[Federal Register Volume 68, Number 153 (Friday, August 8, 2003)]
[Notices]
[Pages 47332-47339]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-20241]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003N-0324]


Certain Antibiotic New Animal Drug Products and Use Combinations 
Subject to Listings in the New Animal Drug Regulations; Drug Efficacy 
Study Implementation; Notice of Opportunity for Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of opportunity for hearing.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
effective conditions of use for certain drug products and use 
combinations in the following four categories: Bacitracin methylene 
disalicylate single-ingredient Type A medicated articles, 
oxytetracycline and neomycin fixed-combination Type A medicated 
articles, and combination drug Type B and Type C medicated feeds for 
poultry containing bacitracin. The agency is also proposing to withdraw 
the new animal drug applications (NADAs) for those products or use 
combinations lacking substantial evidence of effectiveness, following a 
90-day opportunity to supplement the NADAs with labeling conforming to 
the relevant findings of effectiveness. For applications proposed to be 
withdrawn, the agency is providing an opportunity for hearing. 
Elsewhere in this issue of the Federal Register, FDA is publishing a 
proposed rule to remove certain obsolete or redundant sections of the 
new animal

[[Page 47333]]

drug regulations where these subject drug products and use combinations 
are listed. That proposed rule contains background information about 
those regulations and also for this action.

DATES: Submit written appearances and a request for a hearing by 
September 8, 2003. Submit all data and analysis upon which a request 
for a hearing relies by October 7, 2003. Submit supplemental NADAs by 
November 6, 2003.

ADDRESSES: Written requests for a hearing, data and analysis, and other 
written appearances are to be identified with Docket No. 2003N-0324 and 
submitted to the Division of Dockets Management (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 
Submit supplemental new animal drug applications to the Director, 
Office of New Animal Drug Evaluation, c/o Document Control Unit (HFV-
199), Center for Veterinary Medicine, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT: Andrew J. Beaulieu, Center for 
Veterinary Medicine (HFV-1), 7519 Standish Pl., Rockville, MD 20855, 
301-827-2954, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    In 1962, Congress amended the new drug provisions, which then 
applied to new drugs intended for both man and other animals, to 
require that a new drug be shown to be both safe and effective before 
marketing (the Drug Amendments of 1962, Public Law 87-781, 76 Stat. 
780). Before 1962, animal drug approvals did not require a 
demonstration of effectiveness. Under the 1962 amendments, the 
effectiveness requirement was made applicable, after a 2-year 
transition period, to animal drugs approved before 1962. This pre-1962 
drug evaluation is known as the Drug Efficacy Study Implementation 
(DESI) program. In response to the need for an integrated approach, the 
DESI program evaluated the efficacy of all animal drug products, 
including antibiotic new animal drugs used in feed and antibiotic feed 
use combinations (see, e.g., Sec.  558.15(b)(3) (21 CFR 558.15(b)(3)) 
and 37 FR 21279 (October 7, 1972)). Under the DESI program, a new 
animal drug approved before October 10, 1962, could continue to be 
approved if the sponsor submitted a supplemental NADA to revise the 
indications for use to those for which the agency determined the drug 
to be effective.
    This document announces the effective indications for which certain 
new animal drugs and drug combinations may be marketed, and provides an 
opportunity for hearing on those indications for which products may not 
be marketed because they lack substantial evidence of effectiveness. 
There are nine products subject to this notice, and they fall into the 
following four categories:
    1. Bacitracin methylene disalicylate (BMD) single-ingredient Type A 
medicated article,
    2. Oxytetracycline and neomycin fixed-combination Type A medicated 
articles,
    3. Combination drug Type B and Type C medicated feeds for poultry 
containing nicarbazin, and
    4. Combination drug Type B and Type C medicated feeds for poultry 
containing bacitracin.
    Under section 108(b)(2) of Public Law 90-399 (82 Stat. 353), the 
Animal Drug Amendments of 1968, any approval of a new animal drug 
granted prior to the law's effective date, whether through approval of 
a new drug application, master file, antibiotic regulation, or food 
additive regulation, continues in effect and is subject to change in 
accordance with the provisions of section 512 of the Federal Food, 
Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). The nine products 
that are the subject of this notice are subject to this transitional 
approval provision.
    In addition, they are all listed in the interim marketing 
provisions of Sec.  558.15. A history of the interim marketing 
provisions and the approval status of the products listed in them is 
contained in a notice of proposed rulemaking published elsewhere in 
this issue of the Federal Register. The agency has DESI finalized many 
of the products subject to the listings in Sec.  558.15, codifying 
their approvals in part 558 (21 CFR part 558) subpart B (see, e.g., 61 
FR 35949, July 9, 1996). The nine products subject to this notice are 
the only ones listed in Sec.  558.15 that are subject to DESI and that 
have not yet been DESI finalized.

