Prescription Drug User Fee 
Act Waivers for Fixed-
Combination Antiretroviral 
Drugs for the Presidents 
Emergency Plan for AIDS 
Relief 
Guidance for Industry 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Division of User Fee Management 
and Budget Formulation 301-796-7900.  
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2018 
User Fees 
 
   
Prescription Drug User Fee 
Act Waivers for Fixed-
Combination Antiretroviral 
Drugs for the Presidents 
Emergency Plan for AIDS 
Relief 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
June 2018 
User Fees 
 
   
 
 
 
 
TABLE OF CONTENTS 
 
 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  BASIS FOR ASSESSING PDUFA USER FEES ........................................................... 2 
IV.  FEE WAIVERS AND REFUNDS ................................................................................... 3 
V.  SUBMITTING REQUESTS FOR WAIVERS, REDUCTIONS, AND REFUNDS ... 5 
VI.  FDA RESPONSES TO REQUESTS FOR WAIVERS AND REDUCTIONS ............ 6 
VII.  DISCLOSURE OF PUBLIC INFORMATION ............................................................. 6 
 
  Contains Nonbinding Recommendations 
Prescription Drug User Fee Act Waivers for Fixed-Combination 
Antiretroviral Drugs for the Presidents Emergency Plan for AIDS 
Relief 
Guidance for Industry1 
 
 
 
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
for this guidance as listed on the title page. 
 
 
 
 
I.  INTRODUCTION 
 
This guidance describes circumstances in which an applicant may be eligible for a barrier-to-
innovation waiver under the Prescription Drug User Fee Act (PDUFA)2 for some new drug 
applications (NDA) for fixed-combination (FC)3 and single-entity versions of previously 
approved antiretroviral therapies for the treatment of human immunodeficiency virus (HIV).4  
FDA expects that most of the applications and post-approval fees for fixed-combination and  
HIV therapies proposed for use in the President's Emergency Plan for AIDS Relief (PEPFAR) 
will qualify for a waiver under the barrier-to-innovation user fee waiver.   
 
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.  
 
 
                                                 
1This guidance has been prepared by the Division of User Fee Management and Budget Formulation in the Center 
for Drug Evaluation and Research (CDER) in cooperation with the Division of Antiviral Products, CDER, and the 
Office of International Programs, Office of the Commissioner.  
2 Sections 735 and 736 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 379g and 379h). 
Unless otherwise specified, all references to user fees in this guidance mean user fees assessed under these 
sections of the FD&C Act, and not fees assessed under other provisions in the FD&C Act or the Public Health 
Service Act (PHS Act). 
3 For the purposes of this guidance, a fixed-combination product is one in which two or more separate drug 
ingredients are combined in a single dosage form. 
4 The Prescription Drug User Fee Act of 1992 (PDUFA I) authorized FDA to assess user fees for 5 years in 
conjunction with the review of human drug applications. This authorization to assess user fees was for fiscal years 
(FY) 1993 through 1997. PDUFA has been reauthorized five times. The FDA Reauthorization Act of 2017 
reauthorized the user fee provisions for another 5 years, beginning in FY 2018 (PDUFA VI). Among other changes, 
PDUFA VI amended the annual PDUFA user fee structure by removing annual product and establishment fees and 
adding annual prescription drug program fees. 
  Contains Nonbinding Recommendations 
II.  BACKGROUND 
 
The President's Emergency Plan for AIDS Relief (PEPFAR) is a U.S. Government response to 
help save the lives of those suffering from HIV/AIDS around the world.  It was originally 
announced in President Bushs State of the Union address in 2003 and was reauthorized in 2008 
and 2013.  This historic commitment is the largest by any nation to combat a single disease 
internationally.  Drug treatment plays a major role in this relief plan, and it is important that 
resources are spent on treatments that have been demonstrated to be safe and effective.  It is also 
important for antiretroviral drugs to conform to expected regulatory standards of safety, efficacy, 
and quality to avoid the risks of treatment failure and the emergence and spread of resistant 
virus.  Of note, only antiretroviral drugs that undergo a stringent review by a regulatory authority 
such as FDA are eligible for procurement under PEPFAR.   
 
