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


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