II. Findings of Effectiveness of Certain Drugs Listed in Sec.  558.15

A. Bacitracin Methylene Disalicylate Single-Ingredient Type A Medicated 
Articles

    The following drug is covered by the DESI findings of effectiveness 
for BMD in animal feed:
    [sbull] NADA 141-137, FORTRACIN MD 50 (BMD) Type A medicated 
article used to make Type B and Type C medicated feeds. Pennfield Oil 
Co., 14040 Industrial Rd., Omaha, NE 68137.
    In 1970, FDA announced its DESI findings of effectiveness for feed 
use of BMD (35 FR 11531, July 17, 1970, as corrected by 35 FR 15408, 
October 2, 1970). Table 1 of this document summarizes FDA's 
conclusions.

Table 1.--DESI Findings of Effectiveness For Use of Bacitracin Methylene
                       Disalicylate in Animal Feed
------------------------------------------------------------------------
    Bacitracin methylene
 disalicylate in grams per       Indications for use        Limitations
        ton (g/ton)
------------------------------------------------------------------------
4 to 50                      Chickens, turkeys, and       ..............
                              pheasants: For increased
                              rate of weight gain and
                              improved feed efficiency.
------------------------------------------------------------------------
 5 to 20                     Quail not over 5 weeks of    ..............
                              age: For increased rate of
                              weight gain and improved
                              feed efficiency.
------------------------------------------------------------------------

    The agency notes that there are several potential sources of 
confusion regarding NADA 141-137 and the interim marketing provision 
for BMD in Sec.  558.15(g)(1) (further information about this provision 
is contained in a notice of proposed rulemaking published elsewhere in 
this issue of the Federal Register). Section 558.15(g)(1) contains a 
table that lists antibacterial Type A medicated articles that are 
eligible for interim marketing based on compliance with other 
provisions of Sec.  558.15, and specifies the sponsors of these 
articles and their approved species, use levels, and indications for 
use. An example of the problems with this table is that the sponsors it 
lists for BMD--A. L. Laboratories, Inc., and Fermenta Animal Health 
Co.--are outdated. These companies are predecessors in interest

[[Page 47334]]

to the current sponsors, which are Alpharma, Inc., and Pennfield Oil 
Co., respectively.
    A second, more complicated example involves BMD's approved 
conditions of use. Rather than listing the use levels and indications 
for use for which interim marketing is permitted, the table in Sec.  
558.15(g)(1) contains a reference to another section of the 
regulations. When the table was first published in 1976, this reference 
was to the uses and indications listed in 21 CFR 121.225 and 121.252 
(see 41 FR 8282, February 25, 1976). These were the conditions of use 
for which the BMD products were approved, under the transitional 
approval provisions of the Animal Drug Amendments of 1968. Shortly 
thereafter, these uses were recodified in Sec.  558.76 and the 
reference in Sec.  558.15(g)(1) was adjusted accordingly (41 FR 10984, 
March 15, 1976). Since that recodification, Sec.  558.76 has been 
amended numerous times to reflect the approval of supplemental 
applications, based on proprietary data, that were filed by sponsors 
other than Pennfield Oil Co. or its predecessors in interest (see, 
e.g., 63 FR 40824, July 31, 1998). At the time of these amendments to 
Sec.  558.76, the table in Sec.  558.15(g)(1) was not updated by 
removing the simple cross reference to Sec.  558.76 and by adding in 
its place a correct reference or a correct listing of the uses for 
which interim marketing was permitted. Thus, the table is misleading 
unless the reader already knows the indications for which the sponsors 
are approved or reviews the changes made over time to Sec. Sec.  558.15 
and 558.76.
    The confusion caused by the reference in Sec.  558.15(g)(1) to the 
use levels and indications for use in Sec.  558.76 is illustrated by, 
and perhaps exacerbated by, the administrative record for NADA 141-137. 
As happened with several other products listed in Sec.  558.15, it 
became apparent in the 1990s that the administrative record for this 
NADA was incomplete, calling into question its approval status. This is 
described in more detail in the proposed rule to remove Sec.  558.15 
published elsewhere in this issue of the Federal Register. In 1998, to 
help resolve the approval status, the company that owned the product at 
the time, Boehringer Ingelheim Vetmedica, Inc. (BIVI), certified that 
the product was approved pre-1968 and provided supporting information. 
This certification was made by a letter dated September 18, 1998, as 
amended by a letter dated November 17, 1998. It provided historical 
information about the product, stated that the product had been 
approved prior to 1968, and stated that it was subject to the 
transitional approval provisions of the Animal Drug Amendments of 1968. 
The company also provided information about the approved indications. 
One piece of information, included with the September letter, is a 
product label dated February 1969. BIVI stated that this label is 
consistent with Sec.  558.15. This was probably intended to mean the 
interim marketing table in Sec.  558.15 as it was originally issued in 
1976 since the label's indications are generally consistent with, 
albeit somewhat narrower than, BMD's indications listed in the table at 
the time. Given this consistency and given that the date of the label 
is just a few months before the effective date of the transitional 
approval provision, the label provides good evidence that the product 
was subject to transitional approval and the indications for which it 
was transitionally approved.
    However, two other pieces of information appear to be inconsistent 
with the indications for which FDA believes Pennfield Oil Co.'s BMD 
product is transitionally approved. The November 1998 letter from BIVI 
states that the product was approved for ``the indications for use 
itemized in 21 CFR Sec.  558.78,'' which was presumably meant to be 
Sec.  558.76 since the other regulation (Sec.  558.78) concerns 
bacitracin zinc. It is unclear whether BIVI meant the indications in 
Sec.  558.76 in 1976 or 1998. Also unclear is the meaning of two labels 
faxed by BIVI to FDA on December 9, 1998. These are in the product's 
current NADA file, although without any cover page or other explanatory 
notes. These labels, one a subset of the other, specify indications 
that are much closer to those listed in Sec.  558.76 in 1998 than to 
those that were transitionally-approved. It is possible that the labels 
BIVI faxed to FDA on December 9, 1998, were based on Sec.  558.76 as it 
existed at that time, given that the BMD listing in Sec.  558.15 
contained the misleading cross-reference to Sec.  558.76.
    On December 17, 1998, FDA sent BIVI a letter stating that the 
agency received the company's November certification that amended the 
September letter, that the certification would be used as part of the 
administrative record of approval, and that the agency planned to 
codify this approval as soon as possible given resource constraints and 
public health priorities. FDA's letter also referred to the indications 
``specified in the labeling attached to [BIVI's] letter.'' However, 
FDA's letter does not state to which labeling it is referring.
    We are not aware of any additional approved indications beyond 
those listed in the original Sec.  558.76 from 1976 for Pennfield Oil 
Co.'s product. If the sponsor has additional information on the other 
approved indications, such information should be provided to FDA during 
this administrative process.

