FDA Sends Warning Letter to Novartis Regarding Websites
ROCKVILLE, Md., May 4, 2010 - The FDA today posted on its website a warning letter sent to Novartis Pharmaceuticals Corporation regarding two websites sponsored by Novartis that "represent branded promotional material for Gleevec". The letter is below.
TRANSMITTED BY FACSIMILE
Ludwig Hantson, Ph.D.
CEO
Novartis Pharmaceuticals Corporation
One Health Plaza
East Hanover, NJ 07936-1080
RE: NDA 021588
Gleevec® (imatinib
mesylate)
MACMIS # 18492
WARNING LETTER
Dear Dr. Hantson:
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 two websites
(www.gistalliance.com and www.cmlalliance.com) sponsored by
Novartis. As explained more fully below, these websites represent
branded promotional material for Gleevec® (imatinib mesylate)
(Gleevec). These websites are false and misleading because they
promote the drug for an unapproved use, fail to disclose the risks
associated with the use of Gleevec and make unsubstantiated dosing
claims.1 Therefore, these websites misbrand the drug in
violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21
U.S.C. 352(a), (f)(1) & (n); 321(n), and FDA implementing
regulations. See 21 CFR 201.100(c), 201.115 & 201.128,
21 CFR 202.1(e)(5), (e)(6)(i), (iv) & (xi). Furthermore, it
appears that these materials were neither submitted to FDA 30 days
prior to the intended time of initial dissemination or initial
publication as required by 21 CFR 314.550, nor submitted to FDA on
Form FDA 2253 at the time of initial dissemination or initial
publication, as required by 21 CFR 314.81(b)(3)(i).
These websites are concerning from a public health perspective
because they promote Gleevec for an unapproved use, fail to
disclose the risks associated with the use of Gleevec, and make
unsubstantiated dosing claims about this medication that can put
patients at higher risk of experiencing serious adverse
events.
Background
According to the FDA-approved product labeling (PI), Gleevec is
indicated, among other things, for:
• Newly diagnosed adult patients with Philadelphia chromosome
positive chronic myeloid leukemia [Ph+ CML] in the chronic
phase
• Patients with Philadelphia chromosome positive chronic
myeloid leukemia in blast crisis, accelerated phase, or in chronic
phase after failure of interferon-alpha therapy
• Patients with Kit (CD117) positive unresectable and/or
metastatic malignant gastrointestinal stromal tumors [GIST]
• Adjuvant treatment of adult patients following complete
gross resection of Kit (CD117) positive GIST
Gleevec’s original approval on April 18, 2003, was an
accelerated approval under 21 CFR 314 subpart H, and some of its
indicated uses (e.g. adjuvant GIST) remain under the accelerated
approval regulations.
Gleevec is associated with a number of Warnings and Precautions.
For example:
• Edema and severe fluid retention have occurred. Weigh
patients regularly and manage unexpected rapid weight gain by drug
interruption and diuretics.
• Cytopenias, particularly anemia, neutropenia, and
thrombocytopenia, have occurred. Manage with dose reduction or dose
interruption and in rare cases discontinuation of treatment.
Perform complete blood counts weekly for the first month, biweekly
for the second month, and periodically thereafter.
• Severe congestive heart failure and left ventricular
dysfunction have been reported, particularly in patients with
comorbidities and risk factors. Patients with cardiac disease or
risk factors for cardiac failure should be monitored and
treated.
• Severe hepatotoxicity may occur. Assess liver function
before initiation of treatment and monthly thereafter or as
clinically indicated. Monitor liver function when combined with
chemotherapy known to be associated with liver dysfunction.
• Grade 3/4 hemorrhage has been reported in clinical studies
in patients with newly diagnosed CML and with GIST. GI tumor sites
may be the source of GI bleeds in GIST.
• Gastrointestinal perforations, some fatal, have been
reported.
• Bullous dermatologic reactions (e.g., erythema multiforme
and Stevens-Johnson syndrome) have been reported with the use of
Gleevec.
• Hypothyroidism has been reported in thyroidectomy patients
undergoing levothyroxine replacement. Closely monitor TSH levels in
such patients.
