**Date:** January 29, 2004

**From:** Carl Kraus, MD

Medical Officer,

Division of Special Pathogen and Immunologic Drug Products, HFD-590

**Through:** Renata Albrecht, MD

Director

Division of Special Pathogen and Immunologic Drug Products, HFD-590

**Through:** Edward Cox, MD MPH

Acting Director

Office of Drug Evaluation IV, HFD-104

**To:** Anne Trontell, MD, MPH

Deputy Director

Office of Drug Safety, HFD-400

**Subject: A Synopsis of the Elements of the *S.T.E.P.S.***^®^
**Program**

**Background**

[Thalomid^®^ (thalidomide) and its Approval]{.underline}

Thalomid^®^ (thalidomide) (Celgene, Corp.) was approved by the US FDA in
July 1998 under the restricted distribution provisions of Subpart H, 21
CFR §314.520. Approval under subpart H restricted distribution requires
that postmarketing restrictions are implemented to provide for the safe
use of the drug product. Specifically, Subpart H states the following:

§ 314.520 Approval with restrictions to assure safe use.

(a) If FDA concludes that a drug product shown to be effective can be
    safely used only if distribution or use is restricted, FDA will
    require such postmarketing restrictions as are needed to assure safe
    use of the drug product, such as:

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(1) Distribution restricted to certain facilities or physicians with
    special training or experience; or

(2) Distribution conditioned on the performance of specified medical
    procedures.

> \(b\) The limitations imposed will be commensurate with the specific
> safety concerns presented by the drug product.

The approved indications for Thalomid^®^ are the acute treatment of the
cutaneous manifestations of moderate to severe erythema nodosum leprosum
(ENL) and as maintenance therapy for prevention and suppression of the
cutaneous manifestations of ENL recurrence. The required risk management
program instituted by Celgene Corporation for the distribution of
Thalomid^®^ is the System for Thalidomide Education and Prescribing
Safety (*S.T.E.P.S.*^®^).

[Thalomid^®^ Prescribing Patterns]{.underline}

The major specific safety concern for thalidomide is teratogenicity and
the risk management goals are the prevention of fetal exposures to
thalidomide. An evaluation of recent usage patterns of Thalomid^®^ under
the *S.T.E.P.S.*^®^ program revealed that almost 90% of the prescribing
of Thalomid^®^ is for oncologic conditions. Between September 1998 and
April 2003, approximately 77,000 patients were prescribed Thalomid^®^ (a
total of approximately 400,000 prescriptions). Of these 77,000 patients,
approximately 4000 patients were females of childbearing potential.
Evaluation of the distribution of Thalomid^®^ recipients by gender finds
a slight predominance of male patients. The mean age for patients
receiving Thalomid^®^ in the *S.T.E.P.S.*^®^ program is approximately 65
years of age.

**A Synopsis of the *S.T.E.P.S.*^®^ Program**

[Elements of *S.T.E.P.S.*^®^ Program]{.underline}

The *S.T.E.P.S.*^®^ program includes a number of tools to manage the
risks of Thalomid^®^. The key elements of the *S.T.E.P.S.*^®^ program
include the following:

-   Product labeling informing of the risks of thalidomide and
    containing elements of the *S.T.E.P.S.*^®^ program

-   Required registration of all prescribers, patients, and pharmacists
    who prescribe, receive, or dispense Thalomid^®^ (thalidomide)

-   Six risk groups based on age, gender, and reproductive status

-   A patient acknowledgement / informed consent form

-   Authorization validation prior to dispensing Thalomid^®^

-   A required telephonic survey (utilizes an interactive voice response
    system (IVR)) that patients and prescribers must complete.

-   Required pregnancy testing in females of childbearing potential

-   Compliance with measures to prevent pregnancy and thereby prevent
    fetal exposure to Thalomid^®^

-   Educational materials -- a brochure and a video tape

-   Patient counseling

-   Limiting prescriptions to a 28-day supply that is provided in
    blister packs with safety information on the blister card as well as
    prohibition of telephone prescriptions and automatic refills

-   Distribution of Thalomid^®^ from Celgene to registered pharmacies

-   Any suspected fetal exposures to Thalomid must be reported
    immediately

-   Quality assurance activities of the *S.T.E.P.S.*^®^ program -
    ongoing evaluation of the *S.T.E.P.S.*^®^ program

In the sections that follow further information is provided on the
elements of the *S.T.E.P.S.*^®^ program that are listed above.

