User Fee Waivers for FDC and Co-Packaged HIV Drugs for PEPFAR

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

Guidance for Industry
User Fee Waivers for FDC
and Co-Packaged HIV Drugs
for PEPFAR
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
February 2007
User Fees

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Guidance for Industry
User Fee Waivers for FDC
and Co-Packaged HIV Drugs
for PEPFAR
Additional copies are available from:
Office of Training and Communication
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/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
February 2007
User Fees

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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 1
III. 	SOME APPLICATIONS WILL NOT BE ASSESSED FEES; SOME WILL BE
ASSESSED HALF THE FEE .......................................................................................... 2
IV. 	WAIVERS OF FEES........................................................................................................ 3
A. 	Application Fees ............................................................................................................................. 3
B. 	Annual Product and Establishment Fees..................................................................................... 5
ATTACHMENT: SUMMARY OF AVAILABLE EXEMPTIONS AND WAIVERS.......... 7

Contains Nonbinding Recommendations
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2/6/2007
Guidance for Industry1
User Fee Waivers for FDC and Co-Packaged HIV Drugs for
PEPFAR
This 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. You can
use an alternative approach if the 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 the circumstances under which user fees will not be assessed under the
Prescription Drug User Fee Act (PDUFA) for some applications for fixed dose combination
(FDC) and co-packaged versions of previously approved antiretroviral therapies for the treatment
of human immunodeficiency virus (HIV). The guidance also describes circumstances under
which many of the applications, products, and establishments that will be assessed fees may be
eligible for a public health or a barrier-to-innovation waiver. We expect that most of the
applications, products, and establishments for FDC and co-packaged HIV therapies proposed
for use in the President's Emergency Plan for AIDs Relief (PEPFAR) will either not be
assessed fees in the first instance or will qualify for a waiver under the "other circumstances"
part of the barrier-to-innovation user fee waiver. See the Attachment at the end of the guidance
for a summary of available exemptions and waivers.
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
1 This guidance has been prepared by the Division of Antiviral Drug Products in the Center for Drug Evaluation and
Research (CDER), in cooperation with the Office of Regulatory Policy, CDER.
All guidances mentioned in this document are available at http://www.fda.gov/cder/guidance/index.htm.

Contains Nonbinding Recommendations
2
As part of the President's Emergency Plan for AIDs Relief, the President committed sizeable
resources, including $15 billion over a 5-year period to fund a program to develop programs to
address the treatment of HIV. 2
In May 2004, to encourage applicants to submit applications for HIV combination therapies that
can be used in PEPFAR, FDA issued a draft guidance entitled Fixed Dose Combination and Co-
Packaged Drug Products for the Treatment of HIV (fixed-dose guidance).3 Attachments to the
fixed dose guidance described some scenarios for approval of fixed dose combination (FDC) or
co-packaged products for the treatment of HIV, and provided examples of drug combinations
considered acceptable for FDC/co-packaging and examples of those not considered acceptable
for FDC/co-packaging. The guidance also explained that the Federal Food, Drug, and Cosmetic
Act (the Act) provides for certain circumstances in which FDA can grant applicants a waiver or
reduction in user fees normally assessed for drug applications, drug products, and establishments
where drugs are made. The fixed dose guidance stated that FDA was evaluating the
circumstances under which it can grant user fee waivers or reductions for applicants developing
FDC and co-packaged versions of previously approved antiretroviral therapies for the treatment
of HIV.
Several potential applicants have asked that we clarify whether applicants submitting drug
applications covered by the fixed dose guidance for use in PEPFAR will be required to pay user
fees under PDUFA and, if so, whether they would be eligible for a waiver of those fees.
III. 	SOME APPLICATIONS WILL NOT BE ASSESSED FEES; SOME WILL BE
ASSESSED HALF THE FEE
Under PDUFA, the following types of drug applications are not assessed user fees:
• 	Abbreviated new drug applications (ANDAs) submitted under section 505(j) of the Act
(section 735(1))
• 	Applications submitted under 505(b)(2) of the Act that do not request approval of (1) a
new molecular entity (i.e., an active moiety that has not been approved under an
application under 505(b)) or (2) an indication for a use that has not been approved under
an application under 505(b) (§ 735(1)(B))
Most applications submitted under Scenarios 2 and 3 of Attachment A to the draft fixed dose
guidance could qualify for these fee exemptions.
2 White House Fact Sheet “The President’s Emergency Plan for AIDS Relief,” available on the Internet at
www.whitehouse.gov/news/releases/2003/01/20030129-1.html.
3 The draft guidance has been finalized and renamed Fixed Dose Combination, Co-Packaged Drug Products, and
Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV (HIV guidance). The final
HIV guidance is available on the Internet at www.fda.gov/cder/guidance.

