Guidance for Industry
Referencing Discontinued Labeling for Listed Drugs in Abbreviated New Drug Applications
DRAFT GUIDANCE
[PDF version of this document]
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document
should be submitted within 90 days of publication of the Federal Register notice
announcing the availability of the draft guidance. Submit comments to Dockets Management
Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1601, Rockville, MD
20857. All comments should be identified with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions on the content of the draft document contact
Cecelia M. Parise, 301-827-5845.
U.S. Department of Health and Human
Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2000
OGD
DRAFT GUIDANCE
Additional copies of this Draft Guidance
are available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
TABLE OF CONTENTS
I. INTRODUCTION 1
II. BACKGROUND 1
III. PROPOSED APPROACH 3
IV. SUBMISSION OF ANDAS 3
A. Statutory Requirements 3
B. Regulatory Requirements 4
C. Past Practice 5
V. REFERENCING DISCONTINUED LABELING FOR A LISTED DRUG
IN AN ANDA 5
A. Existence of Exclusivity or Patent Protection 5
B. Identifying Appropriate Labeling
6
C. Submission of Petition Requesting Determination of
Reasons for Change to Labeling 6
D. FDA Determination on Safety and Effectiveness 6
E. Therapeutic Equivalence Ratings 6
F. Expiration of Exclusivity or Patent Protection 7
GUIDANCE FOR INDUSTRY1
Referencing Discontinued
Labeling
for Listed Drugs in
Abbreviated
New Drug Applications
This draft guidance, when finalized, will represent the
Food and Drug Administration_s current thinking on this topic. It does not create or confer any
rights for or on any person and does not operate to bind FDA or the public. An alternative
approach may be used if such approach satisfies the requirements of the applicable
statutes and regulations.
If you plan to submit comments on this
draft guidance, to expedite FDA review of your comments, please:
· Clearly explain each issue/concern and, when appropriate, include a proposed
revision and the rationale/justification for the proposed changes.
· Identify specific comments by line number(s); use the PDF version of the
document, whenever possible.
I. INTRODUCTION
This document is intended to provide guidance to
applicants on referencing discontinued labeling for listed drugs in abbreviated new drug
applications (ANDAs) submitted for approval under section 505(j) of the Federal Food,
Drug, and Cosmetic Act (the Act). This issue is not addressed directly in the regulations
governing the approvals of ANDAs at 21 CFR 314 subpart C. The Office of Generic Drugs
(OGD) is proposing the most appropriate response to this regulatory question, and is
making its current thinking on the matter available to the public through this guidance.
II. BACKGROUND
The Drug Price Competition and Patent Term Restoration Act
of 1984 (the Hatch-Waxman amendments) established the generic drug approval program used
today to ensure that lower price generic drugs are made available to the public promptly
upon the expiration of patent and exclusivity protections covering the innovator products.
The generic drug approval process generally depends on the ANDA applicant establishing
that the generic drug is the same as an approved innovator product (the listed drug) with
respect to active ingredient, dosage form, strength, route of administration, conditions
of use, and labeling.
During the period when an innovator drug is being
marketed, it may undergo a number of changes that are approved through new drug
application (NDA) supplements. Such changes can include the addition of new indications,
changes to the product formulation, and labeling changes. In the past, when ANDAs have
been submitted, they have referenced only the innovator drug product labeling as it
appears at the time of ANDA submission. However, recently a question has been raised as to
whether, in certain circumstances, an ANDA can refer to discontinued labeling for the
listed drug.
