarters, was investigating retinoic acid as a potential treatment for skin cancer. On that front, the chemical was a failure. But it was not a complete loss.
By 1971, Bollag had discovered that retinoic acid, while ineffective in killing cancer cells, was extremely effective in eliminating acne. Bollag abandoned the project, however, upon realizing that retinoic acid, already a known teratogen, would be able to cause severe birth defects. Remember that the thalidomide tragedy, in which a popular sedative caused a generation of children to be born with serious abnormalities, would have been fresh in Bollag’s mind. “The psychological climate” prevailing post-thalidomide, made it “inconceivable to develop an agent with teratogenic properties for the treatment of such a common complaint as acne,” the doctor would later say.
Bollag’s findings, though, never made it out of Hoffman-La Roche’s Swiss enclave. The company has long faced charges of concealing “unfavorable” research, not only from the public, but also from the medical establishment. Bollag’s work on retinoic acid seems to be a perfect example of the company’s tight-lipped approach to science.
Independent Discovery Opens Door For Accutane
In 1975, two researchers at the National Institutes of Health (NIH) made their own accidental discovery, the same discovery Bollag had chanced upon four years earlier: 13-cis retinoic acid cures severe acne. Instead of locking their findings away, Doctors Frank Yoder and Gary Peck published. Dr. Peck would later tell the Columbus Dispatch, “I didn’t know about the 1971 studies until 1986. My first reaction was that I wasn’t sure that I believed it in the first place.”
But with the backing of government research, La Roche decided to enter the acne business. The first step? Animal trials, which revealed that pregnant rodents administered the drug, newly-branded as Accutane, gave birth to offspring with facial deformities.
Female Patients Barred From Clinical Trials
Human subjects came next, but most of the testing centers used by La Roche explicitly excluded women from the trials. Those that did not exclude female subjects, required them to pass a pregnancy test before receiving the drug, and use contraception while taking it. In an affidavit submitted for a subsequent Accutane lawsuit*, David Benjamin, a doctor who worked on the trials, said:
“I felt that the risk of giving birth to a deformed child […] was so great as to make it ethically improper and scientifically foolish to give Accutane to women who were not using an effective form of contraception.”
While La Roche’s eventual application for FDA approval, submitted in 1981, would report that no human fetuses had been exposed to Accutane, Benjamin said differently. At least one woman became pregnant during his own trials, according to his affidavit, and, when La Roche found out, the company “urged” her to seek an abortion. Such inconsistencies wouldn’t come to light until much later.
Drug Reaches Market, With Down-Graded Safety Rating
After 7 months of review, the FDA approved Accutane for sale, but required far stricter labeling than the drug’s manufacturer had proposed.
La Roche wanted the drug put in pregnancy category C, which would indicate that animal studies had found the chemical teratogenic, but no adequate studies on pregnant women had been conducted. The FDA insisted on pregnancy category X, a message to doctors that in no way could Accutane’s potential benefits outweigh its known risks during pregnancy.
Despite this significant downgrade, the drug was still released with a label saying that no evidence of birth defects in human children had been found. It was not revealed that La Roche had actively avoided exposing women to Accutane during clinical trials, indeed had structured the trials to prevent this from happening.
“There Has Never Been A Drug Like It”
Reaching the US market in September 1982, Accutane was met by excitement and widespread accolades. In a Newsweek article titled “Now A Real Cure For Acne,” Matt Farber quoted an apparently overjoyed Stanford dermatologist who had told the reporter, “there has never been a drug like it.”
The drug sold, and it sold well, reaching 200,000 prescriptions within its first six months, according to Julia Green.
Meanwhile, some of the earliest researchers to investigate retinoic acid were voicing concerns – not only about the drug’s risks, but about the way it was being marketed. In a January 1983 letter to the editor of the Journal of the American Medical Association, Dr. Frank Yoder, who had conducted the early trials at NIH, wrote:
“I wish to express my concern and anxiety over the potential tragedy that might arise from abuse and misuse of isotretinoin (Accutane) […] the potential toxicity of this drug has been seriously underemphasized.” [emphasis added]
A similar article, written by Dr. Henry Roenigk, who had worked for La Roche on pre-approval studies, had been published even earlier, in May of 1982.
Beyond warning of Accutane’s dangers, Roenigk and Yoder made a risky decision, and released details from the trials, raising the ire of La Roche. That information, the company insisted, was confidential, and had no business making its way into the public sphere. Returning to the words of Julia Green, who wrote a detailed history of Accutane while at Harvard, Yoder even “claims that he received a hostile phone call from Roche executives.” Soon after, La Roche sent out letters to every scientist who had worked on an Accutane trial, advising them to keep company information confidential.
First Birth Defect Reports Surface
Another letter from the company would quickly follow, but this time it was intended for pharmacists and physicians.
