FDA Sends Letter to Sanofi-Aventis Regarding Eligard Promotion
ROCKVILLE, Md., April 23, 2010 - The FDA today posted on its website a letter sent to Sanofi-Aventis regarding a Patient Profile Piece about cancer drug Eligard. The letter is below.
TRANSMITTED BY FACSIMILE
Mark Gaydos Senior Director, US Regulatory Affairs Marketed
Products sanofi-aventis U.S. Inc. PO Box 5925, 55 Corporate Drive
Bridgewater, NJ 08807
RE: NDA 021731
Eligard 45mg (leuprolide acetate for injectable suspension)
MACMIS #18481
Dear Mr. Gaydos:
As part of its monitoring and surveillance program, the Division
of Drug Marketing, Advertising, and Communications (DDMAC) of the
U.S. Food and Drug Administration (FDA) has reviewed a Patient
Profile Piece (patient profile) entitled, “6 Month Got Time
Patient Profile Piece” (US.LEU.08.10.009) for Eligard 45mg
(leuprolide acetate for injectable suspension) (Eligard) submitted
by sanofi-aventis U.S. Inc. (sanofi) under cover of Form FDA-2253.
The patient profile is false or misleading because it omits and
minimizes important risks for Eligard, overstates the efficacy,
makes misleading presentations, and makes unsubstantiated
efficiency and convenience claims for Eligard. Thus, the patient
profile misbrands the drug in violation of the Federal Food, Drug,
and Cosmetic Act (the Act), 21 U.S.C. 352(a) and 321(n). Cf. 21 CFR
202.1(e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii).
Background
The INDICATIONS AND USAGE section of the FDA-approved product
labeling (PI) for Eligard states:
ELIGARD® is indicated for the palliative treatment of advanced
prostate cancer.
Eligard is associated with several contraindications, warnings,
precautions, and adverse reactions. In particular, the
CONTRAINDICATIONS section of the PI states (in pertinent part,
footnote omitted):
ELIGARD® is contraindicated in patients with hypersensitivity
to GnRH, GnRH agonist analogs or any of the components of ELIGARD.
Anaphylactic reactions to synthetic GnRH or GnRH agonist analogs
have been reported in the literature.
ELIGARD® is contraindicated in women and in pediatric patients
and was not studied in women or children. Moreover, leuprolide
acetate can cause fetal harm when administered to a pregnant
woman.... The possibility exists that spontaneous abortion may
occur.
The WARNINGS section of the PI states (in pertinent part):
…ELIGARD® 45mg causes a transient increase in serum
concentration of testosterone during the first two weeks of
treatment. Patients may experience worsening of symptoms or onset
of new signs and symptoms during the first few weeks of treatment,
including bone pain, neuropathy, hematuria, or bladder outlet
obstruction. Isolated cases of ureteral obstruction and/or spinal
cord compression, which may contribute to paralysis with or without
fatal complications, have been observed in the palliative treatment
of advanced prostate cancer using LH-RH agonists….
If spinal cord compression or ureteral obstruction develops,
standard treatment of
these complications should be instituted.
The PRECAUTIONS section of the PI states (in pertinent part):
General: Patients with metastatic vertebral lesions and/or with
urinary tract obstruction should be closely observed during the
first few weeks of therapy….
Laboratory Tests: Response to ELIGARD® should be monitored by
measuring serum concentrations of testosterone and prostate
specific antigen periodically.
The ADVERSE REACTIONS section of the PI states (in pertinent part,
footnote omitted):
…ELIGARD®, like other LH-RH analogs, caused a transient
increase in serum testosterone concentrations during the first one
to two weeks of treatment. Therefore, potential exacerbations of
signs and symptoms of the disease during the first weeks of
treatment are of concern in patients with vertebral metastases
and/or urinary obstruction or hematuria. If these conditions are
aggravated, it may lead to neurological problems such as weakness
and/or paresthesia of the lower limbs or worsening of urinary
symptoms….
