FDA Sends MGI Pharma Letter Over Gliadel Wafer Advertisement

ROCKVILLE, Md., Jan. 31, 2007-The FDA posted on its website today a letter sent to MGI Pharma over a journal advertisement for Gliadel Wafer.  The letter is below.



DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service
Food and Drug Administration
Rockville, MD 20857

TRANSMITTED BY FACSIMILE

Timothy K. Ressler, MS, MT (ASCP)
Vice President, Regulatory Affairs
MGI PHARMA, Inc.
5775 West Old Shakopee Road
Suite 100
Bloomington, Minnesota 55437-3174

RE: NDA # 20-637
Gliadel® Wafer (polifeprosan 20 with carmustine implant)
MACMIS # 14575

Dear Mr. Ressler:

The Division of Drug Marketing, Advertising, and Communications (DDMAC) of the U.S. Food
and Drug Administration (FDA) has reviewed a journal advertisement (GL0014) (journal ad)
for Gliadel Wafer (polifeprosan 20 with carmustine implant) (Gliadel Wafer) submitted by MGI
PHARMA, Inc. (MGI) under cover of Form FDA 2253. This two-page promotional piece is
misleading because it fails to disclose the full indication and presents unsubstantiated claims
regarding Gliadel Wafer. The journal ad therefore misbrands the drug in violation of Sections
502(n) and 201(n) of the Federal Food, Drug and Cosmetic Act (Act), 21 U.S.C. §§ 352(n) &
321(n) and FDA implementing regulations, 21 CFR 202.1(e)(3)(ii) and 202.1 (e)(6)(i).

Background
As stated in the Indication and Usage section of the approved product labeling (PI), “Gliadel
Wafer is indicated in newly-diagnosed high-grade malignant glioma patients as an adjunct to
surgery and radiation. Gliadel Wafer is [also] indicated in recurrent glioblastoma multiforme
patients as an adjunct to surgery.”

The indication for newly-diagnosed high-grade malignant glioma patients is based on a
randomized, double-blind, placebo-controlled clinical trial that was conducted in two hundred
and forty adult patients with newly-diagnosed high-grade malignant glioma undergoing initial
craniotomy for tumor resection. This trial was designed to determine the safety and efficacy
of Gliadel Wafer implants plus surgery and radiation therapy compared to placebo implants
plus surgery and radiation. Patients were followed for at least three years or until death. The
median survival increased from 11.6 months with placebo to 13.9 months with Gliadel Wafer
(p-value <0.05, log-rank test). The hazard ratio for Gliadel Wafer treatment was 0.73 (95%
CI: 0.56-0.95) in this study population.

Failure to Disclose the Full Indication
Promotional materials are misleading if they fail to reveal facts that are material in light of the
representations made. This promotional piece is misleading because it includes efficacy and
safety data for patients implanted with Gliadel Wafer during initial craniotomy, but fails to
present the corresponding approved indication for Gliadel (i.e., Gliadel Wafer is indicated in
newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and
radiation). See 21 CFR 202.1(e)(3)(ii).

Unsubstantiated Claims
The promotional piece states, “TAKE THE PATH TO AVOID TREATMENT DELAYS,”
“GLIADEL WAFER WORKS AT DAY 1,” “Cells may double after 10 days…,” and “Only 1
therapy…that avoids treatment delays post surgery.” The totality of this presentation
suggests that Gliadel Wafers’ particular advantage, compared to radiation therapy alone, is
avoidance of treatment delay. These claims further imply that early use of Gliadel Wafers
provides a clinical benefit during the fourteen days from implantation to initiation of traditional
radiation therapy, and represents the basis for its effectiveness. While FDA acknowledges
that Gliadel Wafer has demonstrated a survival benefit compared to radiation alone, FDA is
not aware of any evidence that the efficacy of Gliadel Wafer results from the ability to use the
Gliadel Wafer at the time of surgery.

