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`FOCUS - 15 of 24 DOCUMENTS
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`Copyright 1997 Globe Newspaper Company
`The Boston Globe
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`September 14, 1997, Sunday, City Edition
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`SECTION: FOCUS; Pg. D1
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`LENGTH: 2112 words
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`HEADLINE: Thalidomide returns, as do fears;
`MEDICINE;
`Mary Leonard is the Globe's Focus writer.
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`BYLINE: By Mary Leonard, Globe Staff
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`BODY:
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`In 1960, a new federal regulator who doubted the safety of a sedative used widely in Europe, Japan, and Canada
`kept the drug off the American market and averted a medical catastrophe. For the middle-aged and older, the word
`"thalidomide" still conjures up tragic images of grossly deformed babies - as many as 10,000 worldwide - born to
`women who took as little as a dose or two for morning sickness when they were pregnant.
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`Dr. Frances Kelsey, the alert investigator for the US Food and Drug Administration, today retells the thalidomide
`story with the dispassion of a scientist and no hint of pride, despite her legacy of opening the era of national consumer
`protection. Steadied by a cane and speaking in a voice that cracks with age, Kelsey, 83, says she still worries about
`thalidomide - she calls it a "fascinating but rather difficult drug" - as the FDA moves toward allowing its sale.
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`Thalidomide, remarkably, is reemerging. A known teratogen - an agent that causes birth defects - it initially is
`being aimed at a tiny population of carefully monitored patients who suffer a disfiguring form of leprosy.
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`But ethicists, epidemiologists, and patient advocates agree that even the smallest market, the best intentions, and the
`most extraordinary precautions can't reduce the birth-defect risk to zero. They say that thalidomide-damaged babies will
`be conceived and born in the United States if the drug becomes available, as is eventually expected.
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`What makes that prospect even more likely is that thalidomide is showing early promise in treating a host of other,
`far more widespread diseases, including AIDS, tuberculosis, and cancer. Among medical researchers, the anxiety at
`thalidomide's awesome risks is nearly drowned out by the excitement over its potential benefits and uses.
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`Indeed, if the old thalidomide story was a black-and-white morality play with heroes, villains, and victims, the '90s
`revival is more like technicolor experimental theater: It's heavily nuanced in the ethos of "acceptable levels of risk," and
`has a cast of AIDS activists, eager biotech companies, product-liability lawyers, consensus-seeking government
`regulators, and empowered interest groups, including women's health watchdogs and even some thalidomide victims.
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`Case IPR2015-01103
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`CELGENE EXHIBIT 2068
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`Thalidomide returns, as do fears;MEDICINE;Mary Leonard is the Globe's Focus writer. The Boston Globe September
`14, 1997, Sunday, City Edition
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`"We'll never accept a world with thalidomide in it," said Randolph Warren, chairman of the 125-member
`Thalidomide Victims Association of Canada. "But how can we, of all people, suggest that others who are suffering
`should be denied a drug that can help?"
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`Warren, whose mother took two teaspoons of the drug for morning sickness, was born in 1961 with a condition
`called phocomelia. It left him with no legs and only four digits on each hand. Many babies died. Those who survived
`had terrible deformities and severe disabilities: flippers instead of arms; instead of legs, toes attached at the hip; faces
`lacking eyes; missing internal organs; free-floating bones.
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`Worldwide, people in the early 1960s reacted with shock to newspaper stories tying thalidomide to the birth
`defects. But it was the graphic photos of thalidomide babies that appeared in Life and other magazines that made them
`gasp. To make sure that memory isn't lost - or to impress it on younger people for the first time - manufacturers of the
`drug plan to include a photo of a thalidomide baby on product warning labels.
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`Warren believes the best hope for finding a safer form of thalidomide is to give those manufacturers an incentive
`now, by approving the drug's sale. An FDA advisory panel this month recommended issuing the first US license for
`thalidomide. The agency now is studying that recommendation and is expected within months to approve the
`thalidomide marketing application of Celgene Corp., a New Jersey biotechnology company, along with a stringent set
`of safety guidelines.