• Consider potential toxicities, specifically, liver, kidney,
and cardiac toxicity, and immunosuppression from long-term use.
• Fetal harm can occur when administered to a pregnant woman.
Women should be apprised of the potential harm to the fetus.
The PI also states that the most frequently reported adverse
reactions (across indications) (>30%) were edema, nausea,
vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash,
fatigue and abdominal pain.
The DOSAGE AND ADMINISTRATION section states (in pertinent
part):
Treatment may be continued as long as there is no evidence of
progressive disease or unacceptable toxicity.
….Adult Patients with Ph+ CML CP, AP and
BC
The recommended dose of Gleevec is 400 mg/day for adult patients in
chronic phase CML and 600 mg/day for adult patients in accelerated
phase or blast crisis. In CML, a dose increase from 400 mg to 600
mg in adult patients with chronic phase disease, or from 600 mg to
800 mg (given as 400 mg twice daily) in adult patients in
accelerated phase or blast crisis may be considered in the absence
of severe adverse drug reaction and severe non-leukemia related
neutropenia or thrombocytopenia in the following circumstances:
disease progression (at any time), failure to achieve a
satisfactory hematologic response after at least 3 months of
treatment, failure to achieve a cytogenetic response after 6-12
months of treatment, or loss of a previously achieved hematologic
or cytogenetic response.
….GIST
The recommended dose of Gleevec is 400 mg/day for adult patients
with unresectable and/or metastatic, malignant GIST. A dose
increase up to 800 mg daily (given as 400 mg twice daily) may be
considered, as clinically indicated, in patients showing clear
signs or symptoms of disease progression at a lower dose and in the
absence of severe adverse drug reactions.
The recommended dose of Gleevec is 400 mg/day for the adjuvant
treatment of adult patients following complete gross resection of
GIST. In the clinical study, Gleevec was administered for one year.
The optimal treatment duration with Gleevec is not known.
The DOSAGE AND ADMINISTRATION section of the Gleevec PI also
contains important dose modification guidelines for patients with
hepatic or renal impairment.
The likelihood of developing an adverse reaction to Gleevec
increases with higher doses. In the event of certain severe adverse
reactions, such as hepatotoxicity, cytopenias, or severe fluid
retention, the DOSAGE AND ADMINISTRATION section of the Gleevec PI
includes the following detailed instructions for dose reduction or
discontinuation (in pertinent part):
Dose Adjustment for Hepatotoxicity and Non-Hematologic Adverse
Reactions: If elevations in bilirubin >3 x institutional
upper limit of normal (IULN) or in liver transaminases >5 x IULN
occur, Gleevec should be withheld until bilirubin levels have
returned to a <1.5 x IULN and transaminase levels to <2.5 x
IULN. In adults, treatment with Gleevec may then be continued at a
reduced daily dose (i.e., 400 mg to 300 mg, 600 mg to 400 mg or 800
mg to 600 mg)…. If a severe non-hematologic adverse reaction
develops (such as severe hepatotoxicity or severe fluid retention),
Gleevec should be withheld until the event has resolved.
Thereafter, treatment can be resumed as appropriate depending on
the initial severity of the event.
Dose Adjustment for Hematologic Adverse Reactions: Dose reduction
or treatment interruptions for severe neutropenia and
thrombocytopenia [in chronic phase CML and GIST] are recommended as
[follows]:
|
Chronic Phase
CML (starting dose 400 mg)
GIST (stating dose 400 mg) |
ANC <1.0 x 109/L
and/or
platelets <50 x 109/L |
|
Misleading Product Claim Websites
While not using the established name of the Novartis drug product -
Gleevec - the two Novartis-sponsored websites, www.gistalliance.com
and www.cmlalliance.com, effectively promote this drug product for
the treatment of GIST tumors and CML, respectively.
