+--------------------+-------------------------------------------------+
| **M E M O R A N D  | **DEPARTMENT OF HEALTH AND HUMAN SERVICES       |
| U M**              | PUBLIC HEALTH SERVICE**                         |
|                    |                                                 |
|                    | **FOOD AND DRUG ADMINISTRATION**                |
|                    |                                                 |
|                    | **CENTER FOR DRUG EVALUATION AND RESEARCH**     |
+--------------------+-------------------------------------------------+

DATE: February 2, 2004

TO: Paul Seligman, M.D., M.P.H., Acting Director

Anne Trontell, M.D., M.P.H., Deputy Director

Office of Drug Safety

Immediate Office, HFD-400

THROUGH: Mark Avigan, M.D., C.M., Director

Division of Drug Risk Evaluation, HFD-430

Gerald DalPan, M.D., M.H.S., Director

Division of Surveillance, Research, and Communication Support, HFD-410

FROM: Allen Brinker, M.D., M.S., Epidemiologist Team Leader

Parivash Nourjah, Ph.D., Epidemiologist

Karen Lechter, Ph.D., Survey Analyst

Division of Drug Risk Evaluation, HFD-430

Division of Surveillance, Research, and Communication Support, HFD-410

Office of Drug Safety

SUBJECT: PID D030417

Drug: Isotretinoin

> Topic: Review of Isotretinoin Patient Survey Materials and Data with
> Interest in Compliance During the First Year of the System to Manage
> Accutane Related Teratology (SMART) Program.

**[EXECUTIVE SUMMARY]{.underline}**

The analyses presented herein are based upon data supplied by the
primary drug sponsor, Hoffmann-La Roche[^1], and subcontractors Slone
Epidemiology Unit, Boston University Medical School \[Slone\] and The
Degge Group with S.I. International \[Degge/SI\]. Other data resources
include the IMS HEALTH National Prescription Audit (NPA) and National
Disease and Therapeutic Index (NDTI).

**The main findings of the report based on the Divison of Drug Risk
Evaluation (DDRE) analyses are as follows**:

-   Absolute participation in the Accutane Patient Surveys \[Survey(s)\]
    increased from 16% - 19% in the year before SMART to 22%-26% in the
    first year of SMART.

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-   In comparison to two observational cohorts of Accutane-brand
    isotretinoin and/or generic isotretinoin recipients, the youngest
    users of isotretinoin appear to under-represented among participants
    in the Degge/SI cohort and this difference appears clinically
    significant. Further comparison to these observational data also
    suggests patients receiving isotretinoin from non-dermatologists
    appear to be underrepresented in the Survey. In general, results
    from the patient survey should be considered with caution due to
    possible error from a low enrollment rate, recall bias, social
    desirability bias, bias due to both unit non-response and item
    non-response, and poor questionnaire design.

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-   In the Degge/SI cohort, 76% of Survey participants reported they
    signed two consent forms, 4% reported they signed only one form, 9%
    reported that they did not sign any consent forms, and 11% were
    uncertain about whether they signed a consent form or not.

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-   In the Degge/SI cohort, 92% of Survey participants reported that
    they received a prescription with yellow Acutane Qualification
    sticker. The remaining women reported there was no sticker, did not
    answer the question, or reported someone else handled the
    prescription for them.

-   Data reported from the Slone Epidemiology Group suggests that there
    has been some improvement in the rate of ANY pregnancy testing prior
    to initiating therapy with isotretinoin, from 77%-85% to 91% in the
    two year interval 2QTR2001 through 1QTR2003. However, the
    improvement appears to have plateaued shortly after new labeling
    requirements (April 1, 2002).

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-   In the Degge/SI cohort, approximately 68% of apparently fertile and
    sexually active women reported two pregnancy tests prior to
    initiation of isotretinoin, a labeled requirement for isotretinoin
    therapy. Approximately 7% of apparently fertile and sexually active
    women reported no pregnancy testing prior to initiation of
    isotretinoin. Of menstruating, apparently fertile sexually active
    women, 28% had a pregnancy test within the first 5 days of their
    menstrual period immediately before starting isotretinoin.

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-   In Quarterly reports to the sponsor and FDA, the Slone Epidemiology
    Group has reported a low (\<=1%) prevalence of sexual activity
    without birth control based on a denominator of ALL Survey
    respondents. After restriction to a denominator of apparently
    fertile, 15-45 yr-old sexually active participants, this rate
    becomes \~3%.

-   In the Degge/SI cohort, 4.2% of apparently fertile and sexually
    active 15-45 year-old participants reported no form of birth
    control. In total, 46.4% of apparently fertile and sexually active
    15-45 year-old participants reported use of "appropriate" birth
    control consisting of two methods, at least one of which is a
    "primary" birth control method (e.g., oral contraception).

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-   Regarding the presence of a prescription Qualification sticker at
    initiation of isotretinoin treatment, pregnancy testing was
    generally high both in the presence of a sticker (91%) and in the
    absence of a sticker (91%) for apparently fertile, 15 to 45 year old
    survey participants. No difference was seen after imputation for
    records with missing data or upon restriction to sexually active
    Survey participants. Overall 9% of Survey participants who reported
    a qualification sticker was present also indicated a pregnancy test
    was not done.

-   The presence of a prescription Qualification sticker did not
    correlate with use of birth control at initiation of isotretinoin
    treatment. Among sexually active, apparently fertile 15 to 45 year
    old Survey participants, any birth control was noted in 97% of
    enrollees with a sticker and 96% of enrollees without a sticker. No
    difference was seen after imputation for records with missing data.

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-   Review of data reported from the Slone Epidemiology Group suggests
    that there has been some improvement in the rate of ANY pregnancy
    testing during isotretinoin therapy, from \~70% to \~85% in the two
    year interval 2QTR2001 through 1QTR2003. However, the increase
    appears to have plateaued soon after initiation of the SMART program
    and remains at \~85%. Based on DDRE analyses of the Degge/SI DAT2
    cohort, 81% of apparently fertile, 15 to 44 years old Survey
    participants report monthly pregnancy testing in two consecutive
    months during treatment with isotretinoin.

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-   The presence of a prescription Qualification sticker did not appear
    to correlate with performance of the pregnancy test *during*
    isotretinoin therapy. Pregnancy testing was generally high both in
    the presence (99%) and in the absence (98%) of a sticker for
    apparently fertile, 15 to 45 year old survey participants.
    Similarly, the presence of a prescription qualification sticker did
    not appear to effect compliance with birth control *during*
    isotretinoin therapy. Among sexually active, apparently fertile 15
    to 45 year old survey participants, any birth control was noted in
    99% of enrollees with a sticker and 100% of enrollees without a
    sticker. No difference was seen after imputation for records with
    missing data.

-   DDRE has reviewed additional information to the sponsor's "*1 Year
    Report"* and Degge/SI dataset in the form of Quarterly reports for
    2QTR2003 and 3Qtr2003 from Degge/SI (on Accutane-brand isotretinoin)
    and Slone Epidemiology Group (for both Accutane-brand isotretinoin
    and generic isotretinoin). Due to differences in survey, survey
    methods, and operating procedures, it is problematic to compare
    across these disparate surveys. However, a review of selected and
    generally comparable variables (e.g., pregnancy testing, birth
    control practices) suggests similar compliance with these selected
    attributes as for April 1, 2002 through March 30, 2003 as described
    immediately above. Independent FDA validation of results in
    quarterly reports is not possible.

-   The Degge/SI dataset contains 15 reports of pregnancy among 4277
    women on their first-course of isotretinoin therapy. The observed
    pregnancy rate for first-course users within the Degge/SI cohort is
    thus 15/4277 = 3.5 / 1000. Since this rate is censored, it likely
    represents an underestimate of the rate realized when all these
    Survey participants complete follow-up. However, this rate is
    virtually identical to the rate as reported by researchers from the
    Slone Epidemiology Group for their Accutane Survey cohort of 2.9 per
    1,000 women.

# [INTRODUCTION]{.underline}

**Goals/Objectives of SMART**

The System to Manage Accutane Related Teratogenicity (SMART) program was
initiated on April 10, 2002 to address two main goals raised at a public
meeting in September 2000.[^2]

1\) No woman should begin Accutane therapy if she is pregnant;

2\) No pregnancies should occur among women taking Accutane.

**Tools of the SMART program; Required Steps in Process and Patient
labeling**[^3]

The S.M.A.R.T. program requires the following:

-   Prescribers read the S.M.A.R.T. \"Guide to Best Practices\" provided
    by Roche, and then sign and return the Letter of Understanding
    certifying their knowledge of the measures to minimize fetal
    exposures to Accutane. In addition, Accutane prescribers are
    strongly encouraged to participate in a half-day Continuing Medical
    Education (CME) course developed by the manufacturer that includes
    specific, practical information about pregnancy prevention.

-   Prescribers receive self-adhesive Accutane Qualification Stickers
    which are to be attached to the prescription form. These stickers
    indicate to the pharmacist that the patient is \"qualified\" to
    receive Accutane, i.e., the female patient has had negative
    pregnancy tests, as well as education and counseling about pregnancy
    prevention. The pregnancy test is to be repeated every month
    throughout the Accutane treatment course, and no prescriptions
    should be given for more than a one month supply of Accutane.

-   All female patients must have two negative urine or serum pregnancy
    tests before the initial Accutane prescription is written.
    Additionally, patients must have a negative pregnancy test prior to
    receiving subsequent prescriptions, regardless of whether or not
    they are sexually active. Patients who are, or might become,
    sexually active with a male partner must also select and use two
    forms of effective contraception simultaneously for at least one
    month prior to initiation of Accutane therapy, during therapy, and
    for one month following discontinuation of therapy. Patients are
    required to sign a Patient Information/Consent form about Accutane
    and birth defects, in addition to the General Consent Form that all
    patients receive about other potentially serious risks (e.g.,
    suicidality, etc.). Finally, female patients must be given the
    opportunity to enroll in the Accutane Survey. This confidential
    survey collects data on the utility of S.M.A.R.T. in reducing
    pregnancies among female Accutane users. This survey will help to
    identify aspects of S.M.A.R.T. that could be improved upon.

-   Pharmacists dispense Accutane only upon presentation of a
    prescription with the special Accutane Qualification Sticker.
    Moreover, pharmacists dispense a maximum one-month supply of
    Accutane, fill prescriptions within seven days from the date of
    \"qualification,\" (defined above) and provide a Medication Guide
    for patients with each Accutane prescription. Requests for refills
    (i.e. more Accutane without a new prescription) and phoned-in
    prescriptions are not to be filled.

    ::: Definition-Term
    **[METHODS]{.underline}**
    :::

    ::: Definition-Term
    **Background on Patient Survey**
    :::

::: Definition-Term
Accutane (isotretinoin, Hoffmann-La Roche) was initially marketed in the
US in 1982. Isotretinoin is an effective medication for the treatment of
severe recalicitrant acne, although it has potent teratogenic effects.
To minimize the risk of patients becoming pregnant while taking
isotretinoin and avoiding exposure during pregnancy, the sponsor
designed and implemented the Accutane Pregnancy Prevention Program (PPP)
in 1988. In 1989, the Slone Epidemiology Unit of Boston University
designed and conducted the Survey of Accutane Use in Women (Slone Survey
/ Accutane \[Patient\] Survey) to evaluate the PPP program. The general
format[^4] of the survey remains largely unchanged. In the original
survey, women who chose to enroll in the program were randomized (at
initiation of therapy) to either a During and After Treatment \[DAT\]
arm (consisting of 2 or more questionnaires, DAT-1, DAT-2, and DAT-3) or
an After Treatment \[AT\] arm. The DAT arm was restricted to a total
enrollment of 5,000 women per year. Between 1989 and 1994, women in the
DAT arm were queried by phone while women assigned to the AT arm were
queried by mail. Women who enrolled but failed to respond to mailed
questionnaires were contacted by air courier or, if needed, telephone.
Since 1995, mailed questionnaires have been used as the primary contact
instrument for both the DAT and AT arms with follow-up contact by air
courier or telephone for non-responders. The Slone Epidemiology Unit was
the sole administrator of the Accutane patient survey from inception
through September 2002. During the fourth quarter of 2002, Hoffmann-La
Roche re-awarded the contract for the survey of enrollees using
Accutane-brand isotretinoin to Degge/SI. Sponsors of generic
isotretinoin introduced into the market during the fourth quarter of
2002, elected to use the Slone Epidemiology Group to conduct the survey,
a regulatory requirement, on their behalf. The Slone Epidemiology Unit
has continued to survey women who enrolled before the SMART program,
those who enroll with cards addressed to Slone Epidemiology Unit, and
those who declined transfer to Degge/SI. The DAT questionnaire was also
modified to include new questions specifically designed to measure
compliance with SMART.[^5] The new questionnaire was introduced in
4QTR2002 by Degge/SI and in 2QTR2003 by Slone for generic isotretinoin.
Chart 2 provides a timeline for Accutane/generic isotretinoin patient
surveys[^6].
:::

**Data Sources**

The analyses presented herein are based upon data in a report supplied
by the primary drug sponsor, Hoffmann-La Roche[^7] and primary dataset
provided by subcontractors Slone Epidemiology Unit, Boston University
Medical School \[Slone\] and The Degge Group with S.I. International
(Degge/SI). Other data resources include the IMS HEALTH National
Prescription Audit (NPA) and National Disease and Therapeutic Index
(NDTI).

[RESULTS]{.underline}

**1. SURVEY PARTICIPATION, REPRESENTATIVENESS, AND LIMITATIONS**

**1.1 Absolute Participation in Patient Surveys**

Absolute participation in the Patient Survey by quarter, as provided to
FDA by Hoffmann-La Roche is shown in table 1. These data appear to show
that, although participation has generally been poor, participation is
increasing.

  --------------- ---------- -------- -------- -------- ---------- -------- -------- --------
  **Table 1.                                                                         
  Trends in                                                                          
  participation                                                                      
  in Accutane                                                                        
  Patient Survey                                                                     
  per Sponsor**                                                                      

  era             Last four                             First four                   
                  quarters                              quarters                     
                  before                                of SMART                     
                  SMART                                                              

  Qtr             2Qtr01     3Qtr01   4Qtr01   1Qtr02   2Qtr02     3Qtr02   4Qtr02   1Qtr03

  Survey          7,903      7,897    8,211    10,044   8,533      7,560    10,249   10,289
  Enrollees                                                                          

  New female      49,795     47,402   54,348   31,262   42,642     34,424   38,528   19,761
  starts                                                                             

  Enrollment Rate 17.3%      16.8%    15.1%    32.1%    20.0%      22.0%    26.6%    52.1%
  --------------- ---------- -------- -------- -------- ---------- -------- -------- --------

To this end, the sponsor states,

> "Accutane Survey enrollment rate of 28.2% \[for the first year of
> SMART\], based on a denominator of new female patient starts,
> represents an approximate 10 percentage point increase in Survey
> enrollment rate from the 4 quarters prior to SMART and reverses a
> downward trend in Survey enrollment rates observed in a retrospective
> review."

In order to provide for an independent assessment of quarterly
enrollment since initiation of the SMART program (April 1, 2001) though
March 31, 2002, DDRE produced an independent estimate of unique females
on Accutane therapy for the 8 quarters of interest. These data, along
with quarterly Survey enrollees (numerators) shown in Table 1, permit
calculation of enrollment rates. The approach used to calculate
quarterly estimates of unique females on Accutane is based on the
following assumptions: 1) there is a steady-state condition of drug
usage for well-established drugs such as Accutane; and 2) the average
total number of Rxs per unique individual until the end of therapy is
3.7.[^8] This estimate of average number of Rxs per unique patient is
provided in a large, observational study of Accutane recipients followed
to the apparent end of an Accutane treatment course. The assumptions
listed previously, and lack of proven applicability of this metric to
the population of Accutane recipients are limitations of this analytic
approach. Steps taken to calculate enrollment rates were as follows:
First, retail female prescription volume for the 8 quarters of interest
was obtained by dividing the observed quarterly prescription volume by
two and then summed. \[Sum Rx volume to females over the eight quarters
of interest = 1,334,000 Rx.\] Second, the total number of unique females
on Accutane for the 8 quarters of interest was estimated by dividing the
total female Rx volume by 3.7. This is outlined in the following
equation:

Unique females (total for 8 quarters) = (1,334,000 Rx) (unique patient /
3.7 Rx[^9])

= 360,500

Finally, total female utilization (360,500) over the 8 quarters was
multiplied by the fraction of total utilization for any specific quarter
to result in an estimate of unique females for each quarter.

+---------+------+------+------+------+------+------+------+------+
| **Table |      |      |      |      |      |      |      |      |
| 2.      |      |      |      |      |      |      |      |      |
| Trends  |      |      |      |      |      |      |      |      |
| in      |      |      |      |      |      |      |      |      |
| partic  |      |      |      |      |      |      |      |      |
| ipation |      |      |      |      |      |      |      |      |
| in      |      |      |      |      |      |      |      |      |
| A       |      |      |      |      |      |      |      |      |
| ccutane |      |      |      |      |      |      |      |      |
| Patient |      |      |      |      |      |      |      |      |
| Survey  |      |      |      |      |      |      |      |      |
| per     |      |      |      |      |      |      |      |      |
| DDRE    |      |      |      |      |      |      |      |      |
| based   |      |      |      |      |      |      |      |      |
| on      |      |      |      |      |      |      |      |      |
| e       |      |      |      |      |      |      |      |      |
| stimate |      |      |      |      |      |      |      |      |
| of      |      |      |      |      |      |      |      |      |
| unique  |      |      |      |      |      |      |      |      |
| females |      |      |      |      |      |      |      |      |
| on      |      |      |      |      |      |      |      |      |
| the     |      |      |      |      |      |      |      |      |
| rapy.** |      |      |      |      |      |      |      |      |
+=========+======+======+======+======+======+======+======+======+
| era     | Last |      |      |      | F    |      |      |      |
|         | four |      |      |      | irst |      |      |      |
|         | quar |      |      |      | four |      |      |      |
|         | ters |      |      |      | quar |      |      |      |
|         | be   |      |      |      | ters |      |      |      |
|         | fore |      |      |      | of   |      |      |      |
|         | S    |      |      |      | S    |      |      |      |
|         | MART |      |      |      | MART |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| Qtr     | 2Q   | 3Q   | 4Q   | 1Q   | 2Q   | 3Q   | 4Q   | 1Q   |
|         | tr01 | tr01 | tr01 | tr02 | tr02 | tr02 | tr02 | tr03 |
+---------+------+------+------+------+------+------+------+------+
| Survey  | 7    | 7    | 8    | 10   | 8    | 7    | 10   | 10   |
| En      | ,903 | ,897 | ,211 | ,044 | ,533 | ,560 | ,249 | ,289 |
| rollees |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| Rx      | 377  | 338  | 394  | 399  | 295  | 248  | 292  | 325  |
| volume  | ,000 | ,000 | ,000 | ,000 | ,000 | ,000 | ,000 | ,000 |
| for     |      |      |      |      |      |      |      |      |
| qua     |      |      |      |      |      |      |      |      |
| rter^a^ |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| Rx      | 188  | 169  | 197  | 199  | 147  | 124  | 146  | 162  |
| volume  | ,500 | ,000 | ,000 | ,500 | ,500 | ,000 | ,000 | ,500 |
| to      |      |      |      |      |      |      |      |      |
| fe      |      |      |      |      |      |      |      |      |
| male^b^ |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| \% of   | 1    | 1    | 1    | 1    | 1    | 9.3% | 1    | 1    |
| total   | 4.1% | 2.7% | 4.8% | 5.0% | 1.0% |      | 0.9% | 2.2% |
| female  |      |      |      |      |      |      |      |      |
| utiliza |      |      |      |      |      |      |      |      |
| tion^c^ |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| E       | 50   | 45   | 53   | 53   | 39   | 33   | 39   | 43   |
| stimate | ,900 | ,700 | ,200 | ,900 | ,900 | ,500 | ,500 | ,900 |
| of      |      |      |      |      |      |      |      |      |
| total   |      |      |      |      |      |      |      |      |
| unique  |      |      |      |      |      |      |      |      |
| fem     |      |      |      |      |      |      |      |      |
| ales^d^ |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
| Enr     | 1    | 1    | 1    | 1    | 2    | 2    | 2    | 2    |
| ollment | 5.5% | 7.3% | 5.4% | 8.6% | 1.4% | 2.6% | 6.0% | 3.4% |
| Rate    |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+
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|   Based |      |      |      |      |      |      |      |      |
|     on  |      |      |      |      |      |      |      |      |
|     d   |      |      |      |      |      |      |      |      |
| ivision |      |      |      |      |      |      |      |      |
|     by  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  female |      |      |      |      |      |      |      |      |
|     Rx  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  volume |      |      |      |      |      |      |      |      |
|     of  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
| quarter |      |      |      |      |      |      |      |      |
|     by  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|   total |      |      |      |      |      |      |      |      |
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|     to  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
|   (1,33 |      |      |      |      |      |      |      |      |
| 4,000); |      |      |      |      |      |      |      |      |
|     FDA |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  custom |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
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|     by  |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
|   total |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  female |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|    util |      |      |      |      |      |      |      |      |
| ization |      |      |      |      |      |      |      |      |
|     of  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
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|     by  |      |      |      |      |      |      |      |      |
|     3   |      |      |      |      |      |      |      |      |
| 60,500; |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  unique |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  female |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|   count |      |      |      |      |      |      |      |      |
|     of  |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
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|         |      |      |      |      |      |      |      |      |
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| average |      |      |      |      |      |      |      |      |
|     of  |      |      |      |      |      |      |      |      |
|     3.7 |      |      |      |      |      |      |      |      |
|     Rxs |      |      |      |      |      |      |      |      |
|     per |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
| patient |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|    (see |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  text); |      |      |      |      |      |      |      |      |
|     FDA |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  custom |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|   calcu |      |      |      |      |      |      |      |      |
| lations |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|    were |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|   based |      |      |      |      |      |      |      |      |
|     on  |      |      |      |      |      |      |      |      |
|     IMS |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|  Health |      |      |      |      |      |      |      |      |
|         |      |      |      |      |      |      |      |      |
|   data. |      |      |      |      |      |      |      |      |
+---------+------+------+------+------+------+------+------+------+

The analyses provided by the sponsor and by DDRE are highly similar in
all eight quarters before and after initiation of SMART except for 1QTR
2002 and 1QTR 2003. In these quarters, the DDRE analysis of enrollment
is approximately half of the enrollment estimate by the sponsor. Since
the two analyses use the same numerator data, the difference for the two
quarters of interest must be due to differences in the denominators for
1QTR 2002 and 1QTR 2003. This difference is captured in Tables 1 and 2.
In these tables, the respective denominators for 1QTR 2002 and 1QTR 2003
are approximately half of each other. In order to investigate trends due
to seasonality, average duration of treatment in relation to season were
explored within the AdvancePCS claims database. No differences were
observed based on standard calendar quarters (data not shown) for 2002.
Thus, the reason the two models result in almost identical counts for
six quarters yet diverge strikingly for 1Qtr02 and 1Qtr03 is not readily
apparent. Based on DDRE analyses, absolute participation in the patient
surveys increased from 16% - 19% in the year before SMART to 22%-26% in
the first year after implementation of SMART.

