一位勇敢的医生科学家如何拯救美国免于一场出生缺陷灾难

作者：斯蒂芬·菲利普斯 2020年3月9日

https://www.uchicagomedicine.org/forefront/biological-sciences-articles/courageous-physician-scientist-saved-the-us-from-a-birth-defects-catastrophe

1962年，弗朗西丝·奥尔德姆·凯尔西医学博士、哲学博士从约翰·F·肯尼迪总统手中接过总统杰出联邦公务员奖。图片来源：芝加哥大学图书馆特藏研究中心

美国食品药品监督管理局（FDA）总部礼堂里人声鼎沸。对于众多FDA官员来说，这是一个纪念该机构历史上一个重要时刻的契机。几乎整整半个世纪过去了，一位在改变药品监管格局的案件中扮演关键角色的人物重返FDA。

当时已96岁高龄且身体虚弱的弗朗西丝·奥尔德姆·凯尔西（Frances Oldham Kelsey）博士，由她的两个女儿陪同出席了此次活动。FDA领导在向她颁发“弗朗西丝·O·凯尔西博士卓越与勇气公共健康保护奖”之前，发表了讲话，凯尔西博士脸上洋溢着笑容。

“那场面非常感人，”FDA历史学家约翰·斯旺（John Swann）回忆道。

从1960年9月到1961年11月，凯尔西和几位FDA同事是美国免遭沙利度胺毒害的唯一屏障。沙利度胺在全球范围内造成了大规模的出生缺陷和胎儿死亡。当时，包括英国和德国在内的20多个国家都在使用这种药物，在德国，它被用于缓解孕妇的孕吐。

凯尔西于2015年去世，享年101岁。斯旺称，她是FDA“影响最为深远的险情”中的关键人物。这场风波中，芝加哥大学扮演了举足轻重的角色。凯尔西曾在芝加哥大学接受培训，后来与她未来的丈夫F·埃利斯·凯尔西博士（沙利度胺案的另一位关键人物）一同成为该校教员。此外，著名科学家尤金·盖林医学博士、哲学博士也毕业于芝加哥大学，他指导凯尔西并把她带入了美国食品药品监督管理局（FDA）。盖林是众多塑造了药品监管进程的芝加哥大学校友和教员之一。

正是在芝加哥大学，凯尔西第一次亲身感受到了药品监管不力的危害。1937年，作为一名研究生，她参与了20世纪另一桩具有里程碑意义的药品监管案件——该案引发了早期的监管改革，并赋予了FDA权力，而凯尔西在二十多年后正是利用这些权力发挥了巨大的作用。

“一门别致的小课程”

凯尔西在温哥华岛长大，一次偶然的机会，她结识了一位度假的老师，由此激发了她对生物学的兴趣。她在蒙特利尔的麦吉尔大学学习生物化学，并选修了一门名为药理学的“别致的小课程”。之后，她继续攻读硕士学位。1937年，刚从约翰·霍普金斯大学毕业的尤金·盖林在芝加哥大学创建了药理学系，凯尔西被录取为他的第一位博士生。

凯尔西抵达芝加哥时，正值全国性紧急状态。美国食品药品监督管理局（FDA）正紧急查扣S. E. Massengill公司生产的磺胺酏剂的库存。这种药物被广泛用于治疗感冒和其他感染，但却与全国范围内不断攀升的死亡人数有关。凯尔西被安排加入盖林组建的一个小组，负责识别这种有毒物质。该小组最终确定罪魁祸首是二甘醇，它是磺胺酏剂制剂中的一种溶剂。如今，二甘醇更为人所知的身份是防冻剂的活性成分。

这起丑闻暴露了现有监管的不足。马森吉尔公司未能对一种导致107人死亡的药物进行任何毒理学测试，然而，该公司在法律上唯一的过失是将该产品宣传为“灵药”（elixir）——这种描述通常用于酒精类溶液。此案促使1938年立法，要求公司必须向美国食品药品监督管理局（FDA）提交新药上市申请。如果FDA认为该药物不安全，则有60天的时间驳回申请。

