CLINICAL THERAPEUTICSWVOL. 21 , NO. 2, 1999
`
`New Drugs
`
`S.T.E.P.S."': A Comprehensive Program for Controlling and
`Monitoring Access to Thalidomide
`
`Jerome B. Zeldis, MD, PhD,’ Bruce A. Williams}
`Steve D. Thomas, PhD,3 and Marc E. ElsayedL2
`Departments of [Medical Aflairs, ZSales and
`Celgene Corporation, Warren, New Jersey
`
`Marketing, and 31mmunotherapeutics,
`
`ABSTRACT
`
`In July 1998. the US Food and Drug Ad—
`ministration approved the marketing of
`thalidomide for the treatment of cutaneous
`manifestations of erythema nodosum lep-
`rosum. To ensure that fetal exposure to
`this teratogenic agent does not occur, the
`manufacturer has instituted a comprehen—
`sive program to control prescribing, dis—
`pensing, and use of the drug. This program,
`known as the System for Thalidomide
`Education
`and
`Prescribing
`Safety
`(STEPS.m [Celgene Corporation, War—
`nen, New Jersey]), is based in part on ex-
`perience gained with other drugs—specif-
`ically isotretinoin and clozapi‘ne—that
`offer important clinical benefits but carry
`the potential for serious harm. To achieve
`its goal of the lowest possible incidence
`of drug—associated teratogenicity,
`the
`S.T.E.P.S."‘ program uses a three-pronged
`approach: (1) controlling access to the
`
`0149-291 8199/5 l9.00
`
`drug; (2) educating prescribers, pharma-
`cists, and patients; and (3) monitoring
`cowpliance. Clinicians who wish to pre-
`scribe thalidomide must be registered in
`the S.T.E.P.S." Prescriber Registry and
`agree to prescribe the drug in accordance
`with S.T.E.P.S."l patient eligibility criteria
`and monitoring procedures. Pharmacies
`must also register and agree to comply
`with patient identification and monitoring
`criteria. Finally, patients receive visual
`aids, including a videotape, written mate—
`rial, and verbal counseling about the ben—
`efits and risks of thalidomide therapy, the
`importance of not becoming pregnant dur—
`ing therapy, and the typaamntra‘c‘e—p4 "
`tion required (including emergency con—
`traception) and their availability. Women
`of childbearing potential must agree to
`undergo pregnancy testing before starting
`therapy and on a regular schedule during
`therapy. All patients must agree to com—
`plete a confidential survey about their
`
`319
`
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`
`I 1 l I I I
`
`EAL THERAPEUTICS‘
`
`BM, Chazin VR. et at,
`k illneu receptor blocks
`-. plati'n in human breast
`.cer cells. Oncogene,
`
`L, Albanell J, et al. Re-
`sized anti—HERZ anti-
`hances the antitumor
`mic] and doxorubicin
`
`_overexpressing human
`igrafts. Cancer Res.
`‘A.
`
`" ttech, Inc. HHS U.S.
`
`yV‘D, Mendelsohn J. et
`’weekly intravenous
`mized anti-plSSHERZ
`ody in patients with
`' T‘ssing metastatic breast
`.7
`,l996;l4:737—744.
`
`my and safety of her-
`ti-HER—Z antibody) as
`“(.2 women with HER—2
`
`10 relapsed following
`tastatic breast cancer.
`enacts of the American
`
`:1 Oncology meeting.
`:1.
`
`i-lones B, Shak S, et al.
`"tin (humanized-anti-
`
`rst line chemotherapy
`iessing metastatic breast
`creases anti-cancer ac—
`
`and abstracts of the
`“of Clinical Oncology
`77. Abstract.
`
`AMN 1013
`CBM of U.S. Patent No. 8,457,988
`Page 1 of 14
`
`

`

`compliance with contraception, testing,
`and drug therapy. The manufacturer is
`monitoring survey results and outcome
`data and is prepared to make whatever
`modifications to the STEPS.m program
`are necessary to ensure its effectiveness.
`In addition to minimizing the potential
`risk for
`fetal harm associated with
`thalidomide therapy, the S.T.E.P.S.m pro-
`gram may provide a model for future
`cases in which a drug offers compelling
`benefits but poses profound risks unless
`its distributionIS carefully controlled . Key
`words: congenital abnormalities, terato—
`genicity, thalidomide, patient education,
`prevention.
