Reprinted from Clinical Therapeutics@, Vol. 21, NO. 2, OExcerpta Medica, 1999
`
`New Drugs
`
`S.T.E.P.S.TM : A Comprehensive Program for Controlling and
`Monitoring Access to Thalidomide
`
`Jerome B. Zeldis, MD, PhDt Bruce A. Williams:
`Steve D. Thomas, PhDp and Marc E. Elsayea
`Departments of ‘Medical Affairs, 2Sales and Marketing, and ‘Immunotherapeutics,
`Celgene Corporation, Warren, New Jersey
`
`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
`(S .T.E .P.S .TM [Celgene Corporation, War-
`ren, New Jersey]), is based in part on ex-
`perience gained with other drugs-specif-
`ically
`isotretinoin and clozapine-
`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 .TM program uses a three-pronged
`approach: (1) controlling access to the
`
`drug; (2) educating prescribers, pharma-
`cists, and patients; and (3) monitoring
`compliance. Clinicians who wish to pre-
`scribe thalidomide must be registered in
`the S .T.E.P.S .TM Prescriber Registry and
`agree to prescribe the drug in accordance
`with S .T.E.P.S .TM 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 types of contracep-
`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
`
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`
`The System for Thalidomide Education
`and Prescribing Safety (S .T.E.P.S .TM [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
`S.T.E.P.S .TM 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 databases 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.E.P.S.‘” 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 barbituratess 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?
`reported use of
`In 1965, Sheskin
`thalidomide as a sedative in leprosy pa-
`
`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 S .T.E.P.S .TM 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 .TM pro-
`gram may provide a model for future
`cases in which a drug offers compelling
`benefits but poses profound risks unless
`its distribution is 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.* 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.“’ 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: THALOMID’”
`Warren, New Jersey).
`
`(Celgene Corporation,
`
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`J.B. ZELDIS ET AL.
`
`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.6,7 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
`conditions8
`
`THALIDOMIDE-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 defects9 A German retrospective
`study suggested that the greatest risk of
`teratogenicity occurs when thalidomide is
`ingested during the 34th to 50th day of
`pregnancy. lo 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
`lOO-mg dose was determined to cause
`malformations. l1
`
`IN MANAGING
`EXPERIENCE
`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 carry poten-
`
`tially serious risks. Teratogenicity has
`been addressed in the case of isotretinoin,*
`an oral drug capable of producing pro-
`longed remissions in patients with severe,
`recalcitrant cystic acne.12 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.t2 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. ‘I
`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.12 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-
`
`*Trademark: AccutaneB (Roche Pharmaceuticals,
`Nutley, New Jersey).
`
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`CLINICAL THERAPEUTICS”
`
`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.
`
`Clozapine
`
`A different challenge was posed by the
`antipsychotic agent clozapine.* The drug
`benefited patients with schizophrenia who
`did not respond to other medications by
`improving negative as well as positive
`symptoms of the disease.t4J5 Unfortu-
`nately, clinical research findings and for-
`eign postmarketing experience indicated
`that 1% to 2% of patients developed agran-
`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
`could help prevent agranulocytosis.t6
`The FDA’s approval of the drug in 1989
`was contingent on such surveillance, and
`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
`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-
`istry system also provided guidelines for
`
`*Trademark: Clozaril’”
`Hanover, New Jersey).
`
`(Sandoz Pharmaceuticals,
`
`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.t3
`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 199.5, 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
`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-
`
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`J.B. ZELDIS ET AL.
`
`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.17
`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 count-monitoring 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 .TM
`
`Celgene Corporation has incorporated el-
`ements of both these successful programs
`into the S.T.E.P.S.‘” 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 S .T.E.P.S .TM 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 S.T.E.P.S.‘” 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 I. Methods of accomplishing the goal of the System for Thalidomide Education
`and Prescribing Safety (S .T.E.P.S .” ).
`
`Maintenance of electronic databases of registered and compliant prescribers, pharmacists, and
`patients to control access to drug.
`
`Education of prescribers, pharmacists, and patients about the risks associated with thalidomide
`therapy and the requirement for adequate contraceptive measures and pregnancy testing for
`women of childbearing potential.
`
`Continuous compliance monitoring through mandatory patient surveys, reports to a central man-
`agement committee, and regular system-wide audits.
`
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`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 S .T.E.P.S .TM 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 about 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 S.T.E.P.S.‘” man-
`ager, who reports to the president, over-
`sees the initial and follow-up audit to de-
`termine whether distribution
`is
`in
`accordance with S .T.E.P.S .TH program pol-
`icy and procedures; this individual also
`monitors continuing reviews of standard
`operating procedures by Celgene and
`SEU. The thalidomide product manager
`helps monitor the program’s effectiveness
`(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.