The issue of referencing discontinued labeling for the
listed drug arises when the sponsor of the innovator drug product has obtained exclusivity
or patent protection for a new aspect of product labeling and has removed the previous
unprotected labeling for reasons other than safety or effectiveness. When the holder of
the innovator drug obtains approval and market protection for a change to the drug and
removes the corresponding unprotected information from the current labeling, there is no
current complete labeling for the ANDA applicant to reference.2 For example, the NDA holder may obtain approval and market
protection for a new dosing regimen and remove the previous dosing regimen(s) from the
labeling. In this situation, the ANDA applicant, which must include information regarding
dosing regimen in its application, is blocked by the NDA holder's exclusivity from
referencing the new dosing regimen contained in the innovator drug labeling, and all the
previous dosing regimen information has been removed from the current labeling. This
raises the question of whether applicants will be barred from obtaining approval for any
ANDA for that innovator drug until the protection for the new dosing regimen expires,
because relevant labeling is either protected or has been removed from the currently
marketed product.3
In FDA's view, the appropriate approach to the situation
depends on whether the previous labeling was withdrawn from the drug product for reasons
of safety or effectiveness, and whether omission of the protected information will render
the drug unsafe. This is the same approach taken by the Agency when an entire product,
rather than just a portion of the labeling, is withdrawn from the market, and when a
portion of the innovator labeling must be omitted from a generic drug label because of
patent or exclusivity protection.
FDA's proposed approach creates a process intended to
assure that labeling removed from an innovator drug product for reasons of safety or
effectiveness cannot be referenced in an ANDA. At the same time, this process will permit
approval of ANDAs that reference labeling that, although removed from the currently
marketed innovator product, nonetheless describes the safe and effective use of the drug.
This approach will make safe and effective generic drug products available to the public
as promptly as possible when relevant market protections have expired.
III. PROPOSED APPROACH
The Agency has determined that in certain circumstances an
ANDA should be permitted to reference discontinued labeling for a listed drug. This
generally should occur when:
1. The holder of the NDA for the innovator drug has
obtained approval for a change in the drug labeling.
2. That change has received either a patent listed in Approved
Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) or
market exclusivity under the Act.
3. The NDA sponsor has removed or revised the labeling
describing the corresponding unprotected aspects of the drug.
4. The change to the drug product is not one for which a
suitability petition may be filed (21 CFR 314.93).
5. The sponsor wishing to reference the discontinued
labeling has submitted a petition requesting that the Agency determine whether the
previous labeling was withdrawn for reasons of safety or effectiveness, or the Agency has
undertaken its own inquiry regarding the withdrawal of the previous labeling.
6. The Agency has determined that the previous innovator
labeling was not withdrawn for reasons of safety or effectiveness.
7. The Agency has determined that omission of the
protected information will not render the drug product less safe or effective than the
currently marketed innovator product.
IV. SUBMISSION OF ANDAS
A. Statutory Requirements
The generic drug approval process is based on the ANDA
applicant establishing that its product is the same as a drug previously approved by FDA.
Among other things, an ANDA must provide information to show that the conditions of use,
route of administration, dosage form, and strength of the proposed product have been
previously approved for a listed drug (section 505(j)(2)(A) of the Act). If an ANDA
applicant wants approval of a change to the route of administration, dosage form,
strength, or the substitution of an active ingredient in a combination drug product, it
can obtain approval for this change through a suitability petition (section 505(j)(2)(C)).
The ANDA also must include information to show that the labeling for the proposed drug is
the same as the labeling approved for the listed drug, except for differences approved
through a petition, or because the proposed drug and listed drug are produced by different
manufacturers (section 505(j)(2)(A)(v)).
A listed drug is a drug included on a list published by
FDA of drugs approved for safety and effectiveness under section 505(c) (section
505(j)(7)) of the Act. This list is published in the Orange Book. A drug whose
approval was withdrawn or suspended under section 505(e) for reasons of safety or
effectiveness, or that has been withdrawn from sale for reasons of safety or
effectiveness, cannot serve as a listed drug for approval and is removed from the Orange
Book (section 505(j)(4)(I) and (j)(7)(C)).