`
`INTRODUCTION
`
`For the first time, thalidomide is being sold
`commercially for clinical use in the United
`States In July 1998, the US Food and Drug
`Administration (FDA) approved thalido—
`mide for the treatment of cutaneous man-
`ifestations of moderate—to—severe erythema
`nodosum leprosum (ENL) and as mainte-
`nance therapy for the prevention and sup—
`pression of ENL recurrence.‘
`This latest development in the long his— '
`tory of the drug followed much debate
`over its benefits and risks and how, if at
`all. the risks can be managed.2 Thalido-
`mide is now available to those who re-
`quire it, but as the FDA has stated, it is
`“among the most,tightly restricted drugs
`to be marketed in the United States.”1 To
`reduce the risk of thalidomide-related ter—
`atogenicity to the absolute minimum, Cel-
`gene has developed a comprehensive pro—
`gram to control and monitor the drug's
`‘ prescribing, dispensing, and use.
`
`,
`
`-
`
`. Trademark: THAIDMID" (Celgene Corporation.
`Warren. New Jersey).
`
`320
`
`CLINICAL THERAPEUTICS“
`
`J.B. ZELDIS ET AL.
`
`The System for Thalidomide Education
`and Prescribing Safety (S .T.E.P.S ." [Cel-
`gene Corporation, Warren, New Jersey])
`is based partly on 2 existing models—the
`safety programs developed for isotretinoin
`and clozapine. HOWever, the scope of the
`STEPS." program exceeds that of these
`earlier programs by incorporating addi-
`tional mandatory controls and ongoing
`compliance monitoring and by establish-
`ing a set of interrelated databascs and
`standard operating procedures that pro-
`vide mechanisms for improving the pro-
`gram if deficiencies in its operation are
`detected This article describes the orga-
`nization of the S T..ERS. program; the
`roles of prescribers, pharmacists, and pa-
`tients; and the structures and procedures
`in place for monitoring both participant
`compliance and the program’s effective-
`ness in preventing fetal exposure to
`thalidomide.
`
`A BRIEF HISTORY OF
`THALIDOMIDE
`
`First marketed in 1956 in West Germany.
`thalidomide was widely sold outside the
`United States, most commonly as a seda-
`tive; it had a benign safety profile com-
`pared with that of barbiturates.3 By 1961, it
`was clear that use of thalidomide during
`pregnancy was associated with major con-
`genital abnormalities. Withdrawal of the
`drug from markets followed, but approxi-
`mately 12 ,000 infants worldwide were born
`with severe birth defects.4 Because the FDA
`had not yet approved the drug, in part out
`of concern about reported cases of periph-
`eral neuropathy, thalidomide never reached
`the US market, and this country was largely
`spared the tragedy.2
`In 1965, Sheskins reported use of
`thalidomide as a sedative in leprosy pa-
`
`tients with ENL and I]
`drug caused rapid an
`provement in type II
`Subsequent controlled 5
`the efficacy of the drug
`of ENL.6-7 In additior
`widely in the treatment
`mide has been and cont:
`tigatcd for the treatmen'
`conditions.8
`
`THALIDOMIDE-ASSl
`- TERATOGENICITY
`
`-
`
`Fetal abnormalities relat
`
`therapy include amelia
`
`sence of limbs), phoco
`limbs), hypoplasticity t
`sence of bones. extema
`normalities, facial pals:
`heart defects.9 A Gem
`
`study suggested that thx
`teratogenicity occurs wh
`ingested during the 34t
`pregnancy.‘0 However,
`ferred from the historica
`
`any period of pregnan-
`thalidomide administrati
`there any level of expo:
`nancy at which the dru;
`safe. For example, a sin
`lOO—mg dose was dete
`malformations. ”
`
`EXPERIENCE IN MA
`SPECIAL DRUG-ASS!
`RISKS
`
`Isotretinoin
`
`In the past 2 decades,
`Pharmaceutical industry
`PCrience in the use of (it
`POI’Iant clinical benefits
`
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`

`fl .‘THERAPEUTICS'
`
`l.B. ZELDIS ET AL.
`
`domide Education
`" °S.T.E.P.S."' [Cel~
`.-en, New Jersey])
`sting models—the
`r Ed for isotretinoin
`a, the scope of the
`ceeds that of these
`,7 "orporating addi~
`-.ols and ongoing
`and by establish-
`” al databases and
`Vedures that pro-
`nproving the pro-
`#
`its operation are
`escribes the orga~
`_S."‘ program; the
`V Wmacists, and pa-
`»;s and procedures
`; both participant
`. ram‘s effective—
`Hal exposure to
`’W
`
`_.
