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 
 
1
Guidance for Industry
   
 
 
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 FDAs 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.  
   3 Section 735(1) (21 U.S.C. 379g(1)). 
  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 FDAs 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 FDAs 
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. 
8 Section 735(1) of the Act (21 U.S.C. 379g(1)). 
  3  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. 
 
11 Section 736(a)(1)(C) of the Act (21 U.S.C. 379h(a)(1)(C)). 
  5  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 
 
  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. 
  7