ORIGINAL RESEARCH ARTICLE
`
`Drug Safely 2006: 29 (4): 321-329
`0114-6916/06/0004-0321/$39.96/0
`
`©
`
`Thalidomide Use in the US
`Experience with Pregnancy Testing in the
`S.T.E.P.S.® Progranrrnrre
`
`Kathleen UhV Edward Cox} Rose Rogan? Jerome B. Zeldis? Dena Hixon} Lesley(cid:173)
`Anne Furlong, 1 Sarah Singer, 1'3 Tracy Holliman? Joanne Beyer2 and
`William Woolever2
`l US Food & Drug Administration, Center for Drug Evaluation and Research, Rockville,
`Maryland, USA
`2 Cclgene Corporation, Summit, New Jersey, USA
`3 National Institutes of Health, National Library of Medicine, Bethesda, Maryland, USA
`
`Abstract
`
`Introduction: In 1998, thalidomide (TI1alomid®), a known humm1 teratogen, was
`approved by the US FDA for the treatment of erythema nodosum leprosum. To
`prevent fetal exposure to thalidomide, a restricted distribution risk mm1agement
`programme, the System for Thalidomide Education and Prescribing Safety
`(S.T.E.P.S.®), was implemented. All clinicians, pharmacists and patients who
`prescribe, dispense and receive thalidomide, respectively, are required to enrol in
`S.T.E.P.S.®. Sexually active Cemales or childbearing potential must use two
`methods of birth control before, during and after treatment. These patients must
`also have a negative pregnancy test within 24 hours before beginning therapy and
`periodically while on therapy. The objective of this report is to summarise the
`patterns of thalidomide use and to describe the occurrence of positive pregnancy
`tests in females of childbearing potential while they were using thalidomide in the
`S.T.E.P.S.® programme in the US.
`Study design/methods: A retrospective review of patients receiving thalidomide
`within the S.T.E.P.S. ® programme from September 1998 to 31 December 2004 to
`determine the occurrence of positive pregnancy tests whilst on treatment.
`Results: Approximately 124 000 (43% female) patients were registered within
`the S.T.E.P.S.® programme between September 1998 and 31 December 2004.
`Approximately 6000 patients were females of childbearing potential, representing
`5% of all patients and 11% of all female patients. Between 30 July 2001 m1d 31
`December 2004, >88% of thalidomide use was for oncological conditions. Tiwre
`were 72 females of childbearing potential who had positive pregnancy tests.
`Sixty-nine of these patients had false positive pregnm1cy tests. Of the remaining
`three, one womm1 was pregnm1t while on thalidomide. TI1is patient had m1 initial
`negative test m1d received thalidomide. Therapy was stopped when she had a
`positive pregnancy test. This pregnancy resulted in a miscarriage. Two additional
`patients were determined to be pregnant before receiving thalidomide.
`Conclusions: The S.T.E.P.S.® programme is critical to managing the risks of
`thalidomide-associated teratogenicity. Sustained vigilance among healthcare
`providers and patients receiving thalidomide is essential to its continued success.
`
`
`
`CELGENE EXHIBIT 2006
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
`
`Page 1 of 10
`
`

`
`322
`
`Uhl et al.
`
`Healthcare providers should be aware of the occurrence of false-positive pregnan(cid:173)
`cy tests in females of childbearing potential receiving thalidomide.
`
`Introduction
`
`Thalidomide first became available in 1956 in
`West Germany as a sedative-hypnotic agent. By
`1960 it had been introduced in 46 countries (exclud(cid:173)
`ing the US) and was widely used to treat nausea and
`vomiting in early pregnancy. An epidemic of
`phocomelia, an extremely rare congenital abnormal(cid:173)
`ity of the limbs, and other associated malformations
`in an estimated 15 000 babies soon followed.f 1
`1 Ger(cid:173)
`many withdrew thalidomide from its market in No(cid:173)
`vember 1961 and other countries followed over the
`next lO months.
`In 1998 the Thalomid® 1 brand of thalidomide
`(Celgene Corporation, Summit, NJ, USA), was ap(cid:173)
`proved by the US FDA to treat erythema nodosum
`leprosum. Thalidomide is marketed in three coun(cid:173)
`tries outside of the US by the Pharmion Corporation
`through an international licensing agreement with
`Celgene. These three countries include Australia,
`New Zealand and Turkey. There are other compa(cid:173)
`nies worldwide that market and distribute other dose
`presentations of thalidomide; not all of these have
`risk management programmes.
