FDA Sends Teva Warning Letter for Copaxone Promotional Materials
DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health
Service
Food and Drug Administration
Silver Spring, MD 20993
Larry Downey
Executive Vice President, US Branded Pharmaceuticals
Teva Pharmaceuticals USA
c/o Teva Neuroscience, Inc.
901 East 104 th Street, Suite 900
Kansas City, MO 64131
RE: NDA# 020622
COPAXONE ® (glatiramer acetate injection) solution for
subcutaneous injection
MA #762
WARNING LETTER
Dear Mr. Downey:
The Office of Prescription Drug Promotion (OPDP) of the U.S. Food
and Drug Administration
(FDA) has reviewed 2011 AAN Professional Exhibit Panels “AAN
Static Panels G double”
(COP112014807/110193) (2011 AAN Exhibit Panels G) for COPAXONE
® (glatiramer acetate
injection) solution for subcutaneous injection (Copaxone),
submitted by Teva Neuroscience,
Inc. (Teva) under cover of Form FDA-2253, as well as the
“Team COPAXONE ® ” webpage
(COP110006303/110312), “David Kyle” webpage
(COP100006331/102252), and “Karen
Stewart” webpage (COP100006324/102245) for Copaxone. 1
These promotional materials are false or misleading because they
overstate the efficacy,
present unsubstantiated claims, broaden the indication of Copaxone,
omit and minimize
important risk information associated with the drug, present
unsubstantiated superiority
claims, and omit material facts. Thus, the 2011 AAN
Professional Exhibit Panels and “Team
COPAXONE ® ” webpages misbrand Copaxone in violation of
the Federal Food, Drug, and
Cosmetic Act (the FD&C Act), 21 U.S.C. 352(a), (n);
321(n). See 21 CFR 202.1(e)(3)(i);
(e)(5); (e)(6)(i), (ii), (iv), (xviii) & (e)(7)(i). These
violations are concerning from a public health
perspective because they suggest that Copaxone is safer or more
effective than has been
demonstrated by substantial evidence or substantial clinical
experience.
1 “Team COPAXONE
® ” webpage, “David Kyle” webpage, and
“Karen Stewart” webpage, at
http://www.sharedsolutions.com/Living-With-MS/TeamCOPAXONE.aspx,
http://www.sharedsolutions.com/Living-With-MS/TeamCOPAXONE/AboutMe/David-Kyle.aspx,
and
http://www.sharedsolutions.com/Living-With-MS/TeamCOPAXONE/AboutMe/Karen-Stewart.aspx
(last
accessed December 6, 2011), respectively.
Reference ID: 3101410
Larry Downey Page 2
Teva Neuroscience, Inc
NDA#020622/MA#762
Background
Below is the indication and summary of the most serious and most
common risks associated
with the use of Copaxone. 2 According to its
FDA-approved product labeling (PI):
COPAXONE is indicated for reduction of the frequency of relapses in
patients with
Relapsing-Remitting Multiple Sclerosis (RRMS), including patients
who have
experienced a first clinical episode and have MRI features
consistent with multiple
sclerosis.
Copaxone is associated with a number of serious risks.
According to its PI, Copaxone is
contraindicated in patients with known hypersensitivity to
glatiramer acetate or mannitol. In
addition, the PI contains Warnings and Precautions regarding
immediate post-injection
reaction, chest pain, lipoatrophy and skin necrosis, and potential
effects on immune
response.
The most common adverse reactions (≥10% and ≥1.5 times higher
than placebo) reported in
controlled studies were injection site reactions, vasodilatation,
rash, dyspnea, and chest pain.
Overstatement of Efficacy/Unsubstantiated Claims
Promotional materials are misleading if they represent or suggest
that a drug is more
effective or safer than has been demonstrated by substantial
evidence or substantial clinical
experience.
The 2011 AAN Exhibit Panels G include claims and presentations such
as the following
(underlined emphasis added):
• “20 years of proven
safety”
• “No other RRMS therapy can
demonstrate long-term results like
COPAXONE
®
Long-term experience: Results after an average of 22 years with
RRMS” in
conjunction with the claims, “8 years untreated [with a
diagnosis of RRMS since
1983]” and “Up to 15 years continuous COPAXONE
® therapy (mean 14 years),
open label study,” and a graph showing mean EDSS scores over
time, from 1991
to 2006.
• “Expanded Disability Status Scale
(EDSS) scores remained stable after an
average of 15 years on therapy.”
• “OPEN-LABEL FOLLOW-UP—5 YEARS
AFTER RANDOMIZATION
. . .
2 This information is for background purposes only and
does not necessarily represent the risk information that
should be included in the promotional pieces cited in this
letter.
