[Code of Federal Regulations]
[Title 21, Volume 5]
[Revised as of April 1, 2007]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR314.127]

[Page 149-151]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 314_APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG--Table of Contents
 
    Subpart D_FDA Action on Applications and Abbreviated Applications
 
Sec.  314.127  Refusal to approve an abbreviated new drug application.

    (a) FDA will refuse to approve an abbreviated application for a new 
drug under section 505(j) of the act for any of the following reasons:
    (1) The methods used in, or the facilities and controls used for, 
the manufacture, processing, and packing of the drug product are 
inadequate to ensure and preserve its identity, strength, quality, and 
purity.
    (2) Information submitted with the abbreviated new drug application 
is insufficient to show that each of the proposed conditions of use has 
been previously approved for the listed drug referred to in the 
application.
    (3)(i) If the reference listed drug has only one active ingredient, 
information submitted with the abbreviated new drug application is 
insufficient to show that the active ingredient is the same as that of 
the reference listed drug;
    (ii) If the reference listed drug has more than one active 
ingredient, information submitted with the abbreviated new drug 
application is insufficient to show that the active ingredients are the 
same as the active ingredients of the reference listed drug; or
    (iii) If the reference listed drug has more than one active 
ingredient and if the abbreviated new drug application is for a drug 
product that has an active ingredient different from the reference 
listed drug:
    (A) Information submitted with the abbreviated new drug application 
is insufficient to show:
    (1) That the other active ingredients are the same as the active 
ingredients of the reference listed drug; or
    (2) That the different active ingredient is an active ingredient of 
a listed drug or a drug that does not meet the requirements of section 
201(p) of the act; or
    (B) No petition to submit an abbreviated application for the drug 
product with the different active ingredient was approved under Sec.  
314.93.
    (4)(i) If the abbreviated new drug application is for a drug product 
whose route of administration, dosage form, or strength purports to be 
the same as that of the listed drug referred to in the abbreviated new 
drug application, information submitted in the abbreviated new drug 
application is insufficient to show that the route of administration, 
dosage form, or strength is the same as that of the reference listed 
drug; or
    (ii) If the abbreviated new drug application is for a drug product 
whose route of administration, dosage form, or strength is different 
from that of the listed drug referred to in the application, no petition 
to submit an abbreviated new drug application for the drug product with 
the different route of administration, dosage form, or strength was 
approved under Sec.  314.93.
    (5) If the abbreviated new drug application was submitted under the 
approval of a petition under Sec.  314.93, the abbreviated new drug 
application did not contain the information required by FDA with respect 
to the active ingredient, route of administration, dosage form, or 
strength that is not the same as that of the reference listed drug.
    (6)(i) Information submitted in the abbreviated new drug application 
is insufficient to show that the drug product is bioequivalent to the 
listed drug referred to in the abbreviated new drug application; or
    (ii) If the abbreviated new drug application was submitted under a 
petition approved under Sec.  314.93, information submitted in the 
abbreviated new drug application is insufficient to show that the active 
ingredients of the drug product are of the same pharmacological or 
therapeutic class as those of the reference listed drug and that the 
drug product can be expected to have the same therapeutic effect as the 
reference listed drug when administered to patients for each condition 
of use approved for the reference listed drug.
    (7) Information submitted in the abbreviated new drug application is 
insufficient to show that the labeling proposed for the drug is the same 
as the labeling approved for the listed drug

[[Page 150]]