`To prevent fetal exposure to thalidomide, a risk
`management
`programme,
`the
`System
`for
`Thalidomide Education and Prescribing Safety
`(S.T.E.P.S.®), was implemented in the US, and a
`similar programme was implemented internationally
`by Pharmion. All clinicians, pharmacists and pa(cid:173)
`tients who prescribe, dispense and
`receive
`Thalomid®, respectively, are required to enrol in
`this restricted distribution programme, regardless of
`the disease that is being treatedJ2l The S.T.E.P.S.®
`programme is an intensive, multi-component, inte(cid:173)
`grated risk management programme that restricts
`drug use to registered clinicians, pharmacists and
`patients (figure 1).
`
`The purpose of the present study is to summarise
`the patterns of thalidomide use in the US and to
`describe the cases of positive pregnancy tests that
`have occurred in females of childbearing potential.
`This report is a summary of the programme review
`of registered patients receiving Thalomicf® in the
`mandatory S.T.E.P.S.® programme in the US.
`
`Study Design and Methods
`
`A retrospective review was conducted of patients
`in the Celgene database who received Thalomid® in
`S.T.E.P.S.® from September 1998 to 31 December
`2004, including a more in-depth review of all pa(cid:173)
`tients who had positive pregnancy tests. Patient
`identifiers were removed for this S.T.E.P.S.® pro(cid:173)
`gramme evaluation. This research was reviewed and
`approved by the FDA Research Involving Human
`Subjects Committee. Descriptive characteristics of
`all patients with positive pregnancy tests were eval(cid:173)
`uated including patient demographics, the reason for
`thalidomide treatment, concomitant medications
`used and concomitant diseases present.
`Females of childbearing potential were defined
`as postmenarchal women who had not undergone a
`hysterectomy or who had not been naturally postme(cid:173)
`nopausal for at least 24 consecutive months (i.e.
`who have had menses at some time in the preceding
`24 consecutive months), in accordance with the
`Thalomid® product labellingJ3l
`All positive pregnancy tests were further evalu(cid:173)
`ated by the patient's healthcare provider using any
`of the following: serial ~-human chorionic gonado(cid:173)
`tropin (~-hCG) testing, serum hormone testing (e.g.
`luteinising hormone, follicle-stimulating hormone,
`estradiol), medical history, physical evaluation, pel(cid:173)
`vic ultrasound and/or gynaecological consultation
`according to standard operating procedures adjusted
`as clinically appropriate. A true-positive pregnancy
`
`1 Thalomid® and S .T .E.P .S. ® are registered trademarks of Celgene Corporation. The use of trade names is for product
`identification purposes only and does not imply endorsement.
`
`© 2006 Adls Data Information BV, All rights reserved
`
`Drug Safety 2006; 29 (4)
`
`
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`Page 2 of 10
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`

`
`Thalidomide Use in the US
`
`323
`
`test was defined as a postttve pregnancy test in a
`female who was confirmed to he pregnant hased
`upon further evaluation with the aforementioned
`tests or procedures. A false-positive pregnancy test
`was defined as a positive pregnancy test in a female
`
`who was found not to he pregnant hased upon fol(cid:173)
`low-up evaluation. The overall category of false
`positive pregnancy tests included indeterminate a(cid:173)
`hCG test results.
`
`Prescriber: A licensed practitioner and registered in S. T.E.P.S.®. The prescriber calls the interactive voice response (IVR) system and
`responds to a brief series of questions, including the amount of thalidomide (Thalomid®) to be dispensed.
`
`Patient: A person registered within S. T.E.P.S.® and able to receive thalidomide. The patient calls the IVR system and responds to a
`brief series of questions designed to query the patient on procedures to assure safe use of thalidomide.
`
`Pharmacist: A pharmacy registered with S. T.E.P.S.® who will dispense thalidomide. The pharmacist calls the IVR system to check if the
`thalidomide prescription has been authorised (i.e. the physician's and the patient's responses to the IVR queries are in accordance with
`the parameters for safe use of thalidomide) and enter quantity to be dispensed.
`
`IVR: A telephone-based system used by patients and prescribers to complete required surveys and for pharmacists to receive
`verification to dispense thalidomide. The IVR verifies that females of childbearing potential are using two methods of birth control, at
`least one of which is designated as a highly effective method, unless the woman completely abstains from heterosexual sexual contact.
