Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees: Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Submitting Separate
Marketing Applications and
Clinical Data for Purposes of
Assessing User Fees
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2004
User Fees

Guidance for Industry
Submitting Separate
Marketing Applications and
Clinical Data for Purposes of
Assessing User Fees
Additional copies are available from:
Office of Training and Communications
Division of Drug Information, HFD-240
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane, Rockville, MD 20857
(Tel) 301-827-4573
http://www.fda.gov/cder/pdufa/default.htm
Office of Communication,
Training, and Manufacturers Assistance (HFM-40)
Center for Biologics Evaluation and Research (CBER)
1401 Rockville Pike, Rockville, MD 20852-1448
http://www.fda.gov/cber/guidelines.htm
(Voice Information) 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2004
User Fees

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................ 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	PRESCRIPTION DRUG USER FEE BUNDLING POLICY ...................................... 2
A. 	Original Applications and Amendments...................................................................................... 3
1. Different Active Ingredients or Combinations of Active Ingredients or Products........................... 3
2. Different Routes of Administration .................................................................................................. 3
3. Different Dosage Forms .................................................................................................................. 3
4. Different Strengths/Concentrations ................................................................................................. 4
5. Excipients......................................................................................................................................... 4
6. Container Sizes and Configurations ................................................................................................ 4
7. Different Indications or Claims ....................................................................................................... 4
8. Medicare Modernization Act Changes ............................................................................................ 5
B. 	NDA and BLA Supplements ......................................................................................................... 5
1. Changes in Composition .................................................................................................................. 5
2. Other Changes to Approved Products ............................................................................................. 5
3. Changes to Indications .................................................................................................................... 5
IV. 	DEFINITION OF CLINICAL DATA ............................................................................ 6

Contains Nonbinding Recommendations
Guidance for Industry1
Submitting Separate Marketing Applications
and Clinical Data for Purposes of Assessing User Fees
This guidance represents the Food and Drug Administration's (FDA'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 want to discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
number listed on the title page of this guidance.
I. 	INTRODUCTION
This guidance describes FDA’s current thinking on what will be considered a separate marketing
application and what will constitute clinical data for purposes of the user fee provisions of the
Federal Food, Drug, and Cosmetic Act (Act).2
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
The Act levies a user fee on each "human drug application" including applications (1) for
approval of a new drug submitted under section 505(b)(1) after September 1, 1992; (2) for
approval of a new drug submitted pursuant to section 505(b)(2) after September 30, 1992, for
certain molecular entities or indications for a use; and (3) for licensure of certain biological
products under section 351 of the Public Health Service Act submitted after September 1, 1992.3
1 This guidance has been prepared by the User Fee Staff in the Center for Drug Evaluation and Research (CDER) at
the Food and Drug Administration (FDA) in consultation with the Center for Biologics Evaluation and Research
(CBER).
2 The Prescription Drug User Fee Act was originally enacted in 1992, was amended in 1997 by the Food and Drug
Administration Modernization Act, and was amended in June 2002 by the Prescription Drug User Fee Amendments
of 2002.
1
3 Section 735(1) (21 U.S.C. 379g(1)).

Contains Nonbinding Recommendations
The Act provides for different user fees for original applications depending upon whether they
are accompanied by clinical data on safety and/or efficacy (other than bioavailability or
bioequivalence studies).4 The Act also levies fees on supplements to human drug applications
that require clinical data.5 Under the fee schedules provided in the Act, original applications
without clinical data and supplements that require clinical data are assessed approximately one-
half the fee of original applications. This guidance for industry discusses (1) what should be
contained in separate marketing applications and what should be combined into one application
(bundling guidance) for purposes of assessing user fees and (2) the definition of clinical data for
purposes of assessing user fees.
Because different user fees are assessed for original applications and supplements, FDA believes
it is useful to provide guidance to applicants on the Agency's interpretation of what constitutes a
separate original application, amendment, or supplement.
We recommend that a potential applicant consider this guidance when preparing an application
or supplement. If FDA determines that an application has been inappropriately bundled, or that
an applicant has incorrectly concluded that an application did not contain clinical data, then FDA
will notify the applicant and request additional fees, if appropriate. This action will not prevent
the filing of the application if it is otherwise suitable for filing, or its review, if it is otherwise
ready for review. If an applicant disagrees with the determination, the applicant may formally
appeal such disputes to the Office or Center level.6
III. 	PRESCRIPTION DRUG USER FEE BUNDLING POLICY
The factors currently considered by CDER and CBER in determining whether separate
applications should be submitted and assessed separate fees are described below. Section A
contains the guidance for original applications, and Section B contains guidance on supplements.
The Agency may, for administrative reasons (e.g., review across two divisions or offices), assign
separate reference numbers and separately track and take regulatory action on the various parts
of what is considered to be one application under the policy described here.
4 Section 736(a)(1) and (b) (21 U.S.C. 379(a)(1) and (b)). Bioavailability/bioequivalence studies are applicable
only to applications submitted under section 505 of the Federal Food, Drug, and Cosmetic Act. They are not
addressed in section 351 of the Public Health Service Act.
5 Section 736(a)(1) (21 U.S.C. 379h(a)(1)).
6 FDA’s guidance for industry, Formal Dispute Resolution: Appeals Above the Division Level, February 2000.
2

