[Federal Register: March 1, 2004 (Volume 69, Number 40)]
[Notices]
[Page 9630-9631]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr01mr04-84]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 01P-0333]
Determination That Cytoxan (Cyclophosphamide for Injection), 2
Gram Vials (NDA 12-142 054), Was Not Withdrawn From Sale for Reasons of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) has determined that
although Bristol Myers Squibb (Bristol) has discontinued marketing
CYTOXAN, 2 gram (g) vials (cyclophosphamide for injection), this
formulation was not withdrawn from sale for reasons of safety and
effectiveness. As a result of this determination, approved abbreviated
new drug applications (ANDAs) for cyclophosphamide for injection that
referenced Bristol's cyclophosphamide for injection will not be removed
from the market. Because Bristol has supplemented its CYTOXAN NDA and
obtained approval for a new formulation, cyclophosphamide lyophilized,
any unapproved ANDAs seeking to reference CYTOXAN as a reference listed
drug must reference the currently approved formulation,
cyclophosphamide lyophilized.
FOR FURTHER INFORMATION CONTACT: Howard P. Muller, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20855, 301-594-2041.
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
typically a version of the drug that was previously approved under a
new drug application (NDA). Sponsors of ANDAs do not have to repeat the
extensive clinical testing otherwise necessary to gain approval of an
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 Sec. 314.162 (21 CFR 314.162), 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 voluntarily withdrawn from sale by the sponsor
for reasons of safety or effectiveness.
Regulations also provide that 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 (Sec. 314.161(a)(1) (21 CFR 314.161(a)(1))). If the agency
determines that a listed drug was withdrawn for reasons of safety or
effectiveness, the drug must be removed from the list of approved drug
products, and ANDAs referencing that drug may not be approved (Sec.
314.162). Under Sec. 314.161(a)(2), the agency must also determine
whether a listed drug was withdrawn from sale for reasons of safety or
effectiveness if ANDAs that referred to the listed drug have already
been approved prior to its market withdrawal. If the agency determines
that a listed drug was withdrawn from sale for reasons of safety or
effectiveness, and there are approved ANDAs that reference that listed
drug, FDA will initiate a proceeding to determine whether the
suspension of the ANDAs is also required (21 CFR 314.153(b)).
On August 30, 1982, Bristol received approval for CYTOXAN
(cyclophosphamide for injection), 2 g vials, under NDA 12-142 054.
CYTOXAN is an alkylating agent used to treat various types of cancer.
It interferes with the growth of cancer cells, which are eventually
destroyed. On January 4, 1984, Bristol received approval for a new
formulation of CYTOXAN, cyclophosphamide lyophilized, under NDA 12-142
058. Bristol's lyophilized formulation was approved on the basis of a
showing of bioequivalence to the previously approved formulation. No
additional clinical trials were required to demonstrate the safety or
effectiveness of cyclophosphamide lyophilized. ANDAs were approved
before the time the cyclophosphamide lyophilized formulation was
approved. These ANDAs referenced cyclophosphamide for injection.
Bristol discontinued marketing cyclophosphamide for injection, 2 g
vials, in 1997. Cyclophosphamide for injection was moved from the
prescription drug product list to the ``Discontinued Drug Product
List'' section of the Orange Book in May 1997.
On July 26, 2001, ASTA Medica, Inc., submitted a citizen petition
(Docket No. 01P-0333/CP1) to FDA under 21 CFR 10.30 requesting that the
agency determine whether CYTOXAN, cyclophosphamide for injection, 2 g
vials, was withdrawn from sale for reasons of safety or effectiveness.
This determination not only affects whether an ANDA may be submitted
and approved under Sec. Sec. 314.122 and 314.161 using CYTOXAN,
cyclophosphamide for injection, 2 g, as the reference listed drug, but
also affects whether the agency is required to initiate withdrawal
proceedings for the ANDAs that reference cyclophosphamide for injection
and were approved before its market withdrawal.
The agency has determined that Bristol did not withdraw
cyclophosphamide for injection from sale for reasons of safety or
effectiveness. Three grounds support the agency's finding. First,
Bristol continues to market cyclophosphamide lyophilized (which is
pharmaceutically and therapeutically equivalent to Bristol's withdrawn
cyclophosphamide for injection) in a variety of strengths. FDA has no
reason to believe that cyclophosphamide lyophilized has a different
safety or effectiveness profile than cyclophosphamide for injection,
and required Bristol to conduct no clinical trials (other than
bioequivalence trials) to support the formulation change. Second, the
petitioner identified no adverse event data or other information
suggesting that Bristol withdrew cyclophosphamide for injection from
sale as a result of safety
[[Page 9631]]
or effectiveness concerns. Third, FDA has independently evaluated
relevant literature and internal agency data for possible postmarketing
reports associated with cyclophosphamide for injection, and has found
no information that would indicate this product was withdrawn for
reasons of safety or effectiveness.
After considering the citizen petition and reviewing its records,
FDA determines that, for the reasons outlined above, Bristol's
cyclophosphamide for injection was not withdrawn from sale for reasons
of safety or effectiveness. Thus, FDA will not initiate proceedings to
suspend the approvals of ANDAs referencing cyclophosphamide for
injection. However, because Bristol has supplemented its CYTOXAN NDA
and obtained approval for a new formulation, cyclophosphamide
lyophilized, any unapproved ANDAs seeking to reference CYTOXAN (NDA 12-
142 054) must reference the currently approved formulation.
Dated: February 15, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-4505 Filed 2-27-04; 8:45 am]
BILLING CODE 4160-01-S