referred to in the abbreviated new drug application except for changes 
required because of differences approved in a petition under Sec.  
314.93 or because the drug product and the reference listed drug are 
produced or distributed by different manufacturers or because aspects of 
the listed drug's labeling are protected by patent, or by exclusivity, 
and such differences do not render the proposed drug product less safe 
or effective than the listed drug for all remaining, nonprotected 
conditions of use.
    (8)(i) Information submitted in the abbreviated new drug application 
of any other information available to FDA shows that:
    (A) The inactive ingredients of the drug product are unsafe for use, 
as described in paragraph (a)(8)(ii) of this section, under the 
conditions prescribed, recommended, or suggested in the labeling 
proposed for the drug product; or
    (B) The composition of the drug product is unsafe, as described in 
paragraph (a)(8)(ii) of this section, under the conditions prescribed, 
recommended, or suggested in the proposed labeling because of the type 
or quantity of inactive ingredients included or the manner in which the 
inactive ingredients are included.
    (ii)(A) FDA will consider the inactive ingredients or composition of 
a drug product unsafe and refuse to approve an abbreviated new drug 
application under paragraph (a)(8)(i) of this section if, on the basis 
of information available to the agency, there is a reasonable basis to 
conclude that one or more of the inactive ingredients of the proposed 
drug or its composition raises serious questions of safety or efficacy. 
From its experience with reviewing inactive ingredients, and from other 
information available to it, FDA may identify changes in inactive 
ingredients or composition that may adversely affect a drug product's 
safety or efficacy. The inactive ingredients or composition of a 
proposed drug product will be considered to raise serious questions of 
safety or efficacy if the product incorporates one or more of these 
changes. Examples of the changes that may raise serious questions of 
safety or efficacy include, but are not limited to, the following:
    (1) A change in an inactive ingredient so that the product does not 
comply with an official compendium.
    (2) A change in composition to include an inactive ingredient that 
has not been previously approved in a drug product for human use by the 
same route of administration.
    (3) A change in the composition of a parenteral drug product to 
include an inactive ingredient that has not been previously approved in 
a parenteral drug product.
    (4) A change in composition of a drug product for ophthalmic use to 
include an inactive ingredient that has not been previously approved in 
a drug for ophthalmic use.
    (5) The use of a delivery or a modified release mechanism never 
before approved for the drug.
    (6) A change in composition to include a significantly greater 
content of one or more inactive ingredients than previously used in the 
drug product.
    (7) If the drug product is intended for topical administration, a 
change in the properties of the vehicle or base that might increase 
absorption of certain potentially toxic active ingredients thereby 
affecting the safety of the drug product, or a change in the lipophilic 
properties of a vehicle or base, e.g., a change from an oleaginous to a 
water soluble vehicle or base.
    (B) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for parenteral use to be unsafe and will 
refuse to approve the abbreviated new drug application unless it 
contains the same inactive ingredients, other than preservatives, 
buffers, and antioxidants, in the same concentration as the listed drug, 
and, if it differs from the listed drug in a preservative, buffer, or 
antioxidant, the application contains sufficient information to 
demonstrate that the difference does not affect the safety or efficacy 
of the drug product.
    (C) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for ophthalmic or otic use unsafe and will 
refuse to approve the abbreviated new drug application unless it 
contains the same inactive ingredients, other than preservatives, 
buffers, substances to adjust tonicity, or thickening agents, in the

[[Page 151]]

same concentration as the listed drug, and if it differs from the listed 
drug in a preservative, buffer, substance to adjust tonicity, or 
thickening agent, the application contains sufficient information to 
demonstrate that the difference does not affect the safety or efficacy 
of the drug product and the labeling does not claim any therapeutic 
advantage over or difference from the listed drug.
    (9) Approval of the listed drug referred to in the abbreviated new 
drug application has been withdrawn or suspended for grounds described 
in Sec.  314.150(a) or FDA has published a notice of opportunity for 
hearing to withdraw approval of the reference listed drug under Sec.  
314.150(a).
    (10) Approval of the listed drug referred to in the abbreviated new 
drug application has been withdrawn under Sec.  314.151 or FDA has 
proposed to withdraw approval of the reference listed drug under Sec.  
314.151(a).
    (11) FDA has determined that the reference listed drug has been 
withdrawn from sale for safety or effectiveness reasons under Sec.  
314.161, or the reference listed drug has been voluntarily withdrawn 
from sale and the agency has not determined whether the withdrawal is 
for safety or effectiveness reasons, or approval of the reference listed 
drug has been suspended under Sec.  314.153, or the agency has issued an 
initial decision proposing to suspend the reference listed drug under 
Sec.  314.153(a)(1).
    (12) The abbreviated new drug application does not meet any other 
requirement under section 505(j)(2)(A) of the act.
    (13) The abbreviated new drug application contains an untrue 
statement of material fact.
    (b) FDA may refuse to approve an abbreviated application for a new 
drug if the applicant or contract research organization that conducted a 
bioavailability or bioequivalence study described in Sec.  320.63 of 
this chapter that is contained in the abbreviated new drug application 
refuses to permit an inspection of facilities or records relevant to the 
study by a properly authorized officer of employee of the Department of 
Health and Human Services or refuses to submit reserve samples of the 
drug products used in the study when requested by FDA.

[57 FR 17991, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 
FR 25927, Apr. 28, 1993; 67 FR 77672, Dec. 19, 2002]