Annals of Internal Medicine
`
`... Nevvs for internists
`
`Preparing for
`Thalidomide's
`Comeback
`
`T halidomide is on the verge of being
`
`introduced-with great care-into
`the U.S. marketplace. The news
`provokes polarized reactions: disbelief that
`such a potent teratogen could be made
`available after the lessons of almost 40
`years ago, and impatience for a drug that
`can lead to exceptional improvements in
`some rare debilitating immune diseases.
`In early September, an advisory commit(cid:173)
`tee to the U.S. Food and Drug Administration
`(FDA) recommended that the FDA approve
`marketing of thalidomide for erythema
`nodosum leprosum, an inflammatory mani(cid:173)
`festation of leprosy that results in painful
`cutaneous lesions on the arms, legs, and face.
`The committee also strongly recommended
`limiting distribution of thalidomide, with
`stringent safety measures put in place to
`avoid birth defects and other side effects.
`The renewed interest in thalidomide
`comes from studies showing a complete
`response in 90% of patients with erythema
`nodosum leprosum who used thalidomide,
`according to Janet Woodcock, MD, chief
`of the FDA's Center for Drug Evaluation
`and Research. The drug is also under
`investigation to deteonine its effectiveness
`against graft-versus-host disease, the AIDS
`wasting syndrome, some solid tumors, cer(cid:173)
`tain serious primary deonatologic condi(cid:173)
`tions, tuberculosis, aphthous ulcers, and
`macular degene.ration. Woodcock said that
`evidence is most compelling for th.e drug's
`effect on aphthous ulcers in patients with
`HIV infection (N Engl J Med. 1997;335:
`1487-93) and with Beh9et disease. She
`considers the data on the AIDS wasting
`syndrome "promising" but preliminary.
`The committee's recommendation was
`preceded by a year of intensive debate and
`planning because of the drug's potentially
`
`severe side effects. Even one dose of
`thalidomide, when taken during the early
`stages of pregnancy, can cause fetal defor(cid:173)
`mities. The drug can also cause peripheral
`neuropathy, sometimes resulting in perma(cid:173)
`nent nerve damage.
`
`A Brier History
`Thalidomide was originally marketed
`as a sedative and was often used for morn(cid:173)
`ing sickness outside of the United States
`in the 1950s and early 1960s. Although
`thalidomide was the third largest-selling
`drug in Europe-<onsidered so safe it was
`sold over-the-counter in many places-it
`never passed FDA scrutiny. At least 8000
`of the babies born to women who took the
`drug during pregnancy had phocomelia,
`which is characterized by missing digits,
`arms and legs, and internal organ deformi(cid:173)
`ties. In the United States, 17 babies were
`born with the rare birth defect; their moth(cid:173)
`ers had received the drug from overseas
`sources or received premarketing samples
`distributed by drug company represer:lta(cid:173)
`tives. The thalidomide episode resulted in
`stricter review requirements for drug
`approval by the FDA, including proof of
`safety and efficacy plus infooned consent
`by all participants in clinical trials.
`Today, the FDA has in hand new data
`that indicate thalidomide's promise in
`fighting several serious diseases for which
`no effective alternate therapy exists, but the
`risks, of course, remain. Because many of
`the diseases in which thalidomide is poten(cid:173)
`tially beneficial afflict young women
`(Beh9et disease, the Sjogren syndrome,
`Crohn disease, and rheumatoid arthritis),
`issues of teratogenicity are critical.
`Because of a recent study showing thalido(cid:173)
`mide in rabbit semen and uncertainty about
`its presence in human semen, both women
`and men receiving the drug will be
`required to use contraception.
`Concerns about birth defects have been
`so great that investigational use of thalido(cid:173)
`mide for erythema nodosum leprosum has
`been limited to men and postrnenopausal
`
`or surgically sterilized women. The FDA is
`unlikely to limit general use of the drug to
`that extent, but if it is approved as pro(cid:173)
`posed, thalidomide will be the most
`restricted drug in the United States, Wood(cid:173)
`cock confirmed. Every physician, pharma(cid:173)
`cist, and patient involved with thalidomide
`will be required to adhere to a tightly con(cid:173)
`trolled protocol, according to Bruce J.