Reference ID: 3101410
Larry Downey Page 3
Teva Neuroscience, Inc
NDA#020622/MA#762
Early treatment with COPAXONE ® reduced the risk of CDMS
[clinically definite
multiple sclerosis] by 41.1% vs delayed treatment over 5 years
(P=0.0005).”
These presentations misleadingly overstate the safety and efficacy
of Copaxone by implying
that the drug has proven long term (e.g. 20 years, 15 years, etc.)
safety and efficacy, when
this has not been demonstrated by substantial evidence or
substantial clinical experience.
The CLINICAL STUDIES section of the PI only includes data for up to
three years in
duration. The AAN exhibit panels refer to open-label
extension studies, i.e., the PreCISe
study as well as another pivotal trial for Copaxone, neither of
which constitute substantial
evidence to support the above claims. Specifically, these
studies did not account for any
self-selection among the patients who chose to participate in the
open-label studies. In
addition, it is unclear as to why certain patients dropped out or
were lost to follow-up. For
example, in one of the open-label studies described above, only 100
patients remained in
the study at 15 years out of the original 231 patients. Any
conclusions suggested by the
extension study would have to be confirmed in adequate and
well-controlled clinical studies.
Furthermore, the claim, “No other RRMS therapy can
demonstrate long-term results like
COPAXONE ® ,” misleadingly suggests that Copaxone is
superior to other RRMS therapies.
FDA is not aware of adequate and well-controlled clinical trials
demonstrating that
Copaxone is safer, more effective, or otherwise superior to other
treatments for RRMS. If
you have data to support these claims, please submit them to FDA
for review.
Overstatement of Efficacy/Broadening of Indication
Promotional materials are misleading if they suggest that a drug is
more effective or useful
in a broader range of conditions or patients than has been
demonstrated by substantial
evidence or substantial clinical experience.
The “Team COPAXONE ® ” webpage presents the
following claims (underlined emphasis
added):
• “For over ten years . . .
Team COPAXONE ® has honored the accomplishments of people
who refuse to
let MS stand in the way of their ambitions. All of our team
members have one
thing in common: they live the life they’ve
dreamed.”
• “If you are passionate and
dedicated to actively living your life, and if you don’t
let
MS get in the way of your dreams, you could be the next member of
Team
COPAXONE ® .”
In addition, the “David Kyle” and “Karen
Stewart” webpages include claims such as the
following (underlined emphasis added):
“David Kyle” webpage: “Running, Swimming and
Biking Against Multiple Sclerosis”
Before Copaxone
• “It’s hard to believe that
just a few years ago, this energetic and dynamic
athlete
Reference ID: 3101410
Larry Downey Page 4
Teva Neuroscience, Inc
NDA#020622/MA#762
had to use a cane for mobility and often could barely muster enough
energy to
work half a day. This was the case for David, who was
diagnosed with multiple
sclerosis (MS) in 2002. David awoke one morning experiencing
numbness in his
toes.”
• “Over the course of a few weeks,
the numbness moved up his body and he
eventually became partially paralyzed from the chest down.
The symptoms
subsided briefly only to return just six months later, this time
advancing to his
entire right side.”
After Copaxone
• “With the help of his doctor, David
began COPAXONE ® (glatiramer acetate
injection) therapy in 2003”
• “After a year and a half of hard work and
determination, David was the USA
Triathlon National Champion in the physically challenged
category.”
• David went on to compete and win numerous
national and international triathlons
from 2005-2008.
“Karen Stewart” webpage: “Taking on Multiple
Sclerosis, One Step at a Time”
Before Copaxone
• “Karen was diagnosed with
relapsing-remitting multiple sclerosis (RRMS) in 1996,
after experiencing numbness in her leg and optic neuritis, an
inflammation of the
optic nerve causing an acute loss of vision.”
• “In the years following her
diagnosis, Karen’s health began to worsen. She
could
no longer walk unassisted, fatigue became a daily challenge and,
eventually, the
worsening of her symptoms forced her to leave her job.”
After Copaxone
• “In 1998, after discussing therapy
options with her neurologist, she began taking
COPAXONE ® . . . to manage her MS.”
• “Although individual results may
vary, over the past few years, Karen has made
fitness a priority in her life. She exercises six days a
week, added Pilates to her
exercise regimen and continues to work as a registered nurse
(RN). To date,
Karen has walked 22 marathons . . .”