`The methods of birth control must be initiated 4 weeks prior to beginning thalidomide and the woman must have a negative pregnancy
`test within 24 hours before the first dose of thalidomide. All females of childbearing potential must have pregnancy tests weekly for the
`first month of treatment and then monthly until 1 month after stopping therapy. Females with irregular menses must have pregnancy
`tests every 2 weeks while receiving thalidomide therapy. Any positive qualitative pregnancy test must be followed by a quantitative
`pregnancy test.
`
`Risk groups: S. T.E.P.S.® classifies patients into the following risk categories:
`• female child not of childbearing potential
`• female child of childbearing potential
`• adult female not of childbearing potential
`• adult female of childbearing potential
`• adult male
`• male child.
`
`Authorise dispensing: Upon completion of a patient and/or prescriber survey resulting in no survey intervention, drug can be
`dispensed by a registered pharmacy.
`
`Dispense: Pharmacy calls the IVR or customer service to dispense thalidomide to a patient.
`
`Intervention: At-risk responses or inappropriate entries in the IVR system result in transfer of the caller to a Celgene S. T.E.P.S.®
`Intervention Specialist for intervention to evaluate and remedy at-risk behaviours when appropriate.
`
`Fig. 1. Schematic of the procedures for prescription authorisation in the System for Thalidomide Education and Prescribing Safety
`(S.T.E.P.S.®) programme.
`
`© 2006 Adls Data Information BV, All rights reserved
`
`Drug Safety 2006; 29 (4)
`
`
`
`Page 3 of 10
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`

`
`324
`
`Uhl et al.
`
`The rate of false positive pregnancy tests among
`females of childbearing potential was calculated for
`selected reporting period intervals. The numerator
`comprised the number of false positive pregnancy
`tests. The denominator comprised the number of
`pregnancy tests performed during the reporting peri(cid:173)
`od intervals. Two-sided 95% confidence intervals
`were calculated using the normal approximation.
`The Cochran-Armitage Chi-squared test was used to
`test for a linear association between time interval
`(2001, 2002, 2003, 2004) and the rate of false posi(cid:173)
`tive pregnancy tests.
`
`Results
`
`Since its approval in 1998 through to 31 Decem(cid:173)
`ber 2004, approximately 726 000 prescriptions for
`thalidomide were written. Approximately 124 000
`patients (57% male and 43% female [table I]) were
`registered in the S.T.E.P.S.® programme. Approxi(cid:173)
`mately 6000 patients were females of childbearing
`potential, representing 5% of all patients and 11% of
`all female patients. The prescription of thalidomide
`in the US by reporting period interval is summarised
`in table I. The majority of the use of thalidomide
`(during the period 30 July 2001 to 31 December
`2004)
`is
`for conditions other
`than erythema
`nodosum leprosum, the approved indication, with
`>88% used for the treatment of oncological condi(cid:173)
`tions (table II).
`The number of females of childbearing potential
`receiving thalidomide has increased since the ap(cid:173)
`proval of thalidomide (table I), with a corresponding
`increase in the number of pregnancy tests (table III).
`Since females of childbearing potential are required
`to have pregnancy tests before, during and after
`therapy, the number of tests is higher than the num(cid:173)
`ber of such patients enrolled in S.T.E.P.S.®. Quanti(cid:173)
`tative B-hCG test results were provided for 64 cases,
`and 80% of these provided the laboratory reference
`value or ranges for the quantitative test (these data
`are available as supplementary material from http://
`www.adisonline.com/drs).
`By 31 December 2004, 72 positive pregnancy
`tests have been reported in the S.T.E.P.S.® pro(cid:173)
`gramme ( 69 were ultimately determined to be false
`
`positives): four cases in the first 3 years of market(cid:173)
`ing (September 1998-18 June 200 I) and 68 cases
`from July 200 I to 31 December 2004 (table TIT).
`Thalidomide treatment was stopped immediately af(cid:173)
`ter a positive pregnancy test, and while test results
`were being evaluated. Three of the 72 cases repre(cid:173)
`sented true pregnancies (case 1, case 2 and case 3).
`In cases 2 and 3 the mechanism of S.T.E.P.S.®
`detected pregnancy prior to the patient receiving
`thalidomide.