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`Once a drug is on the market, however, physicians are free to prescribe it as they please, and no one is under any
`illusions that thalidomide's use will be limited to leprosy. AIDS is the expected primary market and potentially a
`lucrative one: Some clinical data and a lot of anecdotal evidence says thalidomide works better than any other drug in
`healing painful and debilitating mouth and throat ulcers and in reversing the weight-loss syndrome in HIV-infected
`patients.
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`In fact, it was the risks associated with the growing availability of bootlegged thalidomide on US streets - AIDS
`drug-buying clubs were obtaining it from several countries in South America and in Mexico, where the drug is legal -
`that prompted the FDA in late 1995 to push Celgene, which held the thalidomide patent, to produce studies and data that
`could lead to the drug's licensing.
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`"With illicit distribution, the possibility of fetal exposure to thalidomide was rising," said Janet Woodcock, director
`of the FDA's Center for Drug Evaluation and Research. "Most women under 35 have never heard of it. Those women in
`the population who are most sexually active had no knowledge of it.
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`"It appeared to us," Woodcock said last week at a federal interagency workshop on thalidomide, "that the most
`prudent path would be to get thalidomide evaluated, access to it coordinated, and its distribution under control to
`minimize its adverse effects."
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`There's irony in the FDA's rehabilitation of thalidomide, since it was the close call with the drug that turned the
`agency into an aggressive government watchdog in the first place. In 1962, after thalidomide was banned around the
`world, Congress amended the federal drug-safety law and required pharmaceutical products to be proved effective and
`safe before they could be sold in this country. The law is still in place, and the FDA has been the aggressive gatekeeper,
`a role that has often put it at odds with industry groups and with critics who argue that overregulation strangles
`development of new drugs, and gives foreign companies a competitive edge.
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`Two recent and significant developments, however - one scientific, the other political - make considering
`thalidomide and its medical ethics far more complicated today than it was 40 years ago.
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`Medical research has not unlocked the mystery of how thalidomide works, but it has revealed that the drug has
`more important uses than being a nonaddictive sedative and sleeping pill.
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`Thalidomide returns, as do fears;MEDICINE;Mary Leonard is the Globe's Focus writer. The Boston Globe September
`14, 1997, Sunday, City Edition
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`That research has dramatically changed the risk-benefit calculus on thalidomide, requiring the medical community
`to weigh the danger of birth defects against the drug's life-saving or life-prolonging potential in patients with AIDS or
`cancer, or in rarer ailments such as lupus or Crohn's disease, where there are no known therapeutic alternatives.
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`"Thalidomide's dangers are undeniable, but it is showing to be an effective drug in places where other treatments
`are sorely missing the mark," said Dr. Gail Povar, a medical ethicist at George Washington University School of
`Medicine. "I believe there is a strong ethical justification to promote thalidomide for life-threatening illnesses, which is
`profoundly different from promoting it for insomnia. Doctors must accept certain levels of risk to do good."
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`But who defines doing good? In 1960, Kelsey and a couple of colleagues made a fateful call on thalidomide.
`Today, politics and competing constituencies play a much bigger role, and no decision can be made without public
`hearings, extensive comments, and due consideration of the concerns of every affected group, particularly patient
`advocates The FDA has spent more than a year building consensus and trying to avoid confrontation on thalidomide.
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`So far, it's working, despite the raw emotions attached to the drug. Thalidomide survivors make a compelling case
`for caution. AIDS activists, who have set the modern standard for patient advocacy, threaten to use any means, legal or
`illegal, to get it approved as a drug of last resort. Feminist groups are warning the FDA not to place any restrictions on
`thalidomide distribution that would prevent women of child-bearing age from obtaining it or that would deny women
`free choice in the kind of contraception they choose when they are taking it.
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`Physicians groups have weighed in, urging that the FDA not interfere with the practice of medicine by trying to
`control or limit how to prescribe it. Product-liability lawyers say doctors should proceed at their own risk with
`"off-label" prescriptions, and they predict far more legal wrangling than 40 years ago if thalidomide babies are born.
