Frances Oldham Kelsey；The Political Economy of Thalidomide

http://harvardpress.typepad.com/hup_publicity/2015/08/the-comparative-political-economy-of-thalidomide-monica-prasad.html

10 August 2015

The Political Economy of Thalidomide

Dr. Frances Oldham Kelsey, who became famous for withholding Food and Drug Administration approval for Thalidomide in the early 1960s, died last week at 101. Notice of her death has been accompanied by retellings of the FDA’s early days, and of Kelsey’s heroic stand against the morning sickness drug later linked to terrible birth defects in other parts of the world. Rather than merely a story of one dogged researcher’s triumph, though, sociologist Monica Prasad sees the Thalidomide case as clear evidence against the notion of a laissez-faire United States government. Indeed, in The Land of Too Much: American Abundance and the Paradox of Poverty, excerpted below, Prasad offers the episode as an entry point for considering the weak U.S. welfare state as the product not of an unbridled free market but of a unique and remarkable system of American regulatory institutions.

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Doctors began to notice the first cases of the strange disease in 1959. Thousands of babies with stunted limbs and other severe birth defects were being born all over Germany, Britain, Sweden, Australia, dozens of countries. Many died from their deformities at birth. Others would experience difficulties as they grew, including heart disease and spina bifida. Through 1960 and into 1961, all around the world, the number of cases mounted.

In 1961 two doctors traced the problems to a sedative called Contergan that had been developed in Germany and marketed worldwide under other names. Contergan was prescribed for insomnia and for nausea. It did not seem to have side effects and was not toxic in overdose, and it became so popular that it was called “West Germany’s baby sitter.” But as the incidents rose, pediatricians began to suspect and then to document an extremely strong association between the birth defects and Contergan taken in the first trimester of pregnancy. It was withdrawn from the market in 1961, and eventually conclusive evidence emerged of how the drug caused the malformations. By then it had already affected over 10,000 children in “one of the greatest medical disasters of modern times.”¹

Amid the calamity, a stunning and justly celebrated act of resistance came to light: under the name Thalidomide, the drug had been kept off the American market by Frances Kelsey, a researcher at the Food and Drug Administration (FDA) with a hunch and a streak of self-confidence that led her to delay approval again and again, until the truth was finally known. Kelsey was well prepared for the task. She had done her graduate work in pharmacology at the University of Chicago (she was admitted on the assumption that “Frances” was a male name) in the lab that had identified the toxicity of an over-the-counter drug that had killed 107 people in 1937. The lab’s work led to the Food, Drug, and Cosmetic Act of 1938. During the war, Kelsey’s work on pregnant rabbits had shown her that drugs can cross the placental barrier and that pregnancy can change the body’s response to a drug.

The Thalidomide application was Kelsey’s first case at the FDA. Kelsey realized that the manufacturer’s and distributor’s studies documenting no adverse effects in animals were irrelevant because the drug also did not cause sleepiness in those experimental animals as it did in humans; it simply worked differently in humans. She called it “a peculiar drug.” Because the drug was aimed at relieving minor symptoms, she chose to wait for better evidence of its safety.

While there was no rush for Kelsey, there was a rush for the American distributor, Richardson-Merrell, which wanted approval in time for Christmas—Christmas apparently being the high season for sedatives—and sent representatives to make repeated visits and phone calls to Kelsey. As the months dragged on, nineteen months in all, the company complained to her superiors that Kelsey was being unreasonable. But she held her ground. Again and again the company resubmitted the application, arguing that any effects were so rare as to be negligible, and again and again Kelsey returned it for insufficient evidence of safety. Soon the European doctors had pieced together their conclusions, and Thalidomide stayed off the American market. Twenty cases of birth defects from suspected administrations of Thalidomide in the first trimester were documented in the United States, from travelers bringing the drug from Europe with them and from an early trial distribution of the drug. But the widespread tragedy that would have occurred had Kelsey been less persistent had been averted.