Decreased bone density has been reported in the medical literature
in men who have had orchiectomy or who have been treated with an
LH-RH agonist analog. It can be anticipated that long periods of
medical castration in men will have effects on bone density.
The most commonly reported injection site adverse events include
transient burning/stinging (16%), pain (4.6%), and mild bruising
(2.3%). The most commonly reported systemic adverse events include
hot flashes/sweats (57.7%), malaise and fatigue (11.7%), testicular
atrophy (7.2%), myalgia (4.5%), weakness (3.6%), gynecomastia
(3.6%), night sweats (2.7%), and pain in limb (2.7%).
Omission/Minimization of Risk Information
Promotional materials are misleading if they fail to reveal
material facts in light of the representations made by the
materials or with respect to consequences that may result from the
use of the drug as recommended or suggested by the materials. The
patient profile is misleading because it omits material risk
information relating to warnings and adverse reactions for Eligard,
some of which are fatal. Specifically, the promotional piece fails
to reveal that cases of ureteral obstruction and/or spinal cord
compression have been observed in the palliative treatment of
advance prostate cancer using LH-RH agonists, and may contribute to
paralysis with or without fatal complications. It also fails to
disclose a common injection site adverse event (i.e., bruising
(2.3%)), as well as several common systemic adverse events (i.e.,
sweats (57.7%), malaise (11.7%), myalgia (4.5%), gynecomastia
(3.6%), and weakness (3.6%)).
Additionally, the patient profile claims “ELIGARD, like other
LHRH agonists, causes a transient increase in serum testosterone
during the first week of treatment” (emphasis added). This
claim misleadingly suggests that serum testosterone levels will
decline after the first week of therapy, leading to a direct
decrease in testosterone-related adverse events after this first
week. However, as stated in the Warnings section of the PI, the
transient increase in serum testosterone levels following Eligard
injections may last up to two weeks, rendering patients susceptible
to related adverse events for several weeks following Eligard
injection.
Furthermore, promotional materials are misleading if they fail to
present risks associated with a drug with a prominence and
readability reasonably comparable with the presentation of
information relating to the effectiveness of the drug. The patient
profile, including its four pullout
profile tabs, prominently presents efficacy claims with large
bolded characters, prominent headers, and colorful graphics
throughout the first 11 pages of the piece, but fails to convey any
risks specific to Eligard in these 11 pages. In contrast to the
large and colorful effectiveness presentations contained in these
first 11 pages, a limited risk disclosure is presented on the
bottom of the back page in small font type in single-spaced
paragraph format. As such, the piece fails to present risk
information with a prominence and readability reasonably comparable
with the presentation of information relating to the effectiveness
of the drug.
We note the statement, “Please see Important Safety
Information on the back cover and accompanying Full Prescribing
Information in back pocket,” appears on the bottom of the
second page and the back of the patient profile pages. However,
this statement does not mitigate the misleading omission and
minimization of risk information.
Overstatement of Efficacy
Promotional materials are misleading if they contain
representations or suggestions that a drug is better or more
effective than has been demonstrated by substantial evidence or
substantial clinical experience. The patient profile includes the
following claims concerning several patient types receiving Eligard
therapy (emphasis added):
• “PATIENT TYPE: LIMITED MOBILITY” (describes an
80-year-old mechanic who needs a wheelchair):
- “He is considering moving into an assisted living facility
to have access to more
care”
-“Convenience for patients. . .