`"No matter how good the warnings are, there will be children born of mothers who took thalidomide, and there will be
`lawsuits," said Frank Woodside, a Cincinnati lawyer who has defended many pharmaceutical companies in liability
`suits.
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`The risks from the drug are high. A single dose of thalidomide, taken during the first three weeks of a pregnancy,
`exposes a fetus to a 50 to 90 percent risk of malformation. Recognizing such dangers, the Celgene Corp. has proposed a
`rigorous education and pregnancy-prevention program. That will include contraception counseling, mandatory
`pregnancy testing, and registration for doctors and pharmacists who write or fill thalidomide prescriptions. Patients will
`be required to sign consent forms and participate in surveys to measure compliance with the program and to report
`pregnancies.
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`Since 1989, Dr. Allen Mitchell of the Boston University School of Medicine has surveyed women who take
`Accutane, a proven teratogen, for a severe form of acne. Among 210,000 women who participated in the survey and
`presumably were well-informed of the risks, 632 became pregnant while taking the drug. Of those pregnancies, 11
`percent resulted in live births (68 percent of the pregnancies were voluntarily aborted.) Of the babies born, between 20
`and 30 percent had birth defects.
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`The experience with Accutane is common: Once it reached the market, the drug was prescribed far more widely
`than just for patients with severe symptoms. Some observers expect that thalidomide, too, will be used to treat diseases
`that are not life-threatening and will eventually expose many women of child-bearing age to its risks.
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`"I'm afraid we're on a slippery slope with thalidomide," said Dr. Cynthia Moore, deputy chief of the birth defects
`branch of the Centers for Disease Control and Prevention in Atlanta. "Babies with birth defects will be born, we'll be
`expecting it, so we won't be shocked. Still, at some point we'll have to answer this question: 'When has the risk become
`just too great?' "
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`Thalidomide's history
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`1956: The drug thalidomide is developed by German scientists as a sedative-hypnotic agent. It is marketed in West
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`Page 4
`Thalidomide returns, as do fears;MEDICINE;Mary Leonard is the Globe's Focus writer. The Boston Globe September
`14, 1997, Sunday, City Edition
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`Germany under the name Contergan and sold by prescription and over the counter as a sleeping pill.
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`1958: Marketing of thalidomide extends to more than 40 countries, including the United Kingdom, Canada, and
`Japan, and it is prescribed as a therapy for morning sickness in pregnant women.
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`1960: US Food and Drug Administration receives a "new drug" application for thalidomide. Medical investigator
`Dr. Frances Kelsey blocks the license and requests more information on the drug's safety and side effects.
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`1962: The Richardson-Merrill pharmaceutical company withdraws its application to the FDA for thalidomide after
`the German manufacturer pulls the drug from the market, pending investigation of reports that it is associated with
`phocomelia, a rare birth defect. Over time, 10,000 "thalidomide babies" are identified worldwide.
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`1962: Congress strengthens the 1938 Food, Drug, and Cosmetic Act to require that new drugs must be proved
`effective as well as safe before they rough for treating diseases such as AIDS and tuberculosis.
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`1994: The World Health Organization designates thalidomide as the drug of choice for treating ENL.
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`1994: The FDA begins an interagency thalidomide working group to assess research advances, including successful
`therapies in treating leprosy, as well as mouth ulcers and weight loss in HIV-infected patients, and to address the
`growing availability of illegal thalidomide through AIDS drug-buying clubs.
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`1995: The FDA requests that Celgene Corp., a biotech company with patent rights to thalidomide, step up its
`studies and submit an application for marketing it for leprosy patients. Celgene applies for the license in late 1996.
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`1997: Researchers at Boston's Children's Hospital report that thalidomide, used to slow blood-vessel activity, shows
`significant results in halting or reversing the growth of lethal tumors in patients with brain cancer.
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`1997: An FDA advisory panel recommends that the agency approve licensing thalidomide for treatment of leprosy.
`A decision is pending.
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`GRAPHIC: PHOTO
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`LOAD-DATE: September 16, 1997
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