The above claims misleadingly broaden the indication and overstate
the efficacy of
Copaxone by implying that Copaxone reverses patients’
disability and enables them to lead
an active lifestyle, return to work, accomplish great athletic
feats, and “live the life they’ve
Reference ID: 3101410
Larry Downey Page 5
Teva Neuroscience, Inc
NDA#020622/MA#762
dreamed.” For example, prior to treatment with
Copaxone, “Karen Stewart” was constantly
feeling fatigue, was not able to walk unassisted, and was forced to
leave her job. However,
after Copaxone treatment, she returned to work as a nurse and
walked 22 marathons.
Similarly, “David Kyle” was partially paralyzed and
barely had enough energy to work half a
day prior to Copaxone. However, after Copaxone, he was able
to compete and win many
national and international triathlons for the physically
challenged.
While these statements may be an accurate reflection of these
patients’ experiences, the
patient testimonials misleadingly broaden the indication and
overstate the efficacy of
Copaxone. As described in the Background section, Copaxone
has demonstrated efficacy in
decreasing the frequency of relapses in patients with RRMS.
However, Copaxone is not
indicated for slowing, preventing or reversing physical disability
associated with RRMS.
Moreover, FDA is not aware of substantial evidence or substantial
clinical experience
supporting the implication that Copaxone treatment will result in
the magnitude of effects as
described in the above patient testimonials. We note that
these patient testimonials, in part,
state, “[a]lthough individual results may vary” (Karen
Stewart webpage) or “[w]hile individual
results may vary” (David Kyle webpage). However, these
statements do not mitigate the
misleading impression that Copaxone can prevent or reverse the
physical disability caused
by RRMS. The personal experiences of “Team
Copaxone” patients such as “David Kyle” and
“Karen Stewart,” do not constitute substantial evidence
to support such claims and
presentations. If you have data to support these claims,
please submit them to FDA for
review.
In addition, the totality of the presentation broadens the
indication for Copaxone by implying
that Copaxone is approved to treat all types of MS, when this is
not the case. As described
in the Background section, Copaxone is indicated for reduction of
the frequency of
relapses in patients with RRMS, including patients who have
experienced a first clinical
episode and have MRI features consistent with MS. However, as
detailed above, the
webpages make claims that misleadingly broaden the indication for
Copaxone, such as,
“Running, Swimming and Biking Against Multiple
Sclerosis” (“David Kyle” webpage)
and “Taking on Multiple Sclerosis, One Step at a Time”
(“Karen Stewart” webpage)
(bolded emphasis original; underlined emphasis added). We
acknowledge that the
webpages do make mention of RRMS diagnoses for David Kyle and Karen
Stewart.
However, the presentation is not adequate to mitigate the
overwhelming implication that
Copaxone is approved for the treatment of all types all
MS.
Furthermore, the webpages state that Karen Stewart began taking
Copaxone in 1998, and
David Kyle began Copaxone therapy in 2003. While we
acknowledge that Karen Stewart
and David Kyle may have begun therapy in 1998 and 2003,
respectively, the inclusion of
these dates suggests ongoing treatment and implies that Copaxone is
effective for reducing
the frequency of relapses or exacerbations for a period of time
beyond what has been
demonstrated by substantial evidence or substantial clinical
experience. As previously
stated, the CLINICAL STUDIES section of the PI only includes data
for up to three years in
duration. If you have data to support the long-term safety
and efficacy of Copaxone, please
submit them to FDA for review.
Reference ID: 3101410
Larry Downey Page 6
Teva Neuroscience, Inc
NDA#020622/MA#762
In addition to the “David Kyle” and “Karen
Stewart” webpages, we note that the “Team
COPAXONE ® ” website highlights other patients with MS
who have been treated with
Copaxone and their subsequent athletic accomplishments. The
respective webpages of
these individual patient profiles are misleading for similar
reasons.
The 2011 AAN Exhibit Panels G present the following claims and
presentation (emphasis in
original):
• “Up to 15 years continuous COPAXONE
® therapy (mean 14 years), open label
study” in conjunction with a graph showing mean EDSS scores
over time (1991
2006) and the claim, “82% walking independently (n=100; EDSS
< 6)”
• “Expanded Disability Status Scale
(EDSS) scores remained stable after 15
years on therapy.”
These claims overstate the efficacy of Copaxone by suggesting that
82% of patients on
Copaxone were able to walk independently, as demonstrated by mean
EDSS scores over
15 years, when this has not been supported by substantial evidence
or substantial clinical
experience. As stated above, the open-label extension study
does not constitute substantial
evidence to support the above efficacy claims. Furthermore,
the above claims and
presentation misleadingly broaden the indication by suggesting that
Copaxone prevents the
progression of disability. According to the PI, Copaxone is
only approved for the reduction
of relapses in patients with RRMS, and is not approved for slowing
the progression of
disability of the disease. We acknowledge that there is a
statement at the bottom of the
exhibit panel which reads, “The labeling for COPAXONE
® does not include an indication for
slowing progression of disability”; however, this statement
does not mitigate the above
misleading presentations. As stated above, we are not aware
of substantial evidence to
support claims that Copaxone prevents the progression of physical
disability, or slows the
accumulation of disability associated with RRMS.