`Case l was a 44-ye<tr-old female with "high risk
`malignant melanoma" that had not responded to
`multiple prior therapies. She was unable to tolerate
`oml contraceptives and reported using two b<trrier
`methods of contraception. She had a negative preg(cid:173)
`nancy test on day 8 of her menstnml cycle before
`starting thalidomide, and had two subsequent nega(cid:173)
`tive pregnancy tests during the first month of treat(cid:173)
`ment. On days 35 and 36 of th<Llidomide therapy she
`had positive qtmlitative serum B-hCG
`tests.
`Thalidomide therapy was stopped on day 35. On day
`42 her quantitative B-hCG level was 1883 m[U/mL
`(reference value <5 m[U/mL for non-pregnant wo(cid:173)
`men). No further quantitative B-hCG results were
`reported. She had vaginal bleeding on day 63 and
`ultrasound examination "reve<Lled only blood clots,
`so it was assumed that the patient passed the foetus"
`(wording verbatim from MedWatch form). No fur(cid:173)
`ther follow-up was available.
`Case 2 was a 26-year-old female wilh dennalo(cid:173)
`myosilis who had a posiLive pregnancy Lesl prior Lo
`receiving tluLlidomide. The patient did not receive
`thalidomide, but subsequently miscarried.
`Case 3 was a 28-year-old female witl1 malignant
`neoplasm of tlw vulva who had a positive pregnancy
`test prior to receiving thalidomide. The patient con(cid:173)
`sulted witl1 her physician and elected to undergo a
`termination and a tubal ligation. Subsequently, she
`began thalidomide therapy after it was confirmed
`that she was not pregnant.
`The age range for patients witl1 false-positive
`pregnancy tests was 12-56 years. These patients
`received thalidomide for treatment of multiple my(cid:173)
`eloma (54%), various neoplasms (39%) or other
`disorders (7% ). The total duration of therapy for
`
`© 2006 Adls Data Information BV, All rights reserved
`
`Drug Safety 2006; 29 (4)
`
`
`
`Page 4 of 10
`
`

`
`C)
`
`@
`25
`"' f;
`
`~-
`0
`a
`0
`
`i
`
`~
`
`Risk classification group
`
`Reporting period
`1998'
`1999'
`
`Males [n (%)[
`
`Females not of childbearing
`potential [n (%)[
`
`Females of childbearing
`potential [n (%)[
`
`451
`(57.7)
`
`248
`(31.7)
`
`83
`(10.6)
`
`3633
`(53.7)
`
`2617
`(38.7)
`
`514
`(7.6)
`
`~
`
`Total'1[n (%)[
`
`Table I. Characteristics of patients receiving thalidomide (Thalomid®) in the S.T.E.P.S.® programme according to reporting period 8
`
`2000'
`
`6142
`(54.9)
`
`4413
`(39.4)
`
`633
`(5.7)
`
`11 188
`(100)
`
`January-29
`July 2001"
`
`3889
`(57.0)
`
`2614
`(38.3)
`
`323
`(4.7)
`
`6826
`(100)
`
`30 July-
`December
`2001d
`10555
`(56.9)
`
`7267
`(39.2)
`
`739
`(4.0)
`
`18 561
`(100)
`
`2002'1
`
`2003'1
`
`2004'1
`
`14590
`(57.4)
`
`9603
`(37.8)
`
`1217
`(4.8)
`
`25410
`(100)
`
`15483
`(57.9)
`
`10009
`(37.5)
`
`1237
`(4.6)
`
`26729
`(100)
`
`15889
`(58.2)
`
`10155
`(37.2)
`
`1276
`(4.7)
`
`27 320
`(100)
`
`Totalb
`
`70632
`(57.2)
`
`46926
`(37.9)
`
`6022
`(4.9)
`
`123 580
`(100)
`
`.,
`;1
`[
`0
`~-
`it
`~ (!)
`s·
`9'
`e (fl
`
`(!)
`
`a
`"' 0
`~
`;g
`{6·
`§f
`m
`<
`"
`
`~)
`(Q
`'" Q
`iD'
`-<
`25
`C) "' "
`"'
`:~
`
`782
`(100)
`
`6764
`(100)
`
`Thalidomide therapy
`
`Dose range (mg)
`
`50-1050
`
`50-1400
`
`50-2400
`
`50-2400
`
`50-1400
`
`50-1200
`
`50-1200
`
`50-1200
`
`Mean duration [d (SD)[
`
`35.5
`(19.8)
`
`71.1
`(66.2)
`
`92.9
`(82.5)
`
`101.9
`(86.5)
`
`77.65
`(444.6)
`
`120.95
`(100.4)
`
`126.23
`(1 01 .4)
`
`128.90
`(102.9)
`
`Mean patient age
`
`All patients [y (SD)[
`
`Females of childbearing
`potential [y (SD)[
`
`53.3
`(NA)
`
`NA
`
`57.4
`(NA)
`
`NA
`
`60.9
`(NA)
`
`NA
`
`62.4
`(NA)
`
`NA
`
`66
`(14.1)
`
`42
`(9.3)
`
`65
`(14.4)
`
`42
`(9.0)
`
`67
`(14)
`
`43
`(9)
`
`66
`(14)
`
`42
`(9)
`
`NA
`
`NA
`
`NA
`
`NA
`
`a Represents data from a total of 726 032 prescriptions dispensed.