Specifically:
• The websites discuss the use of tyrosine kinase inhibitors
(TKIs) for the first line treatment of GIST and CML, often in
conjunction with the Novartis name. Gleevec is the only tyrosine
kinase inhibitor (TKI) indicated for first-line treatment of
chronic phase CML; the only TKI indicated for first line treatment
of GIST; and the only TKI made by Novartis that is indicated for
both GIST and CML. These product details are wellknown in the
oncology community.
• The websites contain numerous references to the National
Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in
Oncology, which recommend the use of Gleevec exclusively for the
first-line treatment of CML and GIST.
• The websites are perceptually similar to the Novartis
Gleevec product website, incorporating similar color schemes
(including a distinct orange), design layouts and other
presentation elements.
• The websites are clearly marked with the Novartis Oncology
name and logo and/or the Novartis name and logo and discuss
sponsorship by Novartis Pharmaceuticals Corporation.
• The healthcare professional-directed “Targeting
BCR-ABL” webpage on the CML Alliance website provides a
direct link to the Novartis Gleevec product website in reference to
first-line therapy for CML, while the consumer-directed version of
this page provides a link to the Novartis-sponsored “My CML
Circle Program” website, which discusses Gleevec as a
treatment for CML.2
• The websites are registered to Novartis AG.3
• The websites present data from imatinib clinical studies,
and provide the corresponding literature references, which include
the drug name in the listed publication titles. At least one of the
publications4 recounts the pivotal clinical trial
submitted to FDA in support of the approval of Gleevec in the
treatment of adjuvant GIST.
Based on this combination of factors, these websites are product
specific promotions for the drug Gleevec. Consequently, these
websites are subject to regulation by FDA, and are false or
misleading for the reasons described below.
Promotion of Unapproved Use
The website www.gistalliance.com misleadingly promotes an intended
use for the drug for which safety and effectiveness have not been
established, thereby causing the approved PI to lack adequate
directions for the use recommended in the materials. Specifically,
the healthcare professional-directed portion of the website
contains numerous claims that promote the neoadjuvant use of
Gleevec before surgical resection of GIST tumors,
a use for which the drug is not indicated. These claims
include:
• “Surgical resection is the primary intervention of
treatment for GISTs when the tumor is resectable with minimal
surgical morbidity. However, when the size and/or location of the
tumor makes it inoperable, increases likely morbidity, or renders
the tumor only partially resectable, NCCN treatment guidelines call
for neoadjuvant treatment with a TKI prior to
surgery.”5
• “Pretreatment with a KIT TKI has been shown to
downstage GISTs and/or their metastases and render them resectable
in many cases.”6,7,8
• “The duration of TKI treatment prior to surgical
resection is generally based on the radiographic response to
treatment.”
• “Patients who are responding to treatment should be
treated until maximal tumor reduction is achieved, which may take 3
to 6 months.”5
• “Early surgical intervention is recommended, whenever
possible, in patients who have stable disease, as progressive
disease is associated with a worse outcome[8,9] and
tumors may rapidly become unresectable.”5,8
These claims are accompanied by a series of PET images showing reduction in tumor mass in a GIST patient at baseline and after 3, 6, and 12 months of neoadjuvant TKI therapy.6
We note that these statements do not explicitly include the trade
name “Gleevec.” However, the footnoted references
clearly indicate the established name of the drug (i.e., imatinib)
used in the clinical studies and the text refers readers to the
NCCN Treatment Guidelines for GIST tumors, which exclusively
recommend the use of imatinib for neoadjuvant GIST therapy. The
totality of this presentation misleadingly suggests that Gleevec is
safe and effective for the neoadjuvant therapy of GIST tumors.
Similarly, the consumer-directed portion of the website contains
the following statements:
• “The term ‘neoadjuvant treatment’ refers
to therapy that is given with a goal of reducing the size of a
tumor before surgery.”
• “If your GIST is too large to be surgically removed,
or if the location of the tumor makes surgery too risky, your
doctor may prescribe drug treatment with a TKI.”
Gleevec is not approved for neoadjuvant use in GIST patients (nor
is any other drug), and the approved PI for Gleevec does not
include any information on the safety and efficacy of this drug
when used before surgical resection of GIST
tumors. Therefore, the webpages suggest a use for Gleevec for which
safety and effectiveness has not been established, thereby creating
a new intended use for the drug for which the approved PI lacks
adequate directions.