Contains Nonbinding Recommendations
A. 	Original Applications and Amendments
1. 	Different Active Ingredients or Combinations of Active Ingredients or
Products
a. 	Drugs
Every different active ingredient7 or combination of two or more different active
ingredients should be submitted in a separate original application. Products to be
marketed as both a racemic mixture and a single enantiomer should be in separate
original applications. Similarly, drug substances purified from mixtures with multiple
constituents of an active ingredient (e.g., enantiomers) should also be in separate original
applications.
b. 	Biological Products
A biological product is identified in section 351 of the Public Health Service Act (42
U.S.C. 262(i)) as "any virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, or analogous product . . . applicable to the
prevention, treatment, or cure of a disease or condition of human beings." The Act
describes those biologicals that are assessed user fees.8
Individual biological product applications can include a single or combination biological
product meeting the above definition, which would result in the issuance of a distinct
product license. New applications for combination biological products should be
submitted when any one of the constituents of the combination is altered in a manner
that, for some other reason described in this guidance, warrants a separate application.
2. 	Different Routes of Administration
Products to be administered using different routes of administration (see FDA’s
Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book)
Appendix C) should be submitted in separate original applications unless the product(s)
for use by all routes in a given application are quantitatively and qualitatively identical
(drugs) or alike (biological products) in composition (e.g., an injectable liquid dosage
form intended for use by the intravenous and intraperitoneal routes).
3. 	Different Dosage Forms
Different dosage forms (see the Orange Book, Appendix C) should be submitted in
separate original applications unless the products are identical (drugs) or alike (biological
products) in quantitative and qualitative composition (e.g., a sterile liquid in a single dose
vial that is intended for use as either an injectable or an inhalation solution).
7 For example, different salts, esters, and complexes of the same active moiety are considered to be different active
ingredients.
3
8 Section 735(1) of the Act (21 U.S.C. 379g(1)).

Contains Nonbinding Recommendations
4. 	Different Strengths/Concentrations
Different strengths or concentrations of one drug substance, active biological product, or
combination product, if they are the same dosage form intended for the same route of
administration and the same general indication(s), should be submitted in one original
application if their qualitative composition is identical (drugs) or alike (biologicals).
5. 	Excipients
Single entity or combination products with excipients that differ qualitatively or
quantitatively to accommodate different container sizes and configurations, or that differ
qualitatively or quantitatively with respect to colors, flavorings, adjustment of pH or
osmolality, or preservatives,9 should be submitted in a single original application unless,
for some other reason described in this guidance or elsewhere, a separate application is
warranted. Differences in excipients that require separate clinical studies of safety or
effectiveness should not be included in the same original application. Differences in
excipients in topical products that require separate in vivo demonstration of
bioequivalence should be included in separate original applications.
6. 	Container Sizes and Configurations
Different container sizes and configurations (e.g., filled syringes, ampules, sealed vials)
of one finished pharmaceutical product intended to be for the same route of
administration for the same indication(s) (or otherwise consistent with sections II.A.2 and
II.A.3 above), should be considered one application for purposes of assessing user fees.
7. 	Different Indications or Claims
If submitted simultaneously in one application, requests for approval of different
indications and uses for the same dosage form to be administered by the same route of
administration (or otherwise consistent with sections II.A.2 and II.A.3, above) can be
regarded, for the purposes of assessing user fees, as one application regardless of:
• 	the dose to be administered;
• 	the duration of use;
• 	the schedule of administration;
• 	the population in which the product is indicated; or
• 	the condition for which the product is indicated.
9 Identical products in both single- and multiple-dose vials with and without preservatives can be submitted in a
single application, provided that data are included demonstrating the same clinical activity of the two presentations.
4