B. Oxytetracycline and Neomycin Fixed-Combination Type A Medicated 
Articles

    The agency is making findings of effectiveness for oxytetracycline 
and neomycin fixed-combination Type A medicated articles for use in 
animal feed. These findings cover the following drugs:
    [sbull] NADA 94-975, NEO-TERRAMYCIN (oxytetracycline and neomycin). 
Phibro Animal Health, 710 Route 46 East, suite 401, Fairfield, NJ 
07004.
    [sbull] NADA 138-939, NEO-OXY (oxytetracycline and neomycin). 
Pennfield Oil Co., 14040 Industrial Rd., Omaha, NE 68137.
    Both of these products are two-way, fixed-combination Type A 
medicated articles used to make two-way combination drug Type C 
medicated feeds at use levels for the species and indications listed in 
Sec.  558.15(g)(2). The drug sponsor information in this listing is 
outdated, however, designating Pfizer, Inc., Pennfield Oil Co., and 
VPO, Inc., instead of Phibro Animal Health and Pennfield Oil Co.
    The National Academy of Sciences/National Research Council (NAS/
NRC) assisted FDA in its DESI program for numerous animal drug 
products. While NAS/NRC did not evaluate the efficacy data relating to 
these combinations, FDA has conducted such a review. This review was 
based on the agency's findings of effectiveness for oxytetracycline and 
neomycin single-ingredient feed use products, which in turn were based 
on NAS/NRC's evaluation (see 35 FR 7089, May 5, 1970, and 36 FR 837, 
January 19, 1971). FDA has determined that its previous findings of 
effectiveness for the single ingredients are applicable to the 
combinations in the absence of information indicating interference in 
effectiveness between individual ingredients. The agency's review also 
considered information about the effectiveness submitted to these two 
NADAs, although this information did not alter the agency's conclusions 
based on the single-ingredient findings. Tables 2, 3, 4, and 5 of this 
document summarize FDA's findings of effectiveness for oxytetracycline 
and neomycin fixed-combination Type A medicated articles for use in 
animal feed.

[[Page 47335]]



 Table 2.--DESI Findings of Effectiveness for Use of Oxytetracycline and
          Neomycin Administered in Chicken Feed in a 1:1 Ratio
------------------------------------------------------------------------
  Oxytetracycline
   and  neomycin
amount in g/ton of     Indications for use            Limitations
       feed
------------------------------------------------------------------------
10 to 50            Chickens: For increased    Do not feed to chickens
                     rate of weight gain and    producing eggs for human
                     improved feed              consumption.
                     efficiency.
------------------------------------------------------------------------
100 to 200          Chickens: For control of   Feed continuously for 7
                     infectious synovitis       to 14 days (d); do not
                     caused by Mycoplasma       feed to chickens
                     synoviae; control of       producing eggs for human
                     fowl cholera caused by     consumption; in low
                     Pasteurella multocida      calcium feed, withdraw 3
                     susceptible to             d before slaughter.
                     oxytetracycline.
------------------------------------------------------------------------
400                 Chickens: For control of   Feed continuously for 7
                     chronic respiratory        to 14 d; do not feed to
                     disease (CRD) and air      chickens producing eggs
                     sac infection caused by    for human consumption;
                     M. gallisepticum and       in low calcium feeds,
                     Escherichia coli           withdraw 3 d before
                     susceptible to             slaughter.
                     oxytetracycline.
------------------------------------------------------------------------
500                 Chickens: For reduction    Feed continuously for 5
                     of mortality due to air    d; do not feed to
                     sacculitis (air-sac-       chickens producing eggs
                     infection) caused by E.    for human consumption;
                     coli susceptible to        withdraw 24 hours before
                     oxytetracycline.           slaughter; in low
                                                calcium feeds withdraw 3
                                                d before slaughter.
------------------------------------------------------------------------