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Any ANDA submitted under section 505(j) of the Act would be exempt. However, because only
certain 505(b)(2) applications are exempt, it is important that potential applicants who do not
want to be assessed fees be advised to use active ingredients submitted in applications that have
already been approved under section 505(b) (that is, they can use any of the ingredients listed in
Attachment B to the fixed dose guidance), and they should not seek any new indications for a
use. It is particularly important that they strictly follow the approved labeling for the individual
ingredients. If, for example, applicants seek a different use of the drug, a different dosing
regimen or route of administration, use in a new population, or if they compare their product to
others in the labeling, they will not qualify for the 505(b)(2) exemption from fees.
Finally, any application submitted under 505(b)(1) or 505(b)(2) of the Act that does not require
clinical data for approval would only be assessed a half fee under the Act (section 736(a)(1)(A)).
This half fee would be $448,100 for fiscal year 2007.4 Bioavailability and bioequivalence data
are not considered clinical data for purposes of assessing user fees.5
IV. 	WAIVERS OF FEES
A. 	Application Fees
Sponsors of applications that will be assessed either a full or a half fee may qualify for waivers
of their application fee under several provisions of PDUFA. Waivers must be requested of FDA
not later than 180 days after the fees are due,6 and FDA encourages firms to request a waiver at
least 45 days in advance of submission of an application so that the request can be evaluated
before the fee is due.7
The waivers most likely to be available to PEPFAR participants are:
• 	The small business waiver, which provides for a complete waiver of the application fee for
any company with less than 500 employees (including affiliated companies) for the first
human drug application the company (including its affiliates) submits.8 Applicants must
request this waiver from FDA and provide evidence to the Small Business Administration
regarding the size of the company.
4 October 1, 2006, through September 30, 2007.
5 See FDA's guidance for industry on Submitting Separate Marketing Applications and Clinical Data for Purposes
of Assessing User Fees.
6 Section 736(i), 21 U.S.C. 379h(i).
7 Normally, FDA encourages the submission of requests for waivers 90 days in advance of the submission of an
application. However, to further reduce the burden on sponsors interested in making products available under
PEPFAR, FDA will expedite the processing of waiver requests and try to process such requests within 45 days.
8 Section 736(d)(3), 21 U.S.C. 379h(d)(3).

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• 	The public health waiver and the barrier-to-innovation waiver, which provide for waivers of
application fees and annual product and establishment fees for companies that meet the
criteria.9
FDA’s Attachment G
⎯ Draft Interim Guidance Document for Waivers of and Reductions in
User Fees (waiver guidance), sets out the criteria for each of these waivers.10 FDA evaluates
requests for these waivers on a case-by-case basis.
To reduce financial barriers to the development of these products, FDA has determined that any
FDC or co-packaged drug product for the treatment of HIV that is listed in Attachment B of the
fixed dose guidance will, for the foreseeable future, be considered to benefit the public health,
because making these products available in the 15 countries that are the targets of the PEPFAR
program will have a significant impact on the global efforts to treat HIV.
Furthermore, for the foreseeable future, FDA will consider any FDC or co-packaged drug
product for the treatment of HIV that is listed in Attachment B of the fixed dose guidance to be
innovative because simplified regimens that will facilitate distribution and patient compliance,
particularly in treatment naïve patients, are needed in developing countries. Therefore, FDA has
determined that these products will meet the first part of the two-part PDUFA test for public
health and barrier-to-innovation waivers. At some point, after several alternative treatments have
been made available, FDA may reevaluate whether these products remain innovative or whether
a waiver for these products is necessary to protect the public health, and may find that, because
of the existence of treatment alternatives, user fee waivers may no longer be appropriate.
The second part of the test for granting a public health or barrier-to-innovation waiver is a
financial test. That is, (1) a waiver of a user fee must be necessary to protect the public health, or
(2) the assessment of the fee must be a barrier to innovation because of limited resources or other
circumstances. The statute gives FDA more discretion under the barrier-to-innovation test. 11
Normally, a company with greater than $10 million in total annual revenue would not be found
to have limited resources and would not be eligible for either a public health or a barrier-to-
innovation waiver. However, FDA intends to consider the development of drugs for the
PEPFAR program to be the sort of “other circumstances” that would justify a waiver of
PDUFA user fees under the barrier-to-innovation waiver provision, provided the applicant
meets all of the following conditions:
9 Section 736(d)(1)(A) and (B), 21 U.S.C. 379h(d)(1)(A) and (B).
10 PDUFA also provides for a fees-exceed-the-cost waiver, in which the fees associated with all of an applicant’s
submissions are compared with standard costs associated with FDA’s reviews of the submissions and if the fees
exceed the costs, the applicant gets a refund. FDA does not believe this provision will provide a basis for waivers
for PEPFAR participants but we are mentioning it for completeness. For further information on this waiver see the
guidance entitled Fees-Exceed-The-Cost Waivers Under the Prescription Drug User Fee Act.
11 The statute does not provide FDA with the ability to consider “other circumstances” when determining whether to
grant a public health waiver. Accordingly, a company requesting a public health waiver will have to establish that it
has limited resources to receive a public health waiver.

