[Federal Register Volume 67, Number 93 (Tuesday, May 14, 2002)]
[Notices]
[Pages 34457-34458]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-11971]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 01P-0061]


Determination That IFEX (Ifosfamide for Injection), 1-Gram and 3-
Gram Vials, Was Not Withdrawn From Sale for Reasons of Safety or 
Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY:  The Food and Drug Administration (FDA) is announcing its 
determination that IFEX (ifosfamide for injection), 1 gram (g) and 3 g, 
was not withdrawn from sale for reasons of safety or effectiveness. 
This determination will allow FDA to approve abbreviated new drug 
applications (ANDAs) for ifosfamide.

FOR FURTHER INFORMATION CONTACT: Mitchell Weitzman, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-5670.

SUPPLEMENTARY INFORMATION:  In 1984, Congress enacted the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(the 1984 amendments), which authorized the approval of duplicate 
versions of drug products approved under an ANDA procedure. ANDA 
sponsors must, with certain exceptions, show that the drug for which 
they are seeking approval contains the same active ingredient in the 
same strength and dosage form as the ``listed drug,'' which is a 
version of the drug that was previously approved. Sponsors of ANDAs do 
not have to repeat the extensive clinical testing otherwise necessary 
to gain approval of a new drug application (NDA). The only clinical 
data required in an ANDA are data to show that the drug that is the 
subject of the ANDA is bioequivalent to the listed drug.
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which 
requires FDA to publish a list of all approved drugs. FDA publishes 
this list as part of the ``Approved Drug Products with Therapeutic 
Equivalence Evaluations,'' which is generally known as the ``Orange 
Book.'' Under FDA's regulations, drugs are withdrawn from the list if 
the agency withdraws or suspends approval of the drug's NDA or ANDA for 
reasons of safety or effectiveness or if FDA determines that the listed 
drug was withdrawn from sale for reasons of safety or effectiveness (21 
CFR 314.162).
    Under Sec. 314.161(a)(1) (21 CFR 314.161(a)(1)), the agency must 
determine whether a listed drug was withdrawn from sale for reasons of 
safety or effectiveness before an ANDA that refers to that listed drug 
may be approved. FDA may not approve an ANDA that does not refer to a 
listed drug.
    IFEX is the subject of NDA 19-763, held by Bristol-Myers Squibb Co. 
(BMS). FDA approved NDA 19-763 on December 30, 1988. Used in 
combination with other approved antineoplastic agents, IFEX is 
indicated for third line chemotherapy of germ cell testicular cancer. 
In the IFEX clinical studies, it was observed that urotoxic side 
effects, especially hemorrhagic cystitis, were frequently associated 
with the administration of IFEX. The approved labeling for IFEX stated 
that IFEX ``should ordinarily be used in combination with a 
prophylactic agent for hemorrhagic cystitis, such as mesna.'' FDA 
separately approved BMS's NDA for MESNEX (mesna) Injection on December 
30, 1988. BMS never marketed IFEX alone; instead, it elected to market 
IFEX exclusively in a combination package with MESNEX.
    IFEX as a single agent is currently listed in the ``Discontinued 
Drug Product List'' section of the Orange Book. IFEX is also listed as 
part of a copackaged kit with MESNEX in the Orange Book's prescription 
drug product list. The relocation of IFEX as a single agent to the 
``Discontinued Drug Product List'' coincided with a labeling 
modification on October 10, 1992, to reflect changes in storage 
conditions for IFEX and an approval of copackaging with MESNEX.
    On January 31, 2001, Tom Stothoff submitted a citizen petition 
(Docket No. 01P-0061/CP1) to FDA under 21 CFR 10.30, requesting that 
the agency determine whether IFEX (as a single agent) was withdrawn 
from sale for reasons of safety or effectiveness. The petitioner seeks 
this determination in preparation for filing an ANDA for Ifosfamide for 
Injection, U.S.P.
    On March 9, 2001, BMS filed a comment to the citizen petition 
requesting that FDA find that IFEX has not been withdrawn from sale and 
is not separately marketed by BMS for reasons of safety or 
effectiveness. With respect to safety and effectiveness, BMS argued 
that regardless of whether IFEX was withdrawn, FDA should deny the 
petitioner permission to file an ANDA for ifosfamide as a single agent 
because, as stated in the label, ifosfamide can only be administered 
safely in conjunction with a uroprotective agent such as mesna. BMS 
cited both the medical literature and the potential for urotoxic 
reactions if ifosfamide is used alone in support of this claim.
    BMS contends that it has never withdrawn or ceased to market IFEX 
because it has marketed IFEX in a combination package with MESNEX since 
the time of their approval. However, IFEX was approved under its own 
NDA as a single agent. In previous instances (see, e.g., 61 FR 25497, 
May 21, 1996) (addressing a relisting request for glyburide tablets), 
FDA has concluded that never marketing an approved product is 
equivalent to withdrawing the drug from sale.

[[Page 34458]]

 Therefore, even though BMS has never marketed IFEX alone, it is 
appropriate to categorize IFEX (as a single agent) as having been 
withdrawn from sale. Once a listed drug has been withdrawn from sale, 
FDA must make a determination that the withdrawal from sale was not for 
reasons of safety or effectiveness before it can approve any ANDAs 
referencing the listed drug.
    The agency has determined that IFEX as a single agent has not been 
withdrawn for reasons of safety or effectiveness. FDA agrees with BMS 
that ifosfamide should be used with a uroprotective agent like mesna. 
However, that does not preclude the safe use of ifosfamide as a single 
agent with MESNEX or a generic version of mesna. FDA approved two ANDAs 
for mesna in April 2001. The FDA has no requirement that coadministered 
products must also be copackaged. There are many drugs whose labeling 
identifies them for use in combination with other drugs with which they 
are not copackaged, including Taxol and Taxotere. Neither the 
petitioner nor BMS identified any data suggesting that marketing IFEX 
alone would compromise patients' safety. Moreover, the relevant 
literature and adverse event reports do not bear out BMS's claim that 
marketing IFEX as a single agent would be unsafe. In the absence of 
data suggesting a safety risk, and because IFEX was approved as a 
single agent, we conclude that FDA may approve ANDAs referencing IFEX 
alone.
    After considering the citizen petition and the comments thereon and 
reviewing its records, FDA determines that, for the reasons outlined 
previously in this document, IFEX as a single agent was not withdrawn 
for reasons of safety or effectiveness. Accordingly, the agency will 
continue to list IFEX in the ``Discontinued Drug Product List'' section 
of the Orange Book. The ``Discontinued Drug Product List'' delineates, 
among other items, drug products that have been discontinued from 
marketing for reasons other than safety or effectiveness. ANDAs that 
refer to IFEX, 1-g and 3-g vials, may be approved by the agency.

    Dated: May 6, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-11971 Filed 5-13-02; 8:45 am]
BILLING CODE 4160-01-S