Thalidomide Back\p=m-\Under Strict Control
`
`effects\p=m-\especially
`
`THALIDOMIDE, the notoriously tera-
`togenic agent of the 1960s, is about to
`become a prescribed drug. Just 17 days
`after an advisory committee of the Food
`and Drug Administration (FDA) recom-
`mended that the acting commissioner
`give marketing approval to thalidomide
`for treatment oferythema nodosum lep-
`rosum (ENL), a complication of lepro-
`matous leprosy, FDA informed the
`maker that the drug would be approved.
`This use has been studied since 1965.
`The condition is estimated to affect only a
`
`
`fewthousandpeopleintheUnitedStates,
`but when approval is granted, the door
`will be open for physicians to prescribe
`the drug as they wish. A number of uses
`of thalidomide are under active investi-
`gation and some have shown consider-
`able promise. However, even apart from
`its teratogenic potential, the drug is not
`without such occasional serious adverse
`with long-term use-\p=m-\
`as irreversible peripheral neuropathy.
`Thalidomide is an inhibitor of the cy-
`tokine tumor necrosis factor \g=a\(TNF-\g=a\),
`a property that may make it useful in
`mediating such diseases characterized
`by an excess of TNF-a as human immu¬
`nodeficiency virus (HIV) infection and
`tuberculosis. Other conditions in which
`thalidomide has been clinically studied
`include Behçet disease, lupus erythema-
`tosus, chronic graft-vs-host disease, glio-
`mas, Sjògren syndrome, rheumatoid ar¬
`thritis, and inflammatory bowel disease.
`The drug also seems to have antiangio-
`genic properties that have prompted in¬
`terest in using it to treat some cancers
`and macular degeneration.
`An investigator with Celgene Corpo¬
`ration, Warren, NJ, 1 of 4 US manufac¬
`turers of thalidomide, has said that he
`started to list the potential clinical uses
`and gave up when he got to 50. Overall,
`says the FDA, at least 1000 patients in
`this country are currently using thalido¬
`mide on a compassionate basis or in clini¬
`cal trials. The agency has no figures but
`admits that there is probably also quite
`a bit of "under-the-counter" use.
`In addition to its application for ap¬
`proval of thalidomide for treating ENL,
`Celgene is planning to apply also for mar¬
`keting approval for the use of thalido¬
`mide to treat AIDS wasting syndrome,
`said Sol J. Barer, the company's presi¬
`dent and chief executive officer. "We are
`also looking at its use in AIDS-associ-
`
`ated chronic intractable diarrhea, graft-
`vs-host disease, and severe rheumatoid
`arthritis,"said Barer in an interview,
`adding that the company has an ongoing
`program to develop and study the effec¬
`tiveness of thalidomide analogs, com¬
`pounds that retain its therapeutic ben¬
`efits without the attendant toxic effects.
`In cell assay systems some of these com¬
`pounds have shown potencies more than
`10000 times that of thalidomide,
`re¬
`ported David Stirling, PhD, a research
`scientist at Celgene, at a recent meeting.
`He said he expected that some of these
`compounds would be ready to enter ini¬
`tial clinical trials later this year.
`Federal Agency Workshop
`Stirling spoke at a workship held last
`the National
`Institutes of
`month at
`Health (NIH) by that agency, the FDA,
`and the Centers for Disease Control and
`Prevention (CDC). The workshop was
`prompted by concern about burgeoning
`interest in the drug as atherapeutic agent
`and concomitant concern about thalido-
`mide's teratogenic properties. At the
`meeting, federal officials, pharmaceuti¬
`cal firm representatives, physicians, and
`interested others—including persons
`with thalidomide-associated birth de¬
`fects—reviewed and assessed the contro¬
`versial drug. They discussed its clinical
`potential, risks to patients, ways to pre¬
`vent birth defects associated with its use,
`and steps needed to monitorits safety and
`adverse effects. The meeting was held
`just days after the FDA advisory com¬
`mittee on dermatologie and ophthalmic
`drugs made its recommendation on the
`use of thalidomide to treat ENL.