`Williams, from Celgene Corporation of
`Warren, New Jersey, the drug's marketer.
`To gain access to the drug, patients will
`be required to receive risk-benefit counsel(cid:173)
`ing, sign an informed-consent agreement,
`use two forms of birth control, and partici(cid:173)
`pate in frequent surveys; monthly prescrip(cid:173)
`tions will only be filled after pregnancy
`testing. Compliance and fetal exposures
`will be tracked. Only pharmacists registered
`to participate will be permitted to dispense
`the drug. By registering, they commit to
`dispense thalidomide in 28-day supplies in
`original packaging (special blister-packs
`with pregnancy warnings encasing each
`pill) only after seeing the signed infooned(cid:173)
`consent document. The drug cannot be dis(cid:173)
`pensed as a simple refill, and patients will
`be advised to return unused doses.
`When asked whether a patient using
`thalidomide can decline the use of birth
`control for religious or other reasons,
`Williams responded: "Women can make
`informed choices about whether or not to
`take the drug. But if they are of childbear(cid:173)
`ing age and want the drug, they must
`use contraception." Boston University
`researchers will maintain a thalidomide
`users registry modeled after the registry
`that tracks use and pregnancy outcomes for
`users of isotretinoin, which is marketed by
`Hoffman-La Roche in Nutley, New Jersey,
`under the trade name Accutane (Box).
`
`Zero Risk Impossible
`Even with these unprecedented safety
`measures, experts admit that zero risk is an
`impossible goal. Babies will be born with
`birth defects if thalidomide is made avail(cid:173)
`able. But based on the isotretinoin experi(cid:173)
`ence, 20 years of testing in erythema
`nodosum leprosum, and limited use of
`thalidomide by 72 women with the AIDS
`wasting syndrome or aphthous ulcers, the
`FDA is prepared to move ahead.
`Implications of this regulatory action
`go beyond U.S. borders. It sends a message
`to other countries, said Colin Crawford,
`MB, ChB, DPH&H, from London's Imperial
`
`(Continued on next page)
`
`15 November 1997 • Annals of Internal Medicine • Volume 127 • Number 10
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`N•vvs for Internists
`
`teenager ask for Accutane inappropriately.
`We have to accept the fact that this will
`happen with thalidomide and be prepared."
`Advocates for survivors of thalidomide
`defects are calling for efforts to develop
`
`College of Science, Technology, and Medi(cid:173)
`cine. If the U.S. government makes thalido(cid:173)
`mide available, developing countries may do
`the same, he predicted, most likely without
`the comprehensive safety and tracking pro(cid:173)
`gram being planned for the United States.
`Thalidomide is already available in 8 of
`I 0 South American countries. Thirty-four
`cases of thalidomide embryopathy have been
`reported since 1965. Most have occurred in
`Brazil, wile.re the prevalence of leprosy is
`high and where, until recently, thalidomide
`was available without a prescription.
`In the United States, the communica(cid:173)
`tions challenges are twofold. A population
`of patients vividly remembers the first
`thalidomide tragedy. But an informal FDA
`poll found that most people under age 35
`have never heard of thalidomide and are
`unaware of its potential harmful effects.
`"When communicating about risks of any
`disease lo a patient, we have to be aware of
`the cohort experience that patient brings,"
`said Gail J. Povar, MD, clinical professor
`of medicine and health care sciences at
`George Washington University School of
`Medicine in Washington, D.C. Recalling
`her own reaction to the thalidomide news
`in the 1960s, Povar stated that nothing
`could have convinced her to take the drug
`if she had any chance of becoming preg(cid:173)
`nant. But she predicts that 25-year-olds
`will be furious if their physicians refuse to
`prescribe it for them. She has seen this hap(cid:173)
`pen with isotretinoin. "Every week I have a
`
`I analogues of thalidomide without the
`
`harmful side effects. But analogue devel(cid:173)
`opment may take some time because
`researchers are not sure exactly how
`thalidomide works. Its immunomodulatory
`effects may occur through selective inhibi(cid:173)
`tion of tumor necrosis factor, the inflam(cid:173)
`matory cytokine involved in many dis(cid:173)
`eases. lt may also block angiogenesis, the
`most likely reason for its report.ed effec(cid:173)
`tiveness against some solid tumors and per(cid:173)
`haps the method by which it blocks fetal
`limb and organ development.