`
`for treating various medical conditions,
`and epidemiologists.
`Celgene’s primary responsibilities in-
`clude providing potential prescribers and
`dispensers with S .T.E.P.S.‘” 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
`l-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-
`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-
`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-
`scriber, 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 S .T.E.P.S .TY pro-
`gram experience in patient-compliance
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`

`J.B. ZELDIS ETAL.
`
`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 .TM program.
`On request, these prescribers and others
`who express interest will
`receive a
`S.T.E.P.S.‘” folder with a registration card
`and an educational monograph. Clinicians
`who are interested in prescribing thalido-
`mide must register in the program.
`the
`The registration card outlining
`terms of prescribing must be signed by
`the prescriber and returned to Celgene. To
`participate in the S .T.E.P.S .TM program,
`the prescriber must agree to: (1) 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 document 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 informa-
`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.P.S.‘” program. Pharmacies inter-
`ested in registering may contact Celgene.
`
`Like prescribers, pharmacies must agree
`to the terms of the S.T.E.P.S.‘” program.
`Their participation
`in the program in-
`volves: (1) 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 returning to Celgene) any unused thalido-
`mide returned 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
`S .T.E.P.S .TM 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.‘” program, the pre-
`scriber counsels patients about the bene-
`fits and risks of thalidomide therapy and
`provides patients with the literature and
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`CLINICAL THERAPEUTICS”
`
`that are neces-
`videotape. All materials
`sary for compliance with
`the program
`requirements
`are contained
`in
`the
`S.T.E.P.S.‘” folder (Table II). 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 .TM 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 postmenopausal, or
`who have had no menses for at least 24
`consecutive months are considered inca-
`pable of childbearing. The prescriber must
`
`Table II. Program materials for the System for Thalidomide Education and Prescribing
`Safety (S.T.E.P.S.‘“).*
`
`1. Registration card. The prescriber completes this and returns it to the distributor.
`
`2. Instructions for prescribers. These describe how the S.T.E.P.S.‘” program is implemented.
`
`3. Patient referral form. This can be used to refer patients to another health care provider for
`contraceptive counseling or pregnancy testing.
`
`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 available 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.
`
`6. Emergency Contraception. This pamphlet, also developed by Planned Parenthood, identifies
`situations in which emergency contraception may be necessary, discusses the medications
`employed in emergency contraception and their use, and reviews what the patient can expect
`immediately after use. It is available in English or Spanish.
`
`*Enclosed in each folder provided to clinicians who wish to prescribe thalidomide.
`
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`J.B. ZELDIS ET AL.
`
`provide contraceptive counseling, includ-
`ing information on emergency contracep-
`tion, to women who are capable of con-
`ceiving but do not agree to abstain from
`sexual activity with men. A prescriber who
`feels uncomfortable about doing so may
`refer the patient to a gynecologist or other
`practitioner; a form to facilitate referral is
`included in the S .T.E.P.S .TM folder. Women
`must thoroughly understand the need to
`use 2 forms of contraception simultane-
`ously, beginning 4 weeks before the start
`of therapy with thalidomide and continu-
`ing throughout therapy until 4 weeks af-
`ter stopping therapy; if the patient chooses
`to be abstinent, she must remain so dur-
`ing this entire period. Contraceptive meth-
`ods must include at least 1 highly effec-
`tive method (eg,
`intrauterine device,
`hormone preparation, tubal ligation, or
`partner’s vasectomy) and 1 additional ef-
`fective method (eg, condom, diaphragm,
`or cervical cap). If hormonal contracep-
`tion or an intrauterine device is medically
`contraindicated, 2 other effective or highly
`effective methods must be used.
`Women must also agree to undergo
`pregnancy testing before and during ther-
`apy. Pregnancy testing is required weekly
`during the first month of use and monthly
`thereafter in women with regular men-
`strual cycles and every 2 weeks in women
`whose cycles are irregular. Tests must be
`performed in the prescriber’s office or lab-
`oratory and satisfy a sensitivity of ~50
`mIU/mL. Pregnancy testing must also be
`performed if a patient misses her period
`or there is any abnormality in menstrual
`bleeding. If pregnancy does occur during
`treatment, the drug must be discontinued
`immediately, and the prescriber and pa-
`tient must discuss the implications of the
`pregnancy. Under these conditions, the
`patient must be referred to a board-certified
`
`obstetrician/gynecologist, who will have
`received training in reproductive toxicity.
`To encourage compliance with the preg-
`nancy-testing requirement, it is recom-
`mended that female patients initially re-
`ceive no more than a l-week supply of
`thalidomide for each of the first 4 weeks.