`The imminent availability of thalido¬
`mide and the increasing number ofprom¬
`ising uses for it have raised concern that
`its inadvertent use by pregnant women
`could lead to a repetition of the situation
`in the 1960s when approximately 10 000
`limb-reduction defects and other fetal
`abnormalities occurred worldwide (see
`sidebar). Despite the belief that there is
`considerable clandestine use of thalido¬
`mide, none of the fetal abnormalities
`associated with it have been reported re¬
`cently, said Cynthia A. Moore, MD, act¬
`ing deputy chief ofthe Birth Defects and
`Genetic Diseases Branch of the CDC.
`No one at the workshop suggested ban¬
`ning the drug outright because ofits tera¬
`togenic potential. Rather, the concern
`
`was that its use be adequately controlled
`and distribution carefullymonitored, that
`some system of postmarketing surveil¬
`lance be put in place, and that the medical
`profession and the public be adequately
`educated regarding the drug.
`There is some evidence from a pre¬
`liminary survey by the FDA on over-
`the-counter drug labels that those least
`aware of the teratogenic effects of tha¬
`lidomide are those most at risk: persons
`under the age of 45 years. "We asked
`people to define a series of words just as
`ifthey had seen them in a dictionary, and
`one of them was thalidomide," said
`Louis A. Morris, PhD, chiefofthe FDA's
`Marketing Practices and Communica¬
`tions Branch. "We found that two thirds
`of those under 45 years didn't recognize
`the word, while those over 45 years of
`age at least recognized the word even if
`they didn't get all the details about tha¬
`lidomide correct. Thalidomide rang a bell
`with them." Morris noted that the sur¬
`vey involved only 130 people, a very
`small sample, so, he said, "you don't want
`to make too much out of it. But the re¬
`sults are striking."
`One way to prevent the occurrence of
`birth defects associated with thalidomide
`is to limit it strictly to proven uses and to
`patients who cannot become pregnant.
`This, however, would mean that much of
`the use of the drug would be in uncon¬
`trolled circumstances, said Janet Wood¬
`cock, MD, director of the FDA's Center
`for Drug Evaluation and Research.
`This point was picked up by Randolph
`Warren, chief executive officer of Tha¬
`lidomide Victims Association ofCanada,
`London, Ontario. A thalidomide victim
`himself, he expressed revulsion at the
`prospect of the drug's reappearance.
`"We will never accept a world with tha¬
`lidomide in it," he said; "however, we are
`forced to adopt a position of preferring
`regulated thalidomide over unrestricted
`access." Warren also said he believes
`that when thalidomide is approved, some
`birth defects will inevitably follow.
`He was not alone. Discussing ethical
`issues associated with the use ofthalido¬
`mide by fertile women, Norman Fost,
`MD, director of the Program in Medical
`Ethics at University Hospital, Madison,
`Wis, warned, "There is no system that
`will prevent the single birth of a child
`with phocomelia. The problem is to find
`some middle ground that properly bal-
`
`Downloaded From: http://jama.jamanetwork.com/ by paul skiermont on 04/21/2015
`
`CFAD VI 1033-0001
`
`

`

`The Drug That Changed US Pharmaceutical History
`The NIH workshop opened with a review of the history of thalidomide by
`Frances 0. Kelsey, MD, currently deputy for scientific and medical affairs in
`the FDA's Office ofCompliance. Kelsey was an FDA medical officer reviewing
`thalidomide when the manufacturer, William S. Merrell Company, a division of
`Richardson Merrell Ine, Cincinnati, Ohio, filed an application to market the
`drug as a sedative in September 1960. Kelsey recently related the circum¬
`stances under which drugs were reviewed at that time and summarized the
`accumulation ofthe evidence that finally resulted in the withdrawal ofthe new
`drug application for thalidomide.
`Initially there were a number oftechnical concerns, she said; then there were
`the reports of peripheral neuritis; and, finally, in the fall of 1961, came the
`association of the drug with cases of fetal amelia and phocomelia in Germany,
`where the drug was available. The new drug application was withdrawn in
`March 1962, and Kelsey has long been hailed for the role she played.
`Thalidomide was never approved for use in the United States, but few
`pharmaceutical agents have had a greater impact on drug development. The
`passage in 1962 of the Kefauver-Harris Act, which required that drugs be
`shown to be not only safe but effective (the Food, Drug, and Cosmetic Act of
`1938 having required only safety), was a direct result of the experience with
`thalidomide, as Kelsey pointed out.