**1.2 Representativeness**

The sponsor includes the following summary with regard to the
representativeness of Accutane Survey participants:

::: Definition-Term
> "The representativeness of Accutane Survey respondents to all Accutane
> female patients in the United States was demonstrated for age,
> prescriber, payer and geographic region of the country. While this
> does not ensure absolute comparability of all Survey respondents to
> all Survey non-respondents, it suggests that the convenience sample is
> reasonably representative of the population on these selected
> parameters."
:::

DDRE would agree with the conclusion of the sponsor that the Survey
represents a "convenience sample." With reference to the sponsor's data
(not shown) for clinical characteristics of Slone and Degge/SI cohorts
versus data on the isotretinoin-user population at large, we would note
the following:

-   Age distribution - differences are mild but noticeable

-   Young ([\<]{.underline} 15 years) and 45+ age groups are
    underrepresented in the Accutane Survey populations when compared to
    the female Accutane population/reference population[^10] (For
    [\<]{.underline} 15 year olds: SEC 13.2%, Degge/SI 9.6%, and
    reference population 17.3%; For 45+ age group SEC 3.6%, Degge/SI 5%,
    and reference population 10.9%).

-   The 20-29 year age-group is over-represented (SEC 35.7%, Degge/SI
    37.2%, and reference population 24.9%).

-   Geographic Region - Generally similar, east somewhat
    under-represented in the survey population when compared to
    reference population[^11] (SEC 15.6%, Degge/SI 16.5%, and reference
    population 21.2%)

-   Payor Type - Based solely on Degge/SI cohort; unable to compare
    given the large fraction (12%) of unknown responses.

-   Prescriber - Data suggest that up to 20% of Accutane prescriptions
    are generated by non-dermatologists. However, non-dermatologists
    account for only 5% of prescribers in the Slone cohort and 10% of
    the Degge/SI cohort.[^12] This is also noted by the sponsor.

The Degge/SI primary dataset as provided to FDA by the sponsor does not
include data on geographic region nor payer type. DDRE is unable to
generate tables comparable to the sponsor's. Data on age and prescriber
was provided by the sponsor in their dataset. DDRE analyses of these
data are outlined as follows. The age distribution of the Degge/SI
cohort is compared to the distribution of recipients of isotretinoin
(both Accutane-brand and generic) within the IMS Health NDTI^TM^ and
with recipients of Accutane-brand isotretinoin with coverage managed by
AdvancePCS (described presented previously within the Isotretinoin
Utilization section of this document[^13].) In brief, the IMS Health
National Disease and Therapeutic Index™ (NDTI™) is an ongoing survey
designed to provide descriptive information on the patterns and
treatment of disease encountered in office-based practice in the
continental United States by collecting data on drug products mentioned
during visits to roughly 2,000 - 3,000 office-based physicians. The data
are projected nationally to reflect national prescribing patterns. These
data are displayed in Table 3 below. In comparison to the IMS Health
NDTI™, it appears the youngest isotretinoin users are underrepresented
in the Survey. While the NDTI™ is designed to be representative, it is
limited by size. Thus, the age distribution of Degge/SI participants was
also compared to isotretinoin recipients with drug benefits managed by
AdvancePCS, which is not designed to be representative but is quite
large. These data also suggest that the youngest isotretinoin users
appear to be under-represented among Survey participants. Furthermore,
while it is inappropriate to subject these data to statistical testing,
these comparisons provide evidence that there is a large and clinically
meaningful difference in Survey participation for the youngest
recipients of isotretinoin.

+-----------------+-----------------+------------+-------------------+
| **Table 3. Age  |                 |            |                   |
| distribution of |                 |            |                   |
| the Degge/SI    |                 |            |                   |
| cohort compared |                 |            |                   |
| to female       |                 |            |                   |
| Accutane        |                 |            |                   |
| recipients with |                 |            |                   |
| drug benefits   |                 |            |                   |
| managed by      |                 |            |                   |
| AdvancePCS drug |                 |            |                   |
| benefits and    |                 |            |                   |
| female          |                 |            |                   |
| recipients of   |                 |            |                   |
| isotretinoin    |                 |            |                   |
| (all brands)    |                 |            |                   |
| within the IMS  |                 |            |                   |
| Health          |                 |            |                   |
| NDTI**™**.**    |                 |            |                   |
+=================+=================+============+===================+
| Age group       | Degge/SI        | Adva       | IMS Health        |
| (years)         | cohort\*        | ncePCS\*\* | NDTI™\*\*\*       |
|                 |                 |            |                   |
|                 | (as submitted)  | (          | (4/02-3/03)       |
|                 |                 | 4/02-3/03) |                   |
+-----------------+-----------------+------------+-------------------+
| Up to age 19    | 1917 (35%)      | 43%        | 45%               |
+-----------------+-----------------+------------+-------------------+
| 20-29           | 2092 (38%)      | 28%        | 30%               |
+-----------------+-----------------+------------+-------------------+
| 30-39           | 918 (17%)       | 16%        | 16%               |
+-----------------+-----------------+------------+-------------------+
| 40+             | 536 (10%)       | 13%        | 9%                |
+-----------------+-----------------+------------+-------------------+
| **Total**       | **5463**        | **100%**   | **100%**          |
+-----------------+-----------------+------------+-------------------+
| \*excludes 6    |                 |            |                   |
| records where   |                 |            |                   |
| age was         |                 |            |                   |
| missing + 432   |                 |            |                   |
| records on      |                 |            |                   |
| generic         |                 |            |                   |
| isotretinoin    |                 |            |                   |
|                 |                 |            |                   |
| \*\*Advance     |                 |            |                   |
| PCS™ Dimension  |                 |            |                   |
| Rx, accessed 11 |                 |            |                   |
| December 2003   |                 |            |                   |
|                 |                 |            |                   |
| \*\*\*IMS       |                 |            |                   |
| Health, IMS     |                 |            |                   |
| National        |                 |            |                   |
| Disease and     |                 |            |                   |
| Therapeutic     |                 |            |                   |
| Index^TM^,      |                 |            |                   |
| 4/2002-3/2003,  |                 |            |                   |
| accessed 15     |                 |            |                   |
| December 2003;  |                 |            |                   |
| FDA custom      |                 |            |                   |
| calculations    |                 |            |                   |
| were based on   |                 |            |                   |
| IMS Health data |                 |            |                   |
+-----------------+-----------------+------------+-------------------+

::: Definition-Term
Second, in DDRE analyses of the Degge/SI dataset, 94% of DAT-2
participants indicated their Accutane prescriber was a dermatologist. In
comparison, approximately 80% of recent isotretinoin prescriptions in
the IMS Health NPA^TM^ were associated with dermatologists.[^14] Thus,
as shown in analyses by DDRE and the sponsor, patients receiving care
from non-dermatologists are underrepresented in the Survey. It is not
known if there is differential encouragement for the patient survey
between dermatologists and non-dermatologists or if compliance with
isotretinoin labeling and pregnancy varies between dermatologists and
non-dermatologists*.*
:::

::: Definition-Term
**1.3 Overview of Study Limitations due to Internal Variability**
:::

::: Definition-Term
In consideration of the generalizability of the Survey, the sponsor
notes,
:::

::: Definition-Term
> "Examination of invalid and absent responses to the Accutane Survey
> indicated relatively high proportions of invalid and absent responses
> to several key questions that measure S.M.A.R.T. compliance."
:::

The Slone Survey, implemented in 1989, was designed to, "assess the
compliance of physicians and patients with the Accutane Pregnancy
Prevention Program and to identify the rate of pregnancy during
treatment with isotretinoin and during the month after treatment."
Appendix 6[^15] provides a comprehensive discussion on both the internal
variability and external generalizability of the Survey. DDRE/DSRCS
analyses also indicated a high percentage of missing responses on key
variables. For instance, patient survey information on contraception may
be incomplete or unreliable due to the complexity of the questionnaires.
In addition, some questions may be skipped inappropriately due to
misinterpretation of survey instructions. While the sponsor does not
address what inference should be gleaned from "invalid and absent
responses," we take the position that these issues introduce biases,
degrade interval validity, and preclude statistical testing of Survey
results. Furthermore, it is our position that any changes between
calendar quarters represents too short a time interval to detect
meaningful changes; larger changes over time may be considered more
robust, but not definitive evidence of change.

## 2. DAT-1 SURVEY (INITIATION OF TREATMENT)

## 

## 2.1 DAT-1 Univariate Analyses

::: Definition-Term
**2.1.1 [Timing of Enrollment relative to the start of Accutane
therapy]{.underline}**
:::

::: Definition-Term
Timing of enrollment relative to the start of therapy with isotretinoin
is important to assure accuracy of responses. The sponsor reports 73% of
enrollees enroll within 1 month of starting treatment with isotretinoin.
Approximately 27% of participants enroll at a time point of
[\>]{.underline} 1 month.
:::

Based on a dataset provided by the sponsor, 5489 women responded to a
DAT-1 questionnaire sent by Degge/SI between October 2002 and April 1,
2003. Twenty (20) of the respondents reported no plans to start Accutane
therapy and have been excluded from all further DDRE analyses. Of the
remaining 5469 respondents, 5334 women started treatment with Accutane,
and 135 women reported they will start Accutane therapy later or did not
provide an answer. Of this baseline dataset of 5469 women, 80.9%
completed the questionnaire within 30 days of enrollment. Twelve percent
(12%) responded later than 30 days, and 7.1% had an invalid or missing
date.Thus, we concur with the sponsor in assessment that most enrollees
in the Survey do so early in therapy. Among the baseline dataset of 5469
respondents, 1416 (26%) reported they had undergone a previous course of
Accutane therapy.

::: Definition-Term
**2.1.2 [Consent forms]{.underline}**
:::

::: Definition-Term
The SMART program requires women to sign two consent forms, one required
of all patients on isotretinoin and the other required only of female
patients. The sponsor does not include an analysis of the Degge/SI
cohort for consent.
:::

::: Definition-Term
Based of DDRE analyses of the Degge/SI cohort, 76.3% of women reported
that they signed two consent forms, 3.7% reported they signed only one
form, 9.3% reported they had not signed a consent form, and 10.7% were
uncertain about whether they signed a consent form or not.
:::

::: Definition-Term
**2.1.3 [Medication Guide ]{.underline}**
:::

::: Definition-Term
A Medication Guide should be distributed with each prescription. The
sponsor does not include an analysis of the Degge/SI cohort for receipt
of a Medication Guide within the Degge/SI cohort in their "*1 Year
Report*."
:::

Based of DDRE analyses of the Degge/SI cohort, 81% of respondents
reported receipt of a Medication Guide. Four (4) percent reported that a
Medication Guide was missing and 15% reported they were unsure or did
not answer the question.

**2.1.4 [Patient Recall of Qualification Sticker]{.underline}**

The sponsor's analysis of patient recall of a qualification sticker is
consistent with the analysis of the Pharmacy Compliance Survey[^16] .
Based on data from the 3^rd^ and 4^th^ quarters of SMART, the sponsor
notes 97% of survey enrollees recalled the presence of a qualification
sticker.

In DDRE analysis of the Degge/SI cohort, a yellow Accutane Qualification
sticker on the prescription was reported by 92.1% of the 5469
participants. Another 2.3% reported the Accutane qualification sticker
to be missing and 5.6% of respondents were unsure or did not answer the
question.

::: Definition-Term
**2.1.5 [Compliance with 7-day Limit of Qualified
Prescriptions]{.underline}**
:::

::: Definition-Term
According to the new label for isotretinoin, the qualification sticker
signifies that a patient was "qualified" for therapy upon receipt of the
prescription and the prescription is to be filled within 7 days. The
sponsor conducted no analyses within the Degge/SI Survey on distribution
of receipt and fill dates for Survey participants.
:::

::: Definition-Term
In DDRE analyses of Degge/SI survey data for women who started Accutane
and further reported the presence of a Qualification sticker (n=4403),
89.9% initiated treatment within 7 days of receiving their Accutane
prescription. Among this same group of participants, 93.2% filled their
prescriptions within 7 days of receipt. These data are compared to an
analysis of the Pharmacy Compliance Survey[^17], where, after DDRE
review, 94% to 99% of prescriptions with qualification stickers were
filled within 7 days.
:::

::: Definition-Term
**2.1.6 [Pregnancy Testing]{.underline}**
:::

::: Definition-Term
**2.1.6.1 Any Pregnancy testing:** The sponsor provided the trends in
any pregnancy testing prior to starting isotretinoin therapy based on
the DAT-1 survey data collected by SEC and Degge/SI. As shown in table 4
below, SEC data show that the percentage of women reporting ANY
pregnancy testing during the initial four quarters of SMART appears
constant at about 92%. It follows that 7% to 8% of women reported NO
pregnancy testing.
:::

::: Definition-Term
The data for the Degge/SI cohort are generally similar for the 4QTR02
and 1QTR03. The percentage of women reporting ANY pregnancy testing is
reported as 88% and those reporting no pregnancy testing as 9%. The
difference between the two analyses may be in the larger fraction of
women classified as "unknown" in the Degge/SI survey (3%) versus Slone
(\<1%).
:::

+--------+----------+---------+---------+---------+---------+---------+
| *      |          |         |         |         |         |         |
| *Table |          |         |         |         |         |         |
| 4. Any |          |         |         |         |         |         |
| Pre    |          |         |         |         |         |         |
| gnancy |          |         |         |         |         |         |
| T      |          |         |         |         |         |         |
| esting |          |         |         |         |         |         |
| per    |          |         |         |         |         |         |
| Spo    |          |         |         |         |         |         |
| nsor** |          |         |         |         |         |         |
+--------+----------+---------+---------+---------+---------+---------+
|        | P        | 1^st^   | 2nd qtr | 3rd qtr | 4^th^   | Total   |
|        | re-SMART | qtr     | SMART   | SMART   | qtr     | under   |
|        |          | SMART   |         |         | SMART   | SMART   |
|        | (1/1/95  |         | (       | (       |         |         |
|        | --       | (       | 3Qtr02) | 4Qtr02) | (       |         |
|        | 3/31/02) | 2Qtr02) |         |         | 1Qtr03) |         |
+--------+----------+---------+---------+---------+---------+---------+
| **S    |          |         |         |         |         |         |
| lone** |          |         |         |         |         |         |
+--------+----------+---------+---------+---------+---------+---------+
| Any    | 27753    | 1189    | 1280    | 1096    | 911     | 4476    |
| test   | (76%)    | (92)%   | (93%)   | (92%)   | (92%)   | (92%)   |
+--------+----------+---------+---------+---------+---------+---------+
| No     | 8361     | 96 (7%) | 101     | 93 (8%) | 82 (8%) | 372     |
| test   | (23%)    |         | (7%)    |         |         | (8%)    |
+--------+----------+---------+---------+---------+---------+---------+
| U      | 233 (1%) | 4       | 1       | 2       | 3       | 10      |
| nknown |          | (\<1%)  | (\<1%)  | (\<1%)  | (\<1%)  | (\<1%)  |
+--------+----------+---------+---------+---------+---------+---------+
| **     |          |         |         |         |         |         |
| Degge/ |          |         |         |         |         |         |
| SI\*** |          |         |         |         |         |         |
+--------+----------+---------+---------+---------+---------+---------+
| Any    | \-       | \-      | \-      | 1413    | 2103    | 3516    |
| test   |          |         |         | (86%)   | (89%)   | (88%)   |
+--------+----------+---------+---------+---------+---------+---------+
| No     | \-       | \-      | \-      | 174     | 186     | 360     |
| test   |          |         |         | (11%)   | (8%)    | (9%)    |
+--------+----------+---------+---------+---------+---------+---------+
| U      | \-       | \-      | \-      | 53 (3%) | 65 (3%) | 118     |
| nknown |          |         |         |         |         | (3%)    |
+--------+----------+---------+---------+---------+---------+---------+
| \*De   |          |         |         |         |         |         |
| gge/SI |          |         |         |         |         |         |
| began  |          |         |         |         |         |         |
| enr    |          |         |         |         |         |         |
| olling |          |         |         |         |         |         |
| pa     |          |         |         |         |         |         |
| tients |          |         |         |         |         |         |
| in     |          |         |         |         |         |         |
| survey |          |         |         |         |         |         |
| on     |          |         |         |         |         |         |
| 11     |          |         |         |         |         |         |
| /20/02 |          |         |         |         |         |         |
| (4     |          |         |         |         |         |         |
| Qtr02) |          |         |         |         |         |         |
+--------+----------+---------+---------+---------+---------+---------+

::: Definition-Term
The sponsor also conducted analyses to examine the relation between
pregnancy testing and age (data not shown). These data suggest that
pregnancy testing is related to age to some degree, with slightly higher
compliance among women aged 16-39 (86 to 92% receiving any pregnancy
testing). Poorer compliance with testing at the extremes of the age
distribution was among relatively small numbers of survey participants
at those extremes (78 to 86% for any pregnancy testing).
:::

While the sponsor provides a reference for ANY pregnancy testing (as
shown in Table 4 above) based on the interval 1995-March 2002, this
large time interval averages results during a time of public heightened
attention and regulatory attention to reducing isotretinoin-exposed
pregnancies. Therefore, trends in pregnancy testing before start of
Accutane therapy based on DAT-1 surveys have been compiled by DDRE for
the four quarters prior to April 1, 2002 and the following quarters of
SMART based on Slone Survey quarterly reports (Table 5).

  --------------------------------------------------------------------------------------------------
  **Table 5.                                                                                
  Trends in                                                                                 
  Pregnancy                                                                                 
  Testing                                                                                   
  before start                                                                              
  of Accutane                                                                               
  therapy based                                                                             
  on DAT-1                                                                                  
  surveys                                                                                   
  (aggregated                                                                               
  from Slone                                                                                
  Survey                                                                                    
  quarterly                                                                                 
  reports) for                                                                              
  the four                                                                                  
  quarters                                                                                  
  before SMART                                                                              
  and the first                                                                             
  four quarters                                                                             
  of SMART.**                                                                               
  ------------- ---------- -------- -------- -------- ---------- -------- -------- -------- --------
  Era           Last four                             First four                            
                quarters                              quarters                              
                before                                of SMART                              
                SMART                                                                       

  Qtr           2Qtr01     3Qtr01   4Qtr01   1Qtr02              2Qtr02   3Qtr02   4Qtr02   1Qtr03

  N             1101       1050     1102     1141                1116     1178     1190     966

                (%)        (%)      (%)      (%)                 (%)      (%)      (%)      (%)

  Any test      80         77       81       85                  92       92       92       91

  No Test       19         21       18       15                  8        8        8        8

  Unknown       1          1        1        \<1                 \<1      \<1      \<1      1
  --------------------------------------------------------------------------------------------------

As in the analysis supplied by the sponsor, some 8% of enrollees in the
Slone Survey report no pregnancy testing prior to initiating therapy
with isotretionoin following April 1, 2002. These data also suggest that
there has been some improvement in the rate of pregnancy testing prior
to initiating therapy with isotretinoin, from 77%-85% to 92%. However,
the improvement is not as great when the comparison is to the recent
past and appears to have stabilized / plateaued shortly after
requirements per new labeling (April 2002).

In DDRE analyses of the Degge/SI cohort (N=5469), there were 5334 women
who started treatment with Accutane. All analyses of pregnancy testing
or birth control further exclude 249 women who reported a reproductive
status of menopause or who had undergone hysterectomy and another
341women of age \>=45 years or age \<15 years. Of the remaining 4744
women, the number of available patients for any specific analysis is
further decreased by exclusion of records with missing information. Of
4719 apparently fertile women aged 15 to 45 years who provided
information on sexual activity, 1846 (39.1%) reported no sexual
intercourse during or before treatment, 1855 (39.3%) women reported
sexual activity before and during Accutane treatment, and 1018 (21.6%)
women reported sexual intercourse before starting Accutane treatment but
not during treatment.

DDRE analyses of pregnancy testing are outlined in Table 6. Of 4596
apparently fertile women aged 15 to 45 years who provided information on
pregnancy testing, 1806 (90.8%) reported pregnancy testing prior to
initiating treatment with Accutane. This is generally unaffected upon
stratification by sexual activity status. Any pregnancy testing was
reported by 92.1% among women reporting sexual activity before and
during Accutane treatment, 92.7% among women reporting sexual
intercourse before starting Accutane treatment but not during treatment,
and 88.5% among women reporting no sexual intercourse before or during
Accutane treatment.

  ------------------------------------------------------------------------
  **Table 6. Patient report of                                
  pregnancy testing, all and                                  
  stratified by sexual activity                               
  status, for apparently fertile                              
  women 15-45 years of age who                                
  provided data on pregnancy                                  
  testing.**                                                  
  ----------------------------------- --------- ------------- ------------
                                      N         At least one  Two or more
                                                pregnancy     pregnancy
                                                test          tests

  Total\*                             4596      90.8%         66.0%

  Sexually active since starting      1806      92.1%         68.3%
  Accutane therapy                                            

  Sexually active before but not      993       92.7%         66.8%
  during Accutane therapy                                     

  Not sexually active before or       1797      88.5%         63.0%
  during Accutane therapy                                     

  \*Excludes women who report: (1)                            
  age younger than 15 years old or                            
  older than 45 years, (2) women who                          
  report they have undergone                                  
  hysterectomy or menopause, (3)                              
  women who have not started Accutane                         
  treatment, and (4) records with                             
  missing values.                                             
  ------------------------------------------------------------------------

**2.1.6.2 Two pregnancy tests:** According to the Accutane label, women
should not get the first prescription for Accutane before assessment by
2 pregnancy tests. While this criterion is not new, the number of
pregnancy tests was not included as a question in the old Survey. The
number of pregnancy tests is now included as a question in the new
Survey. Per the sponsor's analysis, 63% of apparently fertile
participants report two pregnancy tests prior to starting Accutane (data
not shown).

Among the subset of 1806 apparently fertile women 15-45 years of age
women who reported sexual activity since starting Accutane therapy,
68.3% reported two pregnancy tests in the month prior to starting their
treatment (Table 6, shaded area).

**2.1.6.3 Pregnancy testing in relation to menses**: According to new
labeling for isotretinoin, the first test must be done when the
prescriber decides to prescribe Accutane, and the second pregnancy test
must be done during the first 5 days of the menstrual period preceding
initiation of Accutane therapy, assuming the woman menstruates.
Compliance with testing around menses is generally poor at 27% (data not
shown), suggesting that clinicians cannot adopt visit / treatment cycles
in sequence with recommendations for testing in relation to menses.

To address whether the test was taken at appropriate time per approved
labeling, the number of days between start of menses and start of
Accutane treatment was examined on the subset of women who received
pregnancy testing between these two events (Table 7).