 Table 3.--DESI Findings of Effectiveness for Use of Oxytetracycline and
           Neomycin Administered in Turkey Feed in a 1:1 Ratio
------------------------------------------------------------------------
  Oxytetracycline
   and  neomycin       Indications for use            Limitations
      amount
------------------------------------------------------------------------
10 to 50 g/ton of   Growing turkeys: For       Do not feed to turkeys
 feed                increased rate of weight   producing eggs for human
                     and improved feed          consumption.
                     efficiency.
------------------------------------------------------------------------
100 g/ton of feed   Turkeys: For control of    Feed continuously for 7
                     hexamitiasis caused by     to 14 d; do not feed to
                     Hexamita meleagridis       turkeys producing eggs
                     susceptible to             for human consumption.
                     oxytetracycline.
------------------------------------------------------------------------
200 g/ton of feed   Turkeys: For control of    Feed continuously for 7
                     infectious synovitis       to 14 d; withdraw 5 d
                     caused by M. synoviae      before slaughter; do not
                     susceptible to             feed to turkeys
                     oxytetracycline.           producing eggs for human
                                                consumption.
------------------------------------------------------------------------
25 milligrams per   Turkeys: For control of    Feed continuously for 7
 pound (mg/lb) of    complicating bacterial     to 14 d; withdraw 5 d
 body weight daily   organisms associated       before slaughter; do not
                     with bluecomb              feed to turkeys
                     (transmissible             producing eggs for human
                     enteritis; coronaviral     consumption.
                     enteritis) susceptible
                     to oxytetracycline.
------------------------------------------------------------------------


 Table 4.--DESI Findings of Effectiveness for Use of Oxytetracycline and
           Neomycin Administered in Swine Feed in a 1:1 Ratio
------------------------------------------------------------------------
  Oxytetracycline
   and  neomycin       Indications for use            Limitations
      amount
------------------------------------------------------------------------
10 to 50 g/ton of   Swine: For increased rate  .........................
 feed                of weight and improved
                     feed efficiency
------------------------------------------------------------------------
10 mg/lb of body    Swine: For treatment of    Feed continuously for 7
 weight daily        bacterial enteritis        to 14 d; withdraw 5 d
                     caused by E. coli and      before slaughter.
                     Salmonella choleraesuis
                     and bacterial pneumonia
                     caused by P. multocida
                     susceptible to
                     oxytetracycline;
                     treatment and control of
                     colibacillosis
                     (bacterial enteritis)
                     caused by E. coli
                     susceptible to neomycin.
------------------------------------------------------------------------
10 mg/lb of body    Breeding swine: For        Feed continuously for not
 weight daily        control and treatment of   more than 14 d; withdraw
                     leptospirosis (reducing    5 d before slaughter.
                     the incidence of
                     abortion and shedding of
                     leptospirae) caused by
                     Leptospira pomona
                     susceptible to
                     oxytetracycline.
------------------------------------------------------------------------


[[Page 47336]]