In July of 1983, according to details revealed in a 1989 session of the FDA’s Dermatologic Drugs Advisory Committee, La Roche informed doctors of the first reported cases of human birth defects.
The FDA responded in short order, publishing an article on the “adverse pregnancy outcomes” in The Lancet, a prestigious British medical journal. La Roche strengthened its warning labels, and sent out red warning stickers for pharmacies to put on packages of the drug. But a petition submitted by Public Citizen, perhaps America’s leading public health advocacy group, which sought to place a “black box” warning on Accutane, was denied.
Public Citizen’s other demand, to add a patient insert explaining Accutane’s risks in easy-to-understand terms, was also turned down.
Labeling Revisions Prove Ineffective
At this point, nearly 400,000 patients had taken Accutane, and La Roche had received at least 20 reports of babies born with severe birth defects. After convening an advisory committee, the FDA decided to revise the warning label again, this time suggesting that female patients use birth control for at least one month before taking Accutane.
In March of 1984, the FDA “alerted blood banks not to accept blood from Accutane users,” Dr. Colonel Evans, the FDA’s group leader for dermatologic drugs, told a later advisory committee.
Similar warning letters, sent directly to thousands of dermatologists across the country, would only increase over the next four years. But first, in 1985, the FDA added a “black box” warning to Accutane, the same warning for which Public Citizen had advocated two years earlier.
Observers often frame this “black box” as the FDA’s way of stepping into the market; the agency’s most serious form of warning, black boxes are generally intended to reduce drug prescriptions, and remain the FDA’s most direct tactic for controlling a public health crisis involving pharmaceuticals.
Lammer: Accutane Increases Birth Defect Risk 250%
In this case, unfortunately, the black box did little to reduce Accutane prescription, or the number of babies being born with serious defects.
In October of 1985, Dr. Edward Lammer’s research first began to shape the debate. His study, conducted with colleagues at the Centers for Disease Control & Prevention, investigated more than 150 pregnancies in which fetuses had been exposed to retinoic acid. The group’s results were shocking. 95 of the women had elected to have abortions, likely on the advice of their doctors. 12 of the pregnancies had ended in spontaneous abortion, while 21 of the babies were born with major malformations, including a characteristic cluster of craniofacial, nervous system and heart defects. Only 26 of the infants had been born without birth defects.
Lammer and his co-authors estimated that Accutane exposure increased a child’s chances of being born with this specific collection of defects by more than 25 times. Despite these results, the first study to look beyond isolated patient reports, the drug remained “markedly over-prescribed,” says Dr. Evans, reaching pregnant women for the next three years.
Leaked Memo Blows Lid Off Birth Defect Crisis
On February 11, 1988, three scientists in the FDA’s epidemiology division sent out an internal memo, pleading with agency executives to begin thinking about taking Accutane off the market. “All efforts to date have been unsuccessful at protecting against pregnancy exposure,” they wrote, estimating that anywhere between 900 and 1,300 American babies had been born with major birth defects as a result. In response to the private letter, the FDA scheduled another advisory meeting.
Four days later, however, the memo’s contents were made extremely public, appearing on the cover of the New York Times. In addition to malformed infants, the Times reported, between 700 and 1,000 “spontaneous abortions” had been “attributed […] to the use of Accutane,” along with 5,000 to 7,000 women who had elected to have abortions “solely because of Accutane exposure and fear of birth defects.”
The Times raised several pointed questions, noting an apparently glaring disparity between the number of probable birth defect cases reported in the memo and a different number, only 62, that had actually been reported to the FDA. Had the agency approved Accutane too hastily? Had the drug’s manufacturer oversold its benefits, while downplaying its risks?
FDA & La Roche Accused Of Mishandling Situation
The Times’ revelations initiated a storm of media attention. Congresspeople accused the FDA of handling the problem improperly, choosing to schedule endless advisory council meetings rather than take active steps to reduce Accutane prescriptions.
La Roche did not escape blame, either. In the Washington Post, Dr. Yoder, at this point one of the company’s most vocal critics, accused La Roche of marketing its drug to non-dermatologists. Reminding observers that the company had actively barred women from participating in clinical trials, Yoder said, “it is incredible to require that in a study but not in a mass market situation […] this was very, very wrong.”
La Roche angrily shot back, critiquing the estimates of birth defect researchers as “essentially meaningless.” At the next committee meeting, held on April 26, 1989 (PDF transcripts), experts gathered by the FDA entered a contentious debate, one that, according to Julia Green, broke roughly between dermatologists and pediatricians. Dermatologists argued that, despite Accutane’s risks, the drug’s remarkable benefits for patients with severe acne could not be ignored. A scheme in which the drug would remain on the market, but only be available through restricted regional facilities, was eventually recommended to the FDA.
