PDUFA Waivers, Reductions, 
and Refunds for Fixed- 
Combinations and Single-Entity 
Versions of Previously 
Approved Antiretrovirals under 
PEPFAR 
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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 
301-796-7900.  
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
August 2023 
User Fees
  PDUFA Waivers, Reductions, 
and Refunds for Fixed- 
Combinations and Single-
Entity Versions of Previously 
Approved Antiretrovirals 
under PEPFAR 
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)  
 
August 2023 
User Fees
 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
 
TABLE OF CONTENTS 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  BASIS FOR ASSESSING PDUFA USER FEES ........................................................... 3 
IV.  PDUFA USER FEE WAIVERS, REDUCTIONS, AND REFUNDS ........................... 4 
A.   Application Fees ............................................................................................................................. 4 
B.  Annual Prescription Drug Program Fees .................................................................................... 6 
V.  SUBMITTING REQUESTS FOR WAIVERS, REDUCTIONS, AND REFUNDS ... 6 
VI.  FDA RESPONSES TO REQUESTS FOR WAIVERS, REDUCTIONS, AND 
REFUNDS .......................................................................................................................... 7 
VII.  DISCLOSURE OF PUBLIC INFORMATION ............................................................. 7 
 
 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
PDUFA Waivers, Reductions, and Refunds for Fixed-Combinations 
and Single-Entity Versions of Previously Approved Antiretrovirals 
under PEPFAR 
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 certain new drug 
applications (NDAs) for single-entity (SE) antiretroviral (ARV) and fixed-combination (FC)3 
ARV drug products for the treatment or prevention of human immunodeficiency virus-1 (HIV-1 
or HIV).  FDA expects that most of the application fees for SE and FC ARV drug products 
proposed for use in the President's Emergency Plan for AIDS Relief (PEPFAR) will qualify for a 
waiver under the barrier-to-innovation waiver provision.4 
 
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.  
 
 
1
This guidance has been prepared by the Division of User Fee Management in the Center for Drug Evaluation and 
Research (CDER) in cooperation with the Division of Antivirals, CDER, and the Office of Global Policy and 
Strategy, 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 antiretroviral drug product is one in which two or more 
antiretroviral drugs are combined in a single dosage form and the contribution of the individual drugs has been 
demonstrated to contribute to the effect(s) of the fixed-combination consistent with the requirements of 21 CFR 
300.50.  For the purposes of this guidance, the term drug product will be used to refer to human prescription drugs, 
under section 505 of the Federal Food, Drug, and Cosmetic (FD&C) Act.  
4
 Section 736(d)(1)(B) of the FD&C Act. 
1 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
II.  BACKGROUND 
 
PEPFAR is a U.S. Government initiative to help save the lives of those suffering from 
HIV/AIDS (acquired immunodeficiency syndrome) around the world.  It was originally 
announced in President George W. Bushs State of the Union address in 2003 and was 
reauthorized in 2008, 2013, and 2018.  To date, this historic commitment is among the largest by 
any nation to combat a single disease internationally.  As of 2012, ARV drug products are also 
available for HIV prevention, and as of 2015, the World Health Organization recommends the 
use of these drug products to reduce the risk of HIV-1 acquisition.  ARV drug products for 
treatment and prevention play a major role in this relief plan, and it is important that resources 
are spent on products that have been demonstrated to be safe and effective.  ARV drug products 
for treatment or prevention of HIV must conform to regulatory standards of safety, efficacy, and 
quality to maximize the success of treatment or prevention and to reduce the emergence and 
spread of resistant virus.  Of note, FDA-approved or tentatively approved ARV drug products 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).  Attachment A of the 2006 Fixed-
Combination Guidance described some scenarios for the approval of fixed-combination and co-
packaged products for the treatment of HIV that might be eligible for the PEPFAR program at 
that time, and Attachment B provided examples of drug combinations that FDA expected could 
be developed without conducting new clinical efficacy and safety studies.  In 2023, FDA issued 
a draft guidance, Fixed-Combinations and Single-Entity Versions of Previously Approved 
Antiretrovirals for the Treatment or Prevention of HIV-1 Under PEPFAR (2023 Fixed-
Combination Guidance),5 which, when finalized, will revise and replace the 2006 Fixed-
Combination Guidance to reflect updated information regarding the PEPFAR program.  To 
replace Attachment B, previously attached to the 2006 Fixed-Combination Guidance, the 
Agency published a separate list, Antiretroviral Drug Products Needed for Use Under 
PEPFAR,6 which includes single-entity ARV and FC ARV drug products supported by clinical 
data and currently needed for PEPFAR procurement.  Applicants should refer to this list when 
considering submission of applications for ARV drugs intended for use under PEPFAR.  The 
2023 Fixed-Combination Guidance provides recommendations for applications for SE and FC 
ARV drug products for the treatment or prevention of HIV infection that are intended for use 
under PEPFAR.  
 