 Table 5.--DESI Findings of Effectiveness for Use of Oxytetracycline and
      Neomycin Administered in Cattle and Sheep Feed in a 1:1 Ratio
------------------------------------------------------------------------
  Oxytetracycline
   and neomycin        Indications for use            Limitations
      amount
------------------------------------------------------------------------
 10 to 20 g/ton of  Sheep: For increased rate  .........................
 feed                of weight gain and
                     improved feed
                     efficiency.
------------------------------------------------------------------------
0.05 to 0.1 mg/lb   Calves (up to 250 lb):     Feed continuously; in
 of body weight      For increased rate of      milk replacers or
 daily               weight gain and improved   starter feed.
                     feed efficiency.
------------------------------------------------------------------------
10 mg/lb of body    Calves and beef and        Feed continuously for 7
 weight daily        nonlactating dairy         to 14 d in feed or milk
                     cattle: For treatment of   replacers. If symptoms
                     bacterial enteritis        persist after using for
                     caused by E. coli and      2 or 3 d, consult a
                     bacterial pneumonia        veterinarian. Treatment
                     (shipping fever complex)   should continue 24 to 48
                     caused by P. multocida     hours beyond remission
                     susceptible to             of disease symptoms. A
                     oxytetracycline;           withdrawal period has
                     treatment and control of   not been established for
                     colibacillosis             use in preruminating
                     (bacterial enteritis)      calves. Do not use in
                     caused by E. coli          calves to be processed
                     susceptible to neomycin.   for veal. A milk discard
                                                time has not been
                                                established for use in
                                                lactating dairy cattle.
                                                Do not use in female
                                                dairy cattle 20 months
                                                of age or older.
                                                Withdraw 5 d before
                                                slaughter.
------------------------------------------------------------------------
10 mg/lb of body    Calves (up to 250 lb):     Feed continuously for 7
 weight daily        For the treatment of       to 14 d in milk
                     bacterial enteritis        replacers or starter
                     caused by E. coli          feed. If symptoms
                     susceptible to             persist after using for
                     oxytetracycline;           2 or 3 d, consult a
                     treatment and control of   veterinarian. Treatment
                     colibacillosis             should continue 24 to 48
                     (bacterial enteritis)      hours beyond remission
                     caused by E. coli          of disease symptoms. A
                     susceptible to neomycin.   withdrawal period has
                                                not been established for
                                                use in preruminating
                                                calves. Do not use in
                                                calves to be processed
                                                for veal. A milk discard
                                                time has not been
                                                established for use in
                                                lactating dairy cattle.
                                                Do not use in female
                                                dairy cattle 20 months
                                                of age or older.
                                                Withdraw 5 d before
                                                slaughter.
------------------------------------------------------------------------
10 mg/lb of body    Sheep: For the treatment   Feed continuously for 7
 weight daily        of bacterial enteritis     to 14 d. If symptoms
                     caused by E. coli and      persist after using for
                     bacterial pneumonia        2 or 3 d, consult a
                     caused by P. multocida     veterinarian. Treatment
                     susceptible to             should continue 24 to 48
                     oxytetracycline;           hours beyond remission
                     treatment and control of   of disease symptoms.
                     colibacillosis             Withdraw 5 d before
                     (bacterial enteritis)      slaughter.
                     caused by E. coli
                     susceptible to neomycin.
------------------------------------------------------------------------
25 mg/head/d        Calves (250 to 400 lb):    .........................
                     For increased rate of
                     weight gain and improved
                     feed efficiency.
------------------------------------------------------------------------
75 mg/head/d        Growing cattle (over 400   .........................
                     lb): For increased rate
                     of weight gain, improved
                     feed efficiency, and
                     reduction of liver
                     condemnation due to
                     liver abscesses.
------------------------------------------------------------------------
0.5 to 2.0 g/head/  Cattle: For prevention     Feed 3 to 5 d before and
 d                   and treatment of the       after arrival in
                     early stages of shipping   feedlots. A withdrawal
                     fever complex.             period has not been
                                                established for use in
                                                preruminating calves. Do
                                                not use in calves to be
                                                processed for veal. A
                                                milk discard time has
                                                not been established for
                                                use in lactating dairy
                                                cattle. Do not use in
                                                female dairy cattle 20
                                                months of age or older.
------------------------------------------------------------------------

C. Combination Drug Type B and Type C Medicated Feeds for Poultry 
Containing Nicarbazin

    The agency is making findings of effectiveness for combination drug 
Type B and Type C medicated feeds containing nicarbazin. These findings 
cover the following drugs:
    [sbull] NADA 98-371, for the combination use of NICARBAZIN 
(nicarbazin), PENICILLIN G PROCAINE (procaine penicillin), and 3-NITRO 
(roxarsone). Phibro Animal Health.
    [sbull] NADA 98-374, for the combination use of NICARBAZIN 
(nicarbazin) and PENICILLIN G PROCAINE (procaine penicillin). Phibro 
Animal Health.
    [sbull] NADA 100-853, for the combination use of NICARBAZIN 
(nicarbazin), BACIFERM (BMD), and 3-NITRO (roxarsone). Phibro Animal 
Health.
These three combination drugs are for uses listed in Sec.  
558.15(g)(2). The drug sponsor information in the listing is outdated, 
designating The Upjohn Co. instead of Phibro Animal Health. In 
addition, rather than itemizing the indications for use, the listing 
gives references to the indications itemized in Sec. Sec.  558.325, 
558.355, and 558.530. These references are not accurate since they are 
for lincomycin, monensin, and roxarsone.
    While NAS/NRC did not evaluate the efficacy data relating to these 
combinations, FDA has conducted such a review. This review was based on 
the agency's findings of effectiveness for bacitracin zinc, nicarbazin, 
procaine penicillin, and roxarsone single-ingredient feed use products, 
which in turn were based on NAS/NRC's evaluation (see 35 FR 12490, 
August 5, 1970 (bacitracin zinc); 34 FR 6495, April 15, 1969 
(nicarbazin); 35 FR 11534, July 17, 1970 (procaine penicillin); and 35 
FR 14273, September 10, 1970 (roxarsone)). FDA has determined that its 
previous findings of effectiveness are applicable to the combinations 
in the absence of information indicating interference in effectiveness 
between individual ingredients. Table 6 of this

[[Page 47337]]

document summarizes FDA's findings of effectiveness for certain 
combination drug Type B and Type C medicated feeds containing 
nicarbazin.

