The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system

The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system Janet Shin, PharmD,a,c T. Craig Cheetham, PharmD, MS,a Linda Wong, MD,b Fang Niu, MS,a Elizabeth Kass, MD,d Monica A. Yoshinaga, PharmD,f Mike Sorel, MPH,e Jeffrey S. McCombs, PhD,c and Stephen Sidney, MD, MPHe Downey, Los Angeles, City of Industry, Stockton, and Oakland, California Background: Preventing fetal exposure to isotretinoin is widely acknowledged as an important safety issue. The iPLEDGE program is the latest in a series of Food and Drug Administrationemandated risk management programs designed to prevent pregnancies in female patients of childbearing potential (FCBP) taking isotretinoin. Objective: We sought to evaluate the effect of iPLEDGE relative to the prior risk management program (system to manage Accutane-related teratogenicity [SMART ]) on the risk of isotretinoin fetal exposure in FCBP in a managed care setting. Methods: All FCBP at Kaiser Permanente Southern and Northern California who filled at least one prescription for isotretinoin during a 4-year period (March 1, 2004, to February 29, 2008) were included in this retrospective cohort study (n = 8344). Chart review was performed to confirm fetal exposures and outcomes. A Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals. Results: There were a total of 29 fetal exposures and 9912 isotretinoin treatment courses. After iPLEDGE was implemented, the unadjusted rate of fetal exposure decreased from 3.11 to 2.67 per 1000 treatment courses (P = .69). The hazard ratio = 0.76 (95% confidence interval 0.36-1.61) for fetal exposures to isotretinoin during treatment courses filled after iPLEDGE implementation compared with SMART. Limitations: Limitations include limited generalizability of results, small sample size (n = 29 total documented fetal exposures), and potential uncontrolled confounders. Conclusion: Evaluating the impact of iPLEDGE on isotretinoin fetal exposures is important in understanding the full risks and benefits of isotretinoin treatment. We found no evidence that iPLEDGE significantly decreased the risk of fetal exposure in FCBP compared to the SMART program. ( J Am Acad Dermatol 2011;65:1117-25.) Key words: fetal exposures; iPLEDGE; isotretinoin; risk management program; SMART.

I

sotretinoin is one of the most effective treatments of severe recalcitrant scarring, nodular acne. Treatment with isotretinoin usually lasts

20 weeks and results in marked improvement or complete remission of acne.1 The main drawback to isotretinoin is its teratogenicity. Isotretinoin

From Pharmacy Analytical Services, Downeya and Dermatology, City of Industry,b Kaiser Permanente Southern California; Pharmaceutical Economics and Policy, University of Southern California, Los Angelesc; Dermatology, Stocktond and Division of Research, Oakland,e Kaiser Permanente Northern California; and Kaiser Permanente Drug Information Services, Downey.f Supported by Kaiser Permanente Southern California Regional Research Committee and Kaiser Permanente Northern California Community Benefit. Disclosure: Dr Cheetham has a first-degree relative employed by Allergan (compensated by salary and stock options). Dr McCombs is an investigator for Eli Lilly (compensated by grants), Bristol-Myers Squibb (compensated by grants and honoraria), and Wyeth (compensated by grants). Dr Shin is a consultant for Bristol-Myers Squibb (compensated by grants).

Drs Wong, Kass, Yoshinaga, and Sidney; Ms Niu; and Mr Sorel have no conflicts of interest to declare. Accepted for publication September 18, 2010. Results from southern California were presented in an abstract as a poster at the 15th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research in Atlanta, Georgia, May 18, 2010. Reprint requests: Janet Shin, PharmD, Pharmacy Analytical Service, Kaiser Permanente, 12254 Bellflower Blvd, Downey, CA 90242. E-mail: [email protected]. Published online May 12, 2011. 0190-9622/$36.00 ª 2010 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2010.09.017