芝加哥渊源

凯尔西获得博士学位后，在二战期间留在芝加哥大学从事抗疟疾药物的研究——这项工作使她对药物对胎儿的独特影响有了更深刻的认识。 1943年，弗朗西丝·凯尔西与同事F·埃利斯·凯尔西结婚。由于当时规定夫妻不得在同一所大学任教，因此，对医学更感兴趣的弗朗西丝·凯尔西——她已经完成了大部分所需的基础科学课程——于1946年进入大学医学院学习。

1950年获得医学博士学位后，她曾在《美国医学会杂志》担任编辑一段时间。1960年，盖林邀请凯尔西加入他领导的美国食品药品监督管理局（FDA）新成立的药理学中心。

仅仅一个月后，凯尔西就被指派审查一项助眠药物的上市申请。这种药物在其他国家已被广泛用于治疗孕吐等疾病。

“这不可能是完美的药物。”

凯尔西回忆起她对这项申请的第一反应时说道。

威廉·S·梅里尔公司（William S. Merrell Co.）获得德国制药商格伦泰尔化学公司（Chemie-Grünenthal）的授权，在美国销售沙利度胺的申请措辞十分强硬。“这药的前景太乐观了；它不可能完美无缺，没有任何风险，”她回忆道。

凯尔西和梅里尔公司随后的通信记录，让我们得以窥见一个遥远的监管时代：当时，对于新药申请所需提交的数据并没有正式的规定，制药公司将与美国食品药品监督管理局（FDA）官员“畅通无阻”视为一种特权。

但即便以当时的眼光来看，梅里尔公司为获得批准所做的努力也堪称激进。1960年，西德人每天要消耗100万剂沙利度胺。如果这种成功能够在美国——全球最大、利润最丰厚的药品市场——复制，该公司有望获得巨额利润。

“游说FDA是可行的，”斯旺说道，“但这次的游说力度更胜一筹。”

默里公司高管F·约瑟夫·默里博士（F. Joseph Murray, PhD）通过电话、信件和拜访等方式不断与凯尔西沟通。鉴于沙利度胺在其他地区的销售情况，默里公司认为在美国以Kevadon为品牌销售该药只是走个形式。但凯尔西坚持要求默里公司提供确凿的证据来支持其关于该药安全性的说法，并且拒绝屈服。

在默里公司最初的申请中，凯尔西注意到他们依赖轶事证词而非临床数据。她将申请材料交给了当时在美国国立卫生研究院担任药理学家的丈夫审阅。他指出申请材料中的某一部分“充斥着毫无意义的伪科学术语，显然是为了给化学知识匮乏的读者留下深刻印象”。他还注意到申请材料中“声称沙利度胺没有致死剂量”的说法非常不寻常。

“没有任何其他物质可以做出这样的声明，”他写道。 1961年2月，凯尔西在《英国医学杂志》上看到一位医生的来信，信中报告了他用沙利度胺治疗的患者中出现了周围神经炎（手脚神经损伤）的病例，这加剧了她的担忧。

“证明药物安全性的举证责任……在于申请人，”凯尔西在1961年5月5日写信给默里说。“在这方面，我们非常担心，您显然知道英国有周围神经炎的证据，但却没有坦诚地披露。”

愤慨的默里打电话给凯尔西的上司，医学博士拉尔夫·史密斯。“他说……他认为（这封信）有点诽谤，”史密斯报告说。“他询问公司是否就此事与凯尔西医生进行过直接沟通，如果是，这封信是否可以重新考虑。”史密斯确认凯尔西得到了机构的支持。

这份周围神经炎报告在另一个方面也意义重大。这促使凯尔西带着不祥的预感要求提供证据，证明该药物对胎儿无害。

梅雷尔公司坚称，这一问题和其他担忧都可以通过警告标签解决，并在9月份再次向美国食品药品监督管理局（FDA）申请批准。大约在同一时间，欧洲和澳大利亚开始陆续传出出生缺陷病例激增的消息。当局争相调查，最终确定沙利度胺是罪魁祸首。凯尔西曾四次援引1938年相关法律赋予她的监管权力，以数据不足为由驳回梅雷尔公司的申请。如今，在公司第五次尝试获得批准之际，梅雷尔公司通知凯尔西，他们将撤回申请。