`"Thalidomide will likely spark dis(cid:173)
`agreements both within the medical com(cid:173)
`munity and between medicine and the pub(cid:173)
`lic about what limits, if any, to impose on
`use in fertile women. In addition, because
`of its exciting potential in the amelioration
`of serious illnesses, thalidomide may tempt
`clinicians to go beyond well-documented
`indications to more experimental applica(cid:173)
`tions," said Povar. " Informed consent
`becomes much more important here. Our
`obligation goes way up. We need to be
`very clear that use is experimental.
`"For the most part, thalidomide poses
`no more-and no less--a challenge to the
`practitioner than any other drug with sub(cid:173)
`stantial promise and potential
`toxic
`effects," she continued. "lt would be unfor(cid:173)
`tunate if thalidomide was considered too
`risky because of its past. Physicians just
`need to work closely with patients."
`('
`
`-Cori Vanchieri
`
`Will Pregnancy Prevention Work?
`A program to reduce pregnancies in women who use isotretinoin, a known
`teratogen, for severe, cystic acne is being considered as a model for thalidomide.
`In 1988, Han unprecedented and novel" pregnancy prevention program was
`developed for isotretinoin users, according to Allen A Mitchell, MD, professor of
`epidemiology and pediatrics at the Boston University School of Public Health.
`Rates of oral contraceptive use and abstinence were higher in the isotretinoin
`users than in the general public. The pregnancy rate was 7% that of the U.S.
`population. Of the 210 009 women with complete follow-up, 623 became preg(cid:173)
`nant. Two thirds of the pregnancies resulted from contraceptive failure; 68%
`were electively aborted, 16% were spontaneously aborted, 3% were ectopic,
`and 11 % resulted in live births. As expected, 25% to 30% of the babies had
`birth defects. Mitchell, who implemented the isotretinoin registry, has suggest(cid:173)
`ed that a more stringent program may be required for thalidomide users.
`-Cori Vanchieri
`
`Heart Disease:
`Women's Unique Risks
`Demand Attention
`
`esponding to what it calls a "silent
`pidemic," the American Heart
`ssociation (AHA) has released
`new guidelines to help physicians prevent,
`diagnose, and treat heart disease in women
`(Circulation. I 997;96:2468-99). The AHA
`also unveiled a national survey of IOOO
`women ages 25 and older in which fewer
`than one third said they had discussed
`heart disease with a physician. Only 8%
`considered heart disease their biggest
`health threat. In reality, heart disease kills
`half a million women each year-more
`than all types of cancer combined (Box).
`"Much of heart disease [in women]
`gets missed or misdiagnosed," said Martha
`Hill, RN, PhD, president of the Dallas(cid:173)
`based AHA. "Now, we're learning a lot
`about the prevalence of heart disease and
`the benefits of treatment. This statement
`shares what we've learned."
`
`Age and Coexisting Conditions
`Differences in coronary heart disease
`(CHO) between men and women con(cid:173)
`tribute to a disparity in the mortality rate.
`Women tend to develop CHO 7 to I 0 years
`later than men-after menopause, when
`the cardiovascular benefit of estrogen is
`apparently lost. Because they present with
`heart disease at later ages, women are also
`more likely to have coexisting conditions
`that can reduce survival.
`Women oft.en present cardiac symp(cid:173)
`toms late, when the disease has progressed.
`And although women frequently experi(cid:173)
`ence the same kind of chest pain as men
`during a myocardial infarction (MI), they
`are also more likely to have confusing
`symptoms of upper abdominal pain, nau(cid:173)
`sea, or fatigue. Finally, basic physiologic
`differences, such as smaller body size-(cid:173)
`hence smaller coronary arteries--make
`bypass surgery more difficult and lead to a
`higher ope.rative mortality rate.
`"All this means that physicians need lO
`recognize that there are unique aspects of
`heart disease in women," said Lori Mosca,
`MD, PhD, a preventive cardiologist at the
`University of Michigan en Ann Arbor and
`lead author of the AHA statement "You
`need to screen for the disease and then
`
`(Continued on next page)
`
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`aggressively treat women who are at risk."