Table 6.--Findings of Effectiveness for Use of Certain Drug Combinations
                  Containing Nicarbazin in Poultry Feed
------------------------------------------------------------------------
    Type A         Type A        Type A
article in g/  article in g/  article in g/  Indications    Limitations
     ton            ton            ton         for use
------------------------------------------------------------------------
Nicarbazin     Bacitracin     Roxarsone     Growing        Feed
 90.8 to        methylene      22.7 to       chickens: As   continuously
 181.6 (0.01    disalicylate   45.4          an aid in      as sole
 to 0.02        4 to 50                      preventing     ration from
 percent                                     outbreaks of   time chicks
 (pct)                                       cecal          are placed
                                             (Eimeria       on litter
                                             tenella) and   until past
                                             intestinal     the time
                                             (E.            when
                                             acervulina,    coccidiosis
                                             E. maxima,     is
                                             E. necatrix,   ordinarily a
                                             and E.         hazard; do
                                             brunetti)      not use as a
                                             coccidiosis,   treatment
                                             and for        for
                                             increased      outbreaks of
                                             rate of        coccidiosis.
                                             weight gain,   As a sole
                                             improved       source of
                                             feed           organic
                                             efficiency,    arsenic;
                                             and improved   drug
                                             pigmentation   overdose or
                                             .              lack of
                                                            water may
                                                            result in
                                                            leg
                                                            weakness. Do
                                                            not use in
                                                            flushing
                                                            mashes. Do
                                                            not feed to
                                                            laying hens
                                                            in
                                                            production.
                                                            Discontinue
                                                            medication 5
                                                            d before
                                                            marketing
                                                            the birds
                                                            for human
                                                            consumption
                                                            to allow for
                                                            elimination
                                                            of the drug
                                                            from edible
                                                            tissue.
------------------------------------------------------------------------
Nicarbazin     Procaine       ............  Growing        Feed
 90.8 to        penicillin                   chickens: As   continuously
 181.6 (0.01    2.4 to 50                    an aid in      as sole
 to 0.02 pct)                                preventing     ration from
                                             outbreaks of   time chicks
                                             cecal          are placed
                                             (Eimeria       on litter
                                             tenella) and   until past
                                             intestinal     the time
                                             (E.            when
                                             acervulina,    coccidiosis
                                             E. maxima,     is
                                             E. necatrix,   ordinarily a
                                             and E.         hazard; do
                                             brunetti)      not use as a
                                             coccidiosis,   treatment
                                             and for        for
                                             increased      outbreaks of
                                             rate of        coccidiosis.
                                             weight gain    Do not use
                                             and improved   in flushing
                                             feed           mashes. Do
                                             efficiency.    not feed to
                                                            chickens
                                                            producing
                                                            eggs for
                                                            human
                                                            consumption.
                                                            Discontinue
                                                            medication 4
                                                            d before
                                                            marketing
                                                            the birds
                                                            for human
                                                            consumption
                                                            to allow for
                                                            elimination
                                                            of the drug
                                                            from edible
                                                            tissue.
------------------------------------------------------------------------
Nicarbazin     Procaine       Roxarsone     Growing        Feed
 90.8 to        penicillin     22.7 to       chickens: As   continuously
 181.6 (0.01    2.4 to 50      45.4          an aid in      as sole
 to 0.02 pct)                                preventing     ration from
                                             outbreaks of   time chicks
                                             cecal          are placed
                                             (Eimeria       on litter
                                             tenella) and   until past
                                             intestinal     the time
                                             (E.            when
                                             acervulina,    coccidiosis
                                             E. maxima,     is
                                             E. necatrix,   ordinarily a
                                             and E.         hazard; do
                                             brunetti)      not use as a
                                             coccidiosis,   treatment
                                             and for        for
                                             increased      outbreaks of
                                             rate of        coccidiosis.
                                             weight gain,   As a sole
                                             improved       source of
                                             feed           organic
                                             efficiency,    arsenic;
                                             and improved   drug
                                             pigmentation   overdose or
                                             .              lack of
                                                            water may
                                                            result in
                                                            leg
                                                            weakness. Do
                                                            not use in
                                                            flushing
                                                            mashes. Do
                                                            not feed to
                                                            chickens
                                                            producing
                                                            eggs for
                                                            human
                                                            consumption.
                                                            Discontinue
                                                            medication 5
                                                            d before
                                                            marketing
                                                            the birds
                                                            for human
                                                            consumption
                                                            to allow for
                                                            elimination
                                                            of the drug
                                                            from edible
                                                            tissue.
------------------------------------------------------------------------


[[Page 47338]]