+---------------------+------+-----+------+--------+--------+-------+
| **Table 7.          |      |     |      |        |        |       |
| Distribution of     |      |     |      |        |        |       |
| days between        |      |     |      |        |        |       |
| starting menses and |      |     |      |        |        |       |
| starting Accutane   |      |     |      |        |        |       |
| treatment for       |      |     |      |        |        |       |
| apparently fertile  |      |     |      |        |        |       |
| women aged 15-45    |      |     |      |        |        |       |
| years who had a     |      |     |      |        |        |       |
| pregnancy test      |      |     |      |        |        |       |
| sometime between    |      |     |      |        |        |       |
| these two events.** |      |     |      |        |        |       |
+=====================+======+=====+======+========+========+=======+
|                     | N    | 0-5 | 6-10 | 11-20  | 21-30  | \>30  |
|                     |      | da  | days | days   | days   | days  |
|                     |      | ys\ |      |        |        |       |
|                     |      | *\* |      |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+
| Total\*             | 1851 | 27  | 2    | 26.0%  | 15.6%  | 7.2%  |
|                     |      | .1% | 3.9% |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+
| Sexually active     | 767  | 28  | 2    | 24.6%  | 16.3%  | 7.2%  |
| before and during   |      | .1% | 3.7% |        |        |       |
| Accutane treatment  |      |     |      |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+
| Sexually active     | 429  | 26  | 2    | 25.9%  | 15.9%  | 7.0%  |
| before Accutane but |      | .8% | 4.5% |        |        |       |
| not during          |      |     |      |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+
| Not sexually active | 655  | 26  | 2    | 27.8%  | 14.7%  | 7.5%  |
| before or during    |      | .3% | 3.8% |        |        |       |
| treatment           |      |     |      |        |        |       |
| w/Accutane          |      |     |      |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+
| \*Excludes women    |      |     |      |        |        |       |
| who report: (1) age |      |     |      |        |        |       |
| younger than 15     |      |     |      |        |        |       |
| years old or older  |      |     |      |        |        |       |
| than 45 years, (2)  |      |     |      |        |        |       |
| women who report    |      |     |      |        |        |       |
| they have undergone |      |     |      |        |        |       |
| hysterectomy or     |      |     |      |        |        |       |
| menopause, and (3)  |      |     |      |        |        |       |
| and women who have  |      |     |      |        |        |       |
| not started         |      |     |      |        |        |       |
| Accutane treatment. |      |     |      |        |        |       |
| Furthermore, 1524   |      |     |      |        |        |       |
| women were not      |      |     |      |        |        |       |
| included in the     |      |     |      |        |        |       |
| analysis because of |      |     |      |        |        |       |
| missing values for  |      |     |      |        |        |       |
| pregnancy testing,  |      |     |      |        |        |       |
| date of starting    |      |     |      |        |        |       |
| Accutane treatment, |      |     |      |        |        |       |
| or date(s) of       |      |     |      |        |        |       |
| menses.             |      |     |      |        |        |       |
|                     |      |     |      |        |        |       |
| \*\* "correct" per  |      |     |      |        |        |       |
| labeling            |      |     |      |        |        |       |
+---------------------+------+-----+------+--------+--------+-------+

Based on DDRE analyses, 27.1% of apparently fertile women aged 15-45
years old on whom data were available received pregnancy testing during
the first 5 days of menses. As is further shown in Table 7, compliance
with pregnancy testing during menses (for menstruating participants)
appeared to be unaffected by sexual activity status. \[It is noteworthy
that the data for about 45% of apparently fertile women aged 15-45 is
unusable due to missing values for either pregnancy testing, dates of
menses, or isotretinoin therapy start date.\]

**2.1.7 [Sexual Activity / Birth Control]{.underline}**

**2.1.7.1 Sexual activity:** The isotretinoin label states that women
should use two separate forms of contraception for at least 1 month
before and during therapy, at least one of which should be a
"primaryError: Reference source not found" method. The sponsor
investigated the reproductive status and contraceptive practices for
women enrolled in the Degge/SI survey which suggest a large fraction of
women report they are not sexually active (50%).

**2.1.7.2 Birth Control:** Among the participants in the Degge/SI
survey, approximately 26% note they are sexually active and use 2 forms
of birth control, one of which is primary. An additional large fraction
of women (18%) report they are sexually active and do not use 2 forms of
birth control. The sponsor further stratified the data by age, where
non-compliance with use of "two forms" of contraception is shown to
generally increase in direct relation to age through age 40 to 44 years
where it peaks at 39%. Non-compliance appears to fall thereafter,
although there is only one remaining age band beyond age 40-44 years. It
should be noted that within the age band with the most members (20-29
years, n=1577)), non-compliance with 2 forms of birth control (one
primary) among sexually active enrollees is reported at 20%.

DDRE further compared trends in fertility/contraceptive status of
enrollees in the Slone survey in the four quarters before April 1, 2002
and the following four quarters (Table 8). These data are derived from
"Pregnancy Risk Category" as used in Slone Survey quarterly reports and
show status (per Slone categorization) at initiation of Accutane therapy
based on DAT-1 surveys.

  ----------------------------------------- ---------- -------- -------- -------- ---------- -------- -------- --------
  **Table 8. Fertility/contraceptive status                                                                    
  of enrollees at initiation of Accutane                                                                       
  therapy in the Slone survey in the four                                                                      
  quarters before SMART and the first four                                                                     
  quarters of SMART.**                                                                                         

  era                                       Last four                             First four                   
                                            quarters                              quarters                     
                                            before                                of SMART                     
                                            SMART                                                              

  Qtr                                       2Qtr01     3Qtr01   4Qtr01   1Qtr02   2Qtr02     3Qtr02   4Qtr02   1Qtr03

  N                                         1148       1103     1153     1177     1165       1233     1234     1024

                                            (%)        (%)      (%)      (%)      (%)        (%)      (%)      (%)

  Hysterectomy /Postmenopausal              4          5        4        3        4          4        4        3

  Not Sexually Active, Birth Control\*      28         29       28       33       32         34       35       38

  Not Sexually Active, No Birth Control     26         28       26       25       26         23       25       23

  Sexually Active, Birth Control            39         36       38       37       36         36       35       25

  Sexually active, No Birth Control         \<1        \<1      \<1      \<1      \<1        \<1      \<1      \<1

  Unknown                                   1          1        1        1        1          2        2        1

  \*Refers to at least one method of birth                                                                     
  control including either primary methods                                                                     
  (e.g., oral contraception, tubal                                                                             
  ligation,                                                                                                    
  injectable/implantable/insertable/patch                                                                      
  contraceptives, vasectomy, IUD) or                                                                           
  secondary methods (e.g., diaphragms,                                                                         
  latex condoms, cervical cap)                                                                                 
  ----------------------------------------- ---------- -------- -------- -------- ---------- -------- -------- --------

Each survey enrollee cohort contains a small group (up to 1%) classified
as "[sexually active, not on birth control]{.underline}." In aggregated
analyses of these Quarterly Reports, this 1% "rate" does not change over
the SMART era and thus appears unaffected by new labeling requirements.
It should be noted that this 1% "rate" is based on a denominator of ALL
Survey respondents. After restriction to a denominator of apparently
fertile, 14-45 yr-old sexually active participants, this rate becomes
\~3%.

Trends on contraceptive type (e.g. birth control pills) stratified by
age bands and are included in Appendix 4[^18]. Although the data for 15
--24 year old enrollees may suggest an increase in use of a "primary"
birth control method (51%-60%), variability precludes assessment of a
definitive trend since initiation of SMART. These data further appear to
indicate that the fraction of enrollees classified as "[Not sexually
active but on birth control]{.underline}" increased after initiation of
SMART (28% to 38%).

Of 4719 apparently fertile women aged 15 to 45 years who provided
information on sexual activity, 1846 (39.1%) reported no sexual
intercourse during or before treatment, 1855 (39.3%) women reported
sexual activity before and during Accutane treatment, and 1018 (21.6%)
women reported sexual intercourse before starting Accutane treatment but
not during treatment. In DDRE analyses of the Degge/SI cohort, 95.8% of
apparently fertile and sexually active 15-45 year-old participants
reported that they used some form of birth control early in the course
of treatment with Accutane (Table 9); 4.2% of such women reported no
form of birth control. This is consistent with the recalculated rate of
\~3% from Slone with restriction to sexually active women. In total,
46.4% of apparently fertile and sexually active women reported use of
"appropriate" birth control consisting of two methods, at least one of
which is a "primary" birth control method (e.g., oral contraception).

+---------------------+-----+---------+----------------+-------------+
| **Table 9.          |     |         |                |             |
| Distribution of     |     |         |                |             |
| birth control       |     |         |                |             |
| method used among   |     |         |                |             |
| apparently fertile  |     |         |                |             |
| women 15-45 years   |     |         |                |             |
| of age within the   |     |         |                |             |
| DAT-1.**            |     |         |                |             |
+---------------------+-----+---------+----------------+-------------+
|                     | #   | Any     | Any primary    | Appropriate |
|                     | ### | form of | method of      | per         |
|                     | ##  | birth   | birth control  | Accutane    |
|                     |     | control |                | label\*\*   |
+---------------------+-----+---------+----------------+-------------+
| Total               | 468 | 70.2%   | 56.8%          | 23.7%       |
|                     | 8\* |         |                |             |
+---------------------+-----+---------+----------------+-------------+
| Sexually active     | 1   | 95.8%   | 83.0%          | 46.4%       |
| since starting      | 841 |         |                |             |
| Accutane therapy    |     |         |                |             |
+---------------------+-----+---------+----------------+-------------+
| Sexually active     | 1   | 76.0%   | 57.7%          | 24.2%       |
| before but not      | 008 |         |                |             |
| during Accutane     |     |         |                |             |
| therapy             |     |         |                |             |
+---------------------+-----+---------+----------------+-------------+
| Not sexually active | 1   | 42.0%   | 30.0%          | 0.7%        |
| before or during    | 838 |         |                |             |
| Accutane therapy    |     |         |                |             |
+---------------------+-----+---------+----------------+-------------+
| \*Excludes women    |     |         |                |             |
| who report: (1) age |     |         |                |             |
| younger than 15     |     |         |                |             |
| years old or older  |     |         |                |             |
| than 45 years, (2)  |     |         |                |             |
| women who report    |     |         |                |             |
| they have undergone |     |         |                |             |
| hysterectomy or     |     |         |                |             |
| menopause, (3)      |     |         |                |             |
| women who have not  |     |         |                |             |
| started Accutane    |     |         |                |             |
| treatment, and (4)  |     |         |                |             |
| records with        |     |         |                |             |
| missing information |     |         |                |             |
| on birth control.   |     |         |                |             |
|                     |     |         |                |             |
| \*\*Appropriate per |     |         |                |             |
| Accutane label      |     |         |                |             |
| requires two forms  |     |         |                |             |
| of which one must   |     |         |                |             |
| be a "primary"      |     |         |                |             |
| method (e.g., oral  |     |         |                |             |
| contraception,      |     |         |                |             |
| tubal ligation,     |     |         |                |             |
| i                   |     |         |                |             |
| njectable/implantab |     |         |                |             |
| le/insertable/patch |     |         |                |             |
| contraceptives,     |     |         |                |             |
| vasectomy, IUD). As |     |         |                |             |
| per the Accutane    |     |         |                |             |
| label, women who    |     |         |                |             |
| claim absolute      |     |         |                |             |
| abstinence may      |     |         |                |             |
| elect not to use    |     |         |                |             |
| birth control.      |     |         |                |             |
| Thus, the latter    |     |         |                |             |
| two rows of the     |     |         |                |             |
| table may include   |     |         |                |             |
| women who chose     |     |         |                |             |
| absolute abstinence |     |         |                |             |
| and this may result |     |         |                |             |
| in lowering for     |     |         |                |             |
| percent             |     |         |                |             |
| appropriate. There  |     |         |                |             |
| is no question in   |     |         |                |             |
| the patient survey  |     |         |                |             |
| for abstinence:     |     |         |                |             |
| sexual activity     |     |         |                |             |
| used as a           |     |         |                |             |
| surrogate.          |     |         |                |             |
+---------------------+-----+---------+----------------+-------------+

::: Definition-Term
Further analyses (data not shown) were conducted to examine changes in
pregnancy testing or birth control over time among apparently fertile
and sexually active women aged 15-45. Between 4QTR2002 and 1QTR2003, we
observed a 3% absolute increase in reporting of two pregnancy tests and
a 4% absolute increase in reporting of using birth control prior to
starting Accutane. Furthermore, the use of a "primary" method of birth
control increased 2% and "appropriate" use of birth control declined by
2%.
:::

::: Definition-Term
**2.2 DAT-1 Bivariate Analyses**
:::

::: Definition-Term
The sponsor does not include bivariate analyses as outlined in the
following section. Thus, this section includes only DDRE analyses. Data
(as tables) are included in this section. The overall effect of the
sticker at initiation of therapy (thus through the DAT1 instrument) is
shown in DDRE analyses of sticker and pre-therapy pregnancy test (Tables
10 through 13) and sticker and birth control (Tables 14 & 15). Due to
the potential bias of imputation of missing data, these tables are shown
initially with exclusion of missing records, and then with imputation of
missing data as a negative result \["missing = NO"\].
:::

**2.2.1 [Relationship between Qualification Sticker and Pregnancy
Testing]{.underline}**

::: Definition-Term
The overall effect of the sticker at initiation of therapy is shown in
DDRE analyses of sticker and pre-therapy pregnancy test in Table 10. As
shown, the sticker does not appear to relate to performance of the
pregnancy test, as pregnancy testing was very high both in the presence
of a sticker (91%) and in the absence of a sticker (90%) for all
apparently fertile women 15 to 45 year old enrollees. Nine (9) percent
of Survey participants who report a Qualification sticker report no
pregnancy test.
:::

+---------------+-----------------+-----------------+-----------------+
| **Table 10.   |                 |                 |                 |
| Relationship  |                 |                 |                 |
| between       |                 |                 |                 |
| Qualification |                 |                 |                 |
| sticker and   |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing for   |                 |                 |                 |
| all,          |                 |                 |                 |
| apparently    |                 |                 |                 |
| fertile\*,    |                 |                 |                 |
| 15-45         |                 |                 |                 |
| year-old      |                 |                 |                 |
| enrollees.    |                 |                 |                 |
| \[Missing     |                 |                 |                 |
| =excluded\]** |                 |                 |                 |
+===============+=================+=================+=================+
|               | Qualification   | Qualification   | Row total       |
|               | sticker         | sticker         |                 |
|               |                 |                 |                 |
|               | **Yes**         | **No**          |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 3908            | 90              | 3998            |
| test          |                 |                 |                 |
|               | (91%)           | (90%)           |                 |
| **Yes**       |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 392             | 10              | 402             |
| test          |                 |                 |                 |
|               | (9%)            | (10%)           |                 |
| **No**        |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | 4300            | 100             | 4400\*\*        |
+---------------+-----------------+-----------------+-----------------+
| \*excludes    |                 |                 |                 |
| women         |                 |                 |                 |
| reporting     |                 |                 |                 |
| hysterectomy  |                 |                 |                 |
| or            |                 |                 |                 |
| p             |                 |                 |                 |
| ostmenopausal |                 |                 |                 |
|               |                 |                 |                 |
| \*\*excludes  |                 |                 |                 |
| 319 records   |                 |                 |                 |
| with missing  |                 |                 |                 |
| data for      |                 |                 |                 |
| either        |                 |                 |                 |
| qualification |                 |                 |                 |
| sticker or    |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| test;         |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| includes any  |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| performed at  |                 |                 |                 |
| physician'    |                 |                 |                 |
| office or     |                 |                 |                 |
| performed at  |                 |                 |                 |
| home but      |                 |                 |                 |
| reported to   |                 |                 |                 |
| the           |                 |                 |                 |
| physician;    |                 |                 |                 |
| restricted to |                 |                 |                 |
| women who     |                 |                 |                 |
| reported      |                 |                 |                 |
| starting      |                 |                 |                 |
| Accutane      |                 |                 |                 |
| therapy.      |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+

::: Definition-Term
As shown in the following table (Table 11), imputation of "NO" for
missing data does not appear to change our assessment. Although
compliance with pregnancy testing falls slightly, it does so
:::

::: Definition-Term
both in the presence of a sticker (89%) and in the absence of a sticker
(85%) for all apparently fertile women 15 to 45 years old.
:::

+---------------+-----------------+-----------------+-----------------+
| **Table 11.   |                 |                 |                 |
| Relationship  |                 |                 |                 |
| between       |                 |                 |                 |
| Qualification |                 |                 |                 |
| sticker and   |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing for   |                 |                 |                 |
| all,          |                 |                 |                 |
| apparently    |                 |                 |                 |
| fertile\*,    |                 |                 |                 |
| 15-45         |                 |                 |                 |
| year-old      |                 |                 |                 |
| enrollees.    |                 |                 |                 |
| \[M           |                 |                 |                 |
| issing=NO\]** |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | Qualification   | Qualification   | Row Total       |
|               | sticker         | sticker         |                 |
|               |                 |                 |                 |
|               | **Yes**         | **No**          |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 3908            | 268             | 4176            |
| test          |                 |                 |                 |
|               | (89%)           | (85%)           |                 |
| **Yes**       |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 495             | 48              | 543             |
| test          |                 |                 |                 |
|               | (11%)           | (15%)           |                 |
| **No**        |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | 4403            | 316             | 4719\*\*        |
+---------------+-----------------+-----------------+-----------------+
| \*excludes    |                 |                 |                 |
| women         |                 |                 |                 |
| reporting     |                 |                 |                 |
| hysterectomy  |                 |                 |                 |
| or            |                 |                 |                 |
| p             |                 |                 |                 |
| ostmenopausal |                 |                 |                 |
|               |                 |                 |                 |
| \*\*pregnancy |                 |                 |                 |
| testing       |                 |                 |                 |
| includes any  |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| performed at  |                 |                 |                 |
| physician's   |                 |                 |                 |
| office or     |                 |                 |                 |
| performed at  |                 |                 |                 |
| home but      |                 |                 |                 |
| reported to   |                 |                 |                 |
| the           |                 |                 |                 |
| physician;    |                 |                 |                 |
| restricted to |                 |                 |                 |
| women who     |                 |                 |                 |
| reported      |                 |                 |                 |
| starting      |                 |                 |                 |
| Accutane      |                 |                 |                 |
| therapy.      |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+

No effect of the Qualification sticker is seen after restriction to
[sexually active]{.underline}, apparently fertile women 15 to 45 year
old enrollees, where the delta between groups is 1% (Table 12).

+---------------+-----------------+-----------------+-----------------+
| **Table 12.   |                 |                 |                 |
| Relationship  |                 |                 |                 |
| between       |                 |                 |                 |
| Qualification |                 |                 |                 |
| sticker and   |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing for   |                 |                 |                 |
| Sexually      |                 |                 |                 |
| active,       |                 |                 |                 |
| apparently    |                 |                 |                 |
| fertile\*,    |                 |                 |                 |
| 15-45         |                 |                 |                 |
| year-old      |                 |                 |                 |
| enrollees.    |                 |                 |                 |
| \[Missing     |                 |                 |                 |
| =excluded\]** |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | Qualification   | Qualification   | Row Total       |
|               | sticker         | sticker         |                 |
|               |                 |                 |                 |
|               | **Yes**         | **No**          |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 1575            | 41              | 1616            |
| test          |                 |                 |                 |
|               | (92%)           | (91%)           |                 |
| **Yes**       |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 136             | 4               | 140             |
| test          |                 |                 |                 |
|               | (8%)            | (9%)            |                 |
| **No**        |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | 1711            | 45              | 1756\*\*        |
+---------------+-----------------+-----------------+-----------------+
| \*excludes    |                 |                 |                 |
| women         |                 |                 |                 |
| reporting     |                 |                 |                 |
| hysterectomy  |                 |                 |                 |
| or            |                 |                 |                 |
| p             |                 |                 |                 |
| ostmenopausal |                 |                 |                 |
|               |                 |                 |                 |
| \*\*excludes  |                 |                 |                 |
| 90 records    |                 |                 |                 |
| with missing  |                 |                 |                 |
| data for      |                 |                 |                 |
| either        |                 |                 |                 |
| qualification |                 |                 |                 |
| sticker or    |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| test;         |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| includes any  |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| performed at  |                 |                 |                 |
| physician'    |                 |                 |                 |
| office or     |                 |                 |                 |
| performed at  |                 |                 |                 |
| home but      |                 |                 |                 |
| reported to   |                 |                 |                 |
| the           |                 |                 |                 |
| physician;    |                 |                 |                 |
| restricted to |                 |                 |                 |
| women who     |                 |                 |                 |
| reported      |                 |                 |                 |
| starting      |                 |                 |                 |
| Accutane      |                 |                 |                 |
| therapy.      |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+

::: Definition-Term
As was seen above, little change is noted with imputation of NO for
missing responses (Table 13, below). Since the vast majority of these
enrollees noted the presence of the qualification sticker, inference
about the "effect" of the sticker is limited.
:::

+---------------+-----------------+-----------------+-----------------+
| **Table 13.   |                 |                 |                 |
| Relationship  |                 |                 |                 |
| between       |                 |                 |                 |
| qualification |                 |                 |                 |
| sticker and   |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing for   |                 |                 |                 |
| Sexually      |                 |                 |                 |
| active,       |                 |                 |                 |
| apparently    |                 |                 |                 |
| fertile\*,    |                 |                 |                 |
| 15-45         |                 |                 |                 |
| year-old      |                 |                 |                 |
| enrollees.    |                 |                 |                 |
| \[M           |                 |                 |                 |
| issing=NO\]** |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | Qualification   | Qualification   | Row Total       |
|               | sticker         | sticker         |                 |
|               |                 |                 |                 |
|               | **Yes**         | **No**          |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 1575            | 90              | 1665            |
| test          |                 |                 |                 |
|               | (90%)           | (87%)           |                 |
| **Yes**       |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
| Pregnancy     | 168             | 13              | 181             |
| test          |                 |                 |                 |
|               | (10%)           | (13%)           |                 |
| **No**        |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+
|               | 1743            | 103             | 1846\*\*        |
+---------------+-----------------+-----------------+-----------------+
| \*excludes    |                 |                 |                 |
| women         |                 |                 |                 |
| reporting     |                 |                 |                 |
| hysterectomy  |                 |                 |                 |
| or            |                 |                 |                 |
| p             |                 |                 |                 |
| ostmenopausal |                 |                 |                 |
|               |                 |                 |                 |
| \*\*pregnancy |                 |                 |                 |
| testing       |                 |                 |                 |
| includes any  |                 |                 |                 |
| pregnancy     |                 |                 |                 |
| testing       |                 |                 |                 |
| performed at  |                 |                 |                 |
| physician'    |                 |                 |                 |
| office or     |                 |                 |                 |
| performed at  |                 |                 |                 |
| home but      |                 |                 |                 |
| reported to   |                 |                 |                 |
| the           |                 |                 |                 |
| physician;    |                 |                 |                 |
| restricted to |                 |                 |                 |
| women who     |                 |                 |                 |
| reported      |                 |                 |                 |
| starting      |                 |                 |                 |
| Accutane      |                 |                 |                 |
| therapy.      |                 |                 |                 |
+---------------+-----------------+-----------------+-----------------+

**2.2.2 [Relationship between Qualification Sticker and ANY Birth
Control]{.underline}**

::: Definition-Term
Per the new isotretinoin label, the Qualification sticker is intended to
document that the patient has received education and counseling on
pregnancy prevention. DDRE conducted analyses of Qualification sticker
and birth control (as ANY birth control) among sexually active Survey
participants (Tables 14 and 15) in order to study the potential impact
of the Qualification sticker. As above, the first table (Table 14)
excludes records with missing data while the second table (Table 15) is
based on imputation of NO for missing data. As was seen above for
pregnancy testing, there does not appear to be a strong relationship of
the Qualification sticker to compliance with birth control as birth
control was noted in 97% of enrollees with a sticker and 96% of
enrollees without a sticker (Table 14). Three (3) percent of sexually
active Survey participants who report a Qualification sticker further
report no use of ANY birth control.
:::