[Product Labeling]{.underline}

The Thalomid^®^ product labeling provides Warnings regarding the
teratogenicity of thalidomide, the elements of the patient
acknowledgement / informed consent form, and describes other elements of
the *S.T.E.P.S.*^®^ program. The label explicitly states the requirement
for enrollment in *S.T.E.P.S.*^®^ prior to institution of drug therapy.
Statements concerning risk to the fetus by mention of "birth defects",
"fetal abnormalities", or "teratogenicity" if thalidomide is taken
during pregnancy are present in several sections of the Thalomid^®^
label. At the top of the Thalomid^®^ label is a boxed Warning entitled
"WARNING: SEVERE, LIFE-THREATENING HUMAN BIRTH DEFECTS." Overall, such
statements are present in the following sections of the label: Warnings
(including the boxed Warning), Contraindications, Precautions, and
Adverse Reactions. The Thalomid^®^ label refers to the *S.T.E.P.S.*^®^
program with explicit mention of the requirement for enrollment prior to
thalidomide therapy. The complete Thalomid^®^ (thalidomide) package
insert also provides additional information on Thalomid^®^ including
other information such as additional Warnings and Precautions,
information on Adverse Events, Indications and Usage, and Dosage and
Administration.

[Required Registration of Prescribers, Patients, and
Pharmacies]{.underline}

All prescribers, patients, and pharmacies are required to register in
the *S.T.E.P.S.*^®^ program in order to prescribe, receive, or dispense
Thalomid^®^. Physician registration requires a DEA# or Social Security
Number as well as the designation of a *S.T.E.P.S.*^®^ coordinator for
that prescriber (this may be the prescriber). The registration form is
faxed to the prescriber and when completed faxed back to Celgene
Corporation. A pharmacy registers by having a designated pharmacist
complete a similar registration form that is returned to Celgene. (For
patient registration information, please see "Patient Acknowledgement/
Informed Consent" below).

[Six Risk Groups]{.underline}

The *S.T.E.P.S.*^®^ program divides patients into six risk groups in
order to provide risk group appropriate information to prevent fetal
exposure to thalidomide. For example, adult females not of childbearing
potential are required to participate in the Interactive Voice Response
System (IVR) survey once every six months whereas females of
childbearing potential (FCBP) are required to participate monthly.

The six risk groups are as follows:

-   Adult females of childbearing potential

-   Adult females not of childbearing potential

-   Female children of childbearing potential

-   Female children not of childbearing potential

-   Adult males

-   Male children

[Patient Acknowledgement / Informed Consent Form]{.underline}

The risk group appropriate patient acknowledgement / informed consent
form can be generated using computer software that is supplied with the
materials for prescribers registered in the *S.T.E.P.S.*^®^ program.
Prescribers are expected to provide these risk group specific forms to
the patient, provide counseling on the risks and benefits of therapy,
provide mandatory contraceptive counseling, pregnancy testing for
females of childbearing potential and then fax the completed
acknowledgement / informed consent forms to Celgene Corporation. When
computer generated forms cannot be used, risk group appropriate forms
can be provided by fax to the prescriber. The patient is registered with
*S.T.E.P.S.*^®^ upon receipt of the acknowledgement / informed consent
form by Celgene.

[Authorization Validation]{.underline}

After the risk group appropriate patient acknowledgement / informed
consent form has been completed and faxed to Celgene Corporation the
patient is then instructed to complete the patient phone survey while
the prescriber completes the physician phone survey. Upon completion of
the survey, the physician obtains an authorization number that is placed
on the prescription which the patient then presents to the pharmacist.
Without the authorization number Thalomid^®^ cannot be dispensed.
(Please see below, IVR system).

[Required Telephonic Survey Utilizing an IVR System]{.underline}

A brief, automated, telephone-based survey that utilizes IVR technology
(IVR=interactive voice response system). The survey questions are
tailored to each of the specific risk group as are the intervals for
completing the required IVR surveys. All patient risk groups complete
the survey with each 28-day interval, except for adult females not of
childbearing potential who complete the IVR survey every 6 months.
Prescribers complete the IVR survey with each prescription (maximum
dispense of a 28-day supply). At the end of the successful completion of
the prescriber survey a number to be written on prescription form is
generated (the authorization number).