Omission of Risk Information
Promotional materials are misleading if they fail to reveal facts
that are material in light of the
representations made or with respect to consequences that may
result from the use of the
drug as recommended or suggested in the materials.
Promotional materials also are
misleading if they fail to include a balanced presentation of
information relating to the risks
associated with the use of a drug along with the presentation of
promotional claims relating to
the effectiveness of the drug.
The “Team COPAXONE ® ” webpage, in addition to the
“David Kyle” and “Karen Stewart”
webpages are misleading because they include numerous claims
regarding the benefits of
Copaxone, but fail to include any risk information associated with
the drug in the body of the
webpages. We note that there are links to the
“Important Safety Information” and to the full
PI on these webpages; however, these links do not mitigate the
misleading omission of risk
information from the body of each of these webpages.
Additionally, other patient
testimonials found on “Team COPAXONE ® ” website,
www.sharedsolutions.com/Living-With
MS/TeamCOPAXONE.aspx, are misleading for similar reasons.
Reference ID: 3101410
Larry Downey Page 7
Teva Neuroscience, Inc
NDA#020622/MA#762
Omission and Minimization of Risk Information/Unsubstantiated
Superiority
Presentation
The 2011 AAN Exhibit Panels G present the claim, “20 years of
proven safety” (emphasis
in original) in conjunction with a table containing two columns,
listing only three risks
associated with Copaxone and highlighting numerous risks not
associated with Copaxone.
In addition, the following claim is included below the table:
“COPAXONE ® has no warnings
or precautions for these serious adverse events.”
The totality of this presentation minimizes the risks associated
with Copaxone and
misleadingly suggests that Copaxone is safer than has been
demonstrated by substantial
evidence or substantial clinical experience. Additionally,
this presentation misleadingly
implies that Copaxone is safer than other treatments for RRMS
because Copaxone is not
associated with many serious risks that are generally attributed to
other RRMS drugs. For
example, the table suggests that Copaxone is not associated
with
immunosuppression/infections, decrease in pulmonary function,
and
anaphylaxis/hypersensitivity, when this is not the case.
While we acknowledge that the PI
for Copaxone does not have these risks listed in the WARNINGS AND
PRECAUTIONS
section, it does not mean that such risks are not associated with
the drug. According to the
ADVERSE REACTIONS section of the PI, infection, influenza,
hypersensitivity, and dyspnea
were reported in clinical trials for Copaxone at a rate higher than
that of the placebo group.
In addition, dyspnea, hypersensitivity, and urticaria were among
the most common adverse
reactions leading to discontinuation of Copaxone. Therefore,
it is misleading to imply that
Copaxone is not associated with risks such as those mentioned
above.
Additionally, this presentation omits material information about
other attributes of Copaxone
therapy, such as Contraindications, Warnings and other serious
risks that are highly relevant
to any decision about whether or not to prescribe Copaxone or
another treatment for RRMS.
Specifically, the table fails to present the Warnings for chest
pain, skin necrosis and the
potential effects of Copaxone on immune response.
Furthermore, it minimizes the serious
risk of immediate post-injection reactions by failing to mention,
as described in the
WARNINGS AND PRECAUTIONS section of the PI, that “[d]uring
the postmarketing period,
there have been reports of patients with similar symptoms [of
immediate post-injection
reactions (IPIRs)] who received emergency medical
care.” Moreover, this presentation fails
to include material information that injection site reactions such
as erythema, pain, pruritus,
mass, edema, hypersensitivity, fibrosis, and atrophy occurred at a
higher rate with
Copaxone than with placebo, and that injection site reactions were
one of the most common
adverse reactions leading to discontinuation of Copaxone. By
omitting these important
risks, the presentation minimizes the risk of Copaxone and implies
that the drug is safer
than has been demonstrated by substantial evidence or substantial
clinical experience.
In addition, the 2011 AAN Exhibit Panels G include the following
claim, “NO initial or routine
monitoring required or recommended” (emphasis in original)
accompanied by a table
showing the initial and routine monitoring recommendations for
Copaxone, IFNβ,
natalizumab, and fingolimod along with a column that shows no
initial or routine monitoring
recommendations for Copaxone.