D. Combination Drug Type B and Type C Medicated Feeds for Poultry 
Containing Bacitracin

    The agency is making findings of effectiveness for combination drug 
Type B and Type C medicated feeds containing bacitracin. These findings 
cover the following drugs:
    [sbull] NADA 141-130, for the combination use of BMD and zoalene. 
Alpharma, Inc., One Executive Dr., P.O. Box 1399, Fort Lee, NJ 07024.
    [sbull] NADA 141-131, for the combination use of BMD, zoalene, and 
roxarsone. Alpharma, Inc.
    [sbull] NADA 141-132, for the combination use of zinc bacitracin 
and nitarsone. Alpharma, Inc.
These three combination drugs are for uses listed in Sec.  
558.15(g)(2). The drug sponsor information in the listing is outdated, 
designating A. L. Laboratories, Inc., instead of Alpharma, Inc.
    While NAS/NRC did not evaluate the efficacy data relating to these 
combinations, FDA has conducted such a review. This review was based on 
the agency's findings of effectiveness for BMD, bacitracin zinc, 
nitarsone, roxarsone, and zoalene single-ingredient feed use products. 
Most of these were based on NAS/NRC's evaluation (see 35 FR 11531, July 
17, 1970 (BMD); 35 FR 12490, August 5, 1970 (bacitracin zinc); 34 FR 
6494, April 15, 1969 (nitarsone); and 35 FR 14273, September 10, 1970 
(roxarsone)). The effectiveness of zoalene in these combinations was 
based on FDA's review of a food additive petition containing 
effectiveness data (see 27 FR 11546, November 24, 1962). FDA has 
determined that its previous findings of effectiveness are applicable 
to the combinations in the absence of information indicating 
interference in effectiveness between individual ingredients. Table 7 
of this document summarizes FDA's findings of effectiveness for certain 
combination drug Type B and Type C medicated feeds containing 
bacitracin.

Table 7.--Findings of Effectiveness for Use of Certain Drug Combinations
                  Containing Bacitracin in Poultry Feed
------------------------------------------------------------------------
    Type A         Type A        Type A
article in g/  article in g/  article in g/  Indications    Limitations
     ton            ton            ton         for use
------------------------------------------------------------------------
 Bacitracin 4  Zoalene 36.3   ............  Replacement    As bacitracin
 to 50          to 113.5.                    chickens:      methylene
                                             For            disalicylate
                                             increased      . Grower
                                             rate of        ration not
                                             weight gain    to be fed to
                                             and improved   birds over
                                             feed           14 weeks of
                                             efficiency;    age; feed as
                                             and for        in Sec.
                                             development    558.680(d)(1
                                             of active      )(i).
                                             immunity to
                                             coccidiosis.
------------------------------------------------------------------------
Bacitracin 4   Zoalene 36.3   Roxarsone     Replacement    As bacitracin
 to 50          to 113.5.      22.7 to       chickens:      methylene
                               45.4          For            disalicylate
                                             increased      ;
                                             rate of        discontinue
                                             weight gain    use 5 d
                                             and improved   before
                                             feed           slaughter;
                                             efficiency;    as sole
                                             for            source of
                                             development    organic
                                             of active      arsenic;
                                             immunity to    drug
                                             coccidiosis;   overdose or
                                             and for        lack of
                                             improved       water may
                                             pigmentation   result in
                                             .              leg
                                                            weakness.
                                                            Grower
                                                            ration not
                                                            to be fed to
                                                            birds over
                                                            14 weeks of
                                                            age; feed as
                                                            in Sec.
                                                            558.680(d)(1
                                                            )(i).
------------------------------------------------------------------------
Bacitracin 4   Nitarsone 170  ............  Growing        As bacitracin
 to 50          (0.01875                     turkeys: For   zinc;
                pct)                         increased      discontinue
                                             rate of        use 5 d
                                             weight gain    before
                                             and improved   slaughter.
                                             feed           Early
                                             efficiency;    medication
                                             and as an      is essential
                                             aid in the     to prevent
                                             prevention     spread of
                                             of             disease.
                                             blackhead.     Adequate
                                                            drinking
                                                            water must
                                                            be provided
                                                            near feeder
                                                            at all
                                                            times. The
                                                            drug is not
                                                            effective in
                                                            preventing
                                                            blackhead in
                                                            birds
                                                            infected
                                                            more than 4
                                                            or 5 d. The
                                                            drug is
                                                            dangerous
                                                            for ducks,
                                                            geese, and
                                                            dogs.
                                                            Overdosage
                                                            or lack of
                                                            water may
                                                            result in
                                                            leg weakness
                                                            or
                                                            paralysis.
                                                            Use as sole
                                                            source of
                                                            arsenic.
------------------------------------------------------------------------

E. Applicability of Findings of Effectiveness

    The findings of effectiveness as described previously in this 
document are concerned only with a drug's effectiveness for the stated 
conditions in the treated animals. Nothing in this document constitutes 
a bar to further proceedings with respect to questions of the safety of 
the subject drugs in treated animals or of the drugs or their 
metabolites in food products derived from treated animals.

F. Applicability of Pending Notices of Opportunity for Hearing

    In the Federal Registers of August 30, 1977 (42 FR 43772), and 
October 21, 1977 (42 FR 56264), the Director of the Center for 
Veterinary Medicine (CVM) issued notices of opportunity for

[[Page 47339]]

hearing (NOOHs) on proposals to withdraw approval of NADAs for all 
penicillin-containing premix products intended for use in animal feed 
and for certain subtherapeutic uses of tetracyclines (chlortetracycline 
and oxytetracycline) in animal feed. Some of these products are listed 
in Sec.  558.15. These NOOHs are still pending and nothing in this 
document constitutes a bar to subsequent action to withdraw approval on 
the grounds cited in the outstanding NOOHs.

