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
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:
(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
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
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:
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
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
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
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:
Patient Acknowledgement /
Informed Consent Form
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
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
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
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
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
Patients must review the Thalomid®
patient brochure and/or view the videotape regarding the safe use of Thalomid®.
Patient Counseling
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
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
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
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
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.