+-----------------+--------------------+-----------------+------------+
| **Table 14.     |                    |                 |            |
| Relationship    |                    |                 |            |
| between         |                    |                 |            |
| qualification   |                    |                 |            |
| sticker and ANY |                    |                 |            |
| birth control   |                    |                 |            |
| for Sexually    |                    |                 |            |
| active,         |                    |                 |            |
| apparently      |                    |                 |            |
| fertile\*,      |                    |                 |            |
| 15-45 year-old  |                    |                 |            |
| enrollees.      |                    |                 |            |
| \[Missi         |                    |                 |            |
| ng=excluded\]** |                    |                 |            |
+-----------------+--------------------+-----------------+------------+
|                 | Qualification      | Qualification   | Row total  |
|                 | sticker            | sticker         |            |
|                 |                    |                 |            |
|                 | **Yes**            | **No**          |            |
+-----------------+--------------------+-----------------+------------+
| Any birth       | 1671               | 70              | 1741       |
| control         |                    |                 |            |
|                 | (97%)              | (96%)           |            |
| **Yes**         |                    |                 |            |
+-----------------+--------------------+-----------------+------------+
| Any birth       | 44                 | 3               | 47         |
| control         |                    |                 |            |
|                 | (3%)               | (4%)            |            |
| **No**          |                    |                 |            |
+-----------------+--------------------+-----------------+------------+
|                 | 1715               | 73              | 1788\*\*   |
+-----------------+--------------------+-----------------+------------+
| \*excludes      |                    |                 |            |
| women reporting |                    |                 |            |
| hysterectomy or |                    |                 |            |
| postmenopausal  |                    |                 |            |
|                 |                    |                 |            |
| \*\*excludes 54 |                    |                 |            |
| records with    |                    |                 |            |
| missing data    |                    |                 |            |
| for             |                    |                 |            |
| qualification   |                    |                 |            |
| sticker; birth  |                    |                 |            |
| control is      |                    |                 |            |
| defined as      |                    |                 |            |
| those who       |                    |                 |            |
| report          |                    |                 |            |
| currently use   |                    |                 |            |
| of ANY birth    |                    |                 |            |
| control method  |                    |                 |            |
| as well as any  |                    |                 |            |
| report of tubal |                    |                 |            |
| ligation or     |                    |                 |            |
| vasectomy in    |                    |                 |            |
| partner. ANY    |                    |                 |            |
| birth control   |                    |                 |            |
| use as shown in |                    |                 |            |
| this analysis   |                    |                 |            |
| is probably an  |                    |                 |            |
| overestimate as |                    |                 |            |
| women who       |                    |                 |            |
| reported        |                    |                 |            |
| ***vasectomy*** |                    |                 |            |
| in their        |                    |                 |            |
| partner were    |                    |                 |            |
| included as ANY |                    |                 |            |
| birth control   |                    |                 |            |
| regardless of   |                    |                 |            |
| whether they    |                    |                 |            |
| indicated       |                    |                 |            |
| another option  |                    |                 |            |
| as required per |                    |                 |            |
| approved        |                    |                 |            |
| labeling. This  |                    |                 |            |
| analysis        |                    |                 |            |
| approach was    |                    |                 |            |
| necessary       |                    |                 |            |
| because of the  |                    |                 |            |
| poor structure  |                    |                 |            |
| of the          |                    |                 |            |
| questionnaire   |                    |                 |            |
| with regard to  |                    |                 |            |
| birth control   |                    |                 |            |
| using tubal     |                    |                 |            |
| ligation and    |                    |                 |            |
| vasectomy       |                    |                 |            |
| leading to      |                    |                 |            |
| potential for   |                    |                 |            |
| confusion. In   |                    |                 |            |
| addition,       |                    |                 |            |
| vasectomy may   |                    |                 |            |
| not pertain to  |                    |                 |            |
| all potential   |                    |                 |            |
| partners;       |                    |                 |            |
| restricted to   |                    |                 |            |
| women who       |                    |                 |            |
| reported        |                    |                 |            |
| starting        |                    |                 |            |
| Accutane        |                    |                 |            |
| therapy.        |                    |                 |            |
+-----------------+--------------------+-----------------+------------+

::: Definition-Term
With imputation of a "NO" for missing information, compliance with any
birth control fell slightly for both arms, to 95% among those reporting
a Qualification sticker and 92% for those indicating no Qualification
sticker (Table 15), but was otherwise high in both arms.
:::

+---------------+-----------------+-----------------+----------------+
| **Table 15.   |                 |                 |                |
| Relationship  |                 |                 |                |
| between       |                 |                 |                |
| qualification |                 |                 |                |
| sticker and   |                 |                 |                |
| ANY birth     |                 |                 |                |
| control for   |                 |                 |                |
| sexually      |                 |                 |                |
| active,       |                 |                 |                |
| apparently    |                 |                 |                |
| fertile\*,    |                 |                 |                |
| 15-45         |                 |                 |                |
| year-old      |                 |                 |                |
| enrollees.    |                 |                 |                |
| \[M           |                 |                 |                |
| issing=NO\]** |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | Qualification   | Qualification   | Row Total      |
|               | sticker         | sticker         |                |
|               |                 |                 |                |
|               | **Yes**         | **No**          |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 1671            | 70              | 1741           |
| control       |                 |                 |                |
|               | (95%)           | (92%)           |                |
| **Yes**       |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 95              | 6               | 101            |
| control       |                 |                 |                |
|               | (5%)            | (8%)            |                |
| **No**        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | 1766            | 76              | 1842\*\*       |
+---------------+-----------------+-----------------+----------------+
| \*excludes    |                 |                 |                |
| women         |                 |                 |                |
| reporting     |                 |                 |                |
| hysterectomy  |                 |                 |                |
| or            |                 |                 |                |
| p             |                 |                 |                |
| ostmenopausal |                 |                 |                |
|               |                 |                 |                |
| \*\*Birth     |                 |                 |                |
| control is    |                 |                 |                |
| defined as    |                 |                 |                |
| those who     |                 |                 |                |
| report        |                 |                 |                |
| currently use |                 |                 |                |
| of ANY birth  |                 |                 |                |
| control       |                 |                 |                |
| method as     |                 |                 |                |
| well as any   |                 |                 |                |
| report of     |                 |                 |                |
| tubal         |                 |                 |                |
| ligation or   |                 |                 |                |
| vasectomy in  |                 |                 |                |
| partner. ANY  |                 |                 |                |
| birth control |                 |                 |                |
| use as shown  |                 |                 |                |
| in this       |                 |                 |                |
| analysis is   |                 |                 |                |
| probably an   |                 |                 |                |
| overestimate  |                 |                 |                |
| as women who  |                 |                 |                |
| reported      |                 |                 |                |
| **            |                 |                 |                |
| *vasectomy*** |                 |                 |                |
| in their      |                 |                 |                |
| partner were  |                 |                 |                |
| included as   |                 |                 |                |
| ANY birth     |                 |                 |                |
| control       |                 |                 |                |
| regardless of |                 |                 |                |
| whether they  |                 |                 |                |
| indicated     |                 |                 |                |
| another       |                 |                 |                |
| option as     |                 |                 |                |
| required per  |                 |                 |                |
| approved      |                 |                 |                |
| labeling.     |                 |                 |                |
| This analysis |                 |                 |                |
| approach was  |                 |                 |                |
| necessary     |                 |                 |                |
| because of    |                 |                 |                |
| the poor      |                 |                 |                |
| structure of  |                 |                 |                |
| the           |                 |                 |                |
| questionnaire |                 |                 |                |
| with regard   |                 |                 |                |
| to birth      |                 |                 |                |
| control using |                 |                 |                |
| tubal         |                 |                 |                |
| ligation and  |                 |                 |                |
| vasectomy     |                 |                 |                |
| leading to    |                 |                 |                |
| potential for |                 |                 |                |
| confusion. In |                 |                 |                |
| addition,     |                 |                 |                |
| vasectomy may |                 |                 |                |
| not pertain   |                 |                 |                |
| to all        |                 |                 |                |
| potential     |                 |                 |                |
| partners;     |                 |                 |                |
| restricted to |                 |                 |                |
| women who     |                 |                 |                |
| reported      |                 |                 |                |
| starting      |                 |                 |                |
| Accutane      |                 |                 |                |
| therapy.      |                 |                 |                |
+---------------+-----------------+-----------------+----------------+

## 3. DAT-2 SURVEY (DURING TREATMENT)

NOTE: The sponsor's submission ("1 Year Report on the SMART Program")
was conducted before accrual of enough DAT-2 questionnaires to be
informative. Thus, the following section describing DDRE analyses of
DAT-2 data from the SI/Degge cohort does not have a direct corollary
within the "1 Year Report on the SMART Program." These data permit
inference on SMART attributes/compliance during the middle and later
windows of Accutane therapy. It should be anticipated that the sponsor
will also conduct similar analyses to present at the Advisory Committee.

A dataset sent to FDA in October 10, 2003 included 3569 women who
enrolled in the Degge/SI Accutane Survey from November, 2002 through
March 31, 2003 and who returned a DAT-2 questionnaire. One hundred
twenty-two (122) of these women apparently never completed a DAT-1
questionnaire and have only a DAT-2. About 47% (N= 1670) of these women
reported that they were still taking Accutane. Thirty-five (35) percent
(N=1246) reported that they completed treatment. The status of remaining
18% (N=652) could not be determined.

**3.1 DAT-2 Univariate Analyses**

**3.1.1 [Qualification Sticker]{.underline}**

As in the DAT1 questionnaire, DAT-2 participants are asked about the
presence of a qualification sticker on prescriptions. Monthly
prescriptions are required for Accutane therapy lasting over 30 days
since no refills are permitted under the SMART program. As shown in
Table 16, 94.7% of DAT-2 respondents who continued on therapy with
Accutane indicated the presence of a qualification sticker on their
prescriptions.

  -------------------------------------------------- --------------------
  **Table 16. Percent distribution of Qualification  
  sticker from DAT2 for participants who continued   
  on therapy with Accutane.**                        

  Total number of sample                             1670

  Yes                                                94.7%

  I saw the prescription but not I did not see a     0.8%
  Qualification sticker                              

  Other\*                                            4.5%

  \*Other includes missing values, someone else      
  filled the prescription, participant did not see   
  the prescription.                                  
  -------------------------------------------------- --------------------

::: Definition-Term
**3.1.2 [Pregnancy Testing]{.underline}**
:::

**3.1.2.1 Per Slone Survey:** Pregnancy testing during Accutane therapy
based on DAT-2 surveys for the interval April 1, 2001 through March 30,
2003 is show in Table 17. As with compliance with pregnancy testing at
initiation of therapy, the proportion of women reporting any testing
appears to increase in close association with the SMART program, from
\~70% to \~85%. As seen before, the increase appears to plateau soon
after initiation of the SMART program and remain at \~85%.

+---------+------+------+------+------+------+------+------+-------+
| **Table |      |      |      |      |      |      |      |       |
| 17.     |      |      |      |      |      |      |      |       |
| Trends  |      |      |      |      |      |      |      |       |
| in      |      |      |      |      |      |      |      |       |
| pr      |      |      |      |      |      |      |      |       |
| egnancy |      |      |      |      |      |      |      |       |
| testing |      |      |      |      |      |      |      |       |
| during  |      |      |      |      |      |      |      |       |
| A       |      |      |      |      |      |      |      |       |
| ccutane |      |      |      |      |      |      |      |       |
| therapy |      |      |      |      |      |      |      |       |
| based   |      |      |      |      |      |      |      |       |
| on      |      |      |      |      |      |      |      |       |
| DAT-2   |      |      |      |      |      |      |      |       |
| surveys |      |      |      |      |      |      |      |       |
| (based  |      |      |      |      |      |      |      |       |
| on      |      |      |      |      |      |      |      |       |
| quarter |      |      |      |      |      |      |      |       |
| of      |      |      |      |      |      |      |      |       |
| enro    |      |      |      |      |      |      |      |       |
| llment, |      |      |      |      |      |      |      |       |
| based   |      |      |      |      |      |      |      |       |
| on      |      |      |      |      |      |      |      |       |
| Slone   |      |      |      |      |      |      |      |       |
| Survey  |      |      |      |      |      |      |      |       |
| Qu      |      |      |      |      |      |      |      |       |
| arterly |      |      |      |      |      |      |      |       |
| Rep     |      |      |      |      |      |      |      |       |
| orts)** |      |      |      |      |      |      |      |       |
+=========+======+======+======+======+======+======+======+=======+
| era     | Last |      |      |      | F    |      |      |       |
|         | four |      |      |      | irst |      |      |       |
|         | quar |      |      |      | four |      |      |       |
|         | ters |      |      |      | quar |      |      |       |
|         | be   |      |      |      | ters |      |      |       |
|         | fore |      |      |      | of   |      |      |       |
|         | S    |      |      |      | S    |      |      |       |
|         | MART |      |      |      | MART |      |      |       |
+---------+------+------+------+------+------+------+------+-------+
| Qtr     | 2Q   | 3Q   | 4Q   | 1Q   | 2Q   | 3Q   | 4Q   | 1Qt   |
|         | tr01 | tr01 | tr01 | tr02 | tr02 | tr02 | tr02 | r03\* |
+---------+------+------+------+------+------+------+------+-------+
| N       | 1281 | 1352 | 1212 | 1324 | 1308 | 1419 | 1224 | 1206  |
+---------+------+------+------+------+------+------+------+-------+
|         | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)   |
+---------+------+------+------+------+------+------+------+-------+
| Any     | 66   | 66   | 71   | 81   | 87   | 86   | 85   | 87    |
| t       |      |      |      |      |      |      |      |       |
| est\*\* |      |      |      |      |      |      |      |       |
+---------+------+------+------+------+------+------+------+-------+
| No Test | 33   | 33   | 29   | 18   | 12   | 14   | 14   | 12    |
+---------+------+------+------+------+------+------+------+-------+
| UK      | 1    | 1    | \<1  | 1    | \<1  | \<1  | 1    | 1     |
+---------+------+------+------+------+------+------+------+-------+
| \*Based |      |      |      |      |      |      |      |       |
| on      |      |      |      |      |      |      |      |       |
| receipt |      |      |      |      |      |      |      |       |
| of      |      |      |      |      |      |      |      |       |
| 10-week |      |      |      |      |      |      |      |       |
| DAT-2:  |      |      |      |      |      |      |      |       |
| these   |      |      |      |      |      |      |      |       |
| counts  |      |      |      |      |      |      |      |       |
| reflect |      |      |      |      |      |      |      |       |
| only    |      |      |      |      |      |      |      |       |
| the     |      |      |      |      |      |      |      |       |
| f       |      |      |      |      |      |      |      |       |
| raction |      |      |      |      |      |      |      |       |
| of      |      |      |      |      |      |      |      |       |
| women   |      |      |      |      |      |      |      |       |
| e       |      |      |      |      |      |      |      |       |
| nrolled |      |      |      |      |      |      |      |       |
| in      |      |      |      |      |      |      |      |       |
| 1Qtr03  |      |      |      |      |      |      |      |       |
| that    |      |      |      |      |      |      |      |       |
| a       |      |      |      |      |      |      |      |       |
| nswered |      |      |      |      |      |      |      |       |
| DAT-2   |      |      |      |      |      |      |      |       |
| through |      |      |      |      |      |      |      |       |
| June    |      |      |      |      |      |      |      |       |
| 30,     |      |      |      |      |      |      |      |       |
| 2003.   |      |      |      |      |      |      |      |       |
|         |      |      |      |      |      |      |      |       |
| \*      |      |      |      |      |      |      |      |       |
| \*Serum |      |      |      |      |      |      |      |       |
| or      |      |      |      |      |      |      |      |       |
| urine   |      |      |      |      |      |      |      |       |
| pr      |      |      |      |      |      |      |      |       |
| egnancy |      |      |      |      |      |      |      |       |
| test    |      |      |      |      |      |      |      |       |
+---------+------+------+------+------+------+------+------+-------+

**3.1.2.2 Per DDRE analyses**: In DDRE analyses of the Degge/SI DAT-2
responder cohort for number of pregnancy tests taken during the past two
months among apparently fertile women aged 15 to 44 years women still on
treatment, 81% of those reporting sexual activity reported apparently
monthly pregnancy testing (Table 18).

+-----------------+-------------------------+-------------------------+
| **Table 18.     |                         |                         |
| Compliance with |                         |                         |
| pregnancy       |                         |                         |
| testing during  |                         |                         |
| Accutane        |                         |                         |
| therapy among   |                         |                         |
| apparently      |                         |                         |
| fertile\*       |                         |                         |
| Survey          |                         |                         |
| participants by |                         |                         |
| sexual activity |                         |                         |
| status.**       |                         |                         |
+-----------------+-------------------------+-------------------------+
|                 | Sexually active         | Not sexually active     |
|                 |                         |                         |
|                 | (N=622)                 | (N=832)                 |
+-----------------+-------------------------+-------------------------+
| Missing         | 3.2%                    | 3.7%                    |
+-----------------+-------------------------+-------------------------+
| Mentioned "0"   | 10.9%                   | 13.5%                   |
| test            |                         |                         |
+-----------------+-------------------------+-------------------------+
| One test        | 4.8%                    | 7.3%                    |
+-----------------+-------------------------+-------------------------+
| Two tests       | 53.4%                   | 51.0%                   |
+-----------------+-------------------------+-------------------------+
| More than 2     | 27.7%                   | 24.5%                   |
| tests           |                         |                         |
+-----------------+-------------------------+-------------------------+
| Appropriate\*\* | 81.1%                   | 75.5%                   |
+-----------------+-------------------------+-------------------------+
| \*excludes      |                         |                         |
| women reporting |                         |                         |
| hysterectomy or |                         |                         |
| postmenopausal  |                         |                         |
|                 |                         |                         |
| \*\*represents  |                         |                         |
| the sum of the  |                         |                         |
| preceding 2     |                         |                         |
| rows as the     |                         |                         |
| DAT2 pregnancy  |                         |                         |
| testing         |                         |                         |
| question        |                         |                         |
| applies to a    |                         |                         |
| \>=2-month      |                         |                         |
| window. Thus,   |                         |                         |
| patients should |                         |                         |
| report \>=2     |                         |                         |
| pregnancy tests |                         |                         |
| to indicate     |                         |                         |
| monthly         |                         |                         |
| pregnancy       |                         |                         |
| testing         |                         |                         |
+-----------------+-------------------------+-------------------------+

::: Definition-Term
**3.1.3 [Contraception Practices]{.underline}**
:::

::: Definition-Term
Birth control practices by sexual activity status /treatment status for
apparently fertile women aged 15 to 44 years is shown in Table 19. As
was seen among respondents to DAT-1, most apparently fertile, sexually
active women who remain on therapy with Accutane (97.6%) or completed
treatment within one month (94.4%) reported use of some birth control.
Compliance with two forms, one of which is primary ("appropriate" per
label) was similar to levels reported in DAT-1 (\~55%). Thus, even
during therapy with Accutane, compliance with two forms of contraception
as outlined in approved labeling is problematic, with compliance among
the highest risk group (young, fertile women who report sexual activity)
to be just above 50%.
:::

+----------------------+------+---------+-------------+--------------+
| **Table 19.          |      |         |             |              |
| Distribution of      |      |         |             |              |
| birth control use by |      |         |             |              |
| sexual activity      |      |         |             |              |
| status/treatment     |      |         |             |              |
| status among         |      |         |             |              |
| apparently           |      |         |             |              |
| fertile\*, 15-45     |      |         |             |              |
| year-old             |      |         |             |              |
| participants in      |      |         |             |              |
| DAT2.**              |      |         |             |              |
+----------------------+------+---------+-------------+--------------+
|                      | T    | Any     | Any primary | Appro        |
|                      | otal | form of | form of     | priate\*\*\* |
|                      | \*\* | birth   | birth       | per Accutane |
|                      |      | control | control     | label        |
+----------------------+------+---------+-------------+--------------+
| Sexually active, on  | 608  | 97.5%   | 91.0%       | 54.9%        |
| treatment w/Accutane |      |         |             |              |
+----------------------+------+---------+-------------+--------------+
| Sexually active,     | 143  | 94.4%   | 87.4%       | 51.1%        |
| completed treatment  |      |         |             |              |
| for [\>]{.underline} |      |         |             |              |
| 1 month              |      |         |             |              |
+----------------------+------+---------+-------------+--------------+
| Not sexually active, | 813  | 54.4%   | 44.2%       | 8.1%         |
| on treatment         |      |         |             |              |
| w/Accutane           |      |         |             |              |
+----------------------+------+---------+-------------+--------------+
| Not sexually active, | 145  | 52.4%   | 47.0%       | 9.0%         |
| completed treatment  |      |         |             |              |
| for [\>]{.underline} |      |         |             |              |
| 1 month              |      |         |             |              |
+----------------------+------+---------+-------------+--------------+
| \*excludes women     |      |         |             |              |
| reporting            |      |         |             |              |
| hysterectomy or      |      |         |             |              |
| postmenopausal       |      |         |             |              |
|                      |      |         |             |              |
| \*\*excludes 37      |      |         |             |              |
| women with missing   |      |         |             |              |
| information on birth |      |         |             |              |
| control              |      |         |             |              |
|                      |      |         |             |              |
| \*\*\*appropriate    |      |         |             |              |
| per Accutane label   |      |         |             |              |
| requires two forms   |      |         |             |              |
| of which one must be |      |         |             |              |
| a "primary" method   |      |         |             |              |
| (e.g., oral          |      |         |             |              |
| contraception, tubal |      |         |             |              |
| ligation,            |      |         |             |              |
| injectable/implanta  |      |         |             |              |
| ble/insertable/patch |      |         |             |              |
| contraceptives,      |      |         |             |              |
| vasectomy, IUD)      |      |         |             |              |
+----------------------+------+---------+-------------+--------------+

**3.2 DAT-2 Bivariate Analyses**

::: Definition-Term
**3.2.1 [Relationship between Qualification Sticker and Pregnancy
Testing]{.underline}**
:::

::: Definition-Term
The relationship between Qualification sticker and pregnancy testing
among all, apparently fertile 15-45 year Survey participants continuing
on Accutane therapy is show in Tables 20 and 21. \[As in the DAT-1
Bivariate Analyses section above, these tables are included in this
section and are stratified by missing=excluded (Table 20) and missing=NO
(Table 21).\]
:::

+---------------+-----------------+-----------------+----------------+
| **Table 20.   |                 |                 |                |
| Relationship  |                 |                 |                |
| between       |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing and   |                 |                 |                |
| Qualification |                 |                 |                |
| sticker for   |                 |                 |                |
| all,          |                 |                 |                |
| apparently    |                 |                 |                |
| fertile\*,    |                 |                 |                |
| 15-45         |                 |                 |                |
| year-old      |                 |                 |                |
| DAT-2         |                 |                 |                |
| participants. |                 |                 |                |
| \[Missing     |                 |                 |                |
| =excluded\]** |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | Qualification   | Qualification   | Row total      |
|               | sticker         | sticker         |                |
|               |                 |                 |                |
|               | **Yes**         | **No**          |                |
+---------------+-----------------+-----------------+----------------+
| Pregnancy     | 1074            | 254             | 1328           |
| test          |                 |                 |                |
|               | (99%)           | (98%)           |                |
| **Yes**       |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
| Pregnancy     | 5               | 5               | 10             |
| test          |                 |                 |                |
|               | (1%)            | (2%)            |                |
| **No**        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | 1079            | 259             | 1338\*\*       |
+---------------+-----------------+-----------------+----------------+
| \*excludes    |                 |                 |                |
| women         |                 |                 |                |
| reporting     |                 |                 |                |
| hysterectomy  |                 |                 |                |
| or            |                 |                 |                |
| p             |                 |                 |                |
| ostmenopausal |                 |                 |                |
|               |                 |                 |                |
| \             |                 |                 |                |
| *\*restricted |                 |                 |                |
| to those      |                 |                 |                |
| participants  |                 |                 |                |
| continuing    |                 |                 |                |
| therapy with  |                 |                 |                |
| Accutane;     |                 |                 |                |
| excludes 116  |                 |                 |                |
| records with  |                 |                 |                |
| missing data; |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| includes any  |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| performed at  |                 |                 |                |
| physician's   |                 |                 |                |
| office or     |                 |                 |                |
| performed at  |                 |                 |                |
| home but      |                 |                 |                |
| reported to   |                 |                 |                |
| the           |                 |                 |                |
| physician; as |                 |                 |                |
| the DAT2      |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| question      |                 |                 |                |
| applies to a  |                 |                 |                |
| \>=2-month    |                 |                 |                |
| window,       |                 |                 |                |
| patients were |                 |                 |                |
| categorized   |                 |                 |                |
| as "Yes" only |                 |                 |                |
| if they       |                 |                 |                |
| reported \>=2 |                 |                 |                |
| pregnancy     |                 |                 |                |
| tests.        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+

As was seen in analyses of DAT-1 data, any "effect" of the qualification
sticker is limited as pregnancy testing is high among both groups.