? Fewer injections helps minimizes trips to his doctors office,
keeping him
at home and more comfortable
? Subcutaneous delivery of medication is optimal for
wheelchair-bound
individuals and preserves patient dignity
? Patient’s comfort is maintained by allowing him to remain
seated during
administration, with the abdomen being an ideal injection
site”
• “PATIENT TYPE: SEASONAL TRAVELER” (describes a
65-year-old retired financial
advisor):
-“Wants his retirement to be interrupted less
frequently”
These claims suggest that treatment with Eligard will be
comfortable for patients, preserve patient dignity, allow patients
to remain at home (rather than moving to an assisted living
facility), and interrupt a patient’s retirement less
frequently. There are no references cited in support of these
claims, and we are unaware of substantial evidence or substantial
clinical experience to support the above-claimed effects of Eligard
treatment. While Eligard can result in a decrease in the frequency
of injections for patients (from injections every three- or
four-months to injections every six-months for this patient
population), such a decrease does not necessarily correlate with
the above implications. The patient population Eligard is approved
to treat has advanced disease and is likely to require monitoring
and other aspects of disease management; it is not known whether a
reduction in the frequency of injections alone would generate a
significant improvement to a patient’s comfort, dignity,
living arrangements and/or interruptions during retirement.
Furthermore, simply because a patient is able to remain seated
during the administration of the drug does not necessarily
guarantee comfort with the overall administration process or side
effects of Eligard therapy, including those related to the
injection (e.g., transient burning/stinging, pain, and bruising).
In the absence of substantial evidence or substantial clinical
experience to support these claims, the above presentations
misleadingly overstate the efficacy of Eligard.
Misleading Presentations
The “SEASONAL TRAVELER” patient profile includes the
following claims (emphasis added):
•
“Doesn’t want the hassle of seeing two doctors in
different cities or traveling for a checkup and an LHRH agonist
injection”
•
“Convenience for patients. . .
-There is no longer a need for a doctor in each city”
These claims are misleading because they suggest that the
inconvenience of visiting doctors in different cities would be
eliminated simply because of Eligard’s dosing schedule. A
decrease in the frequency of injections from three- or four-months
to injections every six-months for this patient population does not
eliminate the need for a doctor in each city of residence. It is
misleading and inappropriate to suggest that this particular
patient population, who are suffering from advanced disease and are
likely to exhibit multiple health issues, would no longer need a
healthcare provider in each city of residence if they use
Eligard.
In addition, the piece claims, “Fewer injections means fewer
reminders that he has cancer; he knows he’s covered without
getting confronted with frequent treatments.” We are not
aware of support for this claim. Patients being treated with
Eligard have advanced disease and are monitored for early and
long-term pharmacological effects such as hot flashes, impotence,
decreased libido, gynecomastia and testicular atrophy. Some of
these adverse events are frequent, common (e.g., hot flashes/sweats
[57.7%]), and/or severe. Such adverse events serve as a reminder of
the underlying ailment, as do any necessary monitoring or treatment
for such adverse events or disease complications. Thus, the
implication that fewer injections will lessen a patient’s
awareness of his cancer is not substantiated.
Unsubstantiated Efficiency and Convenience Claims
The patient profile includes multiple efficiency claims for
healthcare providers regarding the use of Eligard in their
practice. Examples of such claims include:
•
“ELIGARD 45 mg: Time To Do More”
•
“Efficiency for you and your practice”
•
“Reduced frequency of LHRH injections means your practice
benefits1”
•
Chart displaying the following benefits to physicians, nurses, or
office managers: -“More time for new patients”
-“More time with current patients” -“Reduced
paperwork, with only 1 reimbursement submission every 6
months” -“Extra flexibility for follow-up visits”
-“Simplified inventory management”
•
“Efficiency for you
- Two injections a year allows more time for you to see new
patients or perform in-office procedures”
These claims misleadingly suggest that treatment with Eligard will
improve the efficiency of daily office practice activities for
healthcare providers by minimizing time spent on LHRH-associated
activities. The claims suggest that the shift in time requirements
will provide physicians, nurses, or office managers more time with
current patients, more time for new patients and extra flexibility
for follow-up visits.
Similarly, the patient profile includes multiple convenience claims
regarding the use of Eligard for patients. For example:
•
“Convenience for patients
- A 6-month LHRH agonist treatment option instead of a 3- or
4-month option means having the same coverage over the year while
spending less time in his doctor’s office.”