Reference ID: 3101410
Larry Downey Page 8
Teva Neuroscience, Inc
NDA#020622/MA#762
The totality of this presentation misleadingly suggests that
Copaxone is a better and safer
treatment option for RRMS than INFß, natalizumab and
fingolimod because it is the only one
that does not require initial or routine monitoring. We note
that the monitoring
recommendations are consistent with the PIs of INFß,
natalizumab and fingolimod. However,
without a comparison of other attributes associated with the
products, or, potentially other
material facts that may be necessary within the context of a
comparative presentation, the
exhibit panels misleadingly suggest that Copaxone is a safer,
better, or otherwise superior
treatment option for RRMS. As stated above, FDA is not aware
of adequate and well-
controlled head-to-head clinical trials demonstrating that Copaxone
is safer, more effective
than, or otherwise superior to, other RRMS therapies.
Omission of Material Facts
Promotional materials are misleading if they fail to reveal facts
that are material in light of the
representations made or with respect to consequences that may
result from the use of the
drug as recommended or suggested in the materials.
The 2011 AAN Exhibit Panels G present a Kaplan-Meier graph of the
PreCISe study,
showing the time to a second clinical event, in conjunction
with the claim, “45% risk
reduction”(emphasis in original). This presentation of the
relative risk reduction is misleading
because it omits material facts regarding the actual relapse rates
for Copaxone and placebo,
implying a greater reduction in relapse rates than has been
demonstrated. According to the
CLINICAL STUDIES section of the PI, “The Kaplan-Meier
estimates of the percentage of
patients developing a relapse within 36 months were 42.9% in the
placebo group and 24.7%
in the COPAXONE group” (emphasis added).
Conclusion and Requested Action
For reasons discussed above, the 2011 AAN exhibit panels and
webpages misbrand
Copaxone in violation of the FD&C Act, 21 U.S.C. 352(a), (n);
321(n) See 21 CFR 202.1
(e)(3)(i); (e)(5); (e)(6)(i), (ii), (iv), (xviii) &
(e)(7)(i).
OPDP requests that Teva immediately cease the dissemination of
violative promotional
materials for Copaxone such as those described above. Please
submit a written response to
this letter on or before March 28, 2012, stating whether you intend
to comply with this
request, listing all promotional materials (with the 2253
submission date) for Copaxone that
contain violations such as those described above, and explaining
your plan for discontinuing
use of such violative materials. Because the violations described
above are serious, we
request, further, that your submission include a comprehensive plan
of action to disseminate
truthful, non-misleading, and complete corrective messages about
the issues discussed in
this letter to the audience(s) that received the violative
promotional materials. In order to
clearly identify the violative promotional pieces and focus on the
corrective messages, OPDP
recommends that corrective piece(s) include a description of the
violative promotional pieces,
include a summary of the violative messages, provide information to
correct each of the
violative messages, and be free of promotional claims and
presentations. To the extent
possible, corrective messaging should be distributed using the same
media, and generally for
the same duration of time and with the same frequency that the
violative promotional material
was disseminated.
Reference ID: 3101410
Larry Downey Page 9
Teva Neuroscience, Inc
NDA#020622/MA#762
Please direct your response to the undersigned at the Food and Drug
Administration,
Center for Drug Evaluation and Research, Office of Prescription
Drug Promotion,
Division of Professional Promotion, 5901-B Ammendale Road,
Beltsville, MD 20705
1266, or by facsimile at 301-847-8444. Please note that the
Division of Drug Marketing,
Advertising, and Communications (DDMAC) has been reorganized and
elevated to the Office
of Prescription Drug Promotion (OPDP). OPDP consists of the
Immediate Office, the Division
of Professional Promotion (DPP) and the Division of
Direct-to-Consumer Promotion
(DDTCP). To ensure timely delivery of your submissions, please use
the full address above
and include a prominent directional notation (e.g. a sticker) to
indicate that the submission is
intended for OPDP. In addition, OPDP recently migrated to a
different tracking system.
Therefore, OPDP letters will now refer to MA numbers instead of
MACMIS numbers. In all
future correspondence regarding this matter, please refer to MA #
762 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
Copaxone comply with each
applicable requirement of the FD&C Act and FDA implementing
regulations.
Failure to correct the violations discussed above may result in FDA
regulatory action,
including seizure or injunction, without further notice.
Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, RPh, MBA
Director
Office of Prescription Drug Promotion
Reference ID: 3101410
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This is a representation of an electronic record that was
signed
electronically and this page is the manifestation of the
electronic
signature.
/s/
THOMAS W ABRAMS
03/14/2012
Reference ID: 3101410
Posted: March 2012