B. Regulatory Requirements
Identification of a listed drug is a crucial component of
the ANDA approval process. An ANDA must refer to a listed drug (21 CFR 314.94(a)(3)). The
characteristics and labeling of the listed drug generally will be duplicated in the
characteristics and labeling of the product proposed in the ANDA (21 CFR
314.94(a)(3)-(9)). A drug approved in an ANDA must be the same as the listed drug in terms
of active ingredient(s), dosage form, strength, route of administration, and conditions of
use, except for conditions of use for which approval cannot be granted because of
exclusivity or an existing patent (21 CFR 314.92(a)(1)). Certain differences will be
permitted for products for which a suitability petition has been approved, or because the
drug proposed in the ANDA and the listed drug are produced or distributed by different
manufacturers. These differences can include omission of an indication or other aspect of
labeling that is protected by patent or exclusivity (21 CFR 314.94(a)(8)(iv)). Aspects of
a listed drug's labeling that are protected by patent or exclusivity may be omitted from
the labeling proposed in an ANDA if the resulting differences in the labeling do not
render the proposed drug product less safe or effective for all the remaining, unprotected
conditions of use (21 CFR 314.127(a)(7)).
An ANDA may refer to a listed drug that is an approved
product currently being marketed, or that is an approved product which has been withdrawn
from the market by the sponsor.4 If
an ANDA applicant references a listed drug that the sponsor has ceased to market, the FDA
must determine whether the drug was removed from the market for reasons of safety or
effectiveness before the ANDA can be approved (21 CFR 314.161). If the Agency has not made
such a determination on its own initiative, the ANDA relying on the discontinued drug must
be accompanied by a petition requesting FDA to determine whether the drug was withdrawn
from the market for reasons of safety or effectiveness (21 CFR 314.122).
C. Past Practice
In the past, when an applicant submitted an ANDA, the only
labeling available for the listed drug has been labeling on the currently marketed form of
the listed drug. The regulations require an ANDA to include a copy of the "currently
approved labeling for the listed drug" (21 CFR 314.94(a)(8)). If the generic product
will have labeling that is different from that of the listed drug, the ANDA applicant
should state the reason for such differences and explain why such differences are
permitted. As described above, certain differences from the innovator labeling are
permitted.
The question of whether an ANDA could refer to previously
approved but subsequently altered labeling had not arisen previously. Therefore, until
recently, the Agency had not had a reason to develop a policy on the appropriate response
to this situation.5 Now, with what
could be a growing practice among innovator sponsors of substituting protected labeling
for unprotected labeling, the Agency has determined that in certain situations, it may
approve an ANDA for a drug product with labeling that was previously approved for the
listed drug, but which the listed drug is no longer carrying.
V. REFERENCING DISCONTINUED
LABELING FOR A LISTED DRUG IN AN ANDA
For an ANDA applicant to refer to discontinued labeling
for a listed drug, the following conditions should exist.
A. Existence of Exclusivity or
Patent Protection
An ANDA generally should refer to discontinued labeling
for the listed drug only when, at the time the ANDA is submitted (or while it is pending),
an essential part of the labeling for the currently marketed innovator drug is protected
by exclusivity or a patent, and the corresponding unprotected labeling has been removed.
This approach is based on the desire to minimize confusion in the marketplace arising from
the availability of drugs that are the same in many respects, but have slightly different
labeling.6
B. Identifying Appropriate
Labeling
The ANDA applicant should identify the discontinued
labeling for the listed drug to which it will refer. Generally, this will be the labeling
as approved in the innovator application just prior to the addition of the protected part
labeling and deletion of the unprotected part of labeling.
C. Submission of Petition
Requesting Determination of Reasons for Change to Labeling
Once the ANDA applicant has identified the discontinued
labeling for the listed drug to which it will refer, the applicant should submit a
petition as described in 21 CFR 314.122, seeking a determination by FDA that the
discontinued labeling was not withdrawn from the listed drug for reasons of safety or
effectiveness. An ANDA for the drug may be submitted at the same time the petition is
submitted, but the ANDA will not be approved until the Agency has determined that the
discontinued labeling for the listed drug was not withdrawn for reasons of safety or
effectiveness. FDA also may, on its own initiative, begin the process of determining
whether labeling was discontinued for reasons of safety or effectiveness.