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embryopathy, which occurs in about 28% of fetal isotretinoin distribution process including wholeexposures, is associated with craniofacial, central salers, health care providers, pharmacies, and both nervous system, cardiovascular, and thymic defects.2 male and female patients. The goal of iPLEDGE is to Other adverse events related to isotretinoin fetal prevent female patients of childbearing potential exposure include mental development problems, (FCBP) from receiving isotretinoin if they are pregspina bifida, and limb reduction.1-3 Preventing fetal nant, and to prevent them from becoming pregnant if exposure to isotretinoin is widely acknowledged as they are taking isotretinoin. The most prominent an important safety issue, eschanges from the SMART to pecially because half of isoiPLEDGE program are the CAPSULE SUMMARY tretinoin prescriptions are monthly verifications of pregwritten for female patients, nancy tests, monthly assessThe iPLEDGE program was implemented most of whom are of childments of the patient’s to prevent fetal exposure to isotretinoin, bearing age.3 understanding of isotretinoin an important safety issue widely The Food and Drug pregnancy risks, and monthly acknowledged by clinicians and the Administration (FDA) has colidentification of contracepFood and Drug Administration. laborated with isotretinoin tive methods. Other stringent manufacturers in the past to Evaluating the impact of iPLEDGE on requirements of the iPLEDGE undertake several approaches isotretinoin fetal exposures is crucial in program have been deto minimize the risk of fetal understanding the full risks and benefits scribed in detail elsewhere.8 exposure to isotretinoin. On of treating severe acne with isotretinoin. Preliminary results suggest FDA approval in 1982, warnthat iPLEDGE has not been This study also provides insight in ing labels were placed on the effective in reducing the rates understanding how iPLEDGE has prescription bottle and packof fetal exposure.9 affected isotretinoin use and fetal age insert. Patients were also The objective of this study exposure outcomes. given brochures with pregis to evaluate the impact of nancy risk information. Then the iPLEDGE system on rates in 1988 Roche (Nutley, NJ) developed the first risk of fetal exposure to isotretinoin in FCBP relative to management program (RMP) known as the Pregnancy the SMART program. To answer this question we Prevention Program, which required physicians to undertook a retrospective cohort study evaluating have all female patients sign a consent form, take a the rates of fetal exposure before and after implepregnancy test before starting isotretinoin, and select mentation of iPLEDGE within a large managed care two reliable forms of birth control.3 organization. In April 2002 the system to manage Accutanerelated teratogenicity (SMART) program was created METHODS after the Pregnancy Prevention Program was shown This study was conducted at KPSC and KPNC. to be ineffective.4,5 Major components of the SMART Kaiser Permanente is a nonprofit, managed care program included physician education, informed organization that provides integrated health care consent, rigorous negative pregnancy test result services to more than 6 million members in monitoring, and a restrictive dispensing policy (maxCalifornia. The linked patient databases available at imum 30-day supply, no refills, and yellow sticker KPSC and KPNC were used as the primary data verification by the pharmacist).6 In early 2002, Kaiser source. The database contains patient-level informaPermanente in Southern California (KPSC) and tion on pharmacy prescription records, laboratory Northern California (KPNC) actually went beyond results, and outpatient and inpatient procedure and the requirements of SMART and implemented an diagnosis codes. All patient information is linked by isotretinoin RMP that required pharmacists to verify a distinct patient medical record number. Members the negative pregnancy test results before dispensing receive the majority of their health care at Kaiser the prescription.6 Pharmacists were also able to send Permanente facilities and care received outside the patients to the laboratory for pregnancy testing if the system is captured through a claims process. The patient did not have pregnancy test results on file. study was approved by the Kaiser Permanente However, the pregnancy rates did not substantially Institutional Review Boards in southern and northdecrease with the advent of the SMART program.6,7 ern California. Consequently, the SMART program was replaced by the iPLEDGE program on March 1, 2006. The Study population iPLEDGE program is a novel Internet-based system The study population included all FCBP who that requires the registration of all parties in the filled at least one prescription for isotretinoin during d

d

d

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Abbreviations used: CI: FCBP: FDA: HR: KPNC: KPSC: RMP: SMART:

confidence interval female patient of childbearing potential Food and Drug Administration hazard ratio Kaiser Permanente Northern California Kaiser Permanente Southern California risk management program system to manage Accutane-related teratogenicity