`
`b Total of percentages may not equal 100% because of rounding.
`
`Data from Slone Epidemiology Genter reports. Some patient demographic information was not available.
`
`Data from Gelgene's S.T.E.P.S.® programme, modified on 30 July 2001. Because the S.T.E.P.S.® programme was modified 30 July 2001, data for the year 2001 is
`presented in this table for the period January-30 July 2001 and then separately for period 30 July 2001-December 2001.
`
`NA = not available; SO = standard deviation; S.T.E.P.S.® = System for Thalidomide Education and Prescribing Safety.
`
`""
`
`N
`IJl
`
`
`
`Page 5 of 10
`
`

`
`326
`
`Uhl et al.
`
`Table II. Diagnoses of thalidomide (Thalomid®) recipients by risk classification group (30 July 2001-31 December 2004)a
`
`Diagnosis
`(no. [%] patients)b
`
`Males
`(n = 56 517 [57.66%])
`
`Females not of childbearing
`potential
`(n = 37 034 [37.78%])
`
`Females of
`childbearing potential
`(n = 4469 [4.56%])
`
`Total
`(n = 98020 [100%])
`
`Oncological
`25 988 (26.51)
`Multiple myeloma
`4200 (4.28)
`Renal cancer
`Myelodysplastic syndrome 5051 (5.15)
`Brain cancer
`1759 (1.79)
`Melanoma
`2878 (2.94)
`Prostate malignant
`3408 (3.48)
`neoplasm
`Other neoplasms"
`
`7071 (7.2)
`
`20 618 (21.03)
`1567 (1.6)
`3145 (3.21)
`678 (0.69)
`1141 ( 1.16)
`0
`
`1186 (1.21)
`194 (0.2)
`85 (0.09)
`433 (0.44)
`466 (0.48)
`0
`
`47 792 (48.76)
`5961 (6.08)
`8281 (8.45)
`2870 (2.93)
`4485 (4.58)
`3408 (3.48)
`
`5651 (5.77)
`
`870 (0.89)
`
`13 592 (13.87)
`
`Dermatological
`Dermatological diseases
`Erythema nodosum
`leprosum
`
`Haematological
`Haematological diseases
`
`Infectious diseases
`Infectious diseases
`
`Gastrointestinal
`Digestive system/
`genitourinary
`
`324 (0.33)
`92 (0.09)
`
`503 (0.51)
`8 (0.01)
`
`247 (0.25)
`10 (0.01)
`
`1074 (1.1)
`110 (0.11)
`
`1686 (1.72)
`
`1154 (1.18)
`
`68 (0.07)
`
`2908 (2.97)
`
`372 (0.38)
`
`247 (0.25)
`
`162 (0.17)
`
`781 (0.8)
`
`326 (0.33)
`
`148 (0.15)
`
`105 (0.11)
`
`579 (0.59)
`
`212 (0.22)
`
`347 (0.35)
`
`Immunological
`Musculoskeletal/
`rheumatological
`1827 (1.86)
`3050 (3.21)
`Other
`a Data on diagnosis from October 1998 to July 2001 are not available.
`b Total of percentages may not equal 100% because of rounding.
`c Other neoplasms include colorectal, bladder/urethra, liver and other not specified neoplasms.
`
`230 (0.23)
`
`413 (0.42)
`
`789 (0.8)
`
`5390 (5.5)
`
`females of childbearing potential with false positive
`or indeterminate pregnancy test results ranged from
`<1 month to 34 months. The duration of treatment at
`the time of the first false positive pregnancy test in
`patients receiving thalidomide ranged from 4 days to
`L 7 months. Fifteen of 69 patients had positive preg(cid:173)
`nancy tests that were determined to be false positive
`pregnancy tests before thalidomide therapy was ini(cid:173)
`tiated. For 68 of 69 patients, B-hCG levels were
`<350 m[U/mL. One patient with choriocarcinoma, a
`disease that is expected to produce high concentra(cid:173)
`tions of B-hCG,f4
`1 had levels >350 m[U/mL.