+---------------+-----------------+-----------------+----------------+
| **Table 21.   |                 |                 |                |
| Relationship  |                 |                 |                |
| between       |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing and   |                 |                 |                |
| qualification |                 |                 |                |
| sticker for   |                 |                 |                |
| all,          |                 |                 |                |
| apparently    |                 |                 |                |
| fertile\*,    |                 |                 |                |
| 15-45         |                 |                 |                |
| year-old      |                 |                 |                |
| DAT-2         |                 |                 |                |
| participants. |                 |                 |                |
| \[M           |                 |                 |                |
| issing=No\]** |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | Qualification   | Qualification   | Row Total      |
|               | sticker         | sticker         |                |
|               |                 |                 |                |
|               | **Yes**         | **No**          |                |
+---------------+-----------------+-----------------+----------------+
| Pregnancy     | 1074            | 305             | 1379           |
| test          |                 |                 |                |
|               | (95%)           | (95%)           |                |
| **Yes**       |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
| Pregnancy     | 58              | 17              | 75             |
| test          |                 |                 |                |
|               | (5%)            | (5%)            |                |
| **No**        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | 1132            | 322             | 1454\*\*       |
+---------------+-----------------+-----------------+----------------+
| \*excludes    |                 |                 |                |
| women         |                 |                 |                |
| reporting     |                 |                 |                |
| hysterectomy  |                 |                 |                |
| or            |                 |                 |                |
| p             |                 |                 |                |
| ostmenopausal |                 |                 |                |
|               |                 |                 |                |
| \             |                 |                 |                |
| *\*restricted |                 |                 |                |
| to those      |                 |                 |                |
| participants  |                 |                 |                |
| continuing    |                 |                 |                |
| therapy with  |                 |                 |                |
| Accutane;     |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| includes any  |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| performed at  |                 |                 |                |
| physician's   |                 |                 |                |
| office or     |                 |                 |                |
| performed at  |                 |                 |                |
| home but      |                 |                 |                |
| reported to   |                 |                 |                |
| the           |                 |                 |                |
| physician; as |                 |                 |                |
| the DAT2      |                 |                 |                |
| pregnancy     |                 |                 |                |
| testing       |                 |                 |                |
| question      |                 |                 |                |
| applies to a  |                 |                 |                |
| \>=2-month    |                 |                 |                |
| window,       |                 |                 |                |
| patients were |                 |                 |                |
| categorized   |                 |                 |                |
| as "Yes" only |                 |                 |                |
| if they       |                 |                 |                |
| reported \>=2 |                 |                 |                |
| pregnancy     |                 |                 |                |
| tests.        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+

::: Definition-Term
**3.2.2 Relationship of Qualification Sticker and Birth Control**
:::

::: Definition-Term
The impact of the Qualification Sticker on birth control among sexually
active, apparently fertile 15-45 year Survey participants continuing on
Accutane therapy is shown in Tables 22 and 23. These data provide little
potential to examine the relationship of the Qualification sticker to
birth control as these tables are dominated both by Qualification
sticker use and birth control. As noted for bivariate DAT-1 analyses of
Qualification sticker and ANY birth control, it is possible that these
analyses overestimate any birth control as the analysis approach
accepted affirmative responses to questions which should have been
skipped.
:::

+---------------+-----------------+-----------------+----------------+
| **Table 22.   |                 |                 |                |
| Relationship  |                 |                 |                |
| between       |                 |                 |                |
| qualification |                 |                 |                |
| sticker and   |                 |                 |                |
| ANY birth     |                 |                 |                |
| control for   |                 |                 |                |
| sexually      |                 |                 |                |
| active,       |                 |                 |                |
| apparently    |                 |                 |                |
| fertile\*,    |                 |                 |                |
| 15-45         |                 |                 |                |
| year-old      |                 |                 |                |
| DAT-2         |                 |                 |                |
| respondents.  |                 |                 |                |
| \[Missing     |                 |                 |                |
| =excluded\]** |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | Qualification   | Qualification   | Row Total      |
|               | sticker         | sticker         |                |
|               |                 |                 |                |
|               | **Yes**         | **No**          |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 560             | 15              | 575            |
| control       |                 |                 |                |
|               | (99%)           | (100%)          |                |
| **Yes**       |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 5               | 0               | 5              |
| control       |                 |                 |                |
|               | (1%)            | (0%)            |                |
| **No**        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | 565             | 15              | 580\*\*        |
+---------------+-----------------+-----------------+----------------+
| \* excludes   |                 |                 |                |
| women         |                 |                 |                |
| reporting     |                 |                 |                |
| hysterectomy  |                 |                 |                |
| or            |                 |                 |                |
| p             |                 |                 |                |
| ostmenopausal |                 |                 |                |
|               |                 |                 |                |
| \*\*excludes  |                 |                 |                |
| 28 records    |                 |                 |                |
| with missing  |                 |                 |                |
| data for      |                 |                 |                |
| qualification |                 |                 |                |
| sticker;      |                 |                 |                |
| restricted to |                 |                 |                |
| women who are |                 |                 |                |
| currently on  |                 |                 |                |
| treatment or  |                 |                 |                |
| had stopped   |                 |                 |                |
| the treatment |                 |                 |                |
| within the    |                 |                 |                |
| past month.   |                 |                 |                |
| Per approved  |                 |                 |                |
| labeling,     |                 |                 |                |
| sexually      |                 |                 |                |
| active women  |                 |                 |                |
| are to remain |                 |                 |                |
| on birth      |                 |                 |                |
| control /     |                 |                 |                |
| refrain from  |                 |                 |                |
| conception    |                 |                 |                |
| for one month |                 |                 |                |
| following the |                 |                 |                |
| end of        |                 |                 |                |
| Accutane      |                 |                 |                |
| treatment;    |                 |                 |                |
| questions     |                 |                 |                |
| pertaining to |                 |                 |                |
| birth control |                 |                 |                |
| are different |                 |                 |                |
| in the DAT-2  |                 |                 |                |
| instrument in |                 |                 |                |
| comparison to |                 |                 |                |
| the DAT-1     |                 |                 |                |
| instrument.   |                 |                 |                |
| However, it   |                 |                 |                |
| is still      |                 |                 |                |
| possible for  |                 |                 |                |
| women to      |                 |                 |                |
| become        |                 |                 |                |
| confused in   |                 |                 |                |
| answering the |                 |                 |                |
| question.     |                 |                 |                |
| Thus, as in   |                 |                 |                |
| the analysis  |                 |                 |                |
| of ANY birth  |                 |                 |                |
| control use   |                 |                 |                |
| in DAT-1, ANY |                 |                 |                |
| birth control |                 |                 |                |
| was defined   |                 |                 |                |
| as those who  |                 |                 |                |
| reported that |                 |                 |                |
| currently     |                 |                 |                |
| using any     |                 |                 |                |
| birth control |                 |                 |                |
| method        |                 |                 |                |
| including     |                 |                 |                |
| tubal         |                 |                 |                |
| ligation and  |                 |                 |                |
| vasectomy. As |                 |                 |                |
| before,       |                 |                 |                |
| vasectomy was |                 |                 |                |
| considered a  |                 |                 |                |
| birth control |                 |                 |                |
| method        |                 |                 |                |
| regardless of |                 |                 |                |
| selection of  |                 |                 |                |
| an            |                 |                 |                |
| alternative   |                 |                 |                |
| method, as    |                 |                 |                |
| required per  |                 |                 |                |
| labeling;     |                 |                 |                |
+---------------+-----------------+-----------------+----------------+

+---------------+-----------------+-----------------+----------------+
| **Table 23.   |                 |                 |                |
| Relationship  |                 |                 |                |
| between       |                 |                 |                |
| qualification |                 |                 |                |
| sticker and   |                 |                 |                |
| ANY birth     |                 |                 |                |
| control for   |                 |                 |                |
| sexually      |                 |                 |                |
| active,       |                 |                 |                |
| apparently    |                 |                 |                |
| fertile\*,    |                 |                 |                |
| 15-45         |                 |                 |                |
| year-old      |                 |                 |                |
| DAT-2         |                 |                 |                |
| respondents.  |                 |                 |                |
| \[M           |                 |                 |                |
| issing=NO\]** |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | Qualification   | Qualification   | Row total      |
|               | sticker         | sticker         |                |
|               |                 |                 |                |
|               | **Yes**         | **No**          |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 560             | 15              | 575            |
| control       |                 |                 |                |
|               | (94%)           | (100%)          |                |
| **Yes**       |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
| Any birth     | 33              | 0               | 33             |
| control       |                 |                 |                |
|               | (6%)            | (0%)            |                |
| **No**        |                 |                 |                |
+---------------+-----------------+-----------------+----------------+
|               | 593             | 15              | 608\*\*        |
+---------------+-----------------+-----------------+----------------+
| \* excludes   |                 |                 |                |
| women         |                 |                 |                |
| reporting     |                 |                 |                |
| hysterectomy  |                 |                 |                |
| or            |                 |                 |                |
| p             |                 |                 |                |
| ostmenopausal |                 |                 |                |
|               |                 |                 |                |
| \             |                 |                 |                |
| *\*Restricted |                 |                 |                |
| to women who  |                 |                 |                |
| are currently |                 |                 |                |
| on treatment  |                 |                 |                |
| or had        |                 |                 |                |
| stopped the   |                 |                 |                |
| treatment     |                 |                 |                |
| within the    |                 |                 |                |
| past month    |                 |                 |                |
| as, per       |                 |                 |                |
| approved      |                 |                 |                |
| labeling,     |                 |                 |                |
| sexually      |                 |                 |                |
| active women  |                 |                 |                |
| are to remain |                 |                 |                |
| on birth      |                 |                 |                |
| control /     |                 |                 |                |
| refrain from  |                 |                 |                |
| conception    |                 |                 |                |
| for one month |                 |                 |                |
| following the |                 |                 |                |
| end of        |                 |                 |                |
| Accutane      |                 |                 |                |
| treatment;    |                 |                 |                |
| questions     |                 |                 |                |
| pertaining to |                 |                 |                |
| birth control |                 |                 |                |
| are different |                 |                 |                |
| in the DAT-2  |                 |                 |                |
| instrument in |                 |                 |                |
| comparison to |                 |                 |                |
| the DAT-1     |                 |                 |                |
| instrument.   |                 |                 |                |
| However, it   |                 |                 |                |
| is still      |                 |                 |                |
| possible for  |                 |                 |                |
| women to      |                 |                 |                |
| become        |                 |                 |                |
| confused in   |                 |                 |                |
| answering the |                 |                 |                |
| question.     |                 |                 |                |
| Thus, as in   |                 |                 |                |
| the analysis  |                 |                 |                |
| of ANY birth  |                 |                 |                |
| control use   |                 |                 |                |
| in DAT-1, ANY |                 |                 |                |
| birth control |                 |                 |                |
| was defined   |                 |                 |                |
| as those who  |                 |                 |                |
| reported that |                 |                 |                |
| currently     |                 |                 |                |
| using any     |                 |                 |                |
| birth control |                 |                 |                |
| method        |                 |                 |                |
| including     |                 |                 |                |
| tubal         |                 |                 |                |
| ligation and  |                 |                 |                |
| vasectomy. As |                 |                 |                |
| before,       |                 |                 |                |
| vasectomy was |                 |                 |                |
| considered a  |                 |                 |                |
| birth control |                 |                 |                |
| method        |                 |                 |                |
| regardless of |                 |                 |                |
| selection of  |                 |                 |                |
| an            |                 |                 |                |
| alternative   |                 |                 |                |
| method, as    |                 |                 |                |
| required per  |                 |                 |                |
| labeling.     |                 |                 |                |
+---------------+-----------------+-----------------+----------------+

4\. PREGNANCIES, POSSIBLE RISK FACTORS, AND PREGNANCY RATES WITHIN THE
DEGGE/SI COHORT

In other analyses conducted by DDRE but not the Accutane sponsor, the
Degge/SI cohort was examined for reports of pregnancy for calculation of
an Accutane-exposed pregnancy rate. Based on DDRE analyses, the Degge/SI
dataset contains 28 reports of pregnancy among a total cohort of 5469
women as of the lock date on the dataset. This is based entirely on
information received on/within DAT-1 question 37 and DAT-2 question 17
("Have you been pregnant at any time since you first started taking
Accutane?"). However, application of this numerator and denominator to
calculate an Accutane-exposed pregnancy rate is problematic as women
undergoing a repeat course of therapy (\~25% of the total cohort) may
correctly answer this question as "Yes" based on a un-exposed pregnancy
in-between treatment courses. Thus, it is not possible to interpret the
answers reported for this segment of the cohort. This precludes
examination of pregnancy risk among women on repeat therapy.

After restriction to the 4277 women on their first-course of therapy, 15
participants reported the occurrence of a pregnancy since starting
Accutane therapy. At the time of survey, the median age of these 15
women was 22 years (mean 24.5 years) with range 16 to 39 years. For
comparison, the median and mean of the total cohort of first-time users
are 22 years and 24.4 years, respectively. Eight women reported
pregnancy on DAT1; 7 on DAT-2. So as to highlight the problems
encountered in analysis of these data for risk factors, 4 out of these
15 women reported no sexual intercourse in both DAT1 and DAT2
questionnaires. Thus, it is difficult to extract putative risk factors
for an Accutane-exposed pregnancy based on the limited information
captured by the Patient Survey.

In presentation before the FDA Dermatologic Drugs Advisory Committee
Meeting (Gaithersburg, MD) on September 18, 2000, Mitchell et al
reported 992 pregnancies among 339,994 women completing follow-up in the
Survey (through 1999) for a rate of 2.9 per 1,000 women. Based on report
of 15 pregnancies, the crude observed pregnancy rate for first-course
users within the Degge/SI cohort is 15/4277 = 3.5 / 1000. It should also
be noted that the denominator used in this calculation (4277) includes
some women who have not yet completed treatment and thus potentially
able to report an Accutane-exposed pregnancy with further follow-up.
Thus, since this rate is censored, it likely represents an underestimate
of the rate to be realized when all these participants complete
follow-up, as was described by Mitchell.

5\. SURVEY ADDENDUM (RECENT DATA)

FDA has received additional data, in addition to use data, since receipt
of the Degge/SI dataset addendum (Oct 10, 2003) in the form of quarterly
reports. As shown in Chart 2[^19] there are currently three isotretinoin
patient surveys. All three of these groups currently submit "Quarterly
Reports" summarizing data accrued to the end of the quarter. Quarterly
reports from the Slone Epidemiology Group on the Accutane-brand of
isotretinoin have been cited previously in this document and Slone
continues to submit data (using the old survey) for patients who
enrolled to Slone via Accutane materials and/or deferred transfer to
Degge/SI. Degge/SI submitted a Quarterly report for 1QTR2003 based on
very limited enrollment as of March 31, 2003 and two additional (and
larger) Quarterly reports for 2QTR2003 and 3Qtr2003. The Slone
Epidemiology Group has also submitted two quarterly reports for 2QTR2003
and 3Qtr2003 for generic isotretinoin. Due to differences in the survey,
survey methods, and operating procedures, it is problematic to compare
across these disparate surveys. However, for completeness, selected and
generally comparable variables have compiled from the Quarterly reports
for 2QTR2003 and 3Qtr2003.[^20] In general, these data support results
reported for the interval of April 1, 2001 through March 30, 2003.
Specifically:

-   Report of any pregnancy testing prior to initiation of isotretinoin
    therapy continues at \~90%.

-   Report of two (or more) pregnancy tests prior to initiation of
    isotretinoin therapy continues at \~65%

-   Report of NO birth control among apparently fertile, sexually active
    respondents continues at \~3%.

-   Report of any pregnancy testing during therapy (DAT-2) continues at
    \~82%.

Thus, these data DO NOT show any remarkable improvements in compliance
with these selected attributes.

::: Definition-Term
**[DISCUSSION]{.underline}**
:::

::: Definition-Term
On many points, analyses conducted and described herein by DDRE are in
agreement with analyses as reported by the sponsor in their "*1 Year
Report*." Some important items of agreement include:
:::

-   ::: Definition-Term
    absolute participation (22%-26% per DDRE; 28% per the sponsor)
    :::

-   ::: Definition-Term
    [\>]{.underline} 90% report of use of the Qualification sticker
    :::

```{=html}
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```
-   [\>]{.underline} 90% report of one pregnancy test prior to start of
    therapy

-   \~65% report of two pregnancy tests prior to start of therapy

-   use of two forms of contraception (57% per sponsor based on two
    forms; 46% per DDRE based on "appropriate" as per label)

However, bivariate analyses of the Qualification sticker have only been
developed by DDRE. These analyses suggest pregnancy testing and birth
control were generally similar between those reporting Qualification
stickers and those not reporting Qualification stickers. In addition,
results for the respondents noting a Qualification sticker in these
stratified analyses were very similar to those observed in univariate
(un-stratified) analyses.

However interesting and potentially problematic as these results are,
the generation of a pregnancy rate following new labeling could be
argued as the final arbiter for success of the labeling, which was not
limited to the Qualification sticker. To this end, it is noteworthy to
report the pregnancy rate of 3.5 /1000 for the initial Degge/SI cohort
to be identical to the rate reported by the Slone Epidemiology Group for
their Accutane Survey. It appears, therefore, that the efforts
implemented in the new labeling did little to affect the absolute
pregnancy rate within [the population included in the Patient
Surveys.]{.underline} \[As noted above, the denominator used in the
calculation of a pregnancy rate for the Degge/SI cohort (4277) includes
some women who have not yet to completed treatment and thus potentially
able to report an Accutane-exposed pregnancy with further follow-up.
Thus, since this rate is censored, it likely represents an underestimate
of the rate to be realized when all these participants complete
follow-up, as was described by Mitchell.\]

**APPENDIX 1**---**GEOGRAPHIC REGIONS**

**East:** Connecticut, Delaware, Maine, Massachusetts, New Hampshire,
New Jersey, New York, Pennsylvania, Rhode Island, Vermont

**Midwest:** Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota,
Missouri, Nebraska, North Dakota, Ohio, South Dakota, Wisconsin

**South:** Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana,
Maryland, Mississippi, North Carolina, Oklahoma, South Carolina,
Tennessee, Texas, Virginia, Wet Virginia, District of Columbia

**West:** Arizona, California, Colorado, Idaho, Montana, Nevada, New
Mexico, Oregon, Utah, Washington, Wyoming

# APPENDIX 2---DESCRIPTION OF ADVANCEPCS

AdvancePCS is one of the largest pharmacy benefit management companies
in the U.S., currently covering an estimated 50 million patient lives
and processing 300 million prescription claims annually. FDA has on-line
access to AdvancePCS' database of paid claims for prescriptions filled
in 55,000 pharmacies across the country. Patients whose claims are
processed by AdvancePCS include those covered under various types of
insurance plans that cover prescription drugs, including some employer's
self-insured planes, selected managed care plans, Blue Cross/Blue Shield
plans, and some other traditional insurers. Demographically, these
patients appear to represent all 50 states and include substantial
numbers of the elder, children, and women of childbearing age. Their
representativeness of all patients receiving dispensed prescriptions in
the U.S. is not known.

The data in AdvancePCS include date dispensed, drug name, drug strength,
dosage form, quantity, days' supply, and prescriber specialty. All
patients are assigned a unique identifier, and so can be followed
through time for as long as they are in the same prescription plan. Data
are entered into the system within days of dispensing, so that real-time
analysis is possible. At any time, FDA is able to access the most recent
25 months of data online.

# 

# 

# 

# 

# 

# 

# 

# 

# 

**APPENDIX 3**---**RECOMMENDATIONS FOR PCS AND PRESCRIPTION AUDIT**

The following recommendations cover the PCS, and audit, and also
suggestions for making the results of future survey waves easier to
analyze and interpret. The survey recommendations focus on increasing
the number of prescriptions captured for analysis, and consistently
obtaining an adequate number of prescriptions for all of the survey
waves. The operational audit procedures need to be clearly described in
detail, and may need to be altered in order to achieve the goal of data
validation.

Survey

-   Re-examine sample size and recruiting plan to ensure adequate
    capture of [prescriptions]{.underline} for analysis

-   Consider unifying the survey (sponsor and generic companies) to
    increase the response rate and decrease the number of inquiries to
    individual stores for each survey

-   Consider extending the PCS indefinitely (beyond the current 2 year
    limit) as an indirect measure of physician compliance, assuming that
    an adequate number of prescriptions can be captured for analysis. If
    an indefinite extension is not possible, consider extending the
    survey at least until a sufficient number of prescriptions has been
    obtained for a long enough period of time (at least 1 year) to
    permit a valid analysis of compliance.

-   Consider approaching the December 2002 dropouts to discuss their
    possible participation, since they account for a very large
    percentage of the isotretinoin prescriptions. This approach might be
    successful if the separate surveys are unified into a single entity

-   If the December 2002 pharmacies will not reconsider participation,
    consider approaching PBM\'s or switch companies (firms that route
    the prescriptions from the pharmacy to the insurance provider) as a
    way to get to an adequate number of prescriptions. Again, this
    approach might be successful if the separate surveys are unified
    into a single entity

-   Re-evaluate the recruiting process every 1 to 2 surveys until the
    desired number of prescriptions has been captured for 4 surveys (1
    year of data)

    Audit

```{=html}
<!-- -->
```
-   Present a [detailed summary]{.underline} of how the current audit is
    being implemented, focusing on the recruiting procedures are rules.

-   Re-evaluate the current audit implementation, and make the changes
    necessary to ensure that the audited pharmacies are randomly chosen
    from the participants, and balanced across the pharmacy analysis
    strata

    Analysis