`
`'F
`
`West Germany,
`sold outside the
`/ ‘ronly as a seda-
`tety profile com-
`rates.3 By 1961, it
`* idomide during
`, with major con-
`fithdmwal of the
`:d, but approxi-
`adwide were born
`Because the FDA
`
`5mg, in part out
`1 cases of periph-
`de never reached
`
`run was largely
`
`eoorted use of
`
`in leprosy pa«
`
`tients with ENL and indicated that the
`drug caused rapid and dramatic im-
`provement
`in type 'II lepra reactions.
`Subsequent controlled studies confirmed
`the efficacy of the drug in the treatment
`of ENL.5'7 In addition to being used
`widely in the'treatment of ENL, thalido-
`mide has been and continues to be inves—
`tigated for the treatment of various other '
`conditions.8
`
`’I‘HALIDOMIDE-ASSOCIATED
`TERATOGENICITY
`
`Fetal abnormalities related to thalidomide
`therapy include amelia (congenital ab-
`sence of limbs), phocomelia (shortened
`limbs), hypoplasticity of the bones, ab-
`sence of bones, external ear and eye ab-
`normalities, facial palsy, and congenital
`heart defects.9 A German retrospective
`study suggested that the greatest risk of
`teratogenicity occurs when thalidomide is
`ingested during the 34th to 50th day of
`pregnancy.'0 However, it cannot be in-
`ferred from the historical data that there is
`any period of pregnancy during which
`thalidomide administration is safe, nor is
`there any level of exposure during preg—
`nancy at which the drug is known to be
`safe. For example, a single exposure to a
`100—mg dose was determined to cause
`malformations. ‘ '
`
`EXPERIENCE IN MANAGING
`SPECIAL DRUG-ASSOCIATED
`RISKS
`
`Isotretinoin
`
`In the past 2 decades, clinicians and the
`pharmaceutical industry have gained ex-
`perience in the use of drugs that offer im-
`portant clinical benefits but cany poten-
`
`tially serious risks. Teratogenicity has
`been addressed in the case of isotretinoin,“k
`an oral drug capable of producing pro—
`longed remissions in patients with severe,
`recalcitrant cystic acne.’2 In 1988, after
`receiving reports of retinoic acid—induced
`embryopathy, the manufacturer of iso-
`tretinoin implemented a program de—
`signed to allow female patients access to
`the drug while minimizing the teratogenic
`hazard.l3
`
`In contrast to the case of thalidomide,
`retinoic acid's teratogenic effect was
`known before marketing; the initial label—
`ing of isotretinoin included a warning
`against use during pregnancy. Nonethe—
`less, reports of birth defects and sponta-
`neous abortions appeared in women ex-
`posed to isotretinoin during the first
`trimester of pregnancy. ‘2 The reports
`mounted despite warnings to physicians
`through direct mailings, advertisements,
`and the package insert; by 1989, 78 mal—
`formed infants had been born to women
`taking isotretinoin.”
`The FDA and the manufacturer of
`isotretinoin redoubled their efforts to alert
`physicians and patients to the teratogenic
`effects of the drug. In addition, the man—
`ufacturer implemented a variety of educa—
`tional programs and made changes in la-
`beling and packaging.‘2 In 1988 the
`labeling was revised to state that iso—
`tretinoin therapy is contraindicated in
`women capable of becoming pregnant,
`with the exception of those with severe,
`disfiguring nodular acne that is unrespon-
`sive to standard therapies. In addition.
`women who are candidates for isotretinoin
`therapy must be judged capable of com—
`plying with therapy and taking contracep—m
`
`‘Trademark: Accutane® (Roche Pharmaceuticals,
`Nutley, New Jersey).
`
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`

`l 1
`
`CLINICALTHERAPEUTICS“ I1
`
`JB. ZELDIS ET AL.
`
`gram said that they had been told to avoid
`pregnancy. Further, posttherapy tracking
`
`showed that pregnancy rates increased in
`the 4 months after cessation of isotretinoin ;
`therapy, which is consistent with avoid- '
`ance of pregnancy during the period of
`teratogenic risk.