•
“Convenience for patients
- A less demanding injection schedule makes it easy to keep LHRH
appointments in between business trips.”
These patient convenience claims misleadingly suggest that the
six-month dosing of Eligard will make it “easy” for
patients to keep their medical appointments and spend “less
time” at medical appointments.
We are not aware of any evidence to support the above claims and
presentations. One of the summary claims cites to Eligard’s
PI; however, the PI does not provide evidence to support any of the
above suggestions. Treatment of patients with advanced prostate
cancer requires regular monitoring, including the measurement of
serum testosterone concentrations and prostate specific antigen.
Eligard causes a transient increase in serum testosterone
concentrations during the first one to two weeks of therapy.
Accordingly, patients may experience a worsening of symptoms or
onset of new symptoms during the first few weeks of therapy. Some
of these symptoms may be severe, such as bone pain, spinal cord
compression, or allergic reaction, and may require interaction with
healthcare providers. In particular, patients with metastatic
vertebral lesions and/or urinary obstruction must be closely
monitored during initial therapy. Aggravation of these conditions
may lead to paralysis, worsening of urinary symptoms or death.
Patients may require additional interaction with healthcare
providers to address such events as well as other consequences of
treatment with Eligard, such as hot flashes, impotence, decreased
libido, gynecomastia, and testicular atrophy. It can also be
anticipated that long periods of medical castration in men will
affect bone density, and healthcare providers should adequately
monitor patients for potential sequelae.
Thus, the suggestions that a reduction in the frequency of
injections alone has a significant positive impact on time
expenditures for healthcare providers and convenience for patients
are unsubstantiated and misleading. Similarly, the suggestion that
the use of Eligard will increase efficiency in a healthcare
practitioner’s practice, resulting in more time for new and
current patients and enhanced schedule flexibility, is
unsubstantiated and misleading. We are not aware of any evidence to
support the implications that the use of Eligard will improve
efficiency for healthcare providers and convenience for patients.
If you have evidence to support these claims, please submit it to
FDA for review.
In addition, the suggestion that Eligard’s dosing regimen
makes it “easy” for patients to keep their LHRH
appointments in the absence of any evidence is misleading because
there are a multitude of other factors that impact patients’
ability to keep their appointments.
Conclusion and Requested Action
For the reason discussed above, the patient profile misbrands
Eligard in violation of the Act, 21 U.S.C. 352(a) & 321(n). Cf.
21 CFR 202.1(e)(3)(i), (e)(5), (e)(6)(i) & (e)(7)(viii).
DDMAC requests that sanofi immediately cease the dissemination of
violative promotional materials for Eligard such as those described
above. Please submit a written response to this letter on or before
May 4, 2010, stating whether you intend to comply with this
request, listing all promotional materials (with the 2253
submission date) for Eligard that contain violations such as those
described above, and explaining your plan for discontinuing use of
such violative materials.
Please direct your response to me at the Food and Drug
Administration, Center for Drug Evaluation and Research, Division
of Drug Marketing, Advertising, and Communications, 5901-B
Ammendale Road, Beltsville, MD 20705-1266, facsimile at
301-847-8444. In all future correspondence regarding this matter,
please refer to MACMIS # 18481 in addition to the NDA number. We
remind you that only written communications are considered
official.
The violations discussed in this letter do not necessarily
constitute an exhaustive list. It is your responsibility to ensure
that your promotional materials for Eligard comply with each
applicable requirement of the Act and FDA implementing
regulations.
Sincerely,
{See appended electronic signature page}
Keith Olin, Pharm.D. Regulatory Review Officer Division of Drug
Marketing,
Advertising, and Communications
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Application Submission
Submitter Name Product Name
Type/Number Type/Number
NDA-21731 ORIG-1 TOLMAR ELIGARD(LEUPROLIDE THERAPEUTICS
ACETATE)45MG INJ SUSP INC
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
/s/
KEITH J OLIN 04/20/2010
Posted: April 2010