```{=html}
<!-- -->
```
-   Provide an electronic copy of the [cleaned]{.underline} data used
    for the analysis and production of the tables in the PCS reports (in
    addition to the paper report). The data should include information
    on recruited pharmacies, as well as those that responded and were
    audited.

-   Include a table detailing the recruited vs. responded vs. audited
    pharmacies across pharmacy strata in all future reports.

    **APPENDIX 4**---**TABLES AND CHARTS**

+------------+------+------+------+------+------+------+------+------+
| **Table A. |      |      |      |      |      |      |      |      |
| Trends in  |      |      |      |      |      |      |      |      |
| Slone      |      |      |      |      |      |      |      |      |
| Con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| Status for |      |      |      |      |      |      |      |      |
| age group  |      |      |      |      |      |      |      |      |
| 15-24      |      |      |      |      |      |      |      |      |
| years**    |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| era        | Last |      |      |      | F    |      |      |      |
|            | four |      |      |      | irst |      |      |      |
|            | quar |      |      |      | four |      |      |      |
|            | ters |      |      |      | quar |      |      |      |
|            | be   |      |      |      | ters |      |      |      |
|            | fore |      |      |      | of   |      |      |      |
|            | S    |      |      |      | S    |      |      |      |
|            | MART |      |      |      | MART |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Qtr        | 2Q   | 3Q   | 4Q   | 1Q   | 2Q   | 3Q   | 4Q   | 1Q   |
|            | tr01 | tr01 | tr01 | tr02 | tr02 | tr02 | tr02 | tr03 |
+------------+------+------+------+------+------+------+------+------+
| N          | 516  | 531  | 556  | 590  | 602  | 610  | 625  | 534  |
+------------+------+------+------+------+------+------+------+------+
|            | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  |
+------------+------+------+------+------+------+------+------+------+
| ::: Defin  | 2    | 1    | 1    | 1    | 2    | 1    | 2    | 1    |
| ition-Term |      |      |      |      |      |      |      |      |
| sterile\*  |      |      |      |      |      |      |      |      |
| :::        |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| abstinent  | 39   | 38   | 35   | 35   | 33   | 30   | 30   | 31   |
+------------+------+------+------+------+------+------+------+------+
| BCP, BC    | 51   | 52   | 54   | 56   | 58   | 60   | 55   | 60   |
| injection, |      |      |      |      |      |      |      |      |
| IUD        |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Barrier,   | 8    | 9    | 10   | 8    | 7    | 9    | 13   | 8    |
| other, UK, |      |      |      |      |      |      |      |      |
| none\*\*   |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| \*self or  |      |      |      |      |      |      |      |      |
| partner    |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| \*         |      |      |      |      |      |      |      |      |
| \*includes |      |      |      |      |      |      |      |      |
| 0% to 1%   |      |      |      |      |      |      |      |      |
| of         |      |      |      |      |      |      |      |      |
| patients   |      |      |      |      |      |      |      |      |
| per        |      |      |      |      |      |      |      |      |
| quarter    |      |      |      |      |      |      |      |      |
| who report |      |      |      |      |      |      |      |      |
| no         |      |      |      |      |      |      |      |      |
| con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| use and    |      |      |      |      |      |      |      |      |
| sexually   |      |      |      |      |      |      |      |      |
| active     |      |      |      |      |      |      |      |      |
| without a  |      |      |      |      |      |      |      |      |
| history of |      |      |      |      |      |      |      |      |
| sterility  |      |      |      |      |      |      |      |      |
| (self or   |      |      |      |      |      |      |      |      |
| partner).  |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| BCP =      |      |      |      |      |      |      |      |      |
| birth      |      |      |      |      |      |      |      |      |
| control    |      |      |      |      |      |      |      |      |
| pills; BC  |      |      |      |      |      |      |      |      |
| injection  |      |      |      |      |      |      |      |      |
| = includes |      |      |      |      |      |      |      |      |
| all        |      |      |      |      |      |      |      |      |
| injectable |      |      |      |      |      |      |      |      |
| or         |      |      |      |      |      |      |      |      |
| i          |      |      |      |      |      |      |      |      |
| mplantable |      |      |      |      |      |      |      |      |
| contr      |      |      |      |      |      |      |      |      |
| aceptives; |      |      |      |      |      |      |      |      |
| IUD=in     |      |      |      |      |      |      |      |      |
| trauterine |      |      |      |      |      |      |      |      |
| device     |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+

+------------+------+------+------+------+------+------+------+------+
| **Table B. |      |      |      |      |      |      |      |      |
| Trends in  |      |      |      |      |      |      |      |      |
| Slone      |      |      |      |      |      |      |      |      |
| Con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| Status for |      |      |      |      |      |      |      |      |
| age group  |      |      |      |      |      |      |      |      |
| 25-34**.   |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| era        | Last |      |      |      | F    |      |      |      |
|            | four |      |      |      | irst |      |      |      |
|            | quar |      |      |      | four |      |      |      |
|            | ters |      |      |      | quar |      |      |      |
|            | be   |      |      |      | ters |      |      |      |
|            | fore |      |      |      | of   |      |      |      |
|            | S    |      |      |      | S    |      |      |      |
|            | MART |      |      |      | MART |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Qtr        | 2Q   | 3Q   | 4Q   | 1Q   | 2Q   | 3Q   | 4Q   | 1Q   |
|            | tr01 | tr01 | tr01 | tr02 | tr02 | tr02 | tr02 | tr03 |
+------------+------+------+------+------+------+------+------+------+
| N          | 337  | 290  | 322  | 346  | 251  | 326  | 308  | 277  |
+------------+------+------+------+------+------+------+------+------+
|            | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  |
+------------+------+------+------+------+------+------+------+------+
| sterile\*  | 24   | 22   | 20   | 20   | 20   | 28   | 23   | 23   |
+------------+------+------+------+------+------+------+------+------+
| abstinent  | 7    | 11   | 10   | 8    | 10   | 7    | 7    | 5    |
+------------+------+------+------+------+------+------+------+------+
| BCP, BC    | 58   | 59   | 59   | 62   | 61   | 56   | 60   | 60   |
| injection, |      |      |      |      |      |      |      |      |
| IUD        |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Barrier,   | 11   | 8    | 11   | 10   | 9    | 9    | 10   | 12   |
| other, UK, |      |      |      |      |      |      |      |      |
| none\*\*   |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| \*self or  |      |      |      |      |      |      |      |      |
| partner    |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| ::: Defin  |      |      |      |      |      |      |      |      |
| ition-Term |      |      |      |      |      |      |      |      |
| \*         |      |      |      |      |      |      |      |      |
| \*includes |      |      |      |      |      |      |      |      |
| 0% to 1%   |      |      |      |      |      |      |      |      |
| of         |      |      |      |      |      |      |      |      |
| patients   |      |      |      |      |      |      |      |      |
| per        |      |      |      |      |      |      |      |      |
| quarter    |      |      |      |      |      |      |      |      |
| who report |      |      |      |      |      |      |      |      |
| no         |      |      |      |      |      |      |      |      |
| con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| use and    |      |      |      |      |      |      |      |      |
| sexual     |      |      |      |      |      |      |      |      |
| activity   |      |      |      |      |      |      |      |      |
| without a  |      |      |      |      |      |      |      |      |
| history of |      |      |      |      |      |      |      |      |
| sterility  |      |      |      |      |      |      |      |      |
| (self or   |      |      |      |      |      |      |      |      |
| partner).  |      |      |      |      |      |      |      |      |
| :::        |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| BCP =      |      |      |      |      |      |      |      |      |
| birth      |      |      |      |      |      |      |      |      |
| control    |      |      |      |      |      |      |      |      |
| pills; BC  |      |      |      |      |      |      |      |      |
| injection  |      |      |      |      |      |      |      |      |
| = includes |      |      |      |      |      |      |      |      |
| all        |      |      |      |      |      |      |      |      |
| injectable |      |      |      |      |      |      |      |      |
| or         |      |      |      |      |      |      |      |      |
| i          |      |      |      |      |      |      |      |      |
| mplantable |      |      |      |      |      |      |      |      |
| contr      |      |      |      |      |      |      |      |      |
| aceptives, |      |      |      |      |      |      |      |      |
| IUD=in     |      |      |      |      |      |      |      |      |
| trauterine |      |      |      |      |      |      |      |      |
| device     |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+

+------------+------+------+------+------+------+------+------+------+
| **Table C. |      |      |      |      |      |      |      |      |
| Trends in  |      |      |      |      |      |      |      |      |
| Slone      |      |      |      |      |      |      |      |      |
| Con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| Status for |      |      |      |      |      |      |      |      |
| age group  |      |      |      |      |      |      |      |      |
| 35-44      |      |      |      |      |      |      |      |      |
| years.**   |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| era        | Last |      |      |      | F    |      |      |      |
|            | four |      |      |      | irst |      |      |      |
|            | quar |      |      |      | four |      |      |      |
|            | ters |      |      |      | quar |      |      |      |
|            | be   |      |      |      | ters |      |      |      |
|            | fore |      |      |      | of   |      |      |      |
|            | S    |      |      |      | S    |      |      |      |
|            | MART |      |      |      | MART |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Qtr        | 2Q   | 3Q   | 4Q   | 1Q   | 2Q   | 3Q   | 4Q   | 1Q   |
|            | tr01 | tr01 | tr01 | tr02 | tr02 | tr02 | tr02 | tr03 |
+------------+------+------+------+------+------+------+------+------+
| N          | 176  | 158  | 155  | 139  | 176  | 158  | 155  | 106  |
+------------+------+------+------+------+------+------+------+------+
|            | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  | (%)  |
+------------+------+------+------+------+------+------+------+------+
| sterile\*  | 59   | 58   | 59   | 63   | 56   | 62   | 60   | 60   |
+------------+------+------+------+------+------+------+------+------+
| abstinent  | 6    | 7    | 8    | 6    | 6    | 4    | 4    | 6    |
+------------+------+------+------+------+------+------+------+------+
| BCP, BC    | 27   | 26   | 30   | 23   | 32   | 29   | 25   | 28   |
| injection, |      |      |      |      |      |      |      |      |
| IUD        |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| Barrier,   | 8    | 9    | 3    | 8    | 6    | 5    | 11   | 6    |
| other, UK, |      |      |      |      |      |      |      |      |
| none\*\*   |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+
| \*self or  |      |      |      |      |      |      |      |      |
| partner    |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| \*         |      |      |      |      |      |      |      |      |
| \*includes |      |      |      |      |      |      |      |      |
| 0% to 1%   |      |      |      |      |      |      |      |      |
| of         |      |      |      |      |      |      |      |      |
| patients   |      |      |      |      |      |      |      |      |
| per        |      |      |      |      |      |      |      |      |
| quarter    |      |      |      |      |      |      |      |      |
| who report |      |      |      |      |      |      |      |      |
| no         |      |      |      |      |      |      |      |      |
| con        |      |      |      |      |      |      |      |      |
| traceptive |      |      |      |      |      |      |      |      |
| use and    |      |      |      |      |      |      |      |      |
| sexual     |      |      |      |      |      |      |      |      |
| activity   |      |      |      |      |      |      |      |      |
| without a  |      |      |      |      |      |      |      |      |
| history of |      |      |      |      |      |      |      |      |
| sterility  |      |      |      |      |      |      |      |      |
| (self or   |      |      |      |      |      |      |      |      |
| partner).  |      |      |      |      |      |      |      |      |
|            |      |      |      |      |      |      |      |      |
| BCP =      |      |      |      |      |      |      |      |      |
| birth      |      |      |      |      |      |      |      |      |
| control    |      |      |      |      |      |      |      |      |
| pills; BC  |      |      |      |      |      |      |      |      |
| injection  |      |      |      |      |      |      |      |      |
| = includes |      |      |      |      |      |      |      |      |
| all        |      |      |      |      |      |      |      |      |
| injectable |      |      |      |      |      |      |      |      |
| or         |      |      |      |      |      |      |      |      |
| i          |      |      |      |      |      |      |      |      |
| mplantable |      |      |      |      |      |      |      |      |
| contr      |      |      |      |      |      |      |      |      |
| aceptives, |      |      |      |      |      |      |      |      |
| IUD=in     |      |      |      |      |      |      |      |      |
| trauterine |      |      |      |      |      |      |      |      |
| device     |      |      |      |      |      |      |      |      |
+------------+------+------+------+------+------+------+------+------+

+--------------+--------+--------+--------+--------+--------+--------+
| **Table D.   |        |        |        |        |        |        |
| Selected and |        |        |        |        |        |        |
| generally    |        |        |        |        |        |        |
| comparable   |        |        |        |        |        |        |
| variables as |        |        |        |        |        |        |
| reported for |        |        |        |        |        |        |
| two calendar |        |        |        |        |        |        |
| quarters by  |        |        |        |        |        |        |
| three        |        |        |        |        |        |        |
| disparate    |        |        |        |        |        |        |
| Isotretinoin |        |        |        |        |        |        |
| Patient      |        |        |        |        |        |        |
| Surveys**.   |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
|              | 1      |        |        | 1 July |        |        |
|              | April  |        |        | 2003   |        |        |
|              | 2002   |        |        | -- 30  |        |        |
|              | -- 30  |        |        | Sept   |        |        |
|              | June   |        |        | 2003   |        |        |
|              | 2003   |        |        |        |        |        |
|              |        |        |        | 6^th^  |        |        |
|              | 5^th^  |        |        | Q      |        |        |
|              | Q      |        |        | uarter |        |        |
|              | uarter |        |        | after  |        |        |
|              | after  |        |        | SMART  |        |        |
|              | SMART  |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
|              | Slone  | De     | Slone  | Slone  | De     | Slone  |
|              |        | gge/SI |        |        | gge/SI |        |
|              | Ac     |        | ge     | Ac     |        | ge     |
|              | cutane | Ac     | nerics | cutane | Ac     | nerics |
|              |        | cutane |        |        | cutane |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Any          | 92%    | 89%    | 92%    | \-\-\  | 91%    | 92%    |
| pregnancy    |        |        |        | --\*\* |        |        |
| test before  |        |        |        |        |        |        |
| Rx           |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| Two +        | \-\-\  | 64%    | 65%    | \-\-\  | 69%    | 62%    |
| pregnancy    | --^\*^ |        |        | --\*\* |        |        |
| tests        |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| ::: Def      | 1.1%   | 2.8%   | 3.2%   | \-\-\  | 2.6%   | 2.4%   |
| inition-Term |        |        |        | --\*\* |        |        |
| Sexually     |        |        |        |        |        |        |
| active but   |        |        |        |        |        |        |
| deny any     |        |        |        |        |        |        |
| birth        |        |        |        |        |        |        |
| control      |        |        |        |        |        |        |
| :::          |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| §Any         | 87%    | 80%    | \-\    | \-\-\  | 82%    | \-\    |
| pregnancy    |        |        | -\--\* | --\*\* |        | -\--\* |
| test during  |        |        |        |        |        |        |
| Rx           |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+
| \* Data      |        |        |        |        |        |        |
| unavailable  |        |        |        |        |        |        |
| due to time  |        |        |        |        |        |        |
| interval or  |        |        |        |        |        |        |
| instrument   |        |        |        |        |        |        |
|              |        |        |        |        |        |        |
| \*\*Data     |        |        |        |        |        |        |
| unavailable  |        |        |        |        |        |        |
| due to shift |        |        |        |        |        |        |
| to 6-month   |        |        |        |        |        |        |
| frame of     |        |        |        |        |        |        |
| reference    |        |        |        |        |        |        |
|              |        |        |        |        |        |        |
| § pertains   |        |        |        |        |        |        |
| to cohort    |        |        |        |        |        |        |
| establishing |        |        |        |        |        |        |
| in the       |        |        |        |        |        |        |
| preceding    |        |        |        |        |        |        |
| quarter      |        |        |        |        |        |        |
+--------------+--------+--------+--------+--------+--------+--------+

::: Definition-Term
**Chart 1 Accutane / Isotretinoin Patient Survey Operating Schema.**
:::

  -------- --- --------- --- ----------------------------------------------
  Key:                       = Accutane treatment (median)

                             

                             = Routine questionnaires

                             

                             = Optional questionnaires

                             

                             = Period of interest for selected

                             compliance measures (pregnancy

                             testing, contraception, stickers)
  -------- --- --------- --- ----------------------------------------------

  --- --- --- ----- --- ----- --- ----- --- ----- --- --- --- --- --- --- --- --- ---
              10w       18w       26w       34w                                   

                                                                                  
  --- --- --- ----- --- ----- --- ----- --- ----- --- --- --- --- --- --- --- --- ---

-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

  -- ------ --- -- -- --------- -- ------------ -- -- -- --------- --- -- -- --------- --- -- -- -- ------ ---- -- -- ------ ------------ -- --- -- --- -- --- -- ------ -- -- -- -- -- -- -- -- --
                                                                                                                                                                                                 

                                                                                                                                                                                                 

     DAT1             DAT2-10                            DAT2-18             DAT2-26                DAT3              DAT3                                        DAT3                           

                                                                                                                                                                                                 

                                   Random                                                                                    Additional                                                          
                                   assignment                                                                                DAT3's if                                                           
                                   of 1/3 of                                                                                 original                                                            
                                   cohort to                                                                                 DAT3 was                                                            
                                   receive                                                                                   completed                                                           
                                   either                                                                                    \<6 months                                                          
                                   DAT2-10,                                                                                  after stop                                                          