`
`Discussion
`
`The S.T.E.P.S.® programme is a risk manage(cid:173)
`ment programme designed to prevent fetal expo-
`
`sures to thalidomide. S.T.E.P.S.® is an intensive,
`multi-component, integrated risk management pro(cid:173)
`gramme that restricts drug use to registered clini(cid:173)
`cians, pharmacists and patients. Any suspected fetal
`exposure to thalidomide (either in female patients or
`female partners of male patients) in S.T.E.P.S.@
`participants must be reported immediately to the US
`FDA and Celgene.f5 1
`In accordance with the S.T.E.P.S.® programme,
`sexually active females of childbearing potential
`must use two appropriate methods of contraception
`simultaneously to prevent pregnancy for 4 weeks
`before, during and for 4 weeks following treatment
`with thalidomide. Appropriate methods of contra(cid:173)
`ception include at least one highly effective method
`(e.g. intrauterine device, hormonal contraception,
`
`© 2006 Adls Data Information BV. All rights reserved.
`
`Drug Safety 2006; 29 (4)
`
`
`
`Page 6 of 10
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`

`
`Thalidomide Use in the US
`
`327
`
`tubal ligation or partner's vasectomy) and one addi(cid:173)
`tiomLl effective method (e.g. latex condom, dia(cid:173)
`phragm or cervical cap). The aforementioned meth(cid:173)
`ods of pregnancy prevention must he used unless
`continuous complete abstinence from heterosextml
`sexual contact is the chosen method of pregnancy
`prevention. Females that may become pregnant and
`postmemLrchal women who have not undergone a
`surgical menopause or who have not been postme(cid:173)
`nopausal naturally for at least 24 consecutive
`months (i.e. who have had menses at some time in
`the preceding 24 consecutive months) are consid(cid:173)
`ered to be females of childbearing potential in the
`S.T.E.P.S.® programme.
`All patients agreed to comply with the methods
`of pregnancy prevention in S.T.E.P.S.®. Despite
`this, there have been infrequent reports regarding
`patient difficulties with complying with two forms
`of contraception. For female patients, one woman
`reported using two barrier methods, one woman
`reported that she had a tubal ligation and was not
`using another method and two women reported
`missing a dose of birth control pills. Ten male
`patients reported not using a condom.
`According to S.T.E.P.S.@, females of childbear(cid:173)
`ing potential must also have periodic pregnancy
`testing. Such patient must have a pregnancy test
`(sensitivity of at least 50 miU/mL) performed within
`the 24 hours prior to beginning thalidomide therapy.
`Pregnancy testing should occur weekly during the
`first 4 weeks of use, then at 4-week intervals in
`women with regular menstrual cycles or every 2
`weeks in women with irregular menstrual cycles.
`Pregnancy testing should also be done if any female
`of childbearing potential misses her period or has
`any abnonnality in menstrual bleeding. Any positive
`qualitative urine pregnancy test is followed by a
`more sensitive qualitative sennn and/or a quantita(cid:173)
`tive sennn pregnancy test.
`Thalidomide is present in the semen of male
`patients receiving the drug. Male patients receiving
`thalidomide who are sexually active with women
`who are or could become pregnant must always use
`a latex condom during any sexual contact, even if
`the male patient has undergone a successful vasecto-
`
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`© 2006 Adls Data Information BV, All rights reserved
`
`Drug Safety 2006; 29 (4)
`
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`Page 7 of 10
`
`

`
`328
`
`Uhl et al.
`
`my. However, the risk to the fetus from exposure to
`thalidomide in the semen is unknown. To date there
`have been 18 reports to the S.T.E.P.S.® programme
`of pregnancies in female partners of male patients
`thalidomide: 14 normal newborns, one
`taking
`ectopic pregnancy termination and three pregnan(cid:173)
`cies with limited or no available follow-up informa(cid:173)
`tion.