`In a recent interview, she said it was not uncommon at the time for a phar¬
`maceutical firm to send samples of a new drug to 1000 or so physicians before
`it received FDA marketing approval, explaining its use and saying it would
`soon be available—as was in fact the case with thalidomide. Ironically, it was
`a drug that, although effective for some indications, proved unsafe for so many
`that brought about a change in the accepted procedure.
`"The thalidomide tragedy showed up big loopholes in the testing of drugs,"
`Kelsey said. "Some ofus knew what was going on, but we never had the backing
`to change it before. Sooner or later there would have been anothertragedy, but
`it just happened that it was thalidomide that got the [Kefauver-Harris] bill
`through at lightning speed, and that was very satisfactory to us."
`"There has never been a drug that has so profoundly affected drug devel¬
`opment around the world as has thalidomide," said Sol Barer, the chief execu¬
`tive officer of thalidomide manufacturer Celgene Corporation. "It altered at¬
`titudes about drug regulation, it significantly broadened FDA authority, it
`affected all drug development. It changed history."—C. M.
`
`anees the interests offuture children and
`getting reasonable access to the drug."
`Ethics Over Exclusion
`Noting that thalidomide has the po¬
`tential to be an effective agent for a num¬
`ber ofconditions, GailJ. Povar, MD, clini¬
`cal professor ofmedicine and health care
`science at George Washington Univer¬
`sity School of Medicine, Washington,
`DC, addressed the problem of off-label
`use—an issue that cropped up repeat¬
`edly during the workshop discussions.
`The data presented at the meeting pro¬
`vide a strong incentive to approve and
`promote the use of the drug, Povar
`noted, adding, "What worries me is that
`there may be desperate patients who
`will try to go beyond the well-docu¬
`mented indications to more experimen¬
`tal applications. When you do so, the
`ethical requirements go up. They extend
`beyond the informed consent and risk-
`benefit assessments ofstandard medical
`practice to those of clinical research."
`Few drugs carry the pharmacologie
`
`political and emotional baggage that is
`attached to thalidomide, Povar said.
`Therefore, some maintain that the drug
`should be excluded from use by fertile
`women, that its teratogenic effects pose
`an ethical issue that makes it different
`from other drugs. This attitude, she said,
`is a mistake. "Thalidomide poses no more
`and no less of a challenge than any drug
`with substantial promise and toxicity.
`We are simply dealing with an agent
`that, like any pharmacologie agent, pur¬
`chases its effects at a price. There are
`benefits, but there are also risks, and
`physicians must weigh them carefully."
`In the expectation of marketing tha¬
`lidomide, Celgene has drafted a plan that
`it hopes will prevent fetal exposure to the
`drug. "The goal
`is zero defects," said
`Bruce A. Williams, the firm's vice presi¬
`dent for sales and marketing. The plan is
`built on experience with restrictions on
`such other drugs with severe adverse ef¬
`fects as Accutane (Hoffmann-La Roche,
`Nutley, NJ), used to treat severe acne,
`and Clozaril (Novartis Pharmaceuticals
`
`Corporation, East Hanover, NJ), used to
`treat schizophrenia. However, the plan
`has some unique elements, Williams said.
`The manufacturer will exert "a high de¬
`gree of controF'over distribution of the
`drug and, unlike the system used by Hoff-
`mann-LaRoche to control the use of Ac¬
`cutane, a tracking system would be in
`place to ensure compliance.
`The plan has yet to be finalized, but
`Williams said he believes it goes a long
`way toward solving the problem. "It's a
`model for the distribution of drugs that
`have great benefit yet significant risk. It
`is a response to both the need to prevent
`a new thalidomide tragedy and the hu¬
`mane need to ensure that those who need
`this therapy can have appropriate ac¬
`cess to it," he said.
`Essentials of the Plan
`The goal is to limit risk by supporting
`appropriate use for serious, debilitat¬
`ing, life-threatening conditions for which
`current therapy is inadequate or unavail¬
`able. Williams described a scenario in
`which a patient, considering the use of
`thalidomide and in consultation with a
`physician, would agree to counseling re¬
`garding the relative risks and benefits to
`ensure that the risks, including the need
`to avoid fetal exposure, were under¬
`stood. The patient would sign an in¬
`formed consent document that acknowl¬
`edged his or her understanding and would
`agree to participate in a confidential sur¬
`vey at the start, during, and on the
`completion oftherapy. Patients would be
`warned against letting the drug be used
`by anyone for whom it had not been not
`prescribed.