The risk group specific IVR survey is a series of 4 to 6 questions for
each participant (Prescriber and Patient) intended to acquire essential
information and to perform a focused query for at-risk behavior or
program non-compliance. The prescriber and patient must answer all
questions in the IVR survey appropriately before a Thalomid^®^
prescription is "activated". When a response to the IVR system signals
an at-risk behavior, the prescriber or patient is transferred from the
IVR system to a Celgene *S.T.E.P.S.*^®^ intervention specialist for
real-time intervention prior to dispensing of Thalomid® (specialists are
available 8a-8p M-F & Sat).[^1] The response that triggered the
intervention is further addressed and remediated as appropriate.

If the patient and prescriber responses are appropriate to all questions
in the IVR, the Thalomid^®^ prescription is "activated." Then a
registered pharmacist can call the IVR system, enter the number from the
prescription, and the pharmacist then receives authorization to dispense
the "activated" Thalomid^®^ prescription. To reflect the temporal
restriction with regard to recent pregnancy testing. Thalomid^®^
prescriptions are required to be filled within seven days of issue.
Conventional methods (paper, fax, telephone) are available when the IVR
cannot be used (paper forms are also available in fourteen languages).
When a paper based process is used, the handling process is the same as
for the IVR (i.e., real-time intervention).

[Required Pregnancy Testing]{.underline}

Females of childbearing potential are required to have a negative
pregnancy test within 24 hours prior to initiating Thalomid^®^ therapy.
Testing occurs weekly for the first 4 weeks, and then q-28 days
thereafter while on Thalomid^®^, unless menses are irregular in which
case pregnancy testing is performed on a biweekly basis. The prescriber
enters the date and result of the last pregnancy test into the IVR
system with each Thalomid prescription (i.e., every 28-days). Therapy
with Thalomid^®^ must be discontinued immediately if a pregnancy occurs
in a patient receiving Thalomid^®^ therapy.

[Compliance with Measures to Prevent Pregnancy]{.underline}

Females of childbearing potential must use at least one highly effective
method of birth control and one additional method of birth control.[^2]
These methods of contraception must be initiated at least four weeks
before beginning Thalomid^®^ therapy, must be continued during
Thalomid^®^ therapy, and continued for four weeks following
discontinuation of Thalomid^®^ therapy. Females of childbearing
potential must use these birth control methods unless the patient
completely abstains from heterosexual sexual contact. Male patients
receiving Thalomid^®^ must agree to abstain from heterosexual sexual
contact or use a latex condom when he engages in sexual contact with a
woman who can become pregnant or who is pregnant.

[Educational Materials -- Brochure and Video Tape]{.underline}

Patients must review the Thalomid^®^ patient brochure and/or view the
videotape regarding the safe use of Thalomid^®^.

[Patient Counseling]{.underline}

Patients are to receive counseling to review the safe use of Thalomid^®^
at the time of initial *S.T.E.P.S.*^®^ enrollment and subsequently at
each prescription refill.

[Limiting Prescriptions to a 28-day Supply]{.underline}

Thalomid^®^ prescriptions are limited to a duration of 28-days to allow
for appropriate interval follow-up. Telephone prescriptions are not
permitted. A new prescription is required for further dispensing (i.e.
automatic refills are not permitted).

[Distribution of Thalomid^®^ from Celgene to Registered
Pharmacies]{.underline}

Thalomid^®^ is directly shipped from Celgene to registered pharmacies.
This allows Celgene to compare the amount of Thalomid^®^ shipped to
pharmacies with the amount of Thalomid^®^ that specific pharmacies have
been authorized to dispense.

[Any Suspected Fetal Exposures to Thalomid Must be Reported
Immediately]{.underline}

Prescribers must report any suspected fetal exposure to Thalomid
immediately to the FDA and Celgene Corporation. The patient should be
referred to an obstetrician/gynecologist experienced in reproductive
toxicity for further evaluation and counseling. The label provides the
FDA MedWatch phone number (800-FDA-1088) and also includes an "800"
number for Celgene Corporation. Any suspected fetal exposures to
Thalomid^®^ also receive additional follow-up.

[Quality Assurance Activities of the *S.T.E.P.S.*^®^
Program]{.underline}

Ongoing assessments of the *S.T.E.P.S.*^®^ program and a separate
voluntary follow-up survey are performed as part of the quality
assurance activities of the *S.T.E.P.S.*^®^ program.

[^1]: Incorrect responses that occur at off-hours result in an
    inactivated prescription that is followed-up during hours of
    staffing.

[^2]: Highly effective = hormonal, IUD, tubal ligation, partner's
    vasectomy; Effective = latex condom, diaphragm, cervical cap