Historians of the episode have emphasized the role of Kelsey, and it is true that Kelsey’s ability to resist industry pressures requires the kind of explanation that cannot be reduced to social context and can really only be plumbed by close attention to the mysteries of human character. But there is one element in the story that does point to social context, and it does not reduce Frances Kelsey’s heroism to note the circumstances that allowed her resistance to be so powerful: the U.S. government has a long history of disapproving drugs available in other countries, a “drug lag” that has been the source of complaints from doctors as well as industry. This history of stronger drug regulation placed Kelsey in a position to disapprove Thalidomide. In Britain at the time, “any drug manufacturer could market any product, however inadequately tested, however dangerous, without having to satisfy any independent body as to its efficacy or safety”.² Germany had a tradition of self-regulation by pharmacists and physicians. All that the government could do was recommend that a drug be removed from the market after the fact. In these countries there were no Frances Kelseys because there were no FDAs.

The divergent responses to the Thalidomide tragedy also demonstrate the tradition of stronger American drug regulation. Although Europe was more heavily hit, it was the United States that responded with tougher drug laws, so much so that by the 1970s, a widely reported study by physician William Wardell (1973) found that Great Britain had introduced four times as many drugs onto the market as the United States throughout the 1960s. A follow-up study by Wardell and Louis Lasagna (1975), head of Johns Hopkins’s Division of Clinical Pharmacology, found the United States lagging France, Great Britain, and Germany by one to two years in drug approvals. One particular drug for hypertension was introduced in Europe ten years before it was approved in the United States, and Wardell wondered how many deaths had been caused by that delay. In 1985, one study found that it took thirty months to approve a drug in the United States compared to six months in France and Britain; and other research showed that in Britain, 12% of drugs were found unsafe after having been introduced onto the market compared to only 3% in the United States, indicating a stricter preapproval process in the United States.

Although the drug-lag debate fed into a building deregulatory fervor, the issue of drug regulation did not allow for easy solutions. For example, one drug that Wardell had held up as an example of an important drug unnecessarily kept off the American market—Practolol—was later shown to have serious side effects and was eventually withdrawn from the market in Europe. Although the case did not receive much publicity, the FDA had once again been right where other countries had been wrong. While analysts tried to estimate and weigh the suffering caused in Europe by rushed approval, as in this case, against the suffering caused in the United States by delayed approval in other cases, the uncertainties ensured that the FDA would continue on its cautious path throughout the 1970s.

The story of Thalidomide has been interpreted from many different angles—as a tale about the predations of the drug industry, as a warning about the risks of unfettered scientific advance, as a parable of the difficulties of assessing risk in our complicated societies, as a way into the study of the social location of science. But the most surprising fact about it is that in this case it was the laissez-faire United States—the country that supposedly hates state intervention, the country allegedly most favorable to the market—that was the most successful at using the state to protect consumers from a pharmaceutical company wanting to market a dangerous drug, while the drug was welcomed all over statist Europe.

This is a surprise as all our theories of comparative political economy, in the disciplines of sociology, political science, and economics, insist that the United States is a liberal state with a strong tradition of minimal state intervention (using “liberal” here in the classical sense of an ideal of limited government). Within sociology, some analysts argue that national differences in political economy follow different cultural patterns, that the United States has a political culture that is “oriented to the reinforcement of market mechanisms to ensure economic liberties and effect growth, and the prevention of other forms of government meddling with economic life”³ and that the United States “proclaims more than any other [economy] its conformity to the laissez-faire ideals that anchor the dominant streams of modern economic theory.”⁴ Others argue that because of its weak labor movement and absence of a labor-backed political party, the United States has not been able to pass the policies that “modify conditions for and outcomes of market distribution.”⁵ Within political science the dominant tradition of comparative political economy, the “varieties of capitalism” approach, sees the United States as a “liberal” regime in which “deregulation is often the most effective way to improve coordination,”⁶ coordination problems are resolved through market-based rather than state-based solutions, and state intervention is used only to reinforce—not to undermine—market outcomes. The equally strong tradition of historical institutionalism argues that the American state has been unable to develop because of the multiple checks and balances in the political structure. Within economics, two prominent scholars have recently given the national culture argument a familiar twist, arguing that greater racial heterogeneity in the United States has led to persistent preferences for minimal state intervention because citizens believe that intervention will benefit those from other racial groups.