In October 2006, to encourage applicants to submit applications for HIV combination therapies 
that can be used in PEPFAR, FDA issued a final guidance Fixed Dose Combinations, Co-
Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for 
the Treatment of HIV (2006 fixed-combination guidance).5 Attachments to the 2006 fixed-
combination guidance describe some scenarios for approval of fixed-combinations for the 
treatment of HIV, and provide examples of drug combinations considered acceptable as fixed 
combinations and examples of those not considered acceptable as fixed combinations.  Although 
the 2006 fixed-combination guidance focuses on fixed-combinations, the scientific principles 
outlined in the guidance also apply to single ingredient versions of antiretroviral drugs that are 
components of regimens listed in Attachment B. The guidance also explains that the Federal 
Food, Drug, and Cosmetic Act (FD&C Act) provides for certain circumstances in which FDA 
may grant a waiver or reduction in user fees.   
 
This guidance is a revision of the guidance for industry User Fee Waivers for FDC and Co-
Packaged HIV Drugs for PEPFAR, issued February 2007.  In this guidance, FDA provides 
information about circumstances under which certain applications for fixed-combination and 
single-entity versions of previously approved antiretroviral therapies for the treatment of HIV 
under PEPFAR may be eligible for a barrier-to-innovation user fee waiver.  
 
III.  BASIS FOR ASSESSING PDUFA USER FEES  
 
The Prescription Drug User Fee Act of 1992 (PDUFA I) authorized FDA to assess user fees to 
certain applicants for a five-year period. Beginning in 1997, PDUFA has been reauthorized by 
Congress every five years. Most recently, in 2017, Congress enacted the FDA Reauthorization 
Act of 2017. Under this legislation, FDA generally assesses application fees to an applicant when 
it submits a human drug application (defined by statute to include new drug applications under 
section 505(b) of the FD&C Act and biologics license applications under section 351(a) of the 
Public Health Service Act (PHS Act)), subject to certain statutory exceptions. FDA also assesses 
prescription drug program fees annually, subject to limited exceptions, to applicants of approved 
drugs whose applications were submitted under section 505(b) of the FD&C Act or section 
                                                 
5 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
 
2 
  Contains Nonbinding Recommendations 
351(a) of the PHS Act.6, 7  The PDUFA user fee authorities are codified in section 735 and 736 
of the FD&C Act. 
 
The amount of the application fee assessed for a human drug application depends on whether 
clinical data8 (other than bioavailability or bioequivalence studies) with respect to safety or 
effectiveness are required for approval of the application.9  Specifically, a human drug 
application for which such data is not required is assessed one-half the fee of an application 
whose approval requires such data.10   
 
IV.  FEE WAIVERS AND REFUNDS 
 
  A.   Application Fees 
 
Applicants may qualify for a waiver or refund of their application fee under the statute. FDA 
encourages firms to request a waiver 45 calendar days in advance of submission of an 
application so that the request can be evaluated before the fee is due.11  If the applicant pays the 
fee upon submission of the application and seeks a refund (rather than waiting to submit the 
application until such time as the waiver is granted), under the statute, a request for refund must 
be submitted to FDA not later than 180 calendar days after the day on which the applicant 
submits the application.12, 13  Even if an applicant would otherwise be eligible for a refund, no 
refunds are allowed under the statute if the refund request is received by FDA more than 180 
calendar days after the payment.14  Applicants who pay the fee but believe they will be eligible 
for a refund are encouraged to request a refund simultaneously with payment of the fee.  
Instructions for the submission of waiver and refund requests are found in section V of this 
guidance.  
 