G. Marketing

    Marketing of the products that are the subject of this document, 
and which are approved, may be continued, provided that, on or before 
(see DATES), the holder of the application submits a signed Form FDA 
356v New Animal Drug Application and complete product labeling 
(including specimen labeling for Type B and Type C medicated feeds) 
conforming to the applicable findings of effectiveness.
    Supplemental NADAs that are filed in response to this document and 
comply with the requirements set forth will be approved, and documents 
will be published in the Federal Register amending the approval 
regulations in accordance with the approval and identifying the sponsor 
under section 512(i) of the act.

III. Notice of Opportunity for Hearing

    On the basis of all available data and information, the Director of 
CVM is unaware of any adequate and well-controlled clinical 
investigation, conducted by experts qualified by scientific training 
and experience, meeting the requirements of section 512 of the act that 
demonstrates effectiveness of the drugs listed in section II of this 
document, for their labeled indications of use other than the effective 
claims as stated in this document.
    Therefore, notice is given to the sponsors of the NADAs for the 
nine animal drug products or combination uses described in section II 
of this document, and to all other interested persons, that the 
Director of CVM proposes to issue an order under section 512(e) of the 
act withdrawing approval of the NADAs providing for any claims other 
than those classified in this document as effective. The ground for the 
proposed withdrawal is that new information about the drug products, 
such as that provided by the NAS/NRC reviews, evaluated together with 
the evidence available at the time of approval, show there is a lack of 
substantial evidence that the drug will have the effect it purports or 
is represented to have under the conditions of use prescribed, 
recommended, or suggested in the labeling. An order withdrawing 
approval will not issue with respect to any application supplemented in 
accordance with this document to delete any indication for use lacking 
substantial evidence of effectiveness.
    This notice of opportunity for hearing encompasses, in addition to 
the ground for the proposed withdrawal of the approvals, all issues 
relating to the legal status of the drug products subject to it, e.g., 
any contention that any such product is not a new animal drug within 
the meaning of section 201(w) of the act (21 U.S.C. 321(w)).
    In accordance with section 512 of the act and part 514 (21 CFR part 
514) and under the authority delegated to the Director of CVM (21 CFR 
5.502), a sponsor and all other persons subject to this document are 
hereby given an opportunity for hearing to show why approval of the 
applications should not be withdrawn.
    A sponsor or any other person subject to this document who wishes 
to request a hearing must file: (1) On or before (see DATES), a written 
notice of appearance and request for a hearing, and (2) on or before 
(see DATES), the data, information, and analyses relied on to 
demonstrate that there is a genuine and substantial issue of fact to 
justify a hearing as specified in Sec.  514.200. Any other interested 
person may also submit comments on this document. Procedures and 
requirements governing this notice of opportunity for hearing, a notice 
of appearance and request for a hearing, submission of data, 
information, and analyses to justify a hearing, other comments, and a 
grant or denial of a hearing, are contained in Sec.  514.200 and 21 CFR 
part 12.
    The failure of a holder of an approval, or any other party subject 
to this document, to file a timely written appearance and request for 
hearing as required by Sec.  514.200 constitutes an election not to 
avail itself of the opportunity for hearing and a waiver of any 
contentions concerning the legal status of any such drug product, and 
the Director of CVM will summarily enter a final order withdrawing the 
approval. Any such drug product labeled other than for the effective 
claims identified in this document may not thereafter be marketed 
lawfully, and FDA will initiate appropriate regulatory action to remove 
any such drug product from the market. Any new animal drug product 
marketed without an approved NADA is subject to regulatory action at 
any time.
    A request for hearing may not rest upon mere allegations or 
denials, but must set forth specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If it 
conclusively appears from the face of the data, information, and 
factual analyses in the request for hearing that there is no genuine 
and substantial issue of fact that precludes the withdrawal of approval 
of the application, or when a request for hearing is not made in the 
required format or with the required analyses, the Commissioner of Food 
and Drugs will enter summary judgment against the person who requests a 
hearing, making findings and conclusions, and denying a hearing.
    If a hearing is requested and is justified by the sponsor's 
response to this notice of opportunity for hearing, the issues will be 
defined, an administrative law judge will be assigned, and a written 
notice of the time and place at which the hearing will commence will be 
issued as soon as practicable.
    All submissions under this document must be filed in four copies. 
Except for data and information prohibited from public disclosure by 
law, the submissions may be seen in the Division of Dockets Management 
(see ADDRESSES) between 9 a.m. and 4 p.m. Monday through Friday. This 
document is issued under section 512 of the act and under the authority 
delegated to the Director of CVM (21 CFR 5.502).

IV. Environmental Impact

    The agency has determined under 21 CFR 25.33(g) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

    The collections of information requirements for this document are 
covered under OMB control numbers 0910-0032 and 0910-0184.

    Dated: August 1, 2003.
Stephen F. Sundlof,
Director, Center for Veterinary Medicine.
[FR Doc. 03-20241 Filed 8-5-03; 4:09 pm]
BILLING CODE 4160-01-S