Omission and Minimization of Risk
Promotional materials are misleading if they omit material facts
about the consequences that may result from the use of the drug as
recommended or suggested by the materials. The websites make
prominent claims of effectiveness for Gleevec in GIST and CML, but
omit material facts about the considerable risks associated with
this drug. For example, the GIST Alliance website makes the
following claims about the use of Gleevec in the treatment of GIST
tumors:
• “Several investigators, including DeMatteo et al, reported data that showed increased progression-free survival in patients who had received adjuvant TKI treatment after resection of GIST.[9, 10, 11] These findings led to a multicenter, placebo-controlled trial to evaluate adjunctive therapy in GIST.”
• “In this trial, patients were randomized to receive
daily TKI treatment or placebo for 1 year following complete
surgical resection of GIST. Accrual to the study was halted per the
recommendation of an independent data monitoring committee based on
a planned interim analysis. After a median follow-up of 19.7 months
in recurrence-free patients:[4]
o One-year recurrence-free survival was 98% in the TKI treatment
arm vs. 83% with placebo (hazard ratio, 0.35 [95% CI, 0.22 to
0.53]; (P=.0001)
o No difference in overall survival was detected, as follow-up time
was short and participants in the placebo group were allowed to
cross over to active treatment upon recurrence of GIST.”
This presentation, which is based on the clinical study of Gleevec
submitted to the FDA for the adjuvant GIST approval, provides data
on the efficacy benefits associated with Gleevec, but fails to
adequately describe the risks associated with Gleevec. The
patient-directed portion of the website also presents information
about treatment benefit derived from a Gleevec study, such as:
• “A study of adjuvant treatment in GIST showed that
when patients took daily TKI treatment after surgery, very few had
a return of GIST—only one patient out of 23 (4%). Among
patients who had surgery but did not receive TKI treatment, 32 out
of 48 (67%) had a return of GIST—most within 2
years.”
• “If you have had a GIST surgically removed, ask your
doctor if adjuvant TKI treatment is right for you.”
Similarly, the healthcare professional-directed portion of the CML
Alliance website makes claims about the use of Gleevec in the
treatment of CML, including:
• “Early molecular response may also predict lack of
disease progression. Long-term follow-up data in a large TKI
clinical trial have shown that 100% of patients who achieved both
CCyR and MMR at 12 months remained free from progression to
accelerated phase (AP) or blast crisis (BC) at 5
years.”12
The consumer-directed portion of the website also discusses the
benefits of treatment with presentations such as the following:
• “’TKI treatment’- is designed to block the
action of BCR-ABL. Without this growth signal, the abnormal cells
stop growing and begin to die. Within a few months, healthy cells
begin replacing the abnormal cells, and blood returns to its normal
mixture of cell types. Treatment for CML is based on a class of
drugs called tyrosine kinase inhibitors (TKIs).”
• “Click here for
prescription treatment information for CML” - this link takes
viewers to another Novartis-sponsored webpage that contains
information about treatment with
Gleevec2
Apart from a brief list of examples of supportive care strategies
that can be used to address some of the common and mild side
effects, there is no mention of the serious risks
of Gleevec therapy presented on these websites. The websites
therefore misleadingly suggest that Gleevec is safer than has been
demonstrated by substantial evidence or substantial clinical
experience.
Unsubstantiated Dosing Claims/Omission of Risk
Information
Both the CML Alliance and GIST Alliance websites make numerous
dosing-related claims that are wholly unsubstantiated, and may even
put patients at increased risk for serious adverse events. As noted
in the Background section, the likelihood of developing an adverse
reaction to Gleevec increases with higher doses. However, these
sites urge physicians to measure the plasma concentration of
tyrosine kinase inhibitor in their patients’ blood, and then
use that information to individualize the drug's dosage or
schedule, while failing to reveal any of the serious or potentially
dose-related side effects associated with Gleevec.