the 4-year period from March 1, 2004, to February 29, 2008. FCBP were defined in this study as between the ages of 10 and 55 years who have not experienced menopause, oophorectomy, hysterectomy, or ovarian failure. Outcomes The outcome of interest is fetal exposure to isotretinoin. Potential cases of fetal exposure were electronically identified from the database using pregnancy indicators and specific timing criteria. Indicators of pregnancy included pregnancyand abortion-related International Classification of Diseases, Ninth Revision codes or Current Procedural Terminology codes; laboratory results (pregnancy tests); and prescription records. After chart abstraction, adjudication of both paper and electronic medical charts was performed to determine fetal exposure status defined as: (1) confirmed fetal exposure; (2) no fetal exposure; or (3) unknown fetal exposure. At KPSC, adjudication was performed by a KPSC dermatologist and at KPNC adjudication was done by a research-trained registered nurse in collaboration with a physician researcher. Cases in which fetal exposure was determined by the chart review process as ‘‘unknown’’ were excluded from the analysis. Rates of fetal exposures to isotretinoin were reported in terms of number of fetal exposures per 1000 treatment courses. Unit of analysis The unit of analysis was the treatment course. A treatment course was defined as a group of isotretinoin prescriptions where the time between the completion of one prescription and the start of the next is less than 2 months. If the prescription gap is more than 60 days, then the patient was considered as having started a new course of treatment. If a patient initiated a treatment course before the study period and continued to receive isotretinoin therapy after March 1, 2004, then those prescription records filled before the study period were excluded from the analysis. However, if a patient initiated a

Shin et al 1119

treatment course during the study period and continued to receive isotretinoin after the study period, then the prescriptions filled after the study period were included in the analysis to capture the remaining course of therapy. Statistical analysis We tested the hypothesis that the risk of fetal exposures was significantly reduced during the iPLEDGE RMP compared with the risk during the SMART program. Treatment courses were placed in the SMART group if all isotretinoin prescriptions during that treatment course were filled before March 1, 2006. Treatment courses were placed in the iPLEDGE group if all isotretinoin prescriptions during that treatment course were filled on or after March 1, 2006. Treatment courses that started during the SMART program and continued after iPLEDGE implementation were counted in both RMP groups. For these treatment courses, the number of follow-up days during the SMART program only contributed observation time to the SMART program and the number of follow-up days during the iPLEDGE program only contributed observation time to the iPLEDGE program in the multivariate analysis. Descriptive statistics were used to compare the demographic characteristics of SMART and iPLEDGE treatment courses. In addition, unadjusted fetal exposure rates stratified by risk factor were analyzed. The t test, x2 test, or Fisher exact test was used to derive P values when comparing continuous or categorical variables between study groups. The time to a fetal exposure event was of interest in this study. Cox proportional hazard models, which are often used to model time to an event, were used to estimate the hazard ratio (HR) comparing rates of fetal exposure in the iPLEDGE program with the SMART program. The outcome of interest was time to fetal exposure (in days) and the primary independent variable of interest was the iPLEDGE variable indicating whether the treatment course occurred during the SMART or iPLEDGE program. The iPLEDGE variable was coded as a time-varying regressor and was allowed to change in value over time from SMART to iPLEDGE because some treatment courses started during the SMART program and ended during the iPLEDGE program. Other variables examined in this study included patient characteristics such as age group, region (northern or southern California), prior antiacne medication use, prior isotretinoin courses, and geocoded median household income and education level. Age was calculated at the dispense date of the first prescription of a treatment course. Three age

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categories were created a priori to capture potential differences in fetal exposure risk among patient age groups: younger than 18 years, 18 to 39 years, and 40 years and older. To capture differences in acne severity among treatment groups, prior use of isotretinoin was examined for each FCBP. Prior use of isotretinoin was defined as having a treatment course of isotretinoin before the first treatment course identified during the study period. A period of at least 2 years was used to search for prior isotretinoin use for each patient. The literature suggests that most patients receive only one treatment course of isotretinoin to treat their acne, although some patients who relapse or have more severe acne will receive more than one treatment course.10 The use of other antiacne medications before using isotretinoin was also captured as a potential indicator of acne severity. Specifically, the use of any oral or topical antiacne medication was examined during the 1-year period before the first treatment course of isotretinoin. Antiacne medications included both topicals and systemic medications: adapalene, azelaic acid, benzoyl peroxide, sodium sulfacetamide, sulfur, tazarotene, tretinoin, clindamycin, erythromycin, azithromycin, doxycycline, tetracycline, minocycline, and ethinyl estradiol products. Because systemic antibiotics and oral contraceptives can also be used to treat conditions other than acne, a prescription days supply for greater than 30 days was required to verify its use for acne. Acne treatment guidelines generally recommend treating mild acne with topical therapy and reserving oral therapy for moderate to severe acne.10-12 However, patients with extremely severe, nodulocystic acne may receive isotretinoin as first-line therapy without prior prescriptions for topical or oral antiacne medications. Geo-coded or census-based socioeconomic data based on the patient’s address were available for most patients in the study. Median household income was categorized into 4 groups based on median and quartile values: $0 to $50,000; $50,000 to $75,000; $75,000 to $100,000; and more than $100,000. If median household income was missing for a patient, then the median category of $50,000 to $75,000 was used. The highest attained education level of a household was categorized into 3 groups: high school level (\9th grade to high school graduate); college level (some college but no degree to an associate degree); and bachelor degree or higher (bachelor degree to a graduate or professional degree). If education was missing for a patient, then the mode category of ‘‘Bachelor degree or higher’’ was used.