`
`physicians, pharmacies, p2
`ufacturer, and distributors .
`use of the medication. Clo
`distributed only by registe
`that agreed to follow the
`drug” guideline of the reg
`A review of 5 years’ c
`than 99,000 patients in the
`that the incidence of agrai
`significantly lower than e:
`vs the expected 1% to 2%
`the success of the prograr
`cently approved a modifica
`blood cell count-monitorin
`patients must undergo wee
`iton'ng for the first 6 montl
`clozapine therapy (when th
`ulocytosis is highest),
`f(
`weekly blood tests for patie
`Menu? of hematologic abnr
`
`i l
`
`Clozapine
`
`A different challenge was posed by the
`antipsychotic agent clozapine.t The drug
`benefited patients with schizophrenia who
`did not reSpond to other medications by
`improving negative as well as positive
`‘ symptoms of the disease.”"5 Unfortu— l
`nately, clinical research findings and for-
`i
`eign postmarketing experience indicated i
`that 1% to 2% of patients developed agran- I
`ulocytosis, which is potentially fatal.16 At
`the same time, however, the data showed
`that none of the patients whose agranulo-
`cytosis was detected through laboratory
`tests died before they developed infections.
`This suggested that patient surveillance i
`could help prevent agranulocy’rosis.16
`!
`The FDA’S approval of the drug in 1989 i
`was contingent on such surveillance, and i
`the manufacturer created the Clozaril Na—
`tional Registry, a program designed to reg-
`ister treating physicians and patients. en-
`sure patient monitoring (regular blood
`testing), and limit distribution of the drug _
`. to compliant individuals. All patients Who i
`received clozapine were required to have
`a white-blood cell count at baseline and
`weekly thereafter until 4 weeks after the
`end of treatment. Patients could receive
`medication only when data on their white
`blood cell count were current. The reg—
`isny system also provided guidelines for
`
`,
`
`t'l'rademark: Clozaril" (Sandoz Pharmaceuticals:
`Hanover, New Jersey).
`
`OBJECTIVES AND
`ORGANIZATION OF S.
`
`Celgene Corporation has i
`ements of both these succr
`into the STEPS." progr
`ling the distribution of tha
`Cational materials for path
`cians and label warnings :
`
`Eh“
`
`Table 1. Methods of accr
`and Prescribing .‘M
`
`Maintenance of electronic da!
`patients to control access to d
`
`Education of prescribers, pha
`lhcrapy and the requirement 1
`Women of childbearing poten'
`
`Continuous compliance moni'
`az‘lement committee, and regu
`‘Mh—
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`
`tive measures, must be given verbal and
`written warnings of the teratogenic haz—
`ard, and must have a negative result on a
`serum or urine pregnancy test within 14
`days of starting therapy.
`The manufacturer also instituted the
`Pregnancy Prevention Program to encour-
`age attention to the above requirements.13
`This program comprises a kit containing
`educational material for patients, a stan—
`dard patient consent form, and checklists
`for both the patient and physician to ver—
`ify that the patient meets the criteria for
`therapy with isotretinoin. Awareness of
`the program has been reinforced by peri—
`odic communications to prescribers and
`pharmacists. The elements of the program
`that depart from usual medical practice
`include: (1) a formalized process for en—
`suring informed patient consent, (2) a pro-
`vision by the manufacturer to reimburse
`patients for the cost of contraceptive coun—
`seling, and (3)
`the requirement
`that
`women use the drug solely for its labeled
`indication. Later the manufacturer repack-
`‘ aged isotretinoin in a lO—capsule blister
`, pack containing information directed
`specifically at women: a warning about
`the risks of becoming pregnant while tak—
`ing isotretinoin or during the month after
`treatment, an “avoid pregnancy” icon on
`‘ each capsule, and line drawings of mal-
`, formations associated with the drug.
`In 1995, Mitchell and coworkers,13
`‘ from the Slone Epidemiologic Unit (SEU)
`. at the Boston University School of Medi—
`cine School of Public Health, reported
`' that women receiving isotretinoin under
`1 the Pregnancy Prevention Program had a
`‘ substantially lower pregnancy rate than
`the general population: 8.8 versus 109 per
`. 1000 person-years. In addition, 24,258
`,(99%) of 24,503 women interviewed
`within 1 month of enrollment in the pro-
`
`‘
`,
`
`'
`
`.
