Guidance for Industry
Submitting Separate Marketing Applications
and
Clinical Data for
Purposes of Assessing User Fees
(PDF
version of this document)
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
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
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).
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.
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.
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).
The Act also levies fees on supplements to human drug applications
that require clinical data. 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.
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.
a. Drugs
Every different active ingredient
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.
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.
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).
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).
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).
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,
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.
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.
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.
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.
The Medicare Prescription Drug,
Improvement, and Modernization Act of 2003
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.
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.
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).
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.
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.
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;
·
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.
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).
Section 735(1) (21 U.S.C. 379g(1)).
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.
Section 736(a)(1) (21 U.S.C.
379h(a)(1)).
FDA’s guidance for industry, Formal Dispute Resolution:
Appeals Above the Division Level, February 2000.
For example, different salts, esters, and complexes of the same
active moiety are considered to be different active ingredients.
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.
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Date created: December 28, 2004 |