If the United States is so market oriented, so beholden to the weakness of labor, so liberal, and so suspicious of state intervention, where did that pattern of stricter drug regulation come from? Hundreds or thousands of Americans are walking around today with intact limbs and bodies because of the successful intervention of the American state against the market.

If drug regulation were the only policy to show this pattern, we would be justified in considering this story an absorbing trifle or in brushing it away with teleological arguments that consumer regulation preserves the market.

But in recent years, historically oriented scholars have shown that this example is not an exception—indeed, it seems to be the rule. William Novak summarizes this new generation of scholarship: “[T]he American state is and always has been more powerful, capacious, tenacious, interventionist, and redistributive than was recognized in earlier accounts of U.S. history” (2008, 758). So far, none of this nearly two decades’ worth of work has made it across the disciplinary divide to reorient comparative political economy. All of our theories of comparative political economy—with their implications for our understanding of economic growth and poverty reduction—have been built on a picture of American history that is turning out to be incorrect.

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1. Akhurst, Rosemary. 2010. “Taking Thalidomide Out of Rehab.” Nature Medicine 16(4): 370.

2. Ceccoli, Stephen. 2002. “Divergent Paths to Drug Regulation in the United States and the United Kingdom.” Journal of Policy History 14(2): 139.

3. Dobbin, Frank R. 1994. Forging Industrial Policy: The United States, Britain, and France in the Railway Age. New York: Cambridge University Press: 24.

4. Fouracde, Marion. 2009. Economists and Societies: Discipline and Profession in the United States, Britain, and France, 1890s to 1990s. Princeton: Princeton University Press: 254.

5. Korpi, Walter. 1983. The Democratic Class Struggle. London: Routledge and Kegan Paul: 173.

6. Hall, Peter A., and David W. Soskice. 2001. Varieties of Capitalism: The Institutional Foundations of Comparative Advantage. New York: Oxford University Press: 9.

凱爾西任職美國FDA時，與藥秤合影。（美聯社）

1960年代，歐洲、加拿大和中東地區的數千名孕婦，因為懷孕期間服用了處方藥「沙利竇邁」（thalidomide）而產下畸形兒。沙利竇邁原本也將在美國上市，但當時食品藥物管理局（FDA）負責審查新藥的官員凱爾西（Frances Oldham Kelsey）發現藥商的檢驗報告不太對勁，堅持不發許可證，沙利竇邁因此未能在美國上市，讓2萬名美國人免受畸形之苦，凱爾西也因此被譽為英雄。

凱爾西7日過世，享年101歲。在她過世前一天，凱爾西在女兒位於倫敦的家中獲頒加拿大勳章（Order of Canada）。

菜鳥遇大案

法蘭西絲‧奧爾德姆‧凱爾西1914年出生於加拿大卑詩省（British Columbia），1935年拿到麥基爾大學（McGill University）理科碩士學位，隔年進入芝加哥大學（University of Chicago）攻讀藥理學博士學位。完成學業後，凱爾西留芝加哥大學擔任藥理學教授，在1943年和同事弗里蒙特．埃利斯．凱爾西（Fremont Ellis Kelsey）結婚，育有兩女。

1954年，凱爾西夫婦搬到南達科他州的弗米利恩（Vermillion），在南達科塔大學（University of South Dakota）執教，並在1956年歸化美國籍。1960年，凱爾西進入FDA工作，主要負責審查即將上市的新藥，沒多久，凱爾西就碰到了沙利竇邁的案子。