Contains Nonbinding Recommendations
After initial submission, a pending original or supplemental application should not be
amended to add a new indication or claim. Previously submitted indications or claims
can be modified by, for example, reanalyses of previously submitted data or, in rare
instances, supplementary clinical data. Such amendments could result in subsequent
adjustments to the user fee review clock. Submitting new clinical or in vitro data to
support a new claim(s) to an already submitted original application during the review of
that application is not recommended. Such a submission would be considered developing
the product on the review clock and is contrary to the spirit and intent of the Act.
If the original application is not yet approved, a request for approval of other new
indications or claims should be submitted in a separate, original application. If the initial
application is approved, the application can be subsequently supplemented to add a new
indication. (See section II.B. on supplemental applications.) At the time of submission,
an original application should be complete and ready for a comprehensive review.
8. 	Medicare Modernization Act Changes
The Medicare Prescription Drug, Improvement, and Modernization Act of 200310 may
require a new application to be submitted because of a change to the reference listed
drug. If there are no other material changes to the new application, other than to specify
the new reference listed drug, a fee may not be required consistent with the user fee
exception for previously filed applications.11
B. 	NDA and BLA Supplements
1. 	Changes in Composition
We recommend that a change in the composition of an approved product to support a
change in the dosage form or route of administration (other than those discussed in
section I.A.2 or I.A.3 above) should be submitted as a separate original application.
2. 	Other Changes to Approved Products
A change to an approved product based on chemistry, manufacturing, or controls data
and bioequivalence, or other studies (e.g., safety and immunogenicity), that changes (1)
the strength or concentration; (2) the manufacturing process, equipment, or facility; or (3)
the formulation (e.g., different excipients) can be submitted as a supplement to an
approved application. Such a change would not ordinarily warrant a new original
application unless it changes the dosage form or route of administration (see sections
I.A.2 and I.A.3, above).
3. 	Changes to Indications
10 Public Law 108-173.
5
11 Section 736(a)(1)(C) of the Act (21 U.S.C. 379h(a)(1)(C)).

Contains Nonbinding Recommendations
A request for approval of a new indication, or a modification of a previously approved
indication, should be submitted individually in a separate supplement to an approved
original application.12
The Agency does not recommend that new clinical or in vitro data, submitted in support
of a new indication or claim, other than that required in safety updates be submitted as
part of the pending supplement during the review of a given supplemental application.
Such a submission would be considered developing the product on the review clock and
is contrary to the spirit and intent of the Act. Previously submitted indications or claims
can, however, be modified by, for example, reanalyses of previously submitted data, or,
in rare instances, supplementary clinical data.
FDA recommends the basic operating principle that, at the time of submission, a
supplement should be complete and ready for a comprehensive review. Modifications of
the supplement should be only to clarify part of the already submitted supplement or to
answer specific questions raised by the review team. FDA does not recommend that
modifications expand or broaden the scope of the already submitted supplement unless
they are requested by the Agency.
IV. 	DEFINITION OF CLINICAL DATA
Original applications and supplements may be accompanied by data reporting clinical experience
in humans. However, not all such reports of experience in humans are regarded by the FDA as
clinical data for purposes of assessing user fees. The term clinical data, for purposes of
assessing user fees, encompasses a broad range of studies that are purported to be adequate and
well-controlled investigations submitted in support of approval.
User fees will be assessed for original applications (NDAs or BLAs) and supplements containing
the following types of clinical data required to form the primary basis for approval:
• 	Study reports or literature reports of what are explicitly or implicitly represented by the
applicant to be adequate and well-controlled trials for safety or effectiveness; or
• 	Reports of comparative activity (other than bioequivalence and bioavailability studies),
immunogenicity, or efficacy, where those reports are necessary to support a claim of
comparable clinical effect.
For purposes of assessing user fees, FDA does not consider the following to meet the definition
of clinical data:
• 	Individual case reports describing experience in clinical use submitted in support of a
labeling change to add adverse reactions;
12 The Act states, "The term supplement means a request to the Secretary to approve a change in a human drug
application which has been approved" (21 U.S.C. 379g(2)). Each indication is considered a separate change, for
which a separate supplement should be submitted. FDA can then approve each indication when it is ready for
approval, rather than delaying approval until the last of a group of indications is ready to be approved.
6

Contains Nonbinding Recommendations
7
• 	Data used to modify the labeling to add a restriction that would improve the safe use of
the drug (e.g., to add an adverse reaction, contraindication, or warning to the labeling);
• 	Data from bioequivalence studies or studies of bioavailability of a drug submitted in
supplements to NDAs, even if the studies include clinical endpoints; or
• 	Safety, biochemical equivalence, and/or limited comparative product equivalence data
used to support BLA supplements for manufacturing process or site changes.