For example, the GIST Alliance –
Gastrointestinal Stromal Tumors (GISTs) Blood Level
Testing webpage includes the following statements:
• “Blood level testing, an important component of
therapeutic drug monitoring (TDM), involves measuring a drug's
concentration in a patient's blood and then using that information
to individualize care for your patients.”13
• “Therapeutic drug monitoring is critical for oral
oncology drugs, because oral agents are inherently more susceptible
than IV agents to intra- and interpatient variability in
absorption, bioavailability, and adherence.[14, 15] Sub
therapeutic drug concentrations have been identified as the most
important concern relating to the oral administration of anticancer
agents.”16
• “Although TKI treatment has been shown to be an
effective treatment for GIST, individual patient results may vary.
Blood level testing may help to illuminate causes of inadequate or
unexpectedly slow responses to treatment.”17,
18
• “Studies of TKI Treatment in GIST have shown a
correlation between low drug plasma levels and inadequate response
to treatment.”17, 18
• “Suboptimal plasma levels may be due to patient
non-adherence, or to other factors, including[19]
− Host differences in drug absorption/metabolism
− Comorbidities
− Drug-drug interactions”
• “Establishing a baseline blood level 30 to 90 days
after the initiation of therapy can provide a reference point for
future measurements and may help the clinician optimize treatment
when evaluating response.”
The CML Alliance – Blood Level Testing in the Management of
CML webpage includes the above claims or slightly modified
versions of the above claims, in addition to the following:
• “Therapeutic drug monitoring is used to help:
− Maximize a drug’s therapeutic
effect[13]
− Minimize toxicity[13]
− Assess patient adherence”14
The totality of these presentations suggests that a lack of
response in patients may be due to low plasma levels of Gleevec,
and that the dose of Gleevec should be modified (i.e., increased)
in the event that plasma concentrations of the drug are found to be
“suboptimal.” FDA is not aware of substantial evidence
or substantial clinical experience to support a correlation between
patient outcome and plasma levels of imatinib. The PI for Gleevec
provides very specific dosage recommendations for Gleevec in CML
and GIST, with guidelines for monitoring adverse events and
specific instructions for dose reduction or
discontinuation in the event of serious adverse events
(see Background). The PI does not contain a provision for plasma
level monitoring of Gleevec in patients, nor does it discuss
increasing the dose of Gleevec based on this information. The
referenced publications cited on the GIST Alliance webpage do not
provide substantial evidence or substantial clinical experience to
support these claims. Specifically, only one of the publications
referenced18 to support such an implication is relevant
to GIST patients. The Demetri reference is a brief clinical
monograph from a supplemental edition of Clinical Advances in
Hematology & Oncology. The two page monograph references
an abstract from the 2008 American Society of Clinical Oncology
annual meeting that describes unpublished results of a
retrospective subgroup analysis that makes claims about overall
survival (OS), as well as correlations between OS and plasma
imatinib levels. Such a reference does not constitute substantial
evidence or substantial clinical experience in support of such
claims. The second referenced article describes an exploratory,
uncontrolled, retrospective subgroup analysis of plasma imatinib
levels sampled at a single time point in patients with CML and the
corresponding clinical responses. These data do not constitute
substantial evidence or substantial clinical experience to support
the referenced claims.
Furthermore, the suggestion that the dose of Gleevec should be
modified in the event that plasma concentrations of the drug are
found to be “suboptimal” may put patients at
considerable risk of adverse events, many of which are
dose-related. The fact that these misleading dosing claims are
presented without any discussion of serious or potentially
dose-related side effects, such as neutropenia or thrombocytopenia,
is grossly misleading and greatly minimizes the potential risk to
patients of increasing the dose. We further note that these
websites heavily promote the “CML & GIST Alliance™
Blood Level Testing Program,” which encourages physicians to
test their patients for “suboptimal” plasma levels of
imatinib. Novartis explicitly recommends a laboratory (Avantix
Laboratories) to provide the corresponding testing services and
provides hyperlinks that physicians can use to access these
recommended services. The associated website dedicated to this
specific imatinib blood level testing program,
www.bloodleveltesting.com, makes numerous unsubstantiated claims
about the use of blood tests to optimize outcomes specifically in
patients with GIST or CML who are taking imatinib mesylate. For
example, the website includes many claims that are identical to
those included on the GIST Alliance and CML Alliance websites
(excerpted above). Additional claims correlate patient response
with imatinib pharmacokinetics and specific plasma drug
levels.,20
Although clicking on the prominently displayed links on the CML
Alliance and GIST Alliance websites leading to
www.bloodleveltesting.com produces a pop-up window disclaimer
stating that you are “moving to an external website
independently operated and not managed by the Novartis
Pharmaceuticals Corporation,” we note several indicators that
Novartis is, in fact, responsible for the content of the website.
