**Guidance for Industry**

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

**for PEPFAR**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes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notice announcing the availability of the draft guidance.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
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 Michael Jones at
301-594-2041.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**April 2005**

**User Fees**

**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)**

**April 2005**

**User Fees**

##  {#section .TOC-2}

**TABLE OF CONTENTS**

# 

# I. Introduction [1](#i.-introduction) {#i.-introduction-1 .TOC-1}

# II. BACKGROUND [2](#ii.-background) {#ii.-background-2 .TOC-1}

# III. Some Applications Will Not Be Assessed Fees; Some Will Be Assessed Half the Fee [2](#iii.-some-applications-will-not-be-assessed-fees-some-will-be-assessed-half-the-fee) {#iii.-some-applications-will-not-be-assessed-fees-some-will-be-assessed-half-the-fee-2 .TOC-1}

# IV. Waivers of Fees [3](#iv.-waivers-of-fees) {#iv.-waivers-of-fees-3 .TOC-1}

## A. Application Fees [3](#a.-application-fees) {#a.-application-fees-3 .TOC-2}

## B. Annual Product and Establishment Fees [5](#b.-annual-product-and-establishment-fees) {#b.-annual-product-and-establishment-fees-5 .TOC-2}

# Attachment: Summary of Available Exemptions and Waivers [7](#attachment-summary-of-available-exemptions-and-waivers) {#attachment-summary-of-available-exemptions-and-waivers-7 .TOC-1}

**Guidance for Industry**[^1]

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

This draft guidance, when finalized, will represent 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 some applications
for fixed dose combination (FDC) and co-packaged versions of previously
approved antiretroviral therapies for the treatment of human
immunodeficiency virus (HIV) will not be assessed user fees under the
Prescription Drug User Fee Act (PDUFA). 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 copackaged 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 special 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

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]

To encourage applicants to submit applications for HIV combination
therapies that can be used in PEPFAR, in May 2004, the FDA issued a
draft guidance titled *Fixed Dose Combination and Co-Packaged Drug
Products for the Treatment of HIV* (Fixed-Dose Guidance). 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 may 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 pursuant to the Fixed Dose
Guidance for use in PEPFAR will be required to pay user fees under the
Prescription Drug User Fee Act (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 FD&C Act (§ 735(1))

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-   Applications submitted under 505(b)(2) of the FD&C 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.

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, they seek a different
use of the drug, or a different dosing regimen or route of
administration, or use in a new population, or 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 (§ 736(a)(1)(A)) under the Act. This half fee would
be \$336,000 for Fiscal Year 2005.[^3] Bioavailability and
bioequivalence data are not considered clinical data for purposes of
assessing user fees.[^4]

# IV. Waivers of Fees

##  A. Application Fees

Applicants 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, 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.[^5]

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 application
    the company (including its affiliates) submits.[^6] Applicants must
    request this waiver from FDA and provide evidence to the Small
    Business Administration regarding the size of the company.

-   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.[^7]

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.[^8] 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 parts of the two-part PDUFA test for public health
and barrier to innovation waivers. At some point in time, 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. Therefore, the statute gives FDA more
discretion under the barrier to innovation test. [^9] 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***:

-   The applicant is submitting an application for a 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:***

-   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.

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-   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.

# Attachment: Summary of Available Exemptions and Waivers

**Table 1: User Fee Exemptions**

***[Applications Not Assessed Fees or Assessed Reduced
Fees]{.underline}:***

-   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]{.underline}:***

-   Tentatively approved product or product otherwise not approved

-   Product approved under section 505(b)(2) application that 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 isn't assessed a fee, establishment in which it is made
    also not assessed a fee

**Table 2: User Fee Waivers for PEPFAR Products**

***[Application Fees]{.underline}:***

-   Small business waiver if: \<500 employees (with affiliates), and
    first application submitted to FDA by company (including affiliates)

-   Barrier to innovation waiver if:

> 1\. Application for a FDC or co-packaged drug product for treatment of
> HIV from examples in the Fixed Dose Guidance,
>
> 2\. Only tentative approval in US 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 a 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]{.underline}:***

-   Approval for FDC or co-packaged drug product for treatment of HIV
    from examples,

-   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.

[^1]: This guidance has been prepared by the Division of Anti-Viral 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 draft are available at
    http://www.fda.gov/cder/guidance/index.htm.

[^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]: October 1, 2004, through September 30, 2005.

[^4]: See FDA\'s guidance for industry *Submitting Separate Marketing
    Applications and Clinical Data for Purposes of Assessing User Fees*.

[^5]: Normally, FDA encourages the submission of requests for waivers 90
    days in advance of the submission of an application. But 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.

[^6]: Section 736(d)(3), 21 U.S.C. 379h(d)(3).

[^7]: Section 736(d)(1)(A) and (B), 21 U.S.C. 379h(d)(1)(A) and (B).

[^8]: 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 is mentioning it for
    completeness. For further information on this waiver see the
    *Fees-Exceed-The-Cost Waivers under the Prescription Drug User Fee
    Act* guidance.

[^9]: The statute does not provide FDA 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.