 
5
 FDA updates guidances periodically.  To ensure you have the most recent version of a guidance, check the FDA 
Guidances (Drugs) web page available at https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/guidances-drugs. 
6
 The separate list of ARV drug products, Antiretroviral Drug Products Needed for Use Under PEPFAR, can be 
found under question 6, What PEPFAR products can companies submit for FDA review?, at FDAs PEPFAR 
Database on the Frequently Asked Questions web page: available at https://www.fda.gov/international-
programs/presidents-emergency-plan-aids-relief-pepfar/pepfar-database-frequently-asked-questions.  This list is 
revised periodically to address current public health needs. 
2 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
When final, this guidance will supersede 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 ARV drug 
products for the treatment or prevention of HIV infection that are proposed for use under 
PEPFAR may be eligible for a user fee waiver under the barrier-to-innovation waiver provision.7  
 
III.  BASIS FOR ASSESSING PDUFA USER FEES  
 
The Prescription Drug User Fee Act of 1992 (PDUFA I) directed 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.  Under the Prescription Drug User Fee Amendments of 2022 
(PDUFA VII), which includes the reauthorization of PDUFA through September 2027, FDA 
generally assesses application fees to an applicant when it submits a human drug application 
(defined by statute to include certain new drug applications under section 505(b) of the FD&C 
Act and certain biologics license applications under section 351(a) of the Public Health Service 
Act (PHS Act) 8), subject to limited statutory exceptions.9  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 351(a) of the PHS 
Act.10, 11  The PDUFA user fee authorities are in sections 735 and 736 of the FD&C Act. 
 
The amount of the application fee assessed for a human drug application depends on whether 
clinical data12 (other than bioavailability or bioequivalence studies) with respect to safety or 
effectiveness are required for approval of the application.13  Specifically, a human drug 
application for which such data are not required is assessed one-half the fee of an application that 
requires such data for approval.14   
 
 
 
 
 
 
7
 Section 736(d)(1)(B) of the FD&C Act. 
8
 Section 735(1) of the FD&C Act. 
9
 Section 736(a)(1) of the FD&C Act. 
10
 PDUFA user fee waivers, reductions, and refunds are discussed in FDAs guidance for industry Prescription 
Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products (Oct. 2019).  FDA updates 
guidances periodically.  To ensure you have the most recent version of a guidance, check the FDA Guidances 
(Drugs) web page available at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-
drugs. 
11
 In this guidance, the terms prescription drug program fee and program fee have the same meaning. 
12
 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).  
13
 Section 736(a)(1) and (b) of the FD&C Act (21 U.S.C. 379h(a)(1) and (b)).   
14
 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.   
3 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
IV.  PDUFA USER FEE WAIVERS, REDUCTIONS, AND REFUNDS 
 
  A.   Application Fees 
 
Applicants may qualify for a waiver or refund of their application fee under section 736(d) of the 
FD&C Act.  FDA encourages applicants to request a waiver no later than 45 calendar days in 
advance of submission of an application so that the request can be evaluated before the fee is 
due.15  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 written request for refund must be submitted to FDA not later than 180 calendar days after the 
fee due date.16, 17  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 FDAs guidance for industry Prescription 
Drug User Fee Act Waivers, Reductions, and Refunds for Drug and Biological Products.18  
 
Section 736(d) of the FD&C Act contains three waiver or reduction provisions under which an 
applicant may request a waiver or reduction in user fees based on public health necessity, to 
remove a barrier to innovation, or if the applicant qualifies as a small business submitting its first 
application.  FDAs guidance for industry Prescription Drug User Fee Act Waivers, Reductions, 
and Refunds for Drug and Biological Products describes FDAs interpretation of each of these 
waiver provisions.19  
 
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 under section 736(d)(1)(B) of the FD&C Act, 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 ARV drug products for 
the treatment or prevention of HIV on the Antiretroviral Drug Products Needed for Use Under 
 