For example, the website is registered to Novartis AG21,
contains the CML Alliance and GIST Alliance logos, and makes
repeated reference to Novartis. For example, the site includes the
statement:
• “Novartis, a global leader in oncology, continues to
work with healthcare professionals and patients worldwide to
advance the treatment of Ph+ chronic myeloid leukemia (CML) and
gastrointestinal stromal tumors (GISTs). CML Alliance™ and
GIST Alliance™ are unique support programs created by
Novartis to help healthcare professionals optimize outcomes in
patients with these conditions.”
In addition, the webpages within www.bloodleveltesting.com provide
hyperlinks to the CML Alliance and GIST Alliance home pages. The
website does not mention any TKIs other than imatinib, nor does it
mention pharmaceutical manufacturers other than Novartis.
Furthermore, Novartis provides the Blood Level Testing Program at
no cost to healthcare providers. Thus, it appears that Novartis may
be at least partly responsible for the content on this website.
DDMAC is deeply troubled by the content of the
www.bloodleveltesting.com website and the potential risk to the
public health from the multiple dosing implications for imatinib
contained on this website.
20 von Mehren M, Wang Y, Joensuu H, et al. Imatinib
pharmacokinetics (PK) and its correlation with clinical response in
patients with unresectable/metastatic gastrointestinal stromal
tumor (GIST). J Clin Oncol. 2008;26(15S):4523.
21 www.whois.net domain-based research services. Accessed January 21 2010; re-“www.bloodleveltesting.com.”
Failure to Submit
FDA regulations require companies to submit specimens of any
labeling or advertising devised for promotion of a drug product
approved under Subpart H regulations at least 30 days prior to the
intended time of initial dissemination per 21 CFR 314.550.
Moreover, FDA regulations require companies to submit specimens of
any labeling or advertising devised for promotion of the drug
product at the time of initial dissemination of the labeling and at
the time of initial publication of the advertisement for a
prescription drug product. Each submission is required to be
accompanied by a completed transmittal Form FDA-2253 (Transmittal
of Advertisements and Promotional Labeling for Drugs and Biologics
for Human Use) and is required to include a copy of the
product’s current professional labeling. These materials were
not submitted to FDA 30 days prior to the intended time of initial
dissemination or initial publication as required by 21 CFR 314.550,
and were not submitted to FDA under cover of Form FDA-2253 at the
time of their initial publication, as required by 21 CFR
314.81(b)(3)(i).
Conclusion and Requested Action
For the reasons discussed above, your promotional pieces misbrand
Gleevec in violation of the Federal Food, Drug and Cosmetic Act
(the Act), 21 U.S.C. 352(a), (f)(1) & (n); 321(n), and FDA
implementing regulations. See 21 CFR 201.100(c), 201.115 &
201.128, 21 CFR 202.1(e)(5), (e)(6)(i), (iv) & (xi). In
addition, it appears that the websites were neither submitted as
required by 21 CFR 314.550, nor submitted to FDA under cover of
Form FDA-2253 at the time of their initial publication, as required
by 21 CFR 314.81(b)(3)(i).
DDMAC requests that Novartis immediately cease the dissemination of
violative promotional materials for Gleevec such as those described
above. Please submit a written response to this letter on or before
May 5, 2010, stating whether you intend to comply with this
request, listing all promotional materials (with the 2253
submission date) for Gleevec 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 that your submission include a comprehensive
plan of action to disseminate truthful, nonmisleading, and complete
corrective messages about the issues discussed in this letter to
the audience(s) that received the violative promotional
materials.