全球悲剧

在全球范围内，约有8000名婴儿出生时肢体缺失或畸形（另有5000至7000名婴儿可能在子宫内夭折），这与孕妇广泛使用沙利度胺有关。

美国人也未能完全幸免于这场悲剧。美国食品药品监督管理局（FDA）随后确认了17例病例——其中10例与Merrell公司在其“调查性”试验中分发给1267名医生的Kevadon有关。但美国最终避免了像欧洲那样的大规模灾难。

然而，如果不是当时的政治运作，美国公众可能仍然对这场险情浑然不知。田纳西州民主党参议员埃斯蒂斯·凯弗维尔自1959年以来一直在调查制药公司——主要是它们的定价行为——但他未能争取到足够的支持来推动改革。在欧洲沙利度胺事件曝光后，这位参议员的幕僚深入调查了美国食品药品监督管理局（FDA）关于该药物的审议过程，并揭露了凯尔西与梅雷尔公司的交易。他们意识到此事具有巨大的政治价值，于是将其泄露给了《华盛顿邮报》。1962年7月15日，《华盛顿邮报》将此事报道给了毫不知情的全国民众。

一向谦逊的科学家凯尔西突然成为公众关注的焦点。1962年8月7日，约翰·F·肯尼迪总统在白宫举行的仪式上向她颁发了总统杰出联邦文职人员奖。

此案的强烈反响促使监管改革。肯尼迪于1962年10月签署的法案规定，任何药物的上市都必须获得FDA的批准。

地毯可以出售。

凯尔西被任命为新成立的FDA研究药物部门负责人，该部门负责在一线落实各项法规，主持一项全新的监管机制，彻底改变了药物监管，并进而影响了药物研发。

法规规定，药物安全性和有效性的证据必须“基于充分且控制良好的研究”。FDA以此为依据，推出了一系列全新的临床试验规程，明确了试验的不同阶段和对照研究。此外，FDA还采纳了1962年药物修正案中的一项条款，要求受试者必须签署知情同意书。

后来，凯尔西协助领导成立了新的科学调查部门，负责检查临床试验点，以核实数据的完整性。该部门因此获得了“凯尔西的警察”的绰号。她于2005年以90岁高龄退休。

如今FDA的工作重点与凯尔西鼎盛时期有所不同，但她的个人榜样至今仍激励着人们。 “我立刻就和她产生了共鸣，”莱斯利·鲍尔说道，她是凯尔西的继任者，担任科学调查部主任。“她是一位认真负责、恪尽职守的典范，她所建立的监管体系不仅影响了美国人，也影响了全世界。”

本文最初发表于2011年的《中途岛医学》杂志。

How a courageous physician-scientist saved the U.S. from a birth-defects catastrophe

The auditorium at the Food and Drug Administration’s headquarters was buzzing. For the massed ranks of FDA officials, it was an opportunity to mark a defining moment in the agency’s history. Half a century almost to the day, the central figure in a case that changed the face of drug regulation was returning to the FDA.

Frances Oldham Kelsey, MD, PhD, then 96 and frail, was chaperoned by her two daughters for the occasion. She beamed as FDA leaders honored her in speeches before presenting her with the Dr. Frances O. Kelsey Award for Excellence and Courage in Protecting the Public Health. 

"It was pretty moving," recalled FDA historian John Swann. 

From September 1960 through November 1961, Kelsey and a handful of FDA colleagues were all that stood between the nation and the drug thalidomide, which caused massive birth defects and fetal deaths throughout the world. At the time, the drug was available in more than 20 nations, including Britain and Germany, where it was given to pregnant women to ease morning sickness.