`
`' 322
`
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`

`

`,ZALTHERAPEUTICS°
`
`LB. ZELDIS ET AL.
`
`~mad been told to avoid
`)osttherapy tracking
`‘uCy rates increased in
`gssation of isotretinoin
`nsistent with avoid~
`‘during the period of
`
`ge was posed by the
`‘c’lozapinef The drug
`.ith schizophrenia who
`ther medications by
`3 ’as well as positive
`Jisease.‘4"5 Unfortu-
`
`:h findings and for—
`‘e‘xperience indicated
`ients developed agrari-
`otentially fatal.16 At
`“flier, the data showed
`
`reins whose agranulo—
`through laboratory
`" developed infections.
`- patient surveillance
`anulocytosis.16
`"31 of the drug in 1989
`.uch surveillance, and
`ted the Clozaril Na-
`
`”giam designed to reg—
`laps and patients, en-
`ing (regular blood
`stdbution of the drug
`rials. All patients who
`:re required to have -
`idunt at baseline and
`
`s-til 4 weeks after the ;
`ients could receive :
`in data on their white f‘
`we current. The reg—
`fided guidelines for
`
`_
`
`‘ ~Lndoz Pharmaceuticals,
`
`'
`
`physicians, pharmacies, patients, the man-
`ufacturer, and distributors to ensure proper
`use of the medication. Clozapine could be
`distributed only by registered pharmacies
`that agreed to follow the “no blood—no
`drug” guideline of the registry.[7
`A review of 5 years‘ data from more
`than 99,000 patients in the registry showed
`that the incidence of agranulocytosis was
`significantly lower than expected (0.38%
`vs the expected 1% to 2%). As a result of
`the success of the program, the FDA re—
`cently approved a modification of the white
`blood cell couanonitoring regimen: Now
`patients must undergo weekly blood mon—
`itoring for the first 6 months of continuous
`Clozapine therapy (when the risk for agran-
`ulocytosis is highest), follOWed by bi-
`weekly blood tests for patients with no ev-
`idence of hematologic abnormalities.
`
`OBJECTIVES AND
`ORGANIZATION OF S.T.E.P.S .7"
`
`Celgene Corporation has incorporated el—
`ements of both these successful programs
`into the STEPS." program for control-
`ling the distribution of thalidomide. Edu-
`cational materials for patients and physi‘
`cians and label warnings similar to those
`
`used. in the isotretinoin program are cou-
`pled with clinician and patient registra—
`tion and testing similar to those used in
`the Clozapine program.
`The STEPS.” program is multifo-
`cal—directed at prescribers, pharmacists,
`and both male and female patients. Its goal
`is straightforward: to ensure that fetal ex—
`posure to thalidomide does not occur. The
`methods that are being used to accomplish
`this goal are outlined in Table I.
`A team approach is necessary. Program
`implementation and oversight are per-
`formed by Celgene, the SEU, and the Cel-
`gene STEPS." Management Committee.
`The management committee has overall
`responsibility for monitoring and auditing
`the program. The committee is composed
`of at least 7 persons, including senior Cel-
`gene personnel in the medical affairs, reg-
`ulatory, and drug safety departments, and
`industry experts with expertise in com-
`puterized databases, warehousing and dis
`tribution, manufacturing procedures, com—
`pliance auditing, and other areas. The SEU
`has a separate advisory board composed
`of representatives of various interest
`groups (eg, the Thalidomide Victims As—
`sociation of Canada and the March of
`Dimes), experts in the use of thalidomide
`
`Table 1. Methods of accomplishing the goal of the S
`and Prescribing Safety (S.T.E.P.S.").
`
`'
`
`'
`
`'
`
`Continuous compliance monitoring through mandate
`agement committee, and regular system-wide audits.
`N
`
`ry patient surveys. reports to a central man-
`
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`

`1.3. ZELDIS ET AL.
`
`THE REGISTRATION
`
`Prescribers
`
`l l l
`
`l
`
`Initially, those who an
`prescribe thalidomide arr
`formation about the STE
`On request, these prescri
`who express
`interest
`STEPS." folder with a:
`and an educational monog
`who are interested in pres
`.mide must register in the
`The registration card
`terms of prescribing mu:
`the prescriber and returner
`participate in the S.T.E.