15
 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.  
16
 Sections 736(a)(1)(B) and 736(i) of the FD&C Act (21 U.S.C. 379h(a)(1)(B) and 379h(i)). 
17
 See footnote 10. 
18
 See footnote 10. 
19
 See footnote 10. 
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    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
PEPFAR list20 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 expect to answer the first question in the 
affirmative.  At some point, as alternative options for treatment or prevention become available, 
FDA may reevaluate whether the listed ARV drug products remain innovative and may find that 
an application fee waiver is no longer appropriate for a drug to be procured under the PEPFAR 
program.  For example, a user fee waiver may not be appropriate if, after consultation with the 
agencies that administer the PEPFAR program,21 FDA determines that there are already 
sufficient alternatives available to fulfill the needs of the PEPFAR program.  
 
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 be classified as 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 ARV drug product for the treatment or 
prevention of HIV on the Antiretroviral Drug Products Needed for Use Under PEPFAR 
list;22   
  The applicant is submitting an application that seeks only a tentative approval23 in the United 
States, and at the date of submission the application is not expected to become eligible for a 
final approval as of the user fee goal date;24  
  The applicant certifies by letter25 to The U.S. Agency for International Development 
(USAID) 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, with a copy of the letter included in the waiver request; and  
 
  Certifications are supported with evidence that the product will be offered for procurement 
by PEPFAR, and either:  (1) 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 (2) if such approval has not been obtained, the ARV drug product is listed on an HIV 
 
20
 See footnote 6.  
21
 The PEPFAR program is led by the Office of the U.S. Global AIDS Coordinator and Health Diplomacy at the 
U.S. Department of State with support and collaboration from other United States Government agencies, including 
principally the Office of HIV/AIDS within the Global Health Bureau at U.S. Agency for International Development.  
22
 The separate list on the FDAs PEPFAR Database is not meant to be comprehensive and is expected to evolve as 
HIV clinical research continues and program needs change.  Applicants who have access to data supporting the 
efficacy and safety of drugs or regimens not included in the list of needed ARV drug products are encouraged to 
contact the Division of Antivirals (DAV) within CDERs Office of New Drugs to discuss the available support for 
ARV drug products not on the list.  The DAV PEPFAR Project Manager may be contacted about these questions at 
301-796-1500.   
23
 In the PEPFAR context, applicants who are seeking tentative approval have almost always submitted a Paragraph 
III [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 submission of the application.   
24
 See, e.g., 21 CFR 314.107(b) and (d). 
25
 Applicants should contact USAID at SCH.HIV.Pharma@usaid.gov with the following subject line: Request for 
barrier-to-innovation waiver under PDUFA NDA# (product name). 
5 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
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 requires the collection of annual prescription drug program fees for certain FDA-
approved prescription drug products.  Annual prescription drug program fees are not assessed for 
drug products that are:  
 
1.  Listed on the Discontinued Drug Product List in the FDA publication Approved 
Drug Products with Therapeutic Equivalence Evaluations (commonly known as 
the Orange Book),26 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.27  
 
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 be assessed unless the 
product qualifies for a waiver, exception, or exemption.  Waiver requests are evaluated on a 
case-by-case basis.  FDA does not anticipate that program fees would generally constitute a 
barrier to innovation under the other circumstances criterion because their Orange Book listing 
indicates that the drug product is 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 FD&C Act can be found in FDAs 
guidance for industry Prescription Drug User Fee Act Waivers, Reductions, and Refunds for 
Drug and Biological Products Guidance for Industry.28  Among other things, the guidance 
discusses where to submit requests and what information to include.  
 
 
26
 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 FD&C 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. 
27
 If a tentatively approved product receives final approval, it would be added to the Prescription Drug Product 
List of the Orange Book and, therefore, would be subject to the annual prescription drug program fee at the 
beginning of the fiscal year following final approval. 
28
 See footnote 10.  
 
6 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
VI.  FDA RESPONSES TO REQUESTS FOR WAIVERS, REDUCTIONS, AND 
REFUNDS 
 
FDA will review waiver, reduction, and refund requests, consulting with relevant Agency 
officials as appropriate.  If needed to support an 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 request.  The Agency 
will respond to requests for waivers, reductions, and refunds 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.  Any such disclosure will be consistent with the laws and regulations governing 
the disclosure of confidential commercial or financial information. 
 
 
7