Kelsey, who died in 2015 at the age of 101, was the key figure in what Swann called the FDA's "most impactful near-miss."  It was a drama in which the University of Chicago loomed large. Kelsey had trained at the University and later became a faculty member alongside her future husband, F. Ellis Kelsey, PhD, another key player in the thalidomide case. The University also was home to renowned scientist Eugene Geiling, MD, PhD, who mentored Kelsey and brought her to the agency. Geiling was part of a clutch of University of Chicago alumni and faculty who shaped the course of drug regulation.

It was at the University that Kelsey got her first exposure to the perils of lax drug oversight. As a graduate student in 1937, she played a part in the other landmark drug regulation case of the 20th century — one that triggered an earlier round of regulatory reform and bequeathed to the FDA the very powers that Kelsey would wield to such effect more than two decades later.

"A quaint little course"

Growing up on Vancouver Island, Kelsey’s chance meeting with a vacationing teacher ignited an interest in biology. She studied biochemistry and “a quaint little course called pharmacology” at McGill University in Montreal. She stayed on to pursue a master’s degree, and when Eugene Geiling, fresh from Johns Hopkins, established a pharmacology department at the University of Chicago, she was accepted as his first PhD student in 1937.

Kelsey got to Chicago in the midst of a national emergency. The FDA was scrambling to impound supplies of the S. E. Massengill Co.’s elixir sulfanilamide, a medicine widely prescribed for colds and other infections that was linked to a mounting nationwide death toll. Kelsey was assigned to a team assembled by Geiling to identify the toxic agent. The group identified the culprit as diethylene glycol, used as a solvent in the preparation. It is better known today as the active ingredient in antifreeze.

The scandal exposed the inadequacy of existing regulation. Massengill had failed to conduct any toxicology testing on a drug that claimed 107 lives, yet the only negligence it had committed under the law was an infraction in billing the product as an elixir — a description reserved for alcohol-based solutions. The case spurred legislation in 1938 requiring companies to file an application with the FDA to market a new drug. If the agency was not satisfied the drug was safe, it had a 60-day window in which to reject the application.

Chicago connections

After earning her PhD, Kelsey remained at the University during World War II to conduct research into antimalarials — work that sensitized her to the distinct effect of drugs on fetuses. Having married colleague F. Ellis Kelsey in 1943, the couple faced restrictions on spouses serving on the same faculty, so Frances Kelsey — who was more interested in medicine and had already completed most of the basic science courses required — enrolled in the University's medical school in 1946.

After earning her MD in 1950, she worked for a time as an editor for the Journal of the American Medical Association. In 1960, Geiling recruited Kelsey to work at the FDA in the new pharmacology center he headed.

Just one month in, Kelsey was assigned to review an application to sell a sleeping aid already widely prescribed in other nations for morning sickness, among other conditions.

“This couldn’t be the perfect drug”

Kelsey’s memory of her first reaction to the application from the William S. Merrell Co. to market thalidomide, under license from German manufacturer Chemie-Grünenthal, in the United States is sharp. “It was just too positive; this couldn’t be the perfect drug with no risk,” she recalled.

The transcript of the subsequent communications between Kelsey and Merrell offers a glimpse into a distant era of regulation in which there were no formal requirements governing data submitted in support of new drug applications, and pharmaceutical companies regarded “open-door access” to FDA officials as a prerogative.

But even by the standards of the day, Merrell waged an aggressive campaign for approval. West Germans were consuming 1 million doses a day of thalidomide in 1960. If such success could be replicated in America, the world’s largest and most lucrative drug market, the firm could expect blockbuster profits.

“Lobbying at the FDA could be done,” Swann said, “but this took it up a notch.”

Merrell executive F. Joseph Murray, PhD, peppered Kelsey with phone calls, letters and visits. Based on thalidomide’s distribution elsewhere, Merrell regarded approval to sell it in America — under the brand name Kevadon — as a formality. But Kelsey insisted on hard evidence to back Merrell’s claims for the drug’s safety and refused to be browbeaten.

In Merrell’s initial application, Kelsey noted the reliance on anecdotal testimony in place of clinical data. She ran it by her husband, who then worked as a pharmacologist at the National Institutes of Health. One section of the submission he branded “an interesting collection of meaningless pseudoscientific jargon apparently intended to impress chemically unsophisticated readers.” Elsewhere, he noted “the very unusual claim that thalidomide has no [lethal dose].”