`the prescriber must agree
`comprehensive patient co
`benefits and risks of thalido
`in the informed consent ft
`appropriate contraception
`pregnancy testing; (3) subn
`formed consent forms to SI
`the prescriber portion of t'
`toring survey and return I
`SEU; (5) prescribe a qua:
`greater than is required for
`apy, with no refills; and ((
`tients to return unused thaJ
`pharmacy. The registrant (
`eligible to prescribe until
`tered all the prescriber regi
`tion in the prescriber datab:
`
`Pharmacies
`
`Retail and hospital pl
`also register to dispense tl
`head pharmacist of each p
`director of pharmacy at a
`TCSPonsibility for registeri
`Gating other members of
`die S.T.E.P.S."‘ program. F
`eSted in registering may c
`
`CLINICAL THERAPEUTICS"
`
`surveying from the Accutane Pregnancy
`Prevention Program. By reviewing the
`mandatory confidential survey completed
`by both prescribers and patients, SEU is
`monitoring compliance with the educa-
`tional, informed consent, and pregnancy-
`testing components of the program.
`The STEPS." Management Commit-
`tee is charged with overseeing the entire
`process and making certain that it is work-
`ing. This entails timely transfer of infor-
`mation from the distribution database to
`the SEU database; timely investigation
`and resolution of any concerns abdut pre—
`scriber, pharmacy, or patient compliance
`with the program; and making recom-
`mendations to the FDA for changes in the
`program based on real-time data.
`The committee is chaired by the com~
`pany president. The senior regulatory in-
`dividual is the principal liaison with the
`FDA for company responses
`to the
`agency’s inquiries. The STEPS." man—
`ager, who reports to the president, over-
`sees the initial and follow—up audit to de-
`termine whether distribution
`is.
`in
`accordance with STEPS." program pol-
`icy and procedures; this individual also _
`monitors continuing reviews of standard
`operating procedures by Celgene and i
`SEU. The thalidomide product manager
`,
`helps monitor the program’s efl'ectiveness ;
`(eg, through communications with field-
`based‘Celgene representatives) and will
`implement recommendations made by the
`committee relating to the sale and promo-
`tion of the drug. Medical affairs and drug
`safety personnel on the committee serve
`as liaisons with health care providers and
`SEU and are responsible for ensuring ap-
`propriate professional education on the
`risks of fetal exposure to thalidomide and
`the means of preventing it and for captur-
`ing reports of any adverse experiences.
`
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`
`for treating various medical conditions,
`and epidemiologists.
`Celgene's primary responsibilities in-
`clude providing potential prescribers and
`dispensers with STEPS." program ma-
`terials and supplying educational materi-
`als and drug. The company had prepared
`a variety of educational materials in an—
`ticipation of FDA approval of thalido-
`mide. including patient-oriented video-
`tapes, discussing the risks associated with
`the drug to ensure responsible prescrib-
`ing and diSpensing and to enhance pa-
`tient compliance. These are being sup-
`plied directly to all registered prescribers
`and pharmacies. (Persons interested in re-
`ceiving some of these materials can call
`1-888-4—CELGENE.) In addition, Cel-
`gene is sending monthly letters to pre-
`scribers that highlight prescribing and
`counseling requirements for thalidomide.
`Celgene is providing thalidomide only
`to pharmacies that are registered and com—
`i
`, ply with S.T.E.P.S." requirements. The
`company has designed, constructed, and
`currently maintains the Pharmacy Dis—
`. pensing Registry, which comprises data
`on prescribing, dispensing, and distribu-
`tion. These data are being constructed
`‘
`. from registration cards returned by pre—
`scribers; registration cards, dispensing in-
`7 formation, and drug orders from pharma-
`« cies; and patient
`registration forms.
`‘ Celgene is providing pharmacists with on—
`line and toll-free telephone access to pre—
`' scribe'r, pharmacist, and patient eligibility
`‘ information. Using this on—line registry,
`pharmacists must verify that program re-
`' quirements have been met. Celgene is pro—
`, viding pharmacy dispensing data to SEU
`on a monthly basis for compliance track-
`' ing and quality assurance monitoring.
`The SEU brings to the STEPS.” pro—
`gram experience in patient-compliance
`
`,
`
`324
`
`AMN 1013
`CBM of U.S. Patent No. 8,457,988
`Page 6 of 14
`
`

`

`— IICAL THERAPEUTICS‘
`
`fie Accutane Pregnancy
`rm. By reviewing the
`‘e’ntial survey completed
`J's and patients. SEU is
`iance with the educa-
`"ionsent, and pregnancy-
`V's of the program.