Contains Nonbinding Recommendations
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• 	The applicant is submitting an application for an FDC or co-packaged drug product for
treatment of HIV from among the examples that are listed in Attachment B of the fixed dose
guidance.
• 	The applicant will only obtain a tentative approval in the United States for the product
because, for example, it cannot market the product in the United States because of patents or
exclusivity on the innovator product.
• 	The applicant certifies that upon receipt of tentative approval for the product, the applicant
will make the product available at competitive prices suitable for procurement under
PEPFAR in one or more of the 15 designated PEPFAR countries. FDA will accept
certifications that are supported with one of the following: (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 FDC 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.
To obtain a barrier-to-innovation waiver, applicants should submit a request for a waiver 45 days
before an application will be submitted. The waiver request should contain the certifications
described above.
B. 	Annual Product and Establishment Fees
PDUFA provides for annual user fees for certain prescription drug products and establishments.
However, the following are not assessed annual user fees:
1. 	Products approved under section 505(b)(2) applications that are not assessed
application fees because they are not for a new molecular entity or a new indication
for a use
2. 	Products that are the same as another product approved under an application filed
under section 505(b) or 505(j) of the Act
3. 	Products that are only tentatively approved
If product fees are not assessed, the establishments in which such products are made are not
assessed annual establishment fees, unless other fee paying products are made in the same
establishment. Therefore, a waiver would not be necessary for these product and establishment
fees. However, FDA intends to consider the development of drugs for the PEPFAR program
to be the sort of “other circumstances” that would justify a waiver of PDUFA product and
establishment user fees under the barrier-to-innovation waiver provision, provided the
applicant meets all of the following conditions:
• 	The applicant has obtained approval for an application for an FDC or co-packaged drug
product for treatment of HIV from among the examples that are listed in Attachment B of the
fixed dose guidance.

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• 	The applicant certifies that it is making the product available at competitive prices suitable
for procurement in one or more of the 15 designated PEPFAR countries. FDA will accept
certifications that are supported with one of the following: (1) evidence that the product is
being offered for procurement by PEPFAR and (2) evidence that the product for which the
waiver is sought has been approved for use by the government of one or more PEPFAR
countries; or (3) if such approval has not been obtained, the FDC for which the waiver is
sought 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.
• 	For establishment fees, no other user fee eligible products owned by the applicant are being
manufactured at the establishment at which the PEPFAR product is being manufactured.
The annual product and establishment fees are invoiced in mid-August with fees due to be paid
by October 1 of each fiscal year. We encourage applicants to submit requests for waivers of
annual product and establishment fees by August 15 of each year.
For information about how to request a waiver or reduction, please contact the user fee team in
the Office of Regulatory Policy at 301-594-2041. More information on user fees is available on
the Internet at http://www.fda.gov/cder/pdufa/default.htm.

Contains Nonbinding Recommendations
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ATTACHMENT: SUMMARY OF AVAILABLE EXEMPTIONS AND WAIVERS
Table 1: User Fee Exemptions
Applications Not Assessed Fees or Assessed Reduced Fees:
• 	Generic drug application submitted under 505(j)
• 	Application submitted under 505(b)(2) if not (1) a new molecular entity or (2) a new indication for a use
• 	Application that only requires BA/BE data will be assessed only 1/2 application fee
Products Not Assessed Product Fees:
• 	Tentatively approved product or product otherwise not approved
• 	Product approved under section 505(b)(2) and is not assessed application fees
• 	Products that are the same as another product approved under an application filed under section 505(b) or
505(j) of the Act
• 	If product is not assessed a fee, establishment in which it is made also not assessed a fee
Table 2: User Fee Waivers for PEPFAR Products
Application Fees:
• 	Small business waiver if: <500 employees (with affiliates), and the first human drug application submitted
to FDA by company (including affiliates)
• 	Barrier-to-innovation waiver if:
1. 	Application for an FDC or co-packaged drug product for treatment of HIV from examples in the fixed
dose guidance,
2. 	Only tentative approval in United States because, for example, of patents or exclusivity on the
innovator product, and
3. 	Certification that product will be made available at competitive prices in one or more of the 15
designated PEPFAR countries with supporting evidence.
• 	Public health waiver if:
1. 	Application for an FDC or co-packaged drug product for treatment of HIV from examples in the fixed
dose guidance, and
2. 	Total gross annual revenue of firm and affiliates <$10 million.
Product and Establishment Fees:
• 	Approval for FDC or co-packaged drug product for treatment of HIV from examples in the fixed dose
guidance,
• 	Certification that product will be made available at competitive prices in one or more of the 15 designated
PEPFAR countries with supporting evidence, and
• 	No other user fee eligible products owned by the applicant are being manufactured at the establishment at
which the PEPFAR product is being manufactured.