DECEMBER 2011

The iPLEDGE system mandates that all FCBP must have a follow-up pregnancy test 1 month after their last dose. Therefore, exposure or follow-up time was calculated as the time between the start of the treatment course and 30 days after the treatment course is completed. Patients were followed up on isotretinoin until they completed their course of therapy, reached the end of the study, or reached a pregnancy end point. The date of the pregnancy indicator (eg, date of the positive pregnancy laboratory test, abortion International Classification of Diseases, Ninth Revision code) was used as the censoring date for pregnancy cases. All analysis was done using the STATA 9.1 software package (StataCorp LP; College Station, TX). A two-sided P value less than or equal to .05 was considered as statistically significant.

RESULTS Between March 1, 2004, and February 29, 2008, a total of 8344 FCBP received 9912 treatment courses of isotretinoin. There were 5788 treatment courses during the SMART program, and 4124 treatment courses during the iPLEDGE program. Overall there was a 29% reduction in number of treatment courses and patients treated after the implementation of iPLEDGE. Slightly less than half (46.5%) of patients were from KPSC. The mean patient age was 24.2 years and 67.2% of patients were in the 18- to 39-year age group. Most patients (84.5%) had only one treatment course, 12.9% had two treatment courses, 2.2% had 3 treatment courses, and 0.4% had 4 or more courses. About 76% of patients had been prescribed another antiacne prescription medication (either oral or topical) during the 1-year period before starting isotretinoin. After iPLEDGE implementation, FCBP were more likely to have received a prior course of isotretinoin, more likely to have received previous prescription acne medications, and had longer treatment courses (Table I). A total of 102 patients were identified for chart review. Of these, we confirmed 29 cases of fetal exposure to isotretinoin, 68 cases where there was no fetal exposure, and 5 cases where fetal exposure could not be determined (Table II). Eighteen fetal exposures occurred during the 2-year period before iPLEDGE implementation (SMART) and 11 fetal exposures occurred during the 2-year period after iPLEDGE implementation. Of the 5 cases where fetal exposure was determined as unknown, two cases had inadequate information in their medical chart, one case was missing the paper chart, and two cases had conflicting dates or other information that made it difficult to determine whether or not the fetal exposure occurred.

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Table I. Comparison of isotretinoin treatment courses filled before and after iPLEDGE by female patients of childbearing potential Characteristic

Total No. of patients Region Southern California Northern California Mean age, y (std) Age, y \18 18-39 $ 40 Patients with prior isotretinoin treatment course Patients with prior acne prescription medication use Household median income range $0-$50,000 [$50,000-$75,000 [$75,000-$100,000 [$100,000 Education level # High school graduate Some college to associate degree [Bachelor degree Average treatment course duration, d

Treatment courses filled before iPLEDGE (N = 5788)

Treatment courses filled after iPLEDGE (N = 4124)

5378

3844

48.4% 51.6% 24.2 (8.8)

44.1% 55.9% 24.2 (8.6)

25.9% 66.4% 7.7% 16.2%

26.0% 66.9% 7.1% 19.5%

\.001

73.4%

78.9%

\.001

24.7% 41.5% 21.5% 12.3%

26.5% 41.0% 20.3% 12.1%

30.5% 30.0% 39.5% 116.1

30.0% 32.0% 38.0% 136.0

P value

\.001 .7 .532

.207

.107 \.001

std, Standard deviation.