`
`The initial design of the S.T.E.P.S.® programme
`retrospectively identified patient behaviours provid(cid:173)
`ing a risk of fetal exposure to thalidomide; therefore,
`procedural changes to the S.T.E.P.S.® programme
`were instituted in July 2001. These changes were
`designed to ensure that results from the required
`pregnancy tests were documented and linked to pre(cid:173)
`scription activation and dispensing through an inter(cid:173)
`active voice response (IVR) system or via customer
`service prior to dispensing thalidomide. When an 'at
`risk' behaviour (e.g. a pending, outdated or positive
`pregnancy test result) is identified using the IVR
`system, the caller is transferred to a Celgene
`S. T.E.P.S. ® Intervention SpecialistPl On average,
`5% of surveys require an intervention, verification
`or clarification of a patient or prescriber response
`prior to dispensing thalidomidePl The m<~jority of
`all issues are addressed within 24 hours of identifi(cid:173)
`cation by the IVR system. Thalidomide is not given
`if there is a known non-compliance issue.
`
`Since the approval of Thalomid® in the US, only
`three women in the S.T.E.P.S.® programme have
`been identified as becoming pregmmt: one after
`thalidomide was initiated and two at the time of
`enrolment but before the initiation of treatment with
`thalidomide. There were 69 other females of
`childbearing potential who had false-positive preg(cid:173)
`nancy tests after enrolling in S. T.E.P.S. ® (please see
`http://www.adisonline.com/drs for individual pa(cid:173)
`tient information). Women who have false-positive
`B-hCG pregnancy tests usually have levels that re(cid:173)
`low/6•71 as was
`seen
`in
`main consistently
`thalidomide users in this case series. Early pregnan(cid:173)
`cy loss is associated with rapidly falling B-hCG
`levels;fR,9l therefore, the persistence of low B-hCG
`levels in the 69 cases is not suggestive of a true
`
`pregnancy that underwent early loss after exposure
`of the developing conceptus to thalidomide.
`The frequency of false-positive pregnancy tests
`as a percentage of pregnancy tests performed
`(0.27-0.99%) has remained stable since the begin(cid:173)
`ning of the modified S.T.E.P.S.® programme that
`was initiated in July 2001 (table [[[), and the ob(cid:173)
`served rate of false-positive pregnancy tests is com(cid:173)
`parable to estimated rates of false-positive pregnan(cid:173)
`cy tests in the general population of females of
`childbearing potentialJ7
`1 Pregnancy rates among
`comparable females not taking thalidomide were not
`available for comparison. The occurrence and gen(cid:173)
`eral management of false-positive pregnancy tests
`are reviewed elsewhere.f 10
`1 Serial pregnancy tests,
`specialised laboratory tests, pelvic ultrasound or
`medic<Ll consultation can help distinguish between
`true- and false-positive pregnancy tests. [n this se(cid:173)
`ries, nine cases had further clinic<Ll evaluation for
`positive pregnancy tests beyond repeat B-hCG test(cid:173)
`ing: six had ultrasound studies, three had CT scans
`and one had further laboratory evaluation.
`The institution of the IVR system in July 2001
`was designed
`to
`identify patients exhibiting
`behaviours providing risk for fetal exposure and to
`remedy
`those behaviours prior
`to dispensing
`thalidomide. The continued ongoing evaluation of
`S.T.E.P.S.® will be essential
`to evaluate
`the
`programme's perfonmmce and to guide thture re(cid:173)
`finements to the prognunme, in order for it to
`achieve its objectives.
`Even with the use of thalidomide for a variety of
`medical conditions, the m~jority of which were for
`haematological malignancies (e.g. multiple myelo(cid:173)
`ma) and solid organ tumours,
`the amount of
`thalidomide used in the US is relatively small. Simi(cid:173)
`lar risk management programmes for other drugs
`that have demonstrated adverse risks associated
`with fetal exposure, such as isotretinoin/ 1 11 have
`been developed and implemented by drug manufac(cid:173)
`turers. The Celgene S.T.E.P.S.® programme has
`been licensed to several other drug manufacturers
`with the regulatory involvement of the FDA, for the
`increased surveillance and monitoring of physi(cid:173)
`cians, phannacists and patients, to prevent fetal ex-
`
`© 2006 Adls Data Information BV, All rights reserved
`
`Drug Safety 2006; 29 (4)
`
`
`
`Page 8 of 10
`
`

`
`Thalidomide Use in the US
`
`329
`
`posure to drugs. The vigilance of physicians, phar(cid:173)
`macists, patients, Celgene and the FDA has contrib(cid:173)
`uted to the success of S.T.E.P.S.® in preventing
`pregnancy in females receiving thalidomide.