`Management Commit—
`'tli overseeing the entire
`M, certain that it is work-
`mely transfer of infor-
`distribution database to
`”a; timely investigation
`my concerns about pre-
`~I.Jor patient compliance
`N. and making recom-
`7DA for changes in the
`l real-tune data.
`
`' is chaired by the com-
`: senior regulatory in-
`?ineipal liaison with the
`5my responses to the
`The S.T.E.P.S." man-
`i to the president, over-
`” «follow-up audit to de-
`distribution
`is
`in
`LT.E.P.S." program pol-
`es; this'individual also
`
`g reviews of standard
`“lures by Celgene and
`"hide product manager
`rogram’s effectiveness
`munications with field-
`
`i
`
`:
`
`j
`»
`
`-"resentatives) and will
`)endations made by the
`g to the sale and promo-
`*‘edical affairs and drug
`,
`it the committee serve f
`ealth care providers and ‘
`‘1sible for ensuring ap-
`7 mal education on the ?
`sure to thalidomide and
`
`‘rting it and for captur—
`’
`. )rdverse experiences.
`
`II
`
`l
`
`1 1.3. ZELDIS ET AL.
`
`THE REGISTRATION PROCESS
`
`Prescribers .
`
`Initially, those who are most likely to
`prescribe thalidomide are being sent in-
`formation about the S.T.E.P.S." program.
`On request, these prescribers and others
`who express
`interest will
`receive a
`STEPS." folder with a registration card
`and an educational monograph. Clinicians
`who are interested in prescribing thalido-
`mide must register in the program.
`The registration card outlining the
`terms of prescribing must be signed by
`the prescriber and returned to Celgene. To
`participate in the S.T.E.P.S."' program,
`the prescriber must agree to: (l) provide
`comprehensive patient counseling on the
`- benefits and risks of thalidomide, as outlined
`in the informed consent form; (2) provide
`appropriate contraception counseling and
`pregnancy testing; (3) submit completed in—
`formed consent forms to SEU; (4) complete
`the prescriber portion of the patient—moni—
`toring survey and return the docirment to
`SEU; (5) prescribe a quantity of drug no
`greater than is required for 28 days of ther-
`apy, with no refills; and (6) encourage pa-
`tients to return unused thalidomide to their
`pharmacy. The registrant does not become
`eligible to prescribe until Celgene has en—
`tered all the prescriber registration infoma—
`tion in the prescriber database.
`
`Pharmacies
`
`Retail and hOSpital pharmacies must
`also register to dispense thalidomide. The
`head pharmacist of each pharmacy (or the
`director of pharmacy at a hospital) takes
`responsibility for registering and for edu—
`cating other members of the staff about
`the S..T.E.RS." program. Pharmacies inter—
`ested in registering may contact Celgene.
`
`Like prescribers, pharmacies must agree
`to the terms of the STEPS." program.
`Their participation in the program in—
`volves: (l) collecting and filing the pa-
`tient's signed informed consent form with
`the initial prescription; (2) registering
`thalidomide recipients by fax or telephone;
`(3) dispensing no more than 28 days of
`thalidomide therapy, with no refills (hos—
`pitals will usually dispense a 7-day sup-
`ply); (4) verifying patient registration and
`recording subsequent prescriptions on-line
`or by telephone; (5) accepting and storing
`(or retumién'g to Celgene) any unused thalido-
`rrride remmed by patients; and (6) informing
`all staff pharmacists of the dispensing pro—
`cedure for thalidomide. The pharmacy reg—
`istration card outlining the terms for dis-
`pensing must be signed by the pharmacist
`and returned to Celgene.
`"
`All registration data provided by the
`pharmacy are entered into the dispensing
`database by the distributor. The pharmacy
`is then designated eligible to dispense, and
`a monograph is mailed to the pharmacist.
`
`Patients
`
`Patient registration forms are com—
`pleted by the pharmacist and sent to Cel-
`gene for entry into the distribution data-
`base. The pharmacist registers patients
`only if the patient presents a copy of the
`STEPS.” informed consent document
`signed both by the patient and a regis-
`tered prescriber and a prescription writ—
`ten by the prescriber.