Most fetal exposure cases resulted in elective early termination (n = 19). A total of 9 patients maintained their pregnancy, which resulted in 8 normal births and one infant given the diagnosis of ‘‘polydactyly of fingers with supernumerary digit’’ at birth. The estimated duration of fetal exposure to isotretinoin during this pregnancy was 3 days. One of the 8 normal births was later found as autistic with delayed speech at 18 months of age. The estimated duration of fetal exposure to isotretinoin in this case was 16 days. The majority of patients became pregnant after initiating isotretinoin therapye23 patients were already taking isotretinoin when they became pregnant and 5 patients became pregnant within 30 days of stopping isotretinoin. Among the cases of fetal exposure where the date of conception was available, the average estimated duration of fetal exposure to isotretinoin was about 6 days during SMART and about 18 days during iPLEDGE. The youngest and oldest female patient who became pregnant was 16 and 41 years old at the start of the treatment course, respectively. Most female patients who became pregnant were older than 20 years of age (Table III). The unadjusted fetal exposure rates decreased slightly from 3.11 to 2.67 fetal exposures per 1000 treatment courses (P = .69). Table IV contains the

Table II. Isotretinoin fetal exposures and outcomes confirmed by chart review in female patients of childbearing potential (n = 102) No. of patients

Patients with fetal exposure Patients with unknown fetal exposure Patients without fetal exposure Timing of fetal exposure relative to pregnancy Pregnant when isotretinoin was started Taking isotretinoin when pregnancy occurred Became pregnant within 30 days after stopping isotretinoin therapy Outcomes of fetal exposure Elective early termination Spontaneous abortion Maintained pregnancy resulting in normal birth Maintained pregnancy resulting in fetal abnormalities Unknown*

29 5 68 1 23 5

16 3 8 1 1

*Could not be determined by chart review.

unadjusted fetal exposure rates stratified by risk factors. Fetal exposure rates were not significantly different between groups when stratified by region, age, first observed treatment course, prior acne use,

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Table III. Age at start of treatment course in pregnant versus nonpregnant female patients of childbearing potential

Age range, y

\12 12-15 16-19 20-29 30-39 40-44 $ 45

Nonpregnant (N = 9883) n (%)

12 1088 2619 3830 1601 402 331

(0.1) (11.0) (26.5) (38.8) (16.2) (4.1) (3.3)

Pregnant (N = 29) n (%)

Percent pregnant in age group

0 0 6 (20.7) 17 (58.6) 5 (17.2) 1 (3.4) 0

0 0 0.2 0.4 0.3 0.2 0

household median income, and education level. However, the difference in rates among age groups may suggest a trend of increased risk in the 18- to 39year age group (P = .09) relative to the younger than 18-year age group. Results from the Cox proportional hazard models are presented in Table V. Model 1 estimates the effect of the iPLEDGE program relative to the SMART program while adjusting for region and age group only. These two covariates were selected based on preliminary analysis by statistical and clinical significance. The HR for iPLEDGE versus SMART was 0.76 (95% confidence interval [CI] 0.36-1.61). Women between the ages of 18 and 39 years were 3.5 times more likely to experience fetal exposure to isotretinoin than the reference age group of younger than 18 years. To test the robustness of the estimates in model 1, we also adjusted for age group, region, prior use of antiacne medication and isotretinoin, household median income, and education in model 2. The HR for iPLEDGE versus SMART was 0.74 (95% CI 0.351.57), which was very similar to the HR of 0.76 in model 1. None of the covariates in model 2 were statistically significant. The socioeconomic variables of median household income and education should be interpreted with caution because of the imprecise nature of geo-coded data. The constant proportional hazard assumption for the age variable was tested by recoding the variable in the model as a time-dependent covariate to see if the relative risk changed over time. The resulting P value was not statistically significant (P = .60), which implies that the constant proportionality assumption does not seem to be violated for this age variable.