Section 736(d) of the FD&C Act contains three waiver or refund provisions under which an 
applicant may apply to have user fees waived or refunded: public health, barrier-to-innovation, 
and small business.15 FDAs guidance for industry User Fee Waivers, Reductions, and Refunds 
                                                 
6 More information regarding statutory exemptions for user fees can be found in the guidance for industry User Fee 
Waivers, Reductions, and Refunds for Drug and Biologic Products (Sept. 2011).  .   
7 The terms prescription drug program fee and program fee have the same meaning. 
8 For purposes of assessing user fees, FDAs interpretation of clinical data can be found in the guidance for industry 
Submitting Separate Marketing Applications and Clinical Data for Purposes of Assessing User Fees (Dec. 2004)..  
9 Section 736(a)(1) and (b) of the FD&C Act (21 U.S.C. 379h(a)(1) and (b)).  Bioavailability and bioequivalence 
studies are applicable only to applications submitted under section 505 of the FD&C Act.  They are not addressed in 
section 351 of the PHS Act. 
10 Section 736(a)(1)(A) of the FD&C Act (21 U.S.C. 379h(a)).  Information on application and program fees, 
including fee rates, PDUFA goals, and other various user fee related issues can be found on FDAs PDUFA website:  
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/default.htm.   
11 Normally, FDA encourages the submission of requests for waivers 3 to 4 months in advance of the submission of 
an application.  To further reduce the burden on applicants interested in making products available under PEPFAR, 
FDA will expedite the processing of waiver requests and will aim to process such requests within 45 calendar days.  
12 Section 736(a)(1)(B) and Section 736(i) of the FD&C Act (21 U.S.C. 379h(a)(1)(B) and, 379h(i)). 
13 Information on PDUFA user fee waivers, reductions, and refunds can be found in the guidance for industry User 
Fee Waivers, Reductions, and Refunds for Drug and Biologic Products (Sept. 2011). 
14 Section 736(i) of the Act (21 U.S.C. 379h(i)).  
15 Section 736(d)(1) of the FD&C Act. 
 
3 
  Contains Nonbinding Recommendations 
for Drug and Biological Products describes FDAs interpretation of each of these waiver 
provisions.16  
 
Although the Agency determines whether to grant requests for waivers under the statute on a 
case-by-case basis, at this time FDA expects that PEPFAR participants will generally be eligible 
for a barrier-to-innovation waiver, which provides a waiver of an application fee when the 
assessment of the fee would present a significant barrier to innovation because of the limited 
resources available to such person or other circumstances.  The agency considers the following 
two questions in deciding whether to grant a barrier to innovation waiver: 
 
1.  Is the product or other products or technologies under development by the 
applicant innovative? 
2.  Would the fee(s) be a significant barrier to the applicants ability to develop, 
manufacture, or market innovative products or to pursue innovative technology?  
 
As to the first question, at this time FDA generally intends to consider any fixed-combination for 
the treatment of HIV that is listed in Attachment B of the 2007 fixed-combination guidance to be 
an innovative product because simplified regimens that will facilitate distribution and patient 
compliance, particularly in treatment-naive patients, are needed in developing countries. 
Accordingly, the agency would answer the first question in the affirmative. At some point, as 
alternative treatments become available, FDA may reevaluate whether particular fixed-
combinations remain innovative and may find that an application fee waiver is no longer 
appropriate for a drug product combination listed in Attachment B.  For example, a user fee 
waiver may not be appropriate if, in FDAs judgment, there are sufficient treatment alternatives 
available to the public.  
 
As to the second question, a fee may be a significant barrier because of limited resources 
available or other circumstances. FDA generally intends to consider the development of drugs 
for PEPFAR to present other circumstances that would justify a waiver of PDUFA user fees 
under the barrier-to-innovation waiver provision where: 
 
  The applicant is submitting an application for an fixed-combination product for treatment of 
HIV from among the examples that are listed in Attachment B of the 2006 fixed-combination 
guidance; 17   
  The applicant is only seeking a tentative approval18 in the United States for the product as it 
cannot market the product in the United States because of patents or exclusivity on the 
innovator product; and 
                                                 