In the controlled clinical study used to support the approval of this NDA, Gliadel Wafers or
placebo wafers were implanted during craniotomy for tumor resection, and the majority of
patients received a standard course of radiotherapy, typically starting 3 weeks after surgery.
The timing of Gliadel Wafer implantation in this study was based on necessity (i.e.,
implantation requires craniotomy) rather than any known benefit from treating immediately
after surgery. The “delay” in the treatment of glioma between surgery and the beginning of
radiotherapy was merely the prescribed time to allow for necessary healing after surgery.
FDA is unaware of any substantial evidence to support MGI’s claims implying that the timing
of Gliadel Wafer implantation prior to radiotherapy provides a clinical benefit (e.g., “TAKE
THE PATH TO AVOID TREATMENT DELAYS” and “Only 1 therapy…that avoids treatment
delays post surgery”) or that, in the absence of early Gliadel Wafer implantation, there is a
potential for significant disease progression during the period prior to radiotherapy (e.g.,
“Cells may double after 10 days…”). Furthermore, the reference1 cited in the promotional
piece to support the latter claim regarding tumor size is from an in vitro labeling study utilizing
a new method for calculation of the “potential doubling time” of glioma cells which does not
represent substantial evidence. These in vitro data are not an adequate basis to predict the
effectiveness of Gliadel Wafers on cell growth following cranial implantation.

MGI further states “GLIADEL WAFER WORKS AT DAY 1” and provides two references2,3 in
support of the claim. FDA finds that this claim is misleading because the references discuss
rat and monkey studies—not human studies. Moreover, these animal studies do not measure the time to actual glioma cell death in humans. Instead, these studies reported on
the release of carmustine (from implanted Gliadel Wafers), which is taken up by surrounding
brain tissues including residual glioma. FDA is unaware of substantial evidence to support
MGI’s extrapolation that this carmustine uptake results in immediate glioma cell death or
when actual glioma cell death occurs following Gliadel Wafer implantation.

1 Matsutani M. Cell kinetics. In: Berger MS, Wilson CB, eds. The Gliomas. Philadelphia, Pa: WB Saunders Co; 1999:204-209.
2 Fung LK, Shin M, Tyler B, Brem H, Saltzman WM. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-
1-nitrosourea in the rat brain. Pharm Res. 1996 May;13(5):671-82.
3 Fung LK, Ewend MG, Sills A, Sipos EP, Thompson R, Watts M, et al. Pharmacokinetics of interstitial delivery of carmustine, 4-
hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. Cancer Res. 1998 Feb
15;58(4):672-84.

Conclusion and Requested Action
The promotional piece is misleading because it fails to disclose the full indication that
corresponds to the claims for Gliadel Wafer presented in the piece and presents
unsubstantiated claims for Gliadel Wafer. Therefore, it misbrands the drug in violation of the
Act and FDA implementing regulations. See 21 U.S.C. §§ 352(n) & 321(n) and 21 CFR
202.1(e)(3)(ii) and 202.1(e)(6)(i).

DDMAC requests that MGI immediately cease the dissemination of promotional materials for
Gliadel Wafer the same as or similar to those described above. Please submit a written
response to this letter on or before February 9, 2007, describing your intent to comply with
this request, listing all promotional materials for Gliadel Wafer that contain claims that are the
same as or similar to those described above, and explaining your plan for discontinuing use
of these 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, or by facsimile at
301-796-9877. In all future correspondence regarding this matter, please refer to MACMIS
ID # 14575 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 Gliadel Wafer comply with
each applicable requirement of the Act and FDA implementing regulations.

Sincerely,
{See appended electronic signature page}
Joseph A. Grillo, Pharm.D.
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications
---------------------------------------------------------------------------------------------------------------------
This is a representation of an electronic record that was signed electronically and
this page is the manifestation of the electronic signature.
---------------------------------------------------------------------------------------------------------------------
/s/
---------------------
Joseph Grillo
1/29/2007 04:45:00 PM

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