“No other substance can make that claim,” he wrote. Kelsey’s concerns escalated when in February 1961 she saw a letter from a physician in the British Medical Journal reporting cases of peripheral neuritis — nerve damage in the hands and feet — among patients he’d treated with thalidomide.

“The burden of proof that the drug is safe ... lies with the applicant,” Kelsey wrote Murray on May 5, 1961. “In this connection, we are much concerned that apparently evidence [of] peripheral neuritis in England was known to you but not forthrightly disclosed.”

An indignant Murray telephoned Kelsey’s boss, Ralph Smith, MD. “He said . . . he considered [the letter] somewhat libelous,” Smith reported. “He inquired whether the firm was dealing personally with Dr. Kelsey in this connection and if so whether the letter was subject to reconsideration.” Smith affirmed that Kelsey had the agency’s backing.

The peripheral neuritis report was significant in another respect. It prompted Kelsey to request, with grim prescience, proof the drug was not harmful to the fetus.

Merrell insisted that this and the other concerns could be dealt with through a warning label and in September initiated a fresh push for FDA approval. Around the same time, reports had begun to trickle in of a spike in birth defects in Europe and Australia. Authorities scrambled to connect the dots and identified thalidomide as the common denominator. Four times Kelsey had invoked the regulatory lever available to her under the 1938 legislation to reject Merrell’s application on the grounds of insufficient data. Now on the company’s fifth attempt to secure approval, Merrell notified Kelsey it was rescinding its application.

A global tragedy

Worldwide, the births of roughly 8,000 infants with missing or malformed limbs (a further 5,000 to 7,000 may have perished in utero) were linked to thalidomide’s widespread usage among pregnant women.

Americans did not escape the tragedy completely. The FDA subsequently identified 17 cases — 10 linked to Kevadon that Merrell had distributed to 1,267 doctors under the auspices of its “investigational” trial. But the country was spared the broad-based catastrophe visited upon Europe.

Still, the U.S. public might have remained oblivious to the close call but for contemporary political machinations. Democratic Senator Estes Kefauver of Tennessee had been investigating pharmaceutical companies — chiefly their pricing practices — since 1959, but he had failed to rally support behind reform. In the aftermath of the revelations from Europe about thalidomide, the senator’s staff dug into the FDA’s deliberations on the drug and unearthed Kelsey’s dealings with Merrell. Spotting the story’s political capital, they leaked it to The Washington Post, which reported it to an unsuspecting nation on July 15, 1962.

Kelsey, the self-effacing scientist, found herself thrust into the public eye. On August 7, 1962, President John F. Kennedy presented her with the President’s Award for Distinguished Federal Civilian Service at a ceremony in the White House.

The case’s visceral impact prompted regulatory reform. Legislation signed by Kennedy in October 1962 required the agency’s assent before a drug could be sold.

Kelsey was appointed to head the Investigational Drug Branch, the new FDA division charged with implementing the regulations on the ground, presiding over a new oversight regime that transformed drug regulation and, by extension, drug development.

The regulations stipulated that evidence of drugs’ safety and efficacy be “based on adequate and well-controlled studies.” The agency used the edict to introduce sweeping new protocols governing clinical trials, specifying distinct phases and control studies. It also adopted a provision of the 1962 drug amendments that required human subjects give informed consent.

Later, Kelsey helped spearhead the new Division of Scientific Investigations, tasked with inspecting clinical sites to vet the integrity of data. The group earned the moniker “Kelsey’s cops.” She retired at 90 in 2005.

The agency’s preoccupations today are different from those of Kelsey in her prime. But her personal example still resonates. “I felt an instant connection,” said Leslie Ball, Kelsey’s successor as director of the Division of Scientific Investigations. “She’s the embodiment of someone who took her responsibilities seriously and [impacted] not just Americans, but people worldwide through the regulatory structure that emerged from her.”

This story appeared in Medicine on the Midway in 2011.