`
`The research that is the basis for this study was funded by
`the FDA and Celgene as a part of the routine postmarketing
`surveillance of thalidomide.
`
`Conclusions
`
`The S.T.E.P.S.® programme has been successful
`in preventing fetal exposure to thalidomide. Of the
`6022 females of childbearing potential registered in
`the S.T.E.P.S.® programme, one patient became
`pregnant while receiving the drug and two addition(cid:173)
`al patients were identified as pregnant and were not
`permitted to start thalidomide treatment. This 'real
`time' risk management programme may be a useful
`model to prevent exposure of pregnant women to
`other drugs that are known human teratogens or that
`arc suspected to be teratogenic (based upon drug
`class or findings in experimental animal studies).
`Because important clinical decisions may be made
`on the basis of the results of pregnancy testing,
`clinicians using th<Llidomidc must remain vigilant in
`evaluating every fem<Lle with a positive pregnancy
`test until pregnancy is either confirmed or ruled out.
`Both the FDA and Celgene remain committed to
`preventing fet<Ll exposure to thalidomide.
`
`Acknowledgements
`
`FDA authors have no conflicts of interest. It should be
`noted that Celgene is the US manufacturer and distributor of
`thalidomide.
`The following associates are to be acknowledged for their
`assistance in preparation of this study:
`Celgene Corporation: Francis Brown, Ganesh Vanekat,
`Kevin Milazzo, Mark Deibert, Pam Yurcisin, RN, Max
`Kosoy, John Patin.
`FDA: Dianne Kennedy.
`
`References
`1. Lenz W, Knapp K. Thalidomide embryopathy. Arch Environ
`Health 1962; 5: I 00-5
`
`2. Zeldis JB, Williams BA, Thomas SD, et <~. S.T.E.P.S.®: a
`comprehensive program for controlling and monitoring access
`to thalidomide. Clin Thcr 1999; 21 (2): 319-30
`
`3. THALOM[[)® (thalidomide) 50, 100tng, 200tng capsules, l"ull
`prescribing information, last revised February, 2005
`
`4. Berkowitz RS, Goldstein DP. Gestational trophoblastic disease.
`Cancer 1995; 76 (10 Suppl.): 2079-85
`
`5. Clark TE, Edom N, Larson J, et al. Thalomid® (thalidomide)
`capsules: a review of the first 18 months of spontaneous
`postmarketing adverse event sLU"veillance, including oft~label
`prescribing. Drug Saf 2001; 24 (2): 87-117
`
`6. Rot mensch S, Cole LA. False diagnosis and needless therapy of
`presmned 1naHgnant disease in wmnen with false-positive
`human chorionic gonadotropin concentrations. Lancet 2000;
`355 (9205): 712-5
`
`7. Braunstein GD. False-positive serum human chorionic gonado(cid:173)
`tropin results: causes, characteristics, and recognition. Am J
`Obstet Gynecol 2002; 187 (!): 217-24
`
`8. Kad::u N~ Rmnero R. Fm·ther observations on serial luunan
`chorionic gonadotropin patterns in ectopic pregnancies and
`spontaneous abortions. Fertil Steril 1988; 50 (2): 367-72
`
`9. Canfield RE, O'Connor JF, Wilcon AJ. MeasLU"ing human cho(cid:173)
`rionic gonadotropin for detection of early pregnancy loss.
`Reprod Toxicol 1988; 2: 199-203
`
`10. Avoiding inappropriate clinical decisions based on false posi(cid:173)
`tive human chorionic gonadotropin test results. ACOG Com(cid:173)
`mittee Opinion No. 278. American College of Obstetricians
`and Gynecologists. Obstet Gynecol 2002; I 00: I 057-9
`
`11. Isotretinoin (marketed as Accutane) capsule information [on(cid:173)
`line]. Available fi·om URL: http://www.fda.gov/cderldrug/in(cid:173)
`fopage/accutane/default.htm [Accessed 2005 Aug 26]
`
`Correspondence and offprints: Dr Kathleen Uhl, Center for
`Drug Evaluation and Research, Pregnancy Labeling Task
`Force, Food & Drug Administration, 10903 New Hamp(cid:173)
`shire Avenue, Building 22, Room 6460, Silver Spring, MD
`20993, USA.
`E-mail: kathleen.uhl@oc.fda.gov
`
`© 2006 Adls Data Information BV. All rights reserved
`
`Drug Safety 2006; 29 (4)
`
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`Page 9 of 10
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