`Women would be counseled about con¬
`traception; the results of a pregnancy
`test would have to be in hand before
`therapy was started; and pregnancy
`tests would continue during the course
`of therapy. "This is not a contraceptive
`program, it's a fetal risk-exposure pre¬
`vention program," Williams empha¬
`sized. A prescription would be written
`for only 4 weeks of therapy, and no au¬
`tomatic refills would be allowed.
`Male patients who are prescribed the
`drug would be advised to use condoms if
`they are sexually active. "The authorities
`we've talked to strongly urge us to rec¬
`ommend the use of condoms, in part be¬
`cause it's good policy from the public
`health perspective and in part because
`we can't categorically rule out the risk of
`the drug being transmitted in the ejacu¬
`late, although when it's been looked for
`it has not been found," said Celgene's
`Barer.
`One unusual recommendation the ad¬
`visory committee made was that warn¬
`ings on the package include a photo¬
`graph of a limb-deficient infant as a
`
`Downloaded From: http://jama.jamanetwork.com/ by paul skiermont on 04/21/2015
`
`CFAD VI 1033-0002
`
`

`

`dramatic illustration ofthe potential con¬
`sequences of misuse.
`Only physicians and pharmacies that
`comply with the program will be able to
`prescribe and dispense the drug. Phar¬
`macies filling prescriptions for thalido¬
`mide must agree to participate in a pa-
`
`tient-tracking system that registers all
`patients. The information will be con¬
`fidential, and women patients will be
`surveyed once a month, men every 3
`months. The registry will enable track¬
`ing compliance with the program; the
`data will be independently evaluated by
`
`the Sione Epidemiology Unit at Boston
`University School of Medicine, which
`has long experience evaluating prescrip¬
`tion drug use. "This will provide us with
`constant feedback on how the program
`is working and how we can learn from
`it," said Williams.- \p=m-\by Charles Marwick
`
`New Focus Placed on von Willebrand Disease
`FOR MANY patients, the heavy men-
`strual periods, frequent nosebleeds, and
`ease in bruising seem normal.
`They likely have a sister or mother
`who also has heavy periods. Or a father
`or brother with nosebleeds or bleeding
`gums. "Because others in the family
`have it, they just think this is life," said
`Anne Dilley, PhD, an epidemiologist in
`the Hematologic Diseases Branch ofthe
`Centers for Disease Control and Preven-
`tion (CDC) in Atlanta, Ga.
`Dilley is among a group of research-
`ers, clinicians, and advocates who want
`to assure patients that excessive bleed-
`ing and bruising don't have to be a way of
`life. They're trying to focus more atten-
`tion on the often unrecognized von Wil-
`lebrand disease, an autosomal disorder
`characterized by mucous membrane
`bleeding.
`As Dilley embarks on the last phase of
`the first large-scale epidemiologic study
`examiningthe prevalence ofthe bleeding
`disorder in women, the Food and Drug
`Administration (FDA) is considering a
`label change for hemophilia drugs that
`often are used off-label to treat severe
`forms of von Willebrand. At the same
`time, the National Hemophilia Founda¬
`tion (NHF) in New York, NY, is planning
`a national conference on the diagnosis and
`treatment of von Willebrand disease, set
`for next March in Philadelphia, Pa.
`The recent spotlight on the illness is
`the culmination "of several forces com¬
`ing together at once," Dilley said. While
`women's health has attracted political
`attention in the 1990s, hemophilia orga¬
`nizations found theirpolitical voice in the
`1980s through AIDS risks their mem¬
`bers faced from contaminated clotting
`factors. And scientifically, she adds, "It's
`an interesting public health issue."
`Complex Treatment Questions
`Von Willebrand disease affects about
`1% to 3% of the population worldwide
`and about 1% of people in the United
`States. The vast majority—about 80%—
`have milder type 1 disease in which they
`do not produce enough von Willebrand
`factor, a large multimeric plasma pro¬
`tein that binds platelets to ruptures in
`
`the blood vessel walls and stabilizes fac¬
`tor VIII in the blood. Most ofthe remain¬
`der have more severe type 2 disease, in
`which the amount of von Willebrand fac¬
`tor is adequate but functionally deficient
`{JAMA. 1996;275:1814-1815). Types 1
`and 2 are dominant traits; a rare, severe
`type 3 is recessive.