DISCUSSION In this study we analyzed 9912 courses of treatment and found no evidence that the iPLEDGE program lowered the risk of fetal exposures to

isotretinoin. Results from both the unadjusted analysis of fetal exposure rates (3.11 before vs 2.67 fetal exposures per 1000 treatment courses after, P = .69) and the adjusted Cox proportional hazard model (HR = 0.76, 95% CI 0.36-1.61) failed to show a benefit after implementation of the iPLEDGE program. In 5 of the potential cases, fetal exposure could not be determined from chart review because of conflicting or missing information. In a sensitivity analysis, we assumed all of the unknown cases were positive fetal exposures occurring during SMART. Under this assumption, the HR for fetal exposure after adjusting for age and region decreased to 0.6 (95% CI 0.29-1.23), but did not reach statistical significance, suggesting our original results are robust to the case definition. The majority of fetal exposure cases (19 of 29) resulted in therapeutic or spontaneous abortion. Both SMART and iPLEDGE programs demonstrated the ability to detect pregnancy during the early stages, giving patients in our study population adequate time to abort the pregnancy at an early stage if the patient desired. However, unintended pregnancies still occurred in our patient population despite having the RMPs in place. A previous FDA report found that the most common known reasons for pregnancy during iPLEDGE included contraceptive failure and noncompliance with birth control methods.9 Overall, our results are consistent with previous FDA reports, which suggest no decline in the rates of fetal exposures. The counts of pregnancy exposures from the FDA before and after iPLEDGE implementation are remarkably consistent. In 2004, the FDA reported the number of isotretinoin-exposed pregnancies decreased from 127 during the year before SMART to 120 pregnancies in the year after SMART implementation.7 Then in 2007, the FDA reported a total of 122 pregnancies during the first year of the iPLEDGE program.9 For the rate of fetal exposure to have decreased after iPLEDGE, the total number of isotretinoin prescriptions or treatment courses filled after iPLEDGE implementation would have had to increase. However, data from the FDA reports suggest otherwise. In the FDA report, the total number of prescriptions dispensed decreased 23% during the first year of SMART implementation compared with the year before implementation of the SMART program.7 The number of isotretinoin treatment courses and treated patients in our study similarly declined by 29% in the 2 years after iPLEDGE implementation. Although numbers comparable with ours are not available nationally, the FDA estimated that 1.2 million isotretinoin prescriptions were dispensed during the

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Table IV. Unadjusted rates of fetal exposure to isotretinoin in female patients of childbearing potential, stratified by risk factor

Risk management program SMART iPLEDGE Region Southern California Northern California Age category, y \18 18-39 $ 40 First observed isotretinoin treatment course of patient during study period No Yes Prior antiacne prescription medication use No previous acne medications Has previously used an oral or topical acne medication Household median income level $0-$50,000 [$50,000-$75,000 [$75,000-$100,000 [$100,000 Education level # High school graduate Some college to associate degree [Bachelor degree

No. of fetal exposures

No. of treatment courses

Fetal exposure rate/1000 treatment courses

18 11

5788 4124

3.11 2.67

.69

15 14

4397 4974

3.41 2.81

.60

3 25 1

2400 6265 706

1.25 3.99 1.42

8 21

1666 7705

4.80 2.73

.17

7 22

2287 7084

3.06 3.11

.97

10 11 7 1

2392 3864 1967 1148

4.18 2.85 3.56 0.87

.40

11 9 9

2849 2881 3641

3.86 3.12 2.47

.61

P value

.09

SMART, System to manage Accutane-related teratogenicity.

first year of SMART versus 730,732 prescriptions in the first year of iPLEDGE (a 39% reduction in total prescriptions). This reduction in overall prescriptions is likely a result of multiple factors. Possible causes include providers using more stringent prescribing criteria before a patient is a candidate for isotretinoin, and patients perceiving that isotretinoin is a ‘‘dangerous’’ drug and therefore refusing therapy. In addition, there may be a disincentive for prescribers to use isotretinoin because of the more rigorous and timeconsuming iPLEDGE program. In particular, early months of iPLEDGE implementation resulted in typical wait times for World Wide Web site support of hours to days.13 Significant reductions in the number of total prescriptions dispensed suggest that RMPs for isotretinoin, including iPLEDGE, may be reducing access to a very effective treatment for severe acne. In this study, treatment courses filled after iPLEDGE seem to be restricted to patients exhibiting more