`Prevention, of course, is the best
`approach. Educating all patients-even
`young ones-about the major risk factors,
`including smoking, diet, and lack of exer(cid:173)
`cise, remains the essential first step. These
`factors affect both men and women at
`roughly the same rate.
`Other risk factors disproportionately
`affect women. Diabetes, for example, rais(cid:173)
`es a woman's risk for CHO three to seven
`times above normal while causing only a
`two- to threefold increased risk for men.
`The reasons for this difference are not
`known. As with diabetes, a decreased level
`of high-density lipoprotein is a stronger
`predictor of CHO in women than in men,
`and an elevated level of triglycerides may
`have a more serious consequence for
`women as well.
`
`Routine ScreeninJ!
`The AHA guidelines recommend rou(cid:173)
`tine blood pressure screening every year or
`two and measurement of both total choles(cid:173)
`terol and high-density lipoproteims begin(cid:173)
`ning in a patient's twenties. Risk factor
`awa.reness and an ability to recognize
`warning signs are the keys to prevention
`and early diagnosis for women, according
`to the AHA.
`Diagnosing heart disease may require
`different tests for men and women. For
`example, ordinary treadmill testing may be
`more likely to yield false-positive results in
`
`Numbers Tell the Story
`• Coronary heart disease (CHO)
`kills half a million U.S. women
`every year
`• CHO accounts for 45% of all
`deaths in women, more than all
`forms of cancer combined
`• The mortality rate from CHO is
`69% higher in African-American
`women than in white women
`• 1 in 2 women die of heart disease
`or stroke; 1 in 25 die of breast
`cancer
`• In the Framingham Heart Study,
`63% of women who died suddenly
`of CHO had no previous symptoms
`Source: American Heart Assooaoon
`
`women than in men (Am J Cardiol.
`1995;75:520-600 ). Instead, the AHA rec(cid:173)
`ommends considering the use of stress
`echocardiography to evaluate possible symp(cid:173)
`toms of CHD. New imaging techniques, like
`magnetic resonance imaging or positron
`emission tomography, are still experimental
`but may be useful in the future.
`
`Aggressive Treatment
`Withfo 2 years of an Ml, 36% of
`women die, compared with 21 % of men.
`The mortality rate is particularly high in
`African-American women. Severity of ill(cid:173)
`ness, increased age, and more comorbid
`conditions may all contribute to the higher
`mortality rate in women. But considerable
`evidence, including a recent Canadian
`study, suggests that women receive far
`fewer tests and less medication after an MI
`than men do, even when they see a physi(cid:173)
`cian just as often (Arch Intern Med.
`1997; 157: 1545-51 ).
`The AHA recommends that physicians
`manage heart disease as aggressively in
`women as in men ... There's no such thing as
`a touch of high blood pressure," emphasized
`Kelly Spratt. MD, a cardiologist at the Uni(cid:173)
`versity of Pennsylvania in Philadelphia. "If
`you find it. you've got to treat it" For men
`and women alike, the medications most
`commonly used to treat CHD are aspirin,
`angiotensin-converting enzyme inhibitors,
`6-blockers, and lipid-lowering drugs.
`Preliminary studies suggest that hor(cid:173)
`mone replacement
`therapy
`in post(cid:173)
`menopausal women lowers the risk for
`both CHO and stroke. Accordingly, many
`physicians prescribe estrogen supplements
`for their female patients, depending on the
`patient's comfort level with hormone
`replacement and relative risk for endome(cid:173)
`trial and breast cancers. The AHA state(cid:173)
`ment. like those from a number of other
`organizations, supports an approach that
`weighs the pros and cons of hormone
`replacement therapy for each woman, con(cid:173)
`sidering her health, disease risks, and fam(cid:173)
`ily history.
`The AHA contends that, by applying
`the most up-to-date knowledge about pre(cid:173)
`vention, diagnosis, and treatment of heart
`disease, physicians can revolutionize health
`care for women. 'There is more informa(cid:173)
`tion available than ever before, and physi(cid:173)
`cians are more aware of heart disease's
`challenges," Hill said. "That's a step in the
`f'
`right direction."
`
`-Kathryn S. Brown
`
`Resolution Due in
`Medical Software
`Regulation
`
`TI U.S. Food and Drug Administta(cid:173)
`
`on (FDA) has been trying for more
`than a decade to determine the best
`regulatory approach to the burgeoning
`"stand-alone" medical software industry.