In addition, we request that you respond with the full details of
your involvement with and control over the
www.bloodleveltesting.com website, which may also be in violation
of the Federal Food, Drug, and Cosmetic Act.
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, or facsimile at
301-847-8444. In all future correspondence regarding this matter,
please refer to MACMIS 18492 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 Gleevec comply with each
applicable requirement of the 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
Division of Drug Marketing,
Advertising, and Communications
1 As described in more detail below, DDMAC is also concerned with a third website, www.bloodleveltesting.com, which is linked to the above-mentioned Novartis websites and contains similar dosing claims to these websites.
2 Although beyond the scope of the issues discussed in this letter, we also note that the healthcare-professional portion of the CML Alliance website provides a direct link to the Tasigna product website in reference to second-line therapy for CML, and that the “My CML Circle Program” page (at www.mycmlcircle.com) also discusses Tasigna (another Novartis product) as a second-line therapy for CML.
3 www.whois.net domain-based research services. Accessed
January 21, 2010; re-“www.cmlalliance.com” and
“www.gistalliance.com”
4 DeMatteo RP, Ballman KV, Antonescu CR et al, on behalf of the American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localized, primary gastrointestinal stromal tumor: a randomized, double-blind, placebo-controlled trial. Lancet.2009;373:1097-1104.
5 National Comprehensive Cancer Network. NCCN Clinical
Practice Guidelines in Oncology: soft tissue sarcoma.
V.2.2007.
6 Bumming P, Andersson J, Meis-Kindblom JM, et al.
Neoadjuvant, adjuvant and palliative treatment of gastrointestinal
stromal tumours (GIST) with imatinib: a centre-based study of 17
patients. Br J Cancer. 2003;89(3):460-464.
7 Radkani P, Gheris MM, Paramo JC, Mesko TW. A
multidisciplinary approach for the treatment of GIST liver
metastasis. World J Surg Oncol. 2008;6:46.
8 Andtbacka RHI, Ng CS, Scaife CL, et al. Surgical
resection of gastrointestinal stromal tumors after treatment with
imatinib. Ann Surg Oncol. 2007;14(1):14-24.
9 Gronchi A, Fiore M, Miselli F, et al. Surgery of residual disease following molecular-targeted therapy with imatinib mesylate in advanced/metastatic GIST. Ann Surg. 2007;245(3):341-346.
10 Sym SJ, Ryu MH, Lee JL, et al. Surgical intervention following imatinib treatment in patients with advanced gastrointestinal stromal tumors (GISTs). J Surg Oncol. 2008;98(1):27-33.
11 DeMatteo RP, Maki RG, Singer S, Gonen M, Brennan MF, Antonescu CR. Results of tyrosine kinase inhibitor therapy followed by surgical resection for metastatic gastrointestinal stromal tumor. Ann Surg. 2007;245(3):347-352.
12 Druker BJ, Guilhot F, O’Brien SG, et al.
Five-year follow-up of patients receiving imatinib for chronic
myeloid leukemia. N Engl J Med. 2006;355(23):2408-2417.
13 Alnaim L. Therapeutic drug monitoring of cancer chemotherapy. J Oncol Pharm Practice. 2007;13(4):207-221.
14 Hugen PWH, Burger DM, Aarnoutse RE, et al.
Therapeutic drug monitoring of HIV-protease inhibitors to
assess
noncompliance. Ther Drug Monitor. 2002;24(5):579-587.
15 McLeod HL, Evans W. Oral cancer chemotherapy: the
promise and the pitfalls. Clin Cancer Res.
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| Application Type/Number | Submission Type/Number | Submitter Name | Product Name |
|---|---|---|---|
| NDA-21588 | ORIG-1 | NOVARTIS PHARMACEUTICA LS CORP | GLEEVEC (IMATINIB MESYLATE) 100/400MG |
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This is a representation of an electronic record that was
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/s/
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THOMAS W ABRAMS
04/21/2010
Posted: May 2010