                                   -18, or -26                                                                               date                                                                
  -- ------ --- -- -- --------- -- ------------ -- -- -- --------- --- -- -- --------- --- -- -- -- ------ ---- -- -- ------ ------------ -- --- -- --- -- --- -- ------ -- -- -- -- -- -- -- -- --

Enrollment

  --- --- --- --- --- --- --- --- --- ----- --- --- --- --- --- --- --- --- ---
                                      34w                                   

                                                                            
  --- --- --- --- --- --- --- --- --- ----- --- --- --- --- --- --- --- --- ---

-1 0 5 6 7 8 9

  --- --- --- --- --- --- -- ----- --- -- -- -- ----- ---- -- -- ----- -- --- --- --- -- ----- -- -- --- ---
                                                                                                         

                             AT1                AT2              AT2                     AT2             
  --- --- --- --- --- --- -- ----- --- -- -- -- ----- ---- -- -- ----- -- --- --- --- -- ----- -- -- --- ---

**Chart 2. Overlap of 3 currently active, isotretinoin patient
surveys.**

***+(old) SLONE Accutane Enrollment***
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

***++(new) Degge/SI Accutane***

> Initial Treatment Survey During Treatment Survey

DAT 1 ONLY DAT 2

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Nov 20, 2002 -- March 31, 2003 April 1, 2003\-\-\-\-\-\-\-\--ongoing

***++ (new) SLONE generics enrollment***

DAT 1

> \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

April 1, 2003\-\-\-\-\-\-\-\-\-\-\-\--ongoing

***SMART 1 yEAr Evaluation***

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

April 1, 2002\-\--March 31, 2003

    

  ⇑

April 1^st^ Oct Jan **~1st\ quarter~** March **~2nd\ quarter~** June Aug
15 31 30 cutoff

+Survey does not include questions to determine compliance with certain
elements of SMART including issuance of a qualification sticker.

++Surveys contain questions that are specifically designed to determine
compliance with SMART including issuance of a qualification sticker.

APPENDIX 5---EXECUTIVE SUMMARY OF THE SPONSOR'S ANALYSIS OF THE SMART
PROGRAM

::: Definition-Term
Note: The following excerpt is copied verbatim from pages 11-13 of the
sponsor's submission dated June 30, 2003, "1 Year Report on the SMART
Program, including the patient survey, pharmacy prescription compliance
survey, and global assessment.
:::

This report provides a brief regulatory history of the S.M.A.R.T.
program, a summary of the first year of the S.M.A.R.T. program and an
evaluation of the program based on the predetermined primary and
secondary assessment metrics. The report examines pregnancy reporting
for the first year of S.M.A.R.T. in an exploratory manner. Detailed
methodologies and protocols for both the Accutane Survey and the
Prescription Compliance Survey are included, as well as for pregnancy
reporting.

The data in this report pertain to prescriptions written for Accutane
and patients who initiated Accutane treatment during the period April 1,
2002 -- March 31, 2003. In some cases comparisons are made with
historical data from the four quarters prior to initiation of the
S.M.A.R.T. Program or from earlier years.

This evaluation of the first year of the S.M.A.R.T. Program is affected
by four factors: (1) a change in vendors for the Accutane Survey and an
incomplete transition from one vendor to the other; (2) the entrance of
generic isotretinoin to the US market in November, 2002; (3) decline in
the use of Accutane by females of childbearing potential, and (4) the
classification of spontaneous post-marketing pregnancy reports according
to a discrete time period of Accutane treatment initiation, as well as
according to when they were reported to Roche. Historically pregnancy
case reports have been classified solely on the basis of the date
reported to Roche.

All four of these factors may confound the data in this report to a
lesser or greater extent. Each factor, and its potential impact on the
data, is described in the appropriate section of the report.

The main results of the first year S.M.A.R.T. evaluation include:

**Primary Metrics, Accutane Survey**

-   Accutane Survey enrollment rate of 28.2%, based on a denominator of
    new female patient starts. This represents an approximate 10
    percentage point increase in the Survey enrollment rate from the 4
    quarters prior to S.M.A.R.T., and reverses a downward trend in
    Survey enrollment rates observed in a retrospective review. At this
    time, it falls short of the anticipated 60% enrollment rate. It is
    possible that some enrollees since November of 2002 may be
    double-counted or be taking generic isotretinoin. At this time there
    is no way to conclusively identify these patients.

-   Accutane Survey respondents are generally representative of the
    Accutane female patient universe on age (7 groups), prescriber
    (dermatologist, non-dermatologist), payer (cash Medicaid, third
    party), and geographic region of the country.

    **Primary Metrics, Prescription Compliance Survey**

-   97.2% of Accutane prescriptions have the Accutane Qualification
    Sticker attached

-   96.4% of Accutane prescriptions with Qualification Stickers have the
    Qualification Sticker correctly completed

-   There are no significant differences in Accutane Qualification
    Sticker compliance by geographic region or patient demographics.

The presence of a correctly completed Qualification Sticker on the
Accutane prescription documents that the female patient is qualified,
and includes the date of qualification (confirmatory negative pregnancy
test), patient gender, cut-off date for filling the prescription and a
30 day supply limit with no refills. In order to obtain the
Qualification Stickers, prescribers must have read the S.M.A.R.T. Guide
to Best Practices and signed and returned the completed S.M.A.R.T.
Letter of Understanding which documents that the prescriber understands
the safe and effective use of Accutane as described in the USPI, the
letter itself, and in the Guide to Best Practices.

**Secondary Metrics, Accutane Survey**

-   97% of respondents indicate recall of the Accutane Qualification
    Sticker attached to their prescription (consistent with primary
    metric of sticker use in PCS)

-   92% of patients recall at least one pregnancy test prior to starting
    Accutane therapy; pre-S.M.A.R.T. was 76%

-   63% of patients report two pregnancy tests prior to starting
    Accutane, with slightly higher compliance among women aged 16-39

-   57.5 % of women who indicate the are sexually active report using
    two forms of contraception; 50% of women indicate they are not
    sexually active

-   non-compliance with two forms of contraception is considerably
    higher in women over the age of 20 (20% - 39%), compared with
    younger women (6%)

-   Accutane Survey enrollment via prescriber office is 56%;
    pre-S.M.A.R.T. was 21%

A high level examination of invalid and absent responses to the Accutane
Survey indicated relatively high proportions of invalid and absent
responses to several key questions that measure S.M.A.R.T. compliance.

There were 97 pregnancies with Accutane therapy start date reported or
estimated to be April 1, 2002 -- March 31, 2003 with conception
occurring prior to, during, or within 30 days after stopping Accutane,
reported to Roche as of the cut-off date for this report (May 15, 2003).
At least 6 of these pregnancies occurred in a multi-source environment
for isotretinoin. Because pregnancy case report data are not yet mature
for the first year S.M.A.R.T. cohort, no conclusions can be drawn about
the impact of S.M.A.R.T. on pregnancy prevention. The Accutane Survey is
the source of a pregnancy rate for women taking Accutane. Historically,
since 1989, this rate is not calculated until 6 months after the last
patient entering the cohort completes her Accutane treatment and
completes follow-up. This results in a reporting lag of about 18 months.

**Conclusions**

Although the metric of 60% enrollment in the Accutane Survey has not yet
been met, the 28.2% enrollment, based on a denominator of new Accutane
female patient starts, represents an approximate ten percentage point
increase over the four quarters prior to S.M.A.R.T., and reverses a
downward trend in enrollment rates.

Representativeness of Accutane Survey respondents to the universe of
Accutane female patients in the United States was demonstrated for age,
prescriber, payer and geographic region of the country. While this does
not ensure the absolute comparability of all Survey respondents to all
Survey non-respondents, it suggests that the convenience sample is
reasonably representative of the population on the selected parameters.

The primary assessment metrics for use of the Accutane Qualification
Stickers were met and exceeded. A third metric pertaining to
distribution of the patient Medication Guide was achieved by including
the medication guide with the Accutane blister pack.

The secondary assessment metrics indicate improvements in
pre-prescription pregnancy testing and enrollment in the Accutane Survey
via the prescriber's office compared with pre-S.M.A.R.T. Age-specific
examinations of compliance pre-prescription pregnancy testing and
contraception indicate a small age difference for pregnancy testing. and
that older women are considerably less likely to use two forms of
contraception than younger women.

No final conclusions about pregnancy case reports can be drawn at this
time because the first year S.M.A.R.T. cohort is not yet mature for
pregnancy reporting.

Thus far, the S.M.A.R.T. Program has been successful in some areas
(e.g., use of the Accutane Qualification Sticker, improved enrollment in
physician office, improved recall of pre-prescription pregnancy testing)
and less successful in others (e.g., compliance with two baseline
pregnancy tests, compliance with use of 2 forms of contraception).

The results of this report suggest several areas of potential
improvement including the development of targeted interventions to
prescribers and patients who may have difficulties with various aspects
of the S.M.A.R.T. Program, and improvement in the methods used to
evaluate the effectiveness of the S.M.A.R.T. Program.

::: Definition-Term
**APPENDIX 6**---**DDRE / DSRCS CRITIQUE AND ANALYSIS OF
ACCUTANE/ISOTRETINOIN PATIENT SURVEY(S)**
:::

::: Definition-Term
**[Validity of patient survey questionnaire]{.underline}** - General
methodology and procedural issues with interest in validity and error
:::

Isotretinoin patient surveys are currently administered by two separate
groups (Slone Epi Group and Degge/SI) using three questionnaires[^21].
The Degge/SI and Slone Epi Group use two similar questionnaires for
women enrolling with Accutane-specific material and generic isotretinoin
materials, respectively. These generally similar instruments (see below)
incorporate SMART-specific metrics (e.g., presence of a prescription
qualification sticker). This instrument was first used during 4QTR02 by
Degge/SI. Slone did not introduce this instrument until 2QTR03. Women
submitting Accutane-brand enrollment material to Slone receive the
original (historic) questionnaire that does not include SMART metrics.

Both surveys have two armsError: Reference source not found: a DAT
(during and after treatment) arm and an AT (after treatment) arm. The
DAT arm collects information on the compliance and pregnancy events
during and after isotretinoin treatment. The AT questionnaire is sent
six months after enrollment. Thus, the information regarding compliance
behaviors is gathered retrospectively for the AT arm. The DAT instrument
collects detailed information related to compliance behaviors at
specific times during treatment: DAT-1 collects data soon after
enrollment; DAT-2 at 10, 18 and 26 weeks after enrollment. A DAT-3
questionnaire is sent to participants (who remained on therapy for
DAT-2) between weeks 26 and 34 post-initiation of therapy and thereafter
until treatment is completed.

::: Definition-Term
Follow-up on women who enrolled in the first year of SMART will be
complete in the third quarter of 2004 (i.e., 6 months following the
completion of the traditional 6 month follow-up frame established by
Slone for women who enrolled in the survey during the first quarter of
2003). Therefore, this review covers only the information available as
of October 2003. This includes all data from DAT1 and partial results
from DAT2 from women who enrolled during the first 2 quarters of SMART.
:::

::: Definition-Term
In an effort made to increase the response rate, the Slone Epidemiology
Group conducts a vigorous follow-up telephone process. Three weeks after
a second attempt to collect information from an enrollee via a mail
questionnaire, the enrollee is contacted via telephone. Once she is
reached, the questionnaire is then administered by telephone. Therefore,
patient surveys completed by the Slone Epidemiology Unit incorporate a
mixed mode approach. In general, telephone surveys are not as
appropriate as self-administered surveys to obtain sensitive, personal
information. A higher "social desirability" is expected in interactive
telephone surveys than self-administered surveys. Also, multiple call
backs implemented by the Slone Epidemiology Unit have potential to
increase compliance behavior.
:::

**Measurement error**

Measurement error occurs when the survey questions may not measure the
construct/objective of the survey because of wording, structure, or
concept of the questions. For example, one of the interest areas of DAT1
is to assess whether compliance with pregnancy testing is met at
initiation of Acutane/isotretinoin treatment. The questions regarding
the pregnancy testing, although sufficient to provide a general
assessment about whether the pregnancy test was performed within 4 weeks
of starting treatment, otherwise do not adequately address whether the
test is done at proper time per the label (i.e., during the first 5 days
of menstrual period or 11 days after the last act of unprotected sexual
intercourse). In addition, these questions do not adequately address
whether the pregnancy test is also performed prior receiving the
Accutane/isotretinoin prescription. Thus, it is difficult to access
pregnancy testing per the Accutane label within the survey.

The current Accutane/isotretinoin survey instrument is a follow-up,
mail-based, paper-and-pencil self-administered questionnaire (paper
SAQ). Although paper SAQ's are considered a superior mode to collect
honest responses to sensitive questions in contrast to either telephone
or person-to-person interviews, it still has limitations, particularly
when the responders have concerns regarding the privacy of their
responses.[^22] This is relevant as the Accutane/isotretinoin survey is
a follow-up survey and thus the identity of the enrollee/respondent is
not anonymous to the survey agency. Under both PPP and SMART programs,
female patients are to be educated about the risk of pregnancy exposure
and sign a consent form to verify that she understood the risk. As a
result, when patients are asked about their compliance behavior, they
may report "desirable behavior" more than actual truth in order to avoid
possible embarrassment.

Another problem with the self-administered questionnaire in this setting
is a lack of probing interviewer questioning. If a self-administered
questionnaire with many complex skipping patterns does not effectively
guide the respondent to fill out the questions in a appropriate order,
the respondent may become frustrated and answer the questions without
thought. From, our analysis of the 3^rd^ and 4^th^ quarters of SMART
data (SI/Degge survey), it is clear that a large number of respondents
did not follow the skip patterns and therefore there is concern about
the reliability of the answers.

::: Definition-Term
Another important issue about this survey methodology is reliance on the
memory of participants to recall the events and experience related to
compliance with the SMART program. For example, dates regarding
pregnancy testing, prescription date filling, and start of therapy
should be precise in order to assess the SMART program. The closer in
time between the date of event to collection of data, the lower the
probability of recall bias. Unfortunately, not all women receive and
fill out this survey close to the event under study. A large proportion
(about one-third) of women respond to the DAT-1 questionnaire 30 or more
days after enrollment and initiation of treatment.
:::

**Editing/processing error**

Editing and processing errors arise from 1) data entry problems, 2) lack
of procedures to verify that the data captured are plausible, and 3)
post-hoc coding and redefinitions. Although, Degge/SI has implemented
many procedures to handle invalid values, DDRE analysis of data from
Degge/SI has noted inconsistent skip patterns and invalid/ inconsistent
dates for pregnancy testing, treatment start dates, and receipt of drug
dates.

::: Definition-Term
**Coverage Error**
:::

The enrollment or coverage rate measures the number of women who
enrolled in the Isotretinoin Patient Survey (the sampling frame) in
relation to the women who were eligible to participate (the inference or
target population). Coverage errors occur when all women who are
eligible to participate are not given an equal chance to participate in
the Survey. Because of the volunteer nature of the Survey, potentially
important subgroups of patients may choose not to participate,
compromising the generalizability of the Survey to the target
population.

The calculated enrollment rates were 21% for Slone for the 1^st^ year of
the S.M.A.R.T. program, and 14% for S.I./Degge for the period from
October 1, 2002 to March 30, 2003. The sponsor reported an overall
enrollment rate of 28% for the 1^st^ year of the S.M.A.R.T program. Low
coverage rates such as these do not automatically indicate that coverage
error is present in this Survey; however, the coverage rate is generally
used to assess the degree of uncertainty present when generalizing
results to the target population, with lower coverage rates
corresponding to higher uncertainty. Due to the recruitment methods and
voluntary nature of the survey, there is a real possibility that more
compliant individuals preferentially enrolled. This would lead to a
higher likelihood of coverage error and make interpretation of any
results problematic, and may limit the usefulness of any conclusions
drawn.

::: Definition-Term
**Unit Non-Response Error**
:::

Unit non-response is the failure of participants to respond to the
mailed questionnaire. This type of error would arise if women who
responded to the questionnaire systematically differed in some way,
particularly compliance behavior, from those who did not return the
questionnaire. As with coverage rate, low response rate does not
necessarily mean that any results will be biased, however, the response
rate is often used as an indication for the likelihood of bias occurring
(the lower the response rate, the more likely that survey results will
be biased). Unfortunately, comparison of non-respondents with those who
responded to the questionnaire is often not possible, since relevant
variables are not routinely available for both populations. For example,
information on pregnancy testing done at the physician's office is
available only for women who responded to the survey. If respondents
were more or less likely to have a pregnancy test at the physician's
office than non-respondents, this would result in incorrect survey
conclusions regarding pregnancy testing by physicians.

For the S.I./Degge survey, the sponsor reported 8,269 enrollees, of
which 6,615 (80%) were given the DAT1 questionnaire. The estimated
response rate for the S.I./Degge survey is approximately 83% of
enrollees[^23], or 5,489 individuals. When this rate is combined with
the 14% enrollment rate, the S.I./Degge Accutane Prescription Survey
reflects information on approximately 12% of the women who were
prescribed Accutane.

The Slone survey had a response rate of 97% for the 1^st^ year of the
S.M.A.R.T. program. This very high rate could be the result of intensive
follow-up on the part of Slone. While the S.I./Degge follow-up consisted
of a reminder phone call approximately six weeks after the DAT1
questionnaire was mailed, Slone attempted to contact women repeatedly,
up to 14 attempts in a two-week period. However, despite the high
response rate, when combined with an enrollment rate of 28%, the Slone
Accutane Prescription Survey reflects information on approximately 22%
of women who were prescribed Accutane.

**Item Non-Response Error**

Item non-response is the failure of participants to answer individual
items on the questionnaire. For the Degge/SI Accutane Patient Survey in
particular, some of the questions regarding the recall of exact dates
have relatively high levels of missing data. When examined in
conjunction with the unit non-response rate, the overall non-response
rate is quite high for some variables. For example; the pregnancy test
date is missing for about 27% of women who are apparently fertile and
are 15-45 years of age. Thus the overall non-response rate for pregnancy
test date is 39%. In another words any conclusion about appropriateness
of conducting pregnancy test among the ***enrolled*** population is
questionable since this information is available for 61% of apparently
fertile and 15-45 years of age women who enrolled in Degge/SI Accutane
survey \[83% (response rate) x (100 - 27%)\].

**[Assessment of survey questionnaire]{.underline}**

This section provides detailed comments on individual questions in the
Accutane Patient Survey from both Slone and SI/Degge.

**Overview**

DAT-1 is the first questionnaire filled out after the participant
enrolls in the program. Later questionnaires (DAT-2 and DAT-3) are
shorter and include some questions similar to those in the DAT-1, plus a
few questions that are new. (See the end of this document for a
comparison of question content among the DAT-1 and DAT-2 questionnaires.
We have not yet received data from the DAT-3 questionnaires.)

The Slone questionnaire was developed first, when the survey began in
1989. The SI/Degge questionnaire was developed after the S.M.A.R.T.
program began in 2002. For the most part, the SI/Degge DAT-1
questionnaire includes all of the questions used by Slone and adds some
additional questions relating primarily to aspects of the S.M.A.R.T.
program. The two DAT-2 questionnaires are similar, but do have a few
questions that do not appear on both. The comments below refer primarily
to the DAT-1 questionnaires. The comments below will discuss any notable
features of the DAT-2 and DAT-3 questionnaires for both studies, but
will focus primarily on DAT-1 because it is more comprehensive.

**Specific Questionnaire Comments**

In general, the DAT-1 questionnaires are lengthy, particularly the
SI/Degge version (40 questions, compared with 25 questions on Slone
version). The more lengthy the questionnaire, the more likely that
participants will become fatigued, which can result in less accurate
data for the later questions. The questionnaires also are probably
difficult for many participants to complete for reasons described below.

[Coverage of Important Elements of the S.M.A.R.T. Program]{.underline}

Some important aspects of the S.M.A.R.T. program are not addressed by
the questions. Most importantly, the questions do not completely address

-   whether patients were using two adequate forms of birth control
    continuously during product use

-   whether patients had sex with more than one male. Several questions
    ask about the fertility of a male partner. However, if the woman had
    more than one partner, there is no way to report that fact.

-   whether women with amenorrhea were tested for pregnancy at least 11
    days after the last act of unprotected sex before starting to take
    isotretinoin.

    [Questionnaire Development]{.underline}