severe cases of acne. Patients starting isotretinoin after iPLEDGE were more likely to have had a previous isotretinoin treatment, were more likely to have previous prescription acne medications, and had longer treatment courses. In addition, female patients within Kaiser Permanente California have been disproportionately affected by iPLEDGE compared with male patients (data from KPSC show that, compared with the 2 years before iPLEDGE, female patients had a 36% reduction in use compared with a 20% reduction in male patients). Our study design has several strengths. First, our study spans a 4-year period, which allowed us to capture isotretinoin use 2 years before and after implementation of iPLEDGE. Second, the integrated health care delivery system at Kaiser Permanente improved our ability to electronically capture potential fetal exposures by identifying all pregnancyrelated services and tests provided to our study population. About 90% of treatment courses were compliant with pregnancy testing. From the

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Table V. Estimation of effect of iPLEDGE program relative to system to manage Accutane-related teratogenicity (SMART) program on risk of fetal exposure in female patients of childbearing potential using Cox proportional hazard models Model 2y

Model 1* Hazard ratio

iPLEDGE Northern vs southern Californiaz Age group, y \18z 18-39 $ 40 First observed isotretinoin treatment course of patient during study period Prior use of antiacne prescription medication observed Household median income level $0-$50,000z [$50,000-$75,000 [$75,000-$100,000 [$100,000 Education level # High school graduatez Some college to associate degree [Bachelor degree

95% CI

Hazard ratio

95% CI

0.76 0.78

0.36-1.61 0.37-1.61

0.74 0.77

0.35-1.57 0.36-1.66

3.57 1.39

1.08-11.83 0.14-13.36

3.24 1.22 0.48

0.97-10.85 0.12-11.90 0.21-1.09

0.97

0.41-2.30

0.73 0.94 0.24

0.30-1.80 0.32-2.74 0.03-2.15

0.94 0.88

0.36-2.48 0.32-2.39

CI, Confidence interval. *Model 1 estimates effect of iPLEDGE program relative to SMART program, adjusting for region and age group. y Model 2 estimates effect of iPLEDGE program relative to SMART program, adjusting for region, age group, prior use of isotretinoin or other antiacne medications, household median income level, and education level. z Reference group.

remaining 10% of treatment courses, a random sample of 80 KPSC patients with noncompliant pregnancy testing was selected for chart review. The chart review revealed that 50% of the missing pregnancy tests were actually accounted for as a result of various reasons, such as office testing documented only in the handwritten chart, home pregnancy tests, and tests performed outside of Kaiser. This implies the actual pregnancy testing compliance rate in our population may be around 95%. Another strength of this study was the availability of patient medical records for follow-up and the use of chart review to validate fetal exposures. In addition, we were able to track patients after they had stopped isotretinoin and evaluate pregnancy outcomes as needed. Very few patients were lost to follow-up during the study. There are several limitations of the study. First, KPSC and KPNC had implemented their own risk management strategies during SMART that went beyond the mandates of that particular RMP. Starting in 2002, the KPSC- and KPNC-specific program requirements included verification of a negative pregnancy test result by the pharmacist before the patient could receive the prescription and used quality improvement measures for efficient

monitoring and reporting to pharmacies and providers.6 Thus, the rates of fetal exposures within Kaiser Permanente in the 2 years before iPLEDGE may not be generalizable to the community outside of Kaiser. However, our previous study found no benefit from the pharmacist intervention.6 A second limitation is the potential for important risk factors (eg, contraceptive adherence) that are not captured in the electronic data and are therefore unavailable for statistical analysis using the Cox proportional hazard models. Another limitation of the study is sample size. To maximize study power, all available isotretinoin treatment courses during a 4-year period from southern and northern California regions were combined. Although a total of 9912 courses of isotretinoin therapy were included in the study, the power of the study may be inadequate to reject the null hypothesis (for modest improvements) given the low frequency of fetal exposures. Despite the potential problem of inadequate power, this study provides valuable insight in understanding how iPLEDGE has affected isotretinoin use and fetal exposure outcomes. Over time, the FDA has implemented progressively more restrictive criteria for prescribing and dispensing isotretinoin. To date, these programs