`With the FDA's decision due soon, manu(cid:173)
`facturers of stand-alone software and mem(cid:173)
`bers of the medical informatics community
`alike are optimistic that the agency will fol(cid:173)
`low the path of least regulation.
`Since it began regulating medical
`devices under a 1976 statute, the FDA has
`required stringent review of software that is
`"embedded" inside such devices as pace(cid:173)
`makers and ventilators. Li.kewise, it has
`regulated "accessory" software that can be
`run on general-purpose computers to oper(cid:173)
`ate systems, such as radiation-planning
`systems or brain-mapping software.
`But stand-alone software, which runs on
`conventional computers to process words
`and data, has been in a gray zone. Its appli(cid:173)
`cations range from computerized patient
`record systems and off-line archives to data
`analysis programs that aid in determining
`therapy, and such expert systems as deci(cid:173)
`sion and diagnostic support programs.
`With renewed momentum, the FDA is
`moving to adopt its first formal regulation of
`the $6 billion stand-alone software industry.
`Harvey Rudolph. PhD, acting director of the
`FDA's Office of Science and Technology in
`the Center for Devices and Radiological
`Health, said the agency's position is likely to
`be "deregulatory" or mainly "hands-off."
`Rudolph said the policy options will be dis(cid:173)
`cussed soon with the staff of the secretary
`of Health and Human Services, Donna
`Shalala. Rudolph expects final regulations
`to be in place in another year.
`
`Exempting Low Risk
`Rudolph said the FDA will propose a
`"risk-based approach" that focuses its regu(cid:173)
`latory efforts on software with the greatest
`potential to harm patients, while exempting
`most software that poses minimal risk. For
`some moderate-risk products, manufacturers
`would be required to submit a standard pre(cid:173)
`market notification or make self-declarations
`that their products meet certain standards.
`The FDA is still defining risk categories.
`
`(Continued on next page)
`
`15 November 1997 • Annals of Internal Medicine • Volume 127 • Number 10
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`
`premarket approval. But things have gotten
`more complicated since 1989." Computer
`networking bas resulted in interconnections
`among several software devices. When
`data flow through a combination of pro(cid:173)
`grams, the chance of malfunction can
`increase.
`Still, developers of stand-alone medical
`software hope that the FDA will continue
`its present practice of minimal regulation,
`according to Edward Larsen, president of
`Health Patterns, of LaGrange, Illinois.
`Larsen prepared a proposal on FDA regu(cid:173)
`lation for the Center for Healthcare Infor(cid:173)
`mation Management (CHIM) in Ann
`Arbor, Michigan, which represents about
`100 vendors of stand-alone software and
`computer networking equipment. The
`American Medical Informatics Association
`has also joined with related groups to pro(cid:173)
`pose an approach that keeps federal regula(cid:173)
`tions to a minimum (Ano Intern Med.
`1997; 127:842-5. J Am Med Informatics
`Assoc. 1997;4:442-57).
`"There is no evidence of hazard in
`tenns of death or serious injury attributable
`to 'stand-alone' medical software that
`CHIM has been able to find," according to
`
`the CHIM report. "Mandating new regula(cid:173)
`tions is unwarranted in the face of the
`absence of data showing harm and the
`availability of data showing that stand(cid:173)
`alone software reduces paperwork. errors."
`CHIM has submitted to the FDA an
`algorithm to determine whether a stand(cid:173)
`alone product should be regutated or
`excluded. It would exempt software used
`for education and in financial and adminis(cid:173)
`trative systems. It calls for increased scruti(cid:173)
`ny of software used in immediate decisions
`that could harm or kill patients in the
`absence of compe.tent human review.
`The FDA has met several times with
`CHIM to draft regulations that would serve
`the public health and be acceptable to
`industry. Rudolph said he expects that the
`FDA's deregulatory proposals are "in con(cid:173)
`cert" with CHIM's recommendations.
`But Larsen said he is taking a wait-and(cid:173)
`see approach: "Self-declaration about
`meeting standards in theory is a good
`thing. But who is going to write the stan(cid:173)
`dards? And what are they going to say?
`0
`The devil is in the details."