`
`PRESCRIBING AND DISPENSING
`
`Under the S.T.E.P.S.TM program, the pre-
`scriber counsels patients about the bene—
`fits and risks of thalidomide therapy and
`providespatients with the literature and
`
`325
`
`A M N 1013
`
`CBM ofU.S. Patent No. 8,457,988
`Page 7 of 14
`
`AMN 1013
`CBM of U.S. Patent No. 8,457,988
`Page 7 of 14
`
`

`

`CLINICAL THERAPEUTICS‘
`
`LB. ZELDlS ET AL.
`
`provide contraceptive cou
`ing information on emergr
`tion, to women who are r
`ceiving but do not agree
`sexual activity with men. A
`feels uncomfortable abou'
`refer the patient to a gynec
`practitioner; a form to faci
`included in the S.T.E.P.S ."
`must thoroughly underste
`use 2 forms of contracep
`ously, beginning 4 weeks
`of therapy with thalidomi:
`ing throughout therapy ur
`ter stopping therapy; if the
`to be abstinent, she must
`ing this entire period. Cont
`ods must include at least
`tive method (eg,
`intrar
`hormone preparation, tul
`‘ partner’s vasectomy) and
`fective method (cg, condr
`or cervical cap). If horm:
`tion or an intrauterine dev
`
`contraindicated, 2 other efl
`effective methods must be
`Women must also agr
`pregnancy testing before 2
`flpy. Pregnancy testing is r
`during the first month of u
`thereafter in women witl
`Strual cycles and every 2 v
`Whose cycles are irregular
`performed in the prescribe;
`Oratory and satisfy a sen
`mIU/mL. Pregnancy testir
`Performed if a patient mi
`0r there is any abnorrnali
`bleeding. [f pregnancy dd
`tfttztttnent. the drug must I
`immediately. and the pre
`tient must discuss the im;
`Pregnancy. Under these -
`Patient must be referred to :
`
`AMN 1013
`
`videotape. All materials that are neces—
`sary for compliance with the program
`requirements
`are
`contained
`in
`the
`S.T.E.P.S."‘ folder (Table ll). Various ed-
`ucational materials for facilitating the in-
`formed consent process are included. The
`contents of 1 folder should be used with
`1 patient only and kept with the patient’s
`medical record.
`It is crucial that the prescriber gauge
`the patient’s understanding of the risks of
`thalidomide treatment and the require-
`ments for eligibility for treatment. To fa~
`cilitate this, a brief quiz is included with
`the S .T.E.P.S."l materials. If the patient
`cannot answer all questions on this quiz
`
`correctly, the prescriber is urged to review
`the materials with the patient and assess
`whether the patient is a suitable candidate
`for the program. The patient must be able
`to answer all questions correctly to enter
`the program.
`To receive thalidomide, women of
`childbearing potential must agree to use 2
`reliable forms of contraception, with the
`sole exception of women who agree to
`abstain from sexual intercourse with men.
`Only women who have undergone hys-
`terectomy, who are postmenopagsal, or
`who have had no menses for ate-least 24
`consecutive months are considered inca—
`pable of childbearing. The prescriber must
`
`
`
`_...-......—_r--.
`
`l l
`
`,
`
`Safety (S.T.E.P.S."‘).*
`
`1. Registration card. The prescriber completes this and returns it to the distributor.
`
`lnstructions for prescribers. These describe how the S.T.E.P.S.m program is implemented.
`. 2.
`’ 3. Patient referral form. This can be used to refer
`contraceptive counseling or pregnancy testing.
`
`patients to another health care provider for
`
`,7 4. Important Information for Men and Women Taking THALOMID" (Thalidomide). This
`pamphlet explains the reproductive hazards of the drug (it includes a photograph of an
`infant with severe birth defects), other adverse effects, and requirements for becoming and
`remaining eligible for treatment. On the front page of the pamphlet, there is the warning,
`“If thalidomide is taken during pregnancy, it causes severe birth defects or death to the
`unborn baby. Thalidomide should never be
`used by women who are pregnant or could
`become pregnant." The pamphlet is availab
`le in English and 14 other languages.
`
`. 5. Your Contraceptive Choices. This patient—education pamphlet, developed by Planned
`Parenthood, discusses the effectiveness, advantages, and disadvantages of various methods
`of contraception, including abstinence. it is available in English or Spanish.
`46. Emergency Contraception. This pamphlet, also developed by Flamed Parenthood, identifies
`situations in which emergency contraception may be necessary, discusses the medications
`employed in emergency contraception and