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have not been shown to be effective in eliminating fetal exposures in FCBP. Furthermore, RMPs such as iPLEDGE restrict access to powerful, life-changing therapies, use valuable health care resources, and impose a significant burden on both clinicians and patients. The results of this study and those reported by the FDA have important policy implications with respect to RMPs, their implementation in general, and the isotretinoin RMP in particular. Isotretinoin is a highly effective drug that provides significant benefit to patients with severe scarring, nodular cystic acne. However, the iPLEDGE program currently lacks established benchmarks or criteria for assessing effectiveness of the program and there is no system in place to evaluate the program on an ongoing basis. Instituting ongoing program evaluation and establishing benchmarks would be helpful in understanding the effectiveness of iPLEDGE and help shed light on the specific issues that could be addressed (eg, contraceptive failure or noncompliance with birth control methods, increased risk in certain age groups) to improve the program in the future. Conclusion In conclusion, this study found no evidence that the iPLEDGE program significantly decreased the rate of fetal exposures to isotretinoin in FCBP. There is lack of evidence that the iPLEDGE program and all previous RMPs over the past 28 years have been effective. Before changes are made to the current iPLEDGE program, which already increases the workload burden and cost associated with prescribing isotretinoin, the criteria used to measure the success of the RMP and a method to measure those criteria should first be clearly established. Further examination is needed to analyze the effect of the iPLEDGE system on the patients, health care system, and other issues regarding isotretinoin fetal exposure in a larger population. Without understanding these issues, further increases in patient barriers to isotretinoin therapy in future RMPs will likely be ineffective in reducing pregnancy rates in this patient population.

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The authors would like to acknowledge Alexander S. Carruth and Barbara B. Rowe for their valuable input and support with the chart review process. REFERENCES 1. Accutane (isotretinoin) capsules [package insert]. Nutley, NJ: Roche Laboratories; 2007. 2. Sladden MJ, Harman KE. What is the chance of a normal pregnancy in a woman whose fetus has been exposed to isotretinoin? Arch Dermatol 2007;143:1187-8. 3. Abroms L, Maibach E, Lyon-Daniel K, Feldman SR. What is the best approach to reducing birth defects associated with isotretinoin? PLoS Med 2006;3:1978-83. 4. Atanackovic G, Koren G. Fetal exposure to oral isotretinoin: failure to comply with the pregnancy prevention program. CMAJ 1999;160:1719-20. 5. Schonfeld TL, Amoura NJ, Kratochvil CJ. iPLEDGE allegiance to the pill: evaluation of year 1 of a birth defect prevention and monitoring system. J Law Med Ethics 2009;37:104-17. 6. Cheetham TC, Wagner RA, Chiu G, Day JM, Yoshinaga MA, Wong L. A risk management program aimed at preventing fetal exposure to isotretinoin: retrospective cohort study. J Am Acad Dermatol 2006;55:442-8. 7. Pitts M, Karwoski C, Mendelsohn A (FDA). Isotretinoin pregnancy exposures: spontaneous reports 1 year prior to, and 1 year after implementation of the current RMP. Joint dermatologic and ophthalmic drugs and drug safety and risk management advisory committee meeting. February 26-27, 2004. Available from: URL:http://www.fda.gov/ohrms/dockets/ ac/04/slides/4017S1_06_Pitts.ppt. Accessed July 29, 2008. 8. US Food and Drug Administration. iPLEDGE program. c2005. Available from: URL:http://www.ipledgeprogram.com. Accessed July 29, 2008. 9. Drug Safety and Risk Management Advisory Committee, Dermatologic and Ophthalmic Drugs Advisory Committee. Briefing document for iPLEDGE year 1 update. US Food and Drug Administration; 2007. Available from: URL:http://www. fda.gov/ohrms/dockets/ac/07/briefing/2007-4311b1-02-ipled ge.pdf. Accessed May 9, 2010. 10. Haider A, Shaw JC. Treatment of acne vulgaris. JAMA 2004; 292:726-35. 11. Katsambas AD, Stefanaki C, Cunliffe WJ. Guidelines for treating acne. Clin Dermatol 2004;22:439-44. 12. Strauss JS, Krowchuk DP, Leyden JJ, Lucky AW, Shalita AR, Siegfried EC, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol 2007;56:651-63. 13. Darves B. Dermatologists frustrated with problematic iPLEDGE program. Medscape Medical News. March 9, 2006. Available from: URL:http://www.medscape.com/viewarticle/525664. Accessed July 8, 2010.