`
`-Howard Wolinsky
`
`Some medical catastrophes have
`assured that software-controlled devices
`will receive high-level scrutiny. ln 1986,
`several patients received massive over(cid:173)
`exposure to electron beam radiation from a
`linear accelerator because of a software
`problem. Two patients d.ied and another
`was severely burned, recalled Rudolph.
`He said that about 500 device recalls
`occur annually, I 00 of which involve prod(cid:173)
`ucis with software. Of those 100 products,
`the malfunctions in 40 are related to th.e
`software itself.
`Problems have included software mal(cid:173)
`functions that resulted in improperly
`labeled radiographs and infusion pumps
`with incorrect timing that resulted in over(cid:173)
`doses of medication.
`But the FDA has trod lightly on the
`stand-alone medical software industry. And
`developers of such software, unlike the
`makers of traditional medical devices with
`embedded software, such as pacemakers
`and ventilators, are unaccustomed to regu(cid:173)
`lation. They are worried about the implica(cid:173)
`tions of the new rules. Some software
`developers have feared, for example, that
`even stand-alone programs that run with
`widely used spreadsheet programs, such as
`software for billing systems or patient
`appointment reminders, would have to
`undergo the same scrutiny as a new pace(cid:173)
`maker or infusion pump.
`
`Human Intervention Loophole
`1be argument for exemption is based on
`a draft policy supported in 1989 by then
`FDA Commissioner Frank Young, MD,
`who stated that software, such as expert sys(cid:173)
`tems and products using artificial intelli(cid:173)
`gence, should be exempted if it is "intended
`to involve competent human intervention
`before any impact on human health occurs."
`Rudolph warned that some manufactur(cid:173)
`ers have "purposely or inadvertently" tried
`to apply the "competent human interven(cid:173)
`tion" standard to avoid regulation. Harold
`Schoolman, MD, deputy director for
`research at the National Library of Medi(cid:173)
`cine in Bethesda, Maryland, added, "V./e
`all thought we had a simple solution: As
`Jong as a competent health professional can
`interpret and intervene and make the ulti(cid:173)
`mate decision, then there was no need for
`
`News Notes
`The Shifting Landscape of AIDS
`The mortality rate from HIV and AIDS declined by 26% in 1996. This sub(cid:173)
`stantial drop-from 15.6 deaths per 100 000 persons in 1995 to 11 .6 per 100 000
`in 1996-moved AIDS from the number one to the number two cause of death
`among 25- to 44-year-olds, according to the Centers for Disease Control and
`Prevention in Atlanta. The improvement is being attributed primarily to the
`recent availability of combination therapies for patients with HIV and AIDS.
`This good news is tempered by reports that the number of U.S. women ages
`13 and older diagnosed with AIDS has increased almost sixfold-from 0.9 cases
`per 100 000 in 1991 to 5.2 per 100 000 in 1995. The greatest increases were
`among women who acquired HIV through heterosexual contact rather than
`through use of injection drugs (JAMA. 1997;278:911-16). Women now comprise
`almost 20% of adult patients with AIDS.
`
`Women Confuse Arthritis and Osteoporosis
`U.S. women may mistakenly wait for symptoms of arthritis before taking
`action against osteoporosis, according to a recent telephone survey. Six in ten
`women surveyed think that osteoporosis has warning signs or symptoms. More
`than 70% of respondents cited pain, 50% mentioned stiffness, and 33%
`referred to swollen joints as symptoms of osteoporosis.
`More than 40% of respondents stated that osteoporosis and osteoarthritis
`are related diseases. Half said that they believe the treatments for arthritis and
`osteoporosis are similar. The random-digit dialed telephone survey of 505 women
`was funded by the National Osteoporosis Foundation in Washington, D.C.
`Robert Lindsay, MD, PhD, president of the foundation and chief of internal
`medicine at Helen Hayes Hospital in New York, expressed concern thait confu(cid:173)
`sion surrounding these diseases leads many women to ignore their risk for
`osteoporosis and fail to take steps to protect themselves from the disease.
`
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`15 November 1997 • Annals of Internal Medicine • Volume 127 • Number 10
`15 November Im • Amials of Jnlemal Medidne • Volume 127 • Number 10
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`CFAD VI 1019-0004
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