`Male patients enrolled in the S .T.E.P.S .TM
`program receive written and oral warnings
`of the risk of possible contraception failure
`and the need to use condoms when having
`intercourse with women of childbearing
`age. It is unknown whether thalidomide is
`present in sperm or semen or whether such
`presence would impair fetal development.
`Patients must also agree never to do-
`nate blood or share thalidomide with any-
`one, even if the other individual has sim-
`ilar symptoms. They are cautioned to keep
`the drug out of the reach of children. Fi-
`nally, they must agree to participate in the
`patient survey.
`Patients and prescribers must both sign
`a four-copy
`informed-consent
`form; 1
`copy is retained for the prescriber’s files,
`1 is sent to SEU for inclusion in the data-
`base, 1 is kept by the patient, and 1 is pre-
`sented to the pharmacy for filing.
`In-
`formed consent forms are available in 15
`languages. Patients and prescribers also
`complete a survey form that captures data
`on contraceptive use and the condition be-
`ing treated, explains the survey’s purpose,
`and stresses the survey’s confidentiality.
`The prescriber can write a thalidomide
`prescription after completing the informed
`consent process and, for women of child-
`bearing potential, obtaining a negative re-
`sult from a pregnancy test. As mentioned,
`patients present the prescription and a
`signed copy of the informed consent form
`to a pharmacist at a registered pharmacy.
`If a pharmacy is not registered, the regis-
`tration process can be completed by tele-
`
`321
`
`CFAD VI 1011-0009
`
`

`

`CLINICAL THERAPEUTICS@
`
`dence by SEU (with the exception that
`study records may be examined in con-
`fidence by FDA representatives).
`SEU cross-references data from pa-
`tient surveys with the pharmacy dispens-
`ing registry weekly for the first 3 months
`and monthly thereafter to verify accu-
`racy. When deviations from S .T.E.P.S .TM
`program procedures are found, SEU con-
`tacts prescribers or patients in a timely
`manner by fax, telephone, or mail. Trig-
`gers for such contacts include failure to
`receive a survey form after a known visit,
`indication on a survey form that a sexu-
`ally active woman is not using adequate
`contraception, disclosure by a woman
`that she may be pregnant, a male pa-
`tient’s report that his partner may be
`pregnant, and failure of registered pre-
`scribers to give patients adequate coun-
`seling. SEU periodically forwards rou-
`tine data summaries and information
`(with the exception of patient identity) to
`the S .T.E.P.S .TM management committee
`and immediately informs Celgene of any
`pregnancies, suspected fetal exposures,
`or noncompliant prescribers.
`Data from the pharmacy dispensing reg-
`istry will be sampled by an external audi-
`tor for periodic audits to measure regis-
`tered pharmacies’ compliance with the
`program. Audits will confirm, for exam-
`ple, that the pharmacy has obtained in-
`formed consent from each patient to whom
`it dispenses the drug and that appropriate
`intervals have elapsed between prescrip-
`tions. Subsequent to the initial audit of
`prescriptions, a schedule for ongoing com-
`pliance monitoring is implemented.
`Finally, the management committee is
`charged with monitoring the ongoing ex-
`perience from reports prepared by Cel-
`gene and SEU, ensuring compliance with
`operating procedures. The committee may
`
`phone and fax, and the drug is shipped for
`arrival at the pharmacy within 2 days.
`The packaging for thalidomide reiter-
`ates warnings on teratogenicity and the
`requirements for pregnancy testing and
`contraception. The capsule itself bears a
`simple and direct warning: the silhouette
`of a pregnant woman on which a black
`circle with a slash is superimposed.
`the
`Once a patient
`is entered
`in
`S.T.E.P.S.‘” distribution database, the pre-
`scriber is mailed monthly reminders of the
`counseling and pregnancy-testing require-
`ments. Patients returning to the prescriber’s
`office for subsequent prescriptions: (1) re-
`ceive counseling about appropriate contra-
`ception and the adverse effects associated
`with thalidomide therapy; (2) have a preg-
`nancy test (if the patient is a woman of
`childbearing potential); (3) complete the
`confidential survey form; and (4) receive a
`new prescription for no more than a 28-
`day supply of thalidomide. Subsequent pre-
`scriptions cannot be filled if >7 days of
`therapy remain on the previous prescrip-
`tion or if the prescription was written more
`than 7 days before being presented.
`
`MONITORING OF OUTCOMES
`
`In addition to the survey form at the ini-
`tiation of treatment, patients receiving
`thalidomide and the clinicians who pre-
`scribe it must complete frequent brief
`follow-up survey questionnaires (once a
`month for female patients and once
`every 3 months for male patients). The
`survey
`includes questions on demo-
`graphic characteristics, knowle