16  Further information regarding PDUFA waivers can be found in the guidance for industry User Fee Waivers, 
Reductions, and Refunds for Drug and Biological Products.  
17  Fixed-combination antiretroviral drugs used for the treatment of HIV under PEPFAR that are not listed in 
Attachment B may also be eligible to qualify for user fee waiver under the other circumstances provision of the 
barrier-to-innovation waiver.  The list in Attachment B is not meant to be comprehensive and is expected to evolve 
as HIV clinical research continues and treatment program needs change.  Applicants who have access to data 
supporting the efficacy and safety of drugs or regimens not included in Attachment B are encouraged to contact the 
Division of Antiviral Products within CDERs Office of New Drug Products to discuss the available support for a 
fixed-combination or product not on the list. 
18 Applicants who are seeking tentative approval have almost always submitted a Paragraph III Certification [21 
CFR 314.94(a)(12)(i)(A)(3)] certification to patents listed in the FDAs Approved Drug Products With Therapeutic 
Equivalence Evaluations (also known as the Orange Book) at the time of submitting the application.   
4 
  Contains Nonbinding Recommendations 
 
  The applicant certifies that upon receipt of tentative approval, the applicant will make the 
product available at competitive prices suitable for procurement under PEPFAR in one or 
more of the designated PEPFAR countries.  FDA will accept certifications that are supported 
with:  (1) evidence that the product is being offered for procurement by PEPFAR, and (2) 
evidence that the product for which the application is being submitted has been approved for 
use by the government of one or more PEPFAR countries; or (3) if such approval has not 
been obtained, the fixed-combination is listed on an HIV treatment guideline for one or more 
of the PEPFAR countries and the applicant provides a plan and schedule for the submission 
of an application for approval in one or more of the countries.   
 
B.  Annual Prescription Drug Program Fees 
 
PDUFA provides for annual prescription drug program fees for certain prescription drug 
products.  However, these annual prescription drug program fees are not assessed for drug 
products that are either of the following:  
 
1.  listed as discontinued in the FDA publication Approved Drug Products with 
Therapeutic Equivalence Evaluations (the Orange Book)19 , or  
2.  tentatively approved. 
 
Because a drug product that is either listed as discontinued in the Orange Book or is tentatively 
approved will not be assessed annual prescription drug program fees, a request for a waiver for 
program fees is not necessary.  
 
If a drug product is listed in the Orange Book as an approved prescription drug product and is not 
listed as discontinued, an annual prescription drug program fee would ordinarily be assessed.  
FDA does not anticipate that such fees would generally constitute a barrier to innovation under 
the other circumstances criterion discussed above because the Orange Book listing indicates 
that the drug product is being marketed in the United States, making other marketing 
opportunities available.  
 
V.  SUBMITTING REQUESTS FOR WAIVERS, REDUCTIONS, AND REFUNDS  
 
 Further guidance for applicants regarding the submission of requests for waivers, refunds, and 
reductions of fees assessed under sections 735 and 736 of the Federal Food, Drug, and Cosmetic 
Act (the FD&C Act), can be found in the FDAs guidance for industry User Fee Waivers, 
Reductions, and Refunds for Drug and Biological Products, issued in September 2011. Among 
other things, the guidance discusses where to submit requests and what information to include.  
 
 
                                                 
19 The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/. Prescription drug program fees 
are assessed under section 736(a) of the Act for certain prescription drug products. Section 735(3) of the FD&C 
Act defines a prescription drug product to exclude, among other things, drug products in the discontinued section 
of the Orange Book 
5 
  Contains Nonbinding Recommendations 
VI.  FDA RESPONSES TO REQUESTS FOR WAIVERS AND REDUCTIONS 
 
FDA will review waiver, refund, or reduction request, consulting with relevant Agency officials 
as appropriate.  If needed to support applicants assertions that the applicant qualifies, FDA may 
request additional information and documentation from the applicant during its review of a 
waiver, reduction, or refund request.  Failure to provide the requested information or 
documentation may result in a denial of a waiver, reduction, or refund.  The Agency will respond 
to requests for waivers and reductions in a timely fashion based on available resources and 
collection time for additional information. 
 
VII.  DISCLOSURE OF PUBLIC INFORMATION 
 
FDA may disclose information publicly about its actions granting or denying waivers, refunds 
and reductions.  This disclosure will be consistent with the laws and regulations governing the 
disclosure of confidential commercial or financial information. 
 
 
6