藥廠強力施壓

製藥公司梅里爾（William S. Merrell）在1960年9月向FDA提出申請，希望能批准沙利竇邁上市，當時，沙利竇邁已在歐洲的20多個國家和加拿大熱銷，主要用來減輕孕婦在懷孕初期的害喜症狀。梅里爾公司已準備靠著沙利竇邁大撈一筆，倉庫裡早就備好數噸存貨，也將沙利竇邁提供給1000位醫師做為「研究用藥」，萬事俱備，只差FDA的核准。

當時，美國藥物監管的相關法令雖已建立，但並沒有嚴格執行，大部分的新藥都會獲准上市。梅里爾公司更宣稱，沙利竇邁安全又有效。但到了凱爾西手上，她認為沙利竇邁的成分報告不夠詳盡，要求梅里爾公司提供更多沙利竇邁的毒性分析等數據，否則無法核准上市。

在歐洲與加拿大等國成功上市、讓製藥公司賺飽飽的新藥，居然在美國踢到鐵板，數百萬美金的利潤恐怕將要拱手讓人，梅里爾公司的高層被逼急了，用各種方式向FDA施壓，也批評凱爾西「雞蛋裡挑骨頭，固執、不可理喻的官僚作風。」

基於專業駁回

儘管如此，凱爾西拒絕操之過急，堅持要求梅里爾公司提供更多證明。1961年2月，凱爾西在《英國醫學期刊》（British Medical Journal）上讀到一篇文章指出，沙利竇邁可能造成四肢麻痺，凱爾西馬上通知梅里爾公司。

隨著時間過去，沙利竇邁的安全性越來越受到質疑，許多研究紛紛問世。5月，凱爾西再度警告梅里爾公司，沙利竇邁可能影響胎兒的四肢發育，但梅里爾公司認為凱爾西的證據不足。

凱爾西和梅里爾公司的高層會面後寫道：「我總覺得，有關這種藥物，他們沒有對我完全坦白，每一次會面都是這樣。」

6個月後，1961年11月，歐洲研究顯示，沙利竇邁可能導致胎兒罹患海豹肢症（phocomelia），許多國家也開始出現「沙利竇邁兒」，凱爾西正式駁回沙利竇邁的上市申請，並收回醫生手中的研究用藥，不幸的是，沙利竇邁並沒有完全回收，造成17名嬰兒畸形。

最終研究顯示，沙利竇邁可穿透胎盤，影響胎兒發育。歐洲和加拿大有近1萬名嬰兒因此四肢畸形。

利潤與專業，孰輕孰重？

《華盛頓郵報》（The Washington Post）報導了凱爾西力抗製藥公司的經過，稱她是「英雄」。凱爾西之後繼續在FDA工作，也推動了1962年的藥品監管相關法令的修法，新藥上市需提出嚴謹的成分、效果、副作用分析。

凱爾西在FDA服務45年，2005年從FDA退休。2010年，FDA設立凱爾西獎，用來表彰FDA中的優秀員工。

有研究指出，若不是凱爾西在最後關頭擋下沙利竇邁，美國可能有超過2萬名嬰兒因此受害，凱爾西傑出的判斷力成功阻止悲劇發生。

凱爾西一生獲獎無數，1962年，時任美國總統的甘迺迪（John Fitzgerald Kennedy）特地授予凱爾西傑出聯邦公民總統獎（President's Award for Distinguished Federal Civilian Service），她也在2000年入選美國國家女性名人堂（National Women’s Hall of Fame），和海倫凱勒（Helen Keller）、艾蓮娜‧羅斯福（Eleanor Roosevelt）等傑出女性並列。

不畏藥廠壓力，擋下沙利竇邁的凱爾西7日辭世，享壽101歲。（美聯社）