```{=html}
<!-- -->
```
-   The questionnaires were developed using a set of objectives for the
    study. There should have been sufficient questions to cover all of
    the objectives and every question should relate to an objective. The
    following objectives reflect aspects of the S.M.A.R.T. program that
    were tested by the survey:

1.  to determine female patient awareness of the teratogenic risks of
    Accutane/Isotretinoin

2.  to measure compliance with key elements of S.M.A.R.T., including
    informed consent, pregnancy testing, contraception use, Medication
    Guide, and Accutane/Isotretinoin Qualification Stickers

3.  to calculate the rate of pregnancy among female
    Accutane/isotretinoin users

4.  to identify risk factors for the occurrence of pregnancy

-   It was not clear what the utility was of some of the questions.
    Because the DAT-1 questionnaire, particularly the SI/Degge version,
    was rather long and complex, questions that are not absolutely
    necessary should not have been included.

    [Readability and Complexity of Questionnaires]{.underline}

It may have been difficult for many participants to read and respond
accurately to the questionnaires due to complicated skip patterns, small
print size for some questionnaires, lack of adequate instructions,
complexity of some of the questions, language that could have been
simplified, and other factors. Listed below are some of the possible
problems of readability and complexity that could have led to
difficulties in responding:

-   The overall format is complex, with skip patterns that may be
    difficult to follow.

-   The print size may be too small on the Slone instruments to be read
    comfortably.

-   Fatigue may develop due to the length and complexity of DAT-1,
    particularly the SI/Degge version, making later responses less
    accurate.

-   For some types of questions, there are no examples provided for how
    to fill out the questions. For example, in the SI/Degge
    questionnaire, there are boxes to fill in with numbers for dates,
    ages, and numbers of pregnancy tests. Some participants may not
    understand how to use the boxes, particularly if there is a single
    digit number for the response and there are two boxes available. On
    the SI/Degge form, there is no instruction on how to fill in
    circles. Some participants may have checked them or "X'd" them
    instead of filling them in with a solid circle.

-   For one question, there is a table to fill out that may be
    complicated for some participants. The table lists 12 different
    birth control methods and asks which are currently used and for how
    long they were used. For each of the 12 methods, participants have a
    choice of 13 different responses about the length of use. There is
    no provision to indicate uncertainty.

-   For some questions, choices were not mutually exclusive, yet there
    were no instructions that more than one could be chosen. For
    example, the SI/Degge question about whether there was a yellow
    sticker on the prescription gives among the choices that someone
    else obtained and filled the prescription and that the patient
    didn't see the prescription. Both of these could be correct if
    someone else filled the prescription.

-   A footnote on the bottom of the first page of the SI/Degge
    questionnaire lists a series of questions that should not be
    answered if the woman has not yet started taking
    Accutane/isotretinoin (Q. 2-3, 24-27, 30-32, 36-38). It is possible
    some women would not notice this footnote, which is linked to a
    small asterisk in one of the choices for the first question. Even if
    the footnote had been read, it is highly possible that it would be
    soon forgotten as the woman worked her way through the
    questionnaire. The questions that should have been skipped were not
    marked as such. From the content of the questions, it may have been
    apparent that only those who had taken Accutane/isotretinoin should
    have responded. However, it would have been better to make it more
    obvious which questions were not for women who had not yet started
    treatment.

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```
-   The terminology used for many questions may be difficult to
    understand. Question language could have been simplified.

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```
-   The layout for the question in the SI/Degge questionnaire on whether
    particular materials had been received and read may be confusing.
    There are two lines "pink spiral notebook" and "Self-Assessment"
    that are not clearly associated with response choices. It appears
    that they are connected to the line either below or above them, but
    because there is no indentation, they are aligned the same as the
    other lines, and it is not clear where they belong.

    [Poor or ambiguous questions]{.underline}

Some questions seem to be ambiguous, making it difficult for some
participants to respond accurately or for us to understand the results
fully. Examples are below:

-   One question asks if the doctor told the patient that it is
    important not to become pregnant. It is not clear how a woman should
    answer if another health care provider told her this information,
    but the doctor did not. The participant may not know whether the
    question is designed to find out who delivered this message to find
    out if anyone in the office delivered this message.

-   One question asks if certain materials about Accutane/isotretinoin
    were read. At the end of the list is \"other materials.\"
    Participants may not know what \"other\" refers to. We do not know
    if it refers to materials that are not part of the S.M.A.R.T.
    program, such as advertisements, something from a website, or from
    other sources, if it refers to materials from the sponsor or the
    doctor, or materials from other sources. We do not know if the
    purpose of the question to find out if patients read anything
    besides the documents listed, or whether the question is targeting
    only specific types of documents, such as those from the sponsor.

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```
-   One question asks if the woman had any other blood or urine tests in
    the four weeks before starting Accutane/isotretinoin. We do not know
    if this question should have been limited only to pregnancy tests,
    or whether it includes tests for other purposes. If only for
    pregnancy that should be made clear. Women may have had tests for
    other purposes during this period.

-   There is no provision for responses about more than one male
    partner.

-   One question asks if the pharmacist provided instructions about
    Accutane/isotretinoin treatment. The question does not specify
    whether the instructions were written or oral. Almost all pharmacies
    provide computer-generated printouts of information about
    prescriptions dispensed, and any information pre-packaged with the
    product, such as the Medication Guide for Accutane/isotretinoin,
    would have come from the pharmacist. Thus, 100% should have
    responded that they got instructions. However, if the purpose of
    this question was to determine if participants received oral
    instructions, that purpose was not well served by this question.

-   A question on the SI/Degge form asks if the doctor's office gave the
    woman a home pregnancy test kit. It does not specify a time frame.
    The Slone version of this question asks if the doctor advised the
    woman to do a home pregnancy test in the four weeks before starting
    Accutane/ isotretinoin. The source of the test is not mentioned. If
    it is important to know if doctors are offering test kits to
    patients, the Slone question will not provide that information.

-   The question about whether the woman had been pregnant since first
    starting Accutane/ isotretinoin may be confusing to women who had
    stopped the medication before getting pregnant. Further, one choice
    of responses is \"not sure,\" which is difficult to interpret.

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```
-   The questions about the timing of any pregnancies in relation to
    timing of treatment are not asked directly in DAT-1. As a result,
    the sponsor has had to try to figure out whether women were pregnant
    at inappropriate times based only on the dates given for timing of
    treatment and pregnancies. As these data are frequently missing or
    may be inaccurate, this method is not ideal. The DAT-2 and DAT-3
    questionnaires do ask about pregnancies more directly and may
    provide better data regarding timing of pregnancies in relation to
    product use.

    [Question composition and flow]{.underline}

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```
-   Some questions are leading, making them more likely to elicit a
    correct response. These are questions about knowledge of
    contraception and the effects of isotretinoin on a fetus, as well as
    questions that are likely to elicit a socially desirable response.

-   There are few \"false positive\" questions or choices that would
    enable us to determine if there is a response bias operating for
    some sets of questions. Many of the questions describe actions that
    should have been taken. It would have been better also to include
    actions that would have been inappropriate, to see if participants
    answered them correctly as well.

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```
-   Questions that ask if women knew of certain things, such as the
    toll-free information line, may result in biased responses. Many
    women may be uncomfortable admitting they don\'t know something and
    would therefore be more likely to answer affirmatively. It would
    have been helpful to ask these questions in another way, such as
    with a checklist containing actual and non-existent aspects of the
    program.

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```
-   The questions used to test understanding of the material about birth
    defects and avoiding pregnancy did not test understanding well. They
    included leading questions and simple true/false questions. They did
    not require application of the knowledge to hypothetical situations
    that would better test knowledge, and they contained almost no false
    positive questions. It would have been easy to score well without
    much information about avoiding pregnancy.

    [Memory Issues]{.underline}

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```
-   Questions that rely on memory are problematic. For example, many
    questions ask for specific dates when certain events happened (date
    of partner\'s vasectomy, own tubal ligation; dates received
    prescription and started medication \[SI/Degge\]; date stopped
    medication, if applicable; date of last period before pregnancy;
    specific ages when acne developed; age when first saw doctor for
    acne). For many questions, there are no instructions to provide
    approximations of dates that are not known exactly or to answer
    \"don\'t know.\" Thus, the results may be unreliable or missing
    data. For DAT-2, questions requiring excellent memory or use of
    records included questions about the number of times the woman saw
    her doctor since beginning treatment, numbers of blood and urine
    tests, numbers of times she had sex in the past month, and whether
    sex is more frequent in the past month than in the three months
    before starting Accutane/isotretinoin treatment.

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-   Many of the questions involving dates and pregnancies are indirect
    ways of trying to determine if the woman was pregnant during the
    period of time for which it was inappropriate. It would be better to
    ask such questions more directly or get that information from the
    prescriber rather than relying on faulty memory or ambiguous
    questions.

    [Unnecessary Questions]{.underline}

Some questions do not seem to be necessary, such as age when acne first
developed, when a doctor was first consulted about the acne, whether the
patient ever had intercourse with a male, and whether the doctor's
office told the woman she would receive a survey enrollment form in the
medication package (SI/Degge). Because the DAT-1 questionnaires were
rather lengthy, particularly the SI/Degge questionnaire, any unnecessary
questions should have been eliminated from the instrument.

[Questions that Might Produce Ambiguous Responses or Cause Participants
to Skip Questions]{.underline}

Some questions may be phrased inappropriately to get the answers
desired, or may mislead participants into skipping later questions.

-   In questions about whether certain documents were read, there is no
    provision to ask **how much** of the documents were read. If someone
    answered that she read the document, it may be that just a few
    paragraphs were read, just headings, selected parts, or all. For
    example, one question asks if the person read the information on the
    Accutane/isotretinoin package. The only alternatives were yes and
    no. There is no provision for determining how much was read.

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```
-   One question asks if the woman currently uses birth control. If she
    answers \"no,\" she is to skip the next question with a table about
    which methods were used and for how long. Unfortunately, surgical
    procedures (vasectomy, tubal ligation) and in the Slone survey, the
    rhythm method/natural family planning, are included in the table.
    Some women may respond that they are not using birth control because
    they do not think of the surgical procedures or the rhythm
    method/natural family planning in terms of traditional birth
    control. They are thus likely to skip the table and will not respond
    about using those methods.

    [Unknown Information]{.underline}

Some questions may not be within the knowledge of the participants. For
example, they may not know whether they had serum pregnancy tests or how
many they had. They may not have known the month and year of a partner's
vasectomy, among other dates. Thus, responses to these questions may not
be accurate or may be missing. However, because there was no alternative
to say "don't know," we do not know whether responses were just guesses,
or if responses provided correct information.

**General Conclusions**

The questions do not adequately address all aspects of the S.M.A.R.T
program. In addition, the questionnaires are too complex to provide
accurate data. Many questions rely on memory and may be vague or
confusing to some participants. Shorter questionnaires with more
targeted questions, less ambiguity, simpler language, and no skip
patterns would result in better data. The sponsor should also consider
the advantages and disadvantages of having interviewers ask the
questions or using computer-assisted questionnaires.

**Implications of Questionnaire Problems**

The types of difficulties with these questions that are described here
could result in inaccurate responses, omissions, and data that are
difficult to interpret. Shorter questionnaires with more targeted
questions, less ambiguity, simpler language and no skip patterns would
result in better data. Different methods of administering the
questionnaires should be considered.

**Recommendations for change**

Based on the foregoing discussion, we recommend changes in future
surveys to reduce the possibility of unreliable and missing data.
Suggestions include the following:

-   Pretest the questionnaires with a range of potential or actual
    product users, to be sure the questions are understood, can be
    answered easily, and are not too lengthy. Make changes as necessary.

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```
-   Develop a list of detailed objectives for the study, and design
    questions to address those objectives.

-   Shorten questionnaires to include only the questions that relate to
    the objectives and only that information that cannot be provided by
    the prescriber.

-   Simplify language.

-   Provide examples of how to answer questions that are fill in the
    blank or fill in a circle or box.

-   Include alternatives of \"don\'t know\" where appropriate.
    Otherwise, we do not know if questions are left blank because the
    participant does not have the answer or does not want to respond.

-   Avoid skip patterns.

-   Design the questionnaire so there is less reliance on memory. The
    following suggestions may help:

-   Have questions involving dates filled out as they happen (for
    example, use a diary), and/or have many questions filled out in the
    doctor\'s office under the supervision of a trained person in the
    office.

-   Reframe questions so they do not rely on providing specific dates.

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```
-   To the extent possible, obtain information from the prescriber,
    rather than from the patient, who may have a faulty memory.

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```
-   Consider having trained interviewers ask the questions face to face
    or by telephone, or use computer assisted questionnaires. These
    methods would avoid the problems of skip patterns and complex tables
    that now must be filled in by participants. Using interviewers would
    assure that all questions are understood and answered. Interviews
    could occur in the prescriber's office or could be done by
    telephone. Computer-assisted questionnaires could be administered in
    doctors\' offices, but, for the sake of practicality, might have to
    be done in more central locations. The benefit of using interviewers
    would be a much higher response rate, ability to explain questions,
    to probe, and to use skip patterns properly. The advantages of the
    computer-assisted questionnaires include anonymity and avoidance of
    skip patterns.

> However, the downside of these approaches would be increased cost.
> Further, for the interviews, there is increased potential for women to
> answer falsely because they would believe their responses would not be
> anonymous. Instead, they would answer in socially desirable ways. The
> sponsor may be able to develop a procedure that would assure
> participants that they are anonymous to the interviewers and that
> their information would have no identifying information. A shortcoming
> of telephone interviews might be the possibility that others could
> overhear the participant as she answers questions, which could inhibit
> her responses. Central locations for computer assisted questioning may
> be inconvenient for participants.

Without changes of the type suggested here, it is likely that results
will not provide the best information that would be possible for these
questions. Therefore, some of the data already collected may be
inaccurate.

[Comparison of questionnaires]{.underline}

The following multi-page table provides a comparison of the questions
found in the DAT questionnaires for which we have data at this time
(DAT-1 and DAT-2). There were slight variations in DAT-1, depending on
whether the form was from the doctor, the medication package, or the
toll-free number.

+---+---+---+--------------------------+--------+-------+---------+---------+
| * |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| A |   |   |                          |        |       |         |         |
| P |   |   |                          |        |       |         |         |
| P |   |   |                          |        |       |         |         |
| E |   |   |                          |        |       |         |         |
| N |   |   |                          |        |       |         |         |
| D |   |   |                          |        |       |         |         |
| I |   |   |                          |        |       |         |         |
| X |   |   |                          |        |       |         |         |
| 7 |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| - |   |   |                          |        |       |         |         |
| - |   |   |                          |        |       |         |         |
| - |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| T |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| b |   |   |                          |        |       |         |         |
| l |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| f |   |   |                          |        |       |         |         |
| C |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| m |   |   |                          |        |       |         |         |
| p |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| f |   |   |                          |        |       |         |         |
| A |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| u |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| / |   |   |                          |        |       |         |         |
| I |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| Q |   |   |                          |        |       |         |         |
| u |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
+===+===+===+==========================+========+=======+=========+=========+
| * |   |   |                          | *      | **DA  | **DAT-2 | **DAT-2 |
| * |   |   |                          | *DAT-1 | T-1** | (New)** | (Old)** |
| I |   |   |                          | (      |       |         |         |
| s |   |   |                          | New)** | **(O  |         |         |
| s |   |   |                          |        | ld)** |         |         |
| u |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
| * |   |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+
| D |   |   |                          | x      | x     |         |         |
| i |   |   |                          |        |       |         |         |
| d |   |   |                          |        |       |         |         |
| y |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| u |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| k |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| y |   |   |                          |        |       |         |         |
| A |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| u |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| / |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| n |   |   |                          |        |       |         |         |
| ? |   |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+
|   | * |   |                          | x      | x     |         |         |
|   | I |   |                          |        |       |         |         |
|   | f |   |                          |        |       |         |         |
|   | y |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | s |   |                          |        |       |         |         |
|   | * |   |                          |        |       |         |         |
|   | , |   |                          |        |       |         |         |
|   | d |   |                          |        |       |         |         |
|   | a |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | s |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | a |   |                          |        |       |         |         |
|   | r |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | d |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+
|   | * |   |                          | x      | x     |         |         |
|   | I |   |                          |        |       |         |         |
|   | f |   |                          |        |       |         |         |
|   | n |   |                          |        |       |         |         |
|   | o |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | * |   |                          |        |       |         |         |
|   | , |   |                          |        |       |         |         |
|   | d |   |                          |        |       |         |         |
|   | a |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | x |   |                          |        |       |         |         |
|   | p |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | c |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | o |   |                          |        |       |         |         |
|   | s |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | a |   |                          |        |       |         |         |
|   | r |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+
|   | * |   |                          | x      | x     |         |         |
|   | I |   |                          |        |       |         |         |
|   | f |   |                          |        |       |         |         |
|   | n |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | v |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | r |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | o |   |                          |        |       |         |         |
|   | o |   |                          |        |       |         |         |
|   | k |   |                          |        |       |         |         |
|   | * |   |                          |        |       |         |         |
|   | , |   |                          |        |       |         |         |
|   | t |   |                          |        |       |         |         |
|   | e |   |                          |        |       |         |         |
|   | l |   |                          |        |       |         |         |
|   | l |   |                          |        |       |         |         |
|   | w |   |                          |        |       |         |         |
|   | h |   |                          |        |       |         |         |
|   | y |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+
| D |   |   |                          | x      |       |         |         |
| a |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| f |   |   |                          |        |       |         |         |
| f |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| p |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| e |   |   |                          |        |       |         |         |
| s |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
| p |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
| i |   |   |                          |        |       |         |         |
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| l |   |   |                          |        |       |         |         |
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| w |   |   |                          |        |       |         |         |
| h |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| c |   |   |                          |        |       |         |         |
| a |   |   |                          |        |       |         |         |
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| l |   |   |                          |        |       |         |         |
| p |   |   |                          |        |       |         |         |
| l |   |   |                          |        |       |         |         |
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| a |   |   |                          |        |       |         |         |
| t |   |   |                          |        |       |         |         |
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| y |   |   |                          |        |       |         |         |
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| u |   |   |                          |        |       |         |         |
| f |   |   |                          |        |       |         |         |
| o |   |   |                          |        |       |         |         |
| r |   |   |                          |        |       |         |         |
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| w |   |   |                          |        |       |         |         |
| - |   |   |                          |        |       |         |         |
| u |   |   |                          |        |       |         |         |
| p |   |   |                          |        |       |         |         |
+---+---+---+--------------------------+--------+-------+---------+---------+

**APPENDIX 8**---**EXTRAPOLATION OF PREGNANCY RATES FROM VOLUNTARY
SURVEYS**

The Slone Survey, implemented in 1989, was designed to, "assess the
compliance of physicians and patients with the Accutane Pregnancy
Prevention Program and to identify the rate of pregnancy during
treatment with isotretinoin and during the month after treatment." Allen
Mitchell, MD, the primary investigator for the validity of the Slone
Survey has made comments[^24]^,^[^25] on both the "internal validity"
and "external validity" of the Survey. Internal validity refers to the
degree to which the results of a study are correct for the sample of
patients included in the study. External validity (also referred to as
representativeness or generalizability) refers to the degree to which
the results of a sample hold true to the population at large. Mitchell
et al stated that the internal validity of the survey is supported by
high follow-up rates and an increase in pregnancy rates in the months
following Accutane therapy. The response rate for the DAT arm of the
study is reported as 97-98% (after follow-up telephone calls when
needed). However, the response rate for the AT arm is lower. Briefly,
women followed in the AT arm receive a tracking questionnaire
approximately 6 months after enrollment and the AT questionnaire 6
months after stopping isotretinoin, typically 11 months after
enrollment. For the 1989 through 2001 cohorts, the response rate to the
AT questionnaire is 80%. With the exception of the most recent two
cohorts, the response rate has decreased for each consecutive cohort,
form 90% for the 1989-90 cohorts to 88%-72% for the next nine cohorts.
For the 2000 and 2001 cohorts, the rates are 78% and 76%, respectively.
Data for 2001 are incomplete. Mitchell et al further stated that the
changes in reports of elective abortion (more during treatment with
Accutane in comparison to the months immediately following Accutane
therapy) also support interval validity.

After assurance of internal validity, it is then important to examine
the generalizability of the Slone Survey to the population of
Accutane/isotretinoin users, as "good" data from a skewed population
results in a biased impression. To this end, Mitchell et al stated that
the generalizability of a survey based on voluntary enrollment requires
information on both absolute participation and differences between
participating and non-participating enrollees. For absolute
participation, Mitchell et al reported participation in Slone as 44% to
52% of women treated with isotretinoin in 1995 based on an estimate of
"women of childbearing age prescribed isotretinoin" by Hoffmann-La
Roche. \[Why the denominator was restricted to women of childbearing
age" instead of all women is not stated.\] In his presentation before
the September 2000 DDAC meeting, Mitchell et al reported two additional
estimates of absolute participation in the Slone Survey. In a "Roche
Consumer Survey 1990-1991," Mitchell presented the "proportion reporting
enrollment in the survey" as 239 / 400 = 60%. From a second study
matching patients enrolled in the Slone Survey and all women with a
prescription for Accutane in the United HealthGroup claims database,
Mitchell et al reported 38.4% of women with an Accutane prescription as
"definite" Slone participants. The percent increased to 45.9% with
"definite" and "possible" matches to Slone enrollees. In terms of the
characteristics of Slone enrollees verses non-enrollees, Mitchell has
written,[^26]

> "Whether \[Slone\] participates differed in pregnancy risk from women
> who did not enroll is not known. We assumed, a priori, that women who
> did not enroll were more likely to be noncompliant and at high risk
> for pregnancy; on the other hand, women may not enroll specifically
> because they are infertile or in other ways not at risk for pregnancy.
> Although some underreporting of pregnancies and therapeutic abortions
> is likely, we believe that the survey design and study population
> minimize this problem."

Mitchell et al included some data on patient characteristics in
presentation before the DDAC in September 2000. From the "Roche Consumer
Survey," Slone enrollees appeared similar to non-enrollees on general
demographics. However, among contraceptive users in this survey,
non-enrollees were about as likely as enrollees to report being sexual
active (54% vs. 64%) but much less likely to report use of the birth
control pill (16% vs. 40%). Mitchell et al have proposed to continue
efforts to describe patient characteristics of Slone participants and
non-participants patient characteristics with UHG in a report to Roche
of August 21, 2001 describing the "new" Slone Survey. In discussion,
Mitchell noted use of UHG has the following limitations:

1.  UHG is not representative of the US population.

2.  The matching process is imperfect.

3.  Prescription contraceptive use is problematic to ascertain as not
    all health plans cover prescription contraceptives.

As noted by Mitchell, generalizability is dependent on both absolute
participation and non-differential participation. Low participation
(also termed response rate) can undermine study validity by introducing
a selection bias, unless data are provided to indicate study responders
are similar to non-responders. While there is no formal rate of
participation upon which to delineate generalizability, surveys done
under contract Office of Management and Budget suggest a response rate
in excess of 75%.[^27] Effect and management of low survey
participation, in addition to general survey design issues, are also
addressed in other, selected texts.[^28]^,^[^29]^,^[^30]

Data to indicate non-differential participation might mitigate a low or
borderline impression of participation. However, Mitchell et al
presented data to suggest Slone non-participants are less likely to use
oral contraceptives. This finding is in keeping with Dr. Mitchell's a
priori position (included above) and published research in
cross-sectional surveys which suggests survey responders have less
prevalent disease and healthier life-styles than
non-responders[^31]^,^[^32]^,^ [^33]^,^ [^34] and are also less likely
to smoke, be unmarried, unemployed, and of lower socioeconomic status
than
non-responders.[^35]^,^[^36]^,^[^37]^,^[^38]^,^[^39]^,^[^40]^,^[^41]^,^[^42]

Although this document does not include analyses from the CDC's National
Survey of Family Growth \[NSFG\], comments on this survey are relevant
for review of the Slone Survey since both surveys attempt to collect
data on elective abortions by self-report. The NSFG is a periodic,
federally (CDC) funded, nationally representative survey of women aged
15 to 44 years on family, pregnancy, and fertility issues and has served
as a key source of information on reproductive behaviors of women in the
U.S. In discussion on self-report of elective abortion, CDC researchers
note that respondents in almost all fertility surveys, including the
NSFG, do not report all of their abortions.[^43] Two comparisons of NSFG
data with external data on elective abortions suggest the NSFG captured
only one-half to one-third of actual abortions^.^[^44]^,^ [^45] In
commentary on the extent of abortion underreporting in the most recent
(1995) NSFG, researchers at the Alan Guttmacher Institute stated,

> "Underreporting of induced abortions has rendered surveys such as the
> NSFG virtually unusable for description or analysis of unintended
> pregnancy and induced abortion."[^46]

This commentary is part of an analysisError: Reference source not found
of the most recent (1995) NSFG which included a self-administered
section designed to collect more complete data on elective abortions.
This analysis concluded that the 1995 NSFG collected 59% of actual
abortions, and underreporting varied substantially by demographic
characteristics (e.g., age, marital status, income, education). Since
isotretinoin is a confirmed human teratogen, and abortion a frequent
outcome for many women with an isotretinoin-exposed pregnancy, these
concerns place substantial limitations on projections of self-reported
pregnancies from participants in the Slone Survey.

In summation, the Slone Survey represents a small and biased sample of
female Accutane/ isotretinoin-users and these attributes would result in
under-reporting of abortion and/or pregnancy.

**APPENDIX 9**---**GLOSSARY OF ABBREVIATIONS AND DEFINITIONS OF TERMS**

The following are a list of abbreviations and definitions of terms used
in this review:

  ---------- ------------------------------------------------------------
  ALERT      Adverse Event Learning and Education Regarding
             Teratogenicity

  Degge/SI   The Degge Group with S.I. International

  IMPART     Isotretinoin Medication Program: Alerting you to the Risks
             of Teratogenicity

  ODS        Office of Drug Safety

  PCS        Prescription Compliance Survey

  PCS Audit  Prescription Compliance Survey Audit

  Post-RMP   The 1 year following the implementation of the isotretinoin
             RMP (April 1, 2002 to March 31, 2003) ; also may have been
             referred to post-SMART

  PPP        Pregnancy Prevention Program

  Pre-RMP    The 1 year prior to the implementation of the isotretinoin
             RMP (April 1, 2001 to March 31, 2002); also may have been
             referred to pre-SMART

  RMP        Risk Management Program

  SEU        Slone Epidemiology Unit

  SMART      System to Management Accutane Related Teratogenicity

  SPIRIT     System to Prevent Isotretinoin-Related Issues of
             Teratogenicity
  ---------- ------------------------------------------------------------

[^1]: Hoffmann-La Roche submission-General Correspondence:*1 Year Report
    on the SMART Program*, June 30, 2003

[^2]: Dermatologic and Ophthalmic Drugs Advisory Committee, September
    18, 2000.

[^3]: FDA announces changes to the risk management program to prevent
    birth defects caused by Accutane, FDA Talk Paper, October 31, 2001.

[^4]: See Appendix 4---Tables and Charts, Chart 1 Accutane /isotretinoin
    Patient Survey Operating Schema, pg 79.

[^5]: See Appendix 7---Table of Comparison of Accutane/Isotretinoin
    Questionnaires, pg 94.

[^6]: See Appendix 4---Tables and Charts, Chart 2. Overlap of 3
    currently active, Isotretinoin Patient Surveys, pg 80.

[^7]: Hoffmann-La Roche submission-General Correspondence:*1 Year Report
    on the SMART Program*, June 30, 2003

[^8]: Derived from Jick et al, Isotretinoin use and risk of depression,
    psychotic symptoms, suicide, and attempted suicide. Arch Dermatol
    2000;136:1231-6.

[^9]: Based on the assumption that the average total number of Rxs per
    unique individual until the end of therapy is 3.7. (Derived from
    Jick et al, Isotretinoin use and risk of depression, psychotic
    symptoms, suicide, and attempted suicide. Arch Dermatol
    2000;136:1231-6.)

[^10]: Data Sources per Hoffmann-La Roche 1 Year Report: Accutane Survey
    Enrollment form and NDC Health

[^11]: Data Sources per Hoffmann-La Roche 1 Year Report: Accutane Survey
    Enrollment form and total female prescriptions -- IMS Health

[^12]: Data sources per Hoffmann-La Roche 1 Year Report: reference
    population IMS; Accutane Survey DAT2 questionnaire

[^13]: See Isotretinoin Utilization Review, Table 2, pg 32.

[^14]: See Isotretinoin Utilization Review, pg 30.

[^15]:
    ::: Definition-Term
    See Appendix 6---DDRE / DSRCS Critique and Analysis of
    Accutane/Isotretinoin Patient Survey(s), pg 84.
    :::

[^16]: See Review of Prescription Compliance Survey to Measure
    Compliance with Isotretinoin Qualification Stickers, pg 35.

[^17]: See Review of Prescription Compliance Survey to Measure
    Compliance with Isotretinoin Qualification Stickers, Table 10, pg
    41.

[^18]: Appendix 4---Tables and Charts, Tables A, B, and C. Trends in
    Slone Contraceptive Status for age groups 15-24, 25-34, and 35-44
    years, pgs 77-8.

[^19]: Appendix 4---Tables and Charts, Chart 2. Overlap of 3 currently
    active, isotretinoin patient surveys, pg 80.

[^20]: Appendix 4---Tables and Charts, Table D. Selected and generally
    comparable variables as reported for two calendar quarters by three
    disparate isotretinoin patient surveys, pg 78.

[^21]: See Appendix 4---Tables and Charts, Chart 1.
    Accutane/Isotretinoin Patient Survey Operating Schema, pg 79.

[^22]: Turner C.F., et al. Adolescent sexual behaviour, drug use, and
    violence: increased reporting with computer survey technology.
    Science 1998;280:867-73

[^23]: Response rate is estimated from October, 2003 Survey results. The
    initial response rate, based on information up until July 2003, was
    66%. The sponsor did not provide an explanation for the drastic
    increase in response rate.

[^24]: Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention
    program in women of childbearing age receiving isotretinoin. N Engl
    J Med 1995;333(2):101-6.

[^25]: Letter. Allen Mitchell to Susan Ackermann, August 21, 2001.
    Survey of Accutane use in women protocol, August 21, 2001. As
    included in a submission from Hoffmann-La Roche, September 11, 2002.

[^26]: Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention
    program in women of childbearing age receiving isotretinoin. N Engl
    J Med 1995;333(2):101-6.

[^27]: Survey Research Methods, 2nd ed. F. J. Fowler, Sage Publications,
    London, 1993.

[^28]: Principles of Exposure Measurement in Epidemiology, B Armstrond,
    E White, and R Saracci, Oxford University Press, New York, 1992.

[^29]: Sampling Techniques, 2nd ed. W G Cocharan. Wiley & Sons, New
    York, 1953.

[^30]: Dillman D. mail and telephone surveys: the total design method.
    New York, NY: John Wiley & Sons, Inc, 1978.

[^31]: Criqui MH, Austin M, Barrett-Connor E. The effect of non-response
    on risk ratios in a cardiovascular disease study. J Chronic Diis
    1979;32:633-8.

[^32]: Bergstrand R, Vedin A, Wilhelmsson C, et al. Bias due to
    non-participation and heterogenous sub-groups in population surveys.
    J Chroni Dis 1983;36:725-8.

[^33]: Macera CA, Jackson KL, Davis DR, et al. Patterns of non-response
    to a mail survey. J Clin Epidemiol 1990;43:1427-30.

[^34]: Oakes TW, Freidman GD, Seltzer CC. Mail survey response by health
    status of smokers, non-smokers, and ex-smokers. Am J Epidemiol
    1973;98:50-5.

[^35]: Benfante R, Reed D, MacLean C, et al. Response bias in the
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[^36]: Gordon T, Moore FE, Shurtleleff D, et al. Some methodological
    problems in the long- term study of cardiovascular disease:
    observations from the Framingham Study. J Chronic Dis
    1959;10:186-206.

[^37]: Criqui MH, Barrett-Connor E, Austin M. Differences between
    respondents and non-respondents in a population-based cardiovasular
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[^38]: Heilbrun LK, Nomura A, Stemmermann GN. The effects of nonresponse
    in a prospective study of cancer: 15-year follow-up. Int J Epidemiol
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[^39]: Sheikh K, Mattingly S. Investigating non-response bias in mail
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[^40]: Doll R, Hill AB. Mortality in relation to smoking:ten years'
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[^41]: Selzer CC, Bosse R, Garvey AJ. Mail survey response by smoking
    status. Am J Epidemiol 1974;100:453-7.

[^42]: Walker M, Shaper AG, Cook DG. Non-participation and mortality in
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[^43]: Kelley JE , Mosher WD, Duffer AP, Kinsey SH. Plan and and
    operation of the 1995 National Survey of family Growth. Vital Stat
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[^44]: Jones EF, Forrest JF. Underreporting of abortion in surveys of US
    women: 1976-88. Demography 1992;29(1):113-26.

[^45]: Jones EF, Forrest JF. Contraceptive failure rates based on the
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[^46]: Fu H, Darroch JE, Henshaw SK, Kolb E. Measuring the extent of
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