FDA Denies Committee’s Recommendations
In May, the FDA said that it would not be following the committee’s recommendations, citing worries over intruding on the prescribing decisions of individual doctors. Instead, the agency forced La Roche to add new warnings to Accutane’s label. The manufacturer would now have to provide physicians and their patients with informed consent documents. Pictures of a baby born with birth defects caused by Accutane were included in patient materials, and the FDA began monitoring the impact of what La Roche dubbed its Pregnancy Prevention Program.
By April of 1990, it was clear, at least to the FDA’s Fertility and Maternal Health Drugs Advisory Committee, that La Roche’s program wasn’t working. In (yet another) panel meeting, experts reported that Accutane use in “at-risk populations” remained high. Many doctors were not fulfilling the Pregnancy Prevention Program’s fundamental conditions, failing even to administer pregnancy tests before prescribing their female patients the drug. Still, the groups decided to wait it out, allowing La Roche to continue testing the effectiveness of its newly-instituted measures.
In the meantime, media attention had died, and soon the FDA turned its eye elsewhere. No more advisory committees would meet to discuss Accutane in the 1990s. Throughout this period, women had been filing personal injury lawsuits against La Roche, but the company, choosing to settle the cases confidentially, was able to conceal any sensitive information that may have been revealed in the course of litigation.
Lammer Identifies Pregnancy Prevention Program’s Failings
Edward Lammer remained a constant presence through this time period. He was dedicated, not only to the scientific research behind Accutane, but to the families and children affected most by the drug. He “made flights across the country to meet with and care for families affected by Accutane birth defects,” said colleague Gary Shaw in a recent SFGate obituary.
But it would be a series of interviews with California women who had taken Accutane during pregnancy, conducted by Lammer and co-workers at the CDC, that revived the FDA’s interest in stamping out the drug’s effect on families.
Lammer’s study, available here, found that while the majority of women were aware that Accutane could cause birth defects, none could say that they had been shown all of the materials required by La Roche’s Pregnancy Prevention Program. Shockingly, four of the women had never been presented with any of the materials beyond the pill bottle’s packaging. Eight of the women had not been taking contraception, and only ten had been made to take a pregnancy test before beginning treatment.
SMART: Stricter Regulations Do Little Good
La Roche was forced to respond, defining new prevention measures and even sending pregnancy tests to every known prescriber of Accutane. The FDA, meanwhile, convened another panel, in which La Roche representatives advocated for increased physician education. Dr. Lammer, in attendance, spoke out on the extreme dangers of Accutane, saying:
“in terms of medications, in terms of the magnitude of risk and the severity of malformations, this drug is really unique.”
The panel was not convinced by La Roche’s emphasis on education. Finally, the group voted to restrict access to the drug itself, proposing strict regulations that would eventually become the SMART system. Prescriptions would be limited to 30-day-supplies and pharmacists were required to verify a negative pregnancy test prior to filling a prescription.
But SMART was an abject failure. One year after the program’s implementation, a review of its effects found that exposed pregnancies had actually increased between 2002 and 2003, reaching into the hundreds, according to WebMD.
Regulatory efforts were faced by an additional problem, when La Roche’s patent on Accutane’s active ingredient, isotretinoin, expired. Generic manufacturers quickly entered the market, selling their own versions of the acne medication. Controlling sales of Accutane was no longer enough, and the FDA quickly established a new, even more restrictive program to replace SMART.
iPLEDGE: Unprecedented Regulations
As La Roche’s market share began to slip, and personal injury lawsuits against the company grew, the FDA instituted iPLEDGE, a program unprecedented in its scope and requirements. iPLEDGE remains in effect, although Hoffman-La Roche would leave the stage several years after the program’s implementation.
Today, any doctor who wants to prescribe a drug containing isotretinoin has to register with iPLEDGE, an electronic database maintained by the FDA. To ensure that patients are fully counseled on the drug’s side effects, they have to sign a document verifying that they have been informed. Once the patient has been entered into the iPLEDGE database, they are classified either as “females of child-bearing potential,” “females not of child-bearing potential” or “males.”
Before a prescription can be written, “females of child-bearing potential” must choose and use two forms of birth control and take two pregnancy tests, administered by their doctor, in consecutive months. After the second pregnancy test, a patient has to pass an online course about the potential risks of taking isotretinoin. Only then can the prescription actually be written, but only certain authorized pharmacies can fill it, and females of child-bearing potential have just seven days to pick up their pills.
To receive a new prescription, the patient must return to their doctor, take a new pregnancy test and be re-approved. While they aren’t required to take the online test, males are also restricted to 30-day-supplies of the drug.
By 2009, La Roche had had enough. Citing a paltry market share, and the costs of defending against numerous personal injury lawsuits, the company decided to stop selling Accutane in the US. But it did not disavow the drug entirely. In a press release published soon after its decision, the company said:
“Roche stands behind the safety of Accutane and the rigorous risk management program developed over decades of cooperation with the FDA and the American Academy of Dermatology.”
*Fetterolf v. Hoffman-La Roche, 651 N.E.2d 1309, (Ohio 1995)