D. FDA Determination on Safety
and Effectiveness
The Agency will determine whether the labeling was
discontinued for reasons of safety or effectiveness. If the labeling was discontinued for
reasons of safety or effectiveness, it cannot be referred to by the ANDA applicant. Such a
determination will be based on the same factors and information FDA considers when
determining whether a product withdrawn entirely from the market was withdrawn for reasons
of safety or effectiveness (see 54 FR 28872, 28907-08; July 10, 1989). In addition, the
Agency will determine whether omission of protected information from the labeling would
render the proposed drug product less safe or effective for all the remaining, unprotected
conditions of use.7 The Agency will
publish its determination in the Federal Register, as described in 21 CR 314.161.
E. Therapeutic Equivalence
Ratings
Whether a drug approved in an ANDA that refers to
discontinued labeling for the listed drug will be rated therapeutically equivalent to the
currently marketed innovator product will depend upon the differences in the labeling.
F. Expiration of Exclusivity
or Patent Protection
Once the exclusivity or patent protecting the current
innovator labeling has expired, the ANDA applicant whose product references the
discontinued labeling should file a supplement to its ANDA to make the labeling conform to
the labeling of the marketed innovator product.
1 This
draft guidance has been prepared by the Office of Generic Drugs in the Center for Drug
Evaluation and Research (CDER).
2 Contrast
this with the situation in which an innovator has obtained approval for a new indication
and patent or exclusivity protection that extends beyond the protection for other
indications that remain on the labeling. The ANDA applicant may cite the innovator
labeling that includes all of the approved indications, and only the protected indication
will be omitted from the ANDA labeling when it is approved. See Bristol-Myers
Squibb v. Shalala, 91 F.3d 1493 (D.C.Cir. 1996).
3 In
theory, the innovator could delay generic competition indefinitely by continuing to make
minor - but protectable - changes to the drug, and removing unprotected labeling. If this
approach were effective, the Agency also could expect to review many more labeling
supplements, possibly for changes that, although sufficiently innovative to warrant patent
or exclusivity protection, do not necessarily represent significant improvements in the
currently marketed drug.
4 FDA
regulations define listed drug at 21 CFR 314.3(b) as "a new drug product that
has an effective approval under section 505(c) of the act for safety and effectiveness or
under 505(j) of the act, which has not been withdrawn or suspended under section 505(e)(1)
through (e)(5) or (j)(5) of the act, and which has not been withdrawn from sale for what
FDA has determined are reasons of safety or effectiveness. Listed drug status is evidenced
by the drug product's identification as a drug with an effective approval in the current
edition of [the Orange Book], or any current supplement thereto." Note: section
505(j)(5) of the Act has been renumbered as 505(j)(6).
5 In
1998, the Office of Generic Drugs provided an informal opinion to an innovator company
that had removed unprotected dosing information from its label stating that the Agency
would not approve an ANDA that does not contain the same dosing and administration
information as the listed drug. That opinion, however, was given in a case in which the
discontinued labeling information was determined by the Agency to have been removed from
the innovator drug for reasons of safety or effectiveness. To address any concern that the
approach described in this guidance can be considered a change from past interpretation,
the guidance is being released in draft for public comment prior to implementation.
6 There
are already situations in which ANDAs will be approved for drug products that are
different from the marketed innovator drug. For example, an ANDA may be approved for fewer
than all of the indications approved for the innovator drug. There can also be differences
in labeling related to excipients, handling and administration of the drug related to
excipient differences, and differences arising from revisions in labeling guidelines (21
CFR 314.94(a)(8)(iv)).
7 New
labeling will not be protected by exclusivity if it describes new risks or warnings (54 FR
28872, 28899, July 10, 1989; 59 FR 50338, 50356-57, October 3, 1994).
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