`Appropriate diagnostic tests for von
`Willebrand disease include an activated
`partial thromboplastin time, template
`bleeding time, and ristocetin cofactor,
`von Willebrand antigen, and factor VIII
`assays. Patients with type 1 disease can
`be treated successfully with desmopres-
`sin acetate, available in a nasal spray
`since 1994. It can be used at the onset of
`menstrual periods and prophylactically
`before surgery or invasive dental proce¬
`dures. Treatment issues are much more
`complicated in patients with type 2 dis¬
`ease, however, because they don't ben¬
`efit from desmopressin. For more than a
`decade, in the United States and Eu¬
`rope, clinicians have treated many type
`2 patients with factor VIII concentrate.
`But because proofofefficacy is largely
`anecdotal, the concentrate has never
`been licensed to treat von Willebrand
`disease, only hemophilia. Now treat¬
`ment questions are coming to the fore¬
`front as some third-party payers are re¬
`luctant to pay for drugs used to treat
`conditions for which they aren't indi¬
`cated. "No one questioned that it wasn't
`indicated until the cost of health care
`started rising. Then certain payers ques¬
`tioned it," said Jeanne Lusher, MD, di¬
`rector of the hemostasis program at
`Wayne State University School ofMedi¬
`cine in Detroit, Mich. Cost ofthe concen¬
`trate could approach $1000 a dose for
`some patients, she said.
`In response to payers, clinicians, and
`pharmaceutical companies that make
`factor VIII concentrate, the FDA sched¬
`uled a daylong workshop September 26
`to examine a number ofconcerns. "There
`has been an ongoing problem regarding
`the proper labeling and dosage of this
`product" for the treatment of von Will-
`ebrand disease, said Mark Weinstein,
`PhD, director of the FDA's Division of
`Hematology.
`
`At the moment, Weinstein said, re¬
`searchers and clinicians are not certain
`which assay is best at determining the
`amount of von Willebrand factor con¬
`tained in factor VIII concentrates. It
`varies from lot to lot ofthe manufactured
`drug because of processing steps that
`can alter the molecular weight ofthe von
`Willebrand factor. Weinstein said higher
`weight forms of the protein are believed
`to have greater ability to bind platelets.
`The most commonly used test to de¬
`termine potency of factor VIII concen¬
`trate is the ristocetin cofactor assay.
`"It's an acceptable method," said Ana-
`stassios Retzios, PhD, clinical project
`manager at Alpha Therapeutic Corpo¬
`ration in Los Angeles, Calif, maker of
`the factor VIII concentrate Alphanate.
`"But there are others—collagen-bind¬
`ing assays and antigen measurements."
`However, Weinstein noted, "There is
`no good correlation between these as¬
`says and clinical outcome. We don't know
`how to follow the level of von Willebrand
`factor in the plasma to know what the
`proper dosage is."
`How Common Is the Problem?
`In the meantime, Dilley is trying to
`determine the extent of the disease in
`women. "We hear from the hemophilia
`community. They perceive this as a
`much larger problem than it's currently
`thought to be." The study she is conduct¬
`ing with Carolyn Drews, PhD, of the
`Rollins School ofPublic Health ofEmory
`University in Atlanta, Ga, has surveyed
`physicians on how they diagnose men-
`orrhagia and make appropriate referrals
`to hématologiste. Analysis of those data
`is being completed while collection ofad¬
`ditional findings to help develop a clini¬
`cal screening tool for bleeding disorders
`in women is being concluded.
`The epidemiologie part of the study
`will try to determine the prevalence of
`von Willebrand disease among women
`with menorrhagia, which is the most
`common symptom ofthe disease in wom¬
`en. Dilley said the findings may help to
`eliminate some unnecessary hysterecto¬
`mies. "About 5% of hysterectomies are
`performed for diagnosis ofdysfunctional
`
`Downloaded From: http://jama.jamanetwork.com/ by paul skiermont on 04/21/2015
`
`CFAD VI 1033-0003
`
`