0727 Controlled Correspondence draft DEC 2022

Generic Drug User Fee Program

0727 Controlled Correspondence draft DEC 2022

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Controlled
Correspondence
Related to Generic
Drug Development
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (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 Lisa Bercu 240-402-6902.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2022
Generic Drugs
Revision 1

Controlled
Correspondence
Related to Generic
Drug Development
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: [email protected]

https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2022
Generic Drugs
Revision 1

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

III.

CONTROLLED CORRESPONDENCE ........................................................................ 4

Guidance on Inquiries Within the Scope of Controlled Correspondence That Cannot Be

Answered by FDA................................................................................................................................... 5
1. Controlled Correspondence Related to a Pending Citizen Petition, Petition for Stay of Action, or
Petition for Administrative Reconsideration of Action ........................................................................ 5
2. Requests Related to Matters Still Under Consideration by the Agency ........................................... 5
B. Guidance on Inquiries Outside the Scope of Controlled Correspondence ............................... 6

IV.

1.
2.
3.
4.

Requests More Appropriately Addressed Through Other Mechanisms ........................................... 6
Exceptions to the Definition of Controlled Correspondence ........................................................... 6
Topics Outside the Scope of Controlled Correspondence ............................................................... 8
Entities Outside the Scope of Controlled Correspondence .............................................................. 9

SUBMITTING A CONTROLLED CORRESPONDENCE ....................................... 10

How To Submit a Controlled Correspondence ......................................................................... 10

Content of a Controlled Correspondence .................................................................................. 10

Additional Recommendations on the Content of Specific Types of Controlled

Correspondence Inquiries.................................................................................................................... 12
1.
2.
3.
4.

Requests Related to Inactive Ingredients ....................................................................................... 12
Requests for Formulation Assessment (e.g., Q1/Q2 Sameness)..................................................... 14
Requests Related to Product Quality ............................................................................................. 16
Requests Related to the Evaluation of the User Interface of a Drug-Device Combination Product
17
5. Requests Requiring Review by More Than One Discipline ........................................................... 17
6. Considerations for Specific Types of Level 1 Controlled Correspondence ................................... 18
7. Considerations for Level 2 Controlled Correspondence ............................................................... 19
D. Controlled Correspondence Review Disciplines ....................................................................... 21
1.
2.
3.
4.
5.
6.
7.

OGD’s Office of Bioequivalence ................................................................................................... 21
OGD’s Office of Research and Standards ..................................................................................... 21
OGD’s Office of Safety and Clinical Evaluation ........................................................................... 21
OGD’s Office of Regulatory Operations, Division of Filing Review............................................. 22
OGD’s Office of Regulatory Operations, Division of Labeling Review ........................................ 22
OGD’s Office of Generic Drug Policy........................................................................................... 22
Office of Pharmaceutical Quality .................................................................................................. 22

V.
FDA’S COMMUNICATIONS TO REQUESTORS AND REQUESTS TO
CLARIFY AMBIGUITIES IN FDA’S CONTROLLED CORRESPONDENCE
RESPONSE ................................................................................................................................. 23
A.

Communications Related to Initial Submissions....................................................................... 23

Clarification of the Controlled Correspondence Response ...................................................... 24

Contains Nonbinding Recommendations
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Controlled Correspondence Related to
Generic Drug Development
Guidance for Industry 1

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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.

INTRODUCTION

This guidance provides information regarding the process by which generic drug manufacturers
and related industry or their representatives can submit to FDA controlled correspondence
requesting information related to generic drug development. This guidance also describes the
Agency’s process for providing communications related to such correspondence.
This guidance revises the guidance for industry Controlled Correspondence Related to Generic
Drug Development issued in December 2020. When final, this guidance will replace the
December 2020 guidance. The December 2020 guidance was issued as part of FDA’s
implementation of the Generic Drug User Fee Amendments of 2017 (GDUFA II). 2 This
guidance is being issued to incorporate program enhancements related to the review of controlled
correspondence to which FDA committed, and industry agreed, as part of their negotiations
relating to the reauthorization of the Generic Drug User Fee Amendments (GDUFA) (GDUFA
III), 3 as described in “GDUFA Reauthorization Performance Goals and Program Enhancements
Fiscal Years 2023-2027” (GDUFA III commitment letter). 4 Other significant changes from the
December 2020 version include providing additional recommendations for specific types of
inquiries in controlled correspondence.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the agency’s current thinking on a topic and should be viewed only

This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at
the Food and Drug Administration.

FDA Reauthorization Act of 2017 (Public Law 115-52).

See Division F, Title III, of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023
(Public Law 117-180).

The GDUFA III commitment letter is available at https://www.fda.gov/media/153631/download.
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as recommendations, unless specific regulatory or statutory requirements are cited. The use of
the word should in Agency guidance means that something is suggested or recommended, but
not required.
II.

BACKGROUND

The Generic Drug User Fee Amendments of 2012 (GDUFA I) 5 amended the Federal Food,
Drug, and Cosmetic (FD&C) Act to authorize FDA to assess and collect user fees to provide the
Agency with resources 6 to help ensure patients have access to quality, affordable, safe, and
effective generic drugs. GDUFA fee resources bring greater predictability and timeliness to the
review of generic drug applications. GDUFA has been reauthorized every 5 years to continue
FDA's ability to assess and collect GDUFA fees, and this user fee program has been reauthorized
two times since GDUFA I, most recently in the Continuing Appropriations and Ukraine
Supplemental Appropriations Act, 2023. 7 As described in the GDUFA III commitment letter
applicable to this latest reauthorization, FDA has agreed to performance goals and program
enhancements regarding aspects of the generic drug assessment program that build on previous
authorizations of GDUFA. New enhancements to the program are designed to maximize the
efficiency and utility of each assessment cycle, with the intent of reducing the number of
assessment cycles for abbreviated new drug applications (ANDAs) and facilitating timely access
to generic medicines for American patients.
As further discussed in this guidance, FDA agreed to certain goals and procedures for the review
of controlled correspondence received on or after October 1, 2022. 8 Specifically, the Agency
agreed that:
•

FDA will review and respond to 90 percent of level 1 controlled correspondence 9
within 60 calendar days of the date of submission.

Title III of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144.

User fees are available for obligation in accordance with appropriations acts.

See Division F, Title III, of the Continuing Appropriations and Ukraine Supplemental Appropriations Act, 2023
(Public Law 117-180).

Starting October 1, 2022, FDA will respond to all controlled correspondence submitted before ANDA submission,
during an ANDA assessment cycle to seek further feedback from FDA after a product-specific guidance
teleconference or to seek a Covered Product Authorization, after tentative approval, and after ANDA approval.
FDA also intends to respond to controlled correspondence submitted after issuance of a complete response letter as
long as the complete response letter was issued on or after October 1, 2022.
8

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Level 1 controlled correspondence was called “standard controlled correspondence” in the GDUFA II commitment
letter.

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FDA will review and respond to 90 percent of level 2 controlled correspondence 10
within 120 calendar days of the date of submission.

•

FDA will review and respond to 90 percent of submitter requests to clarify
ambiguities in the controlled correspondence response within 21 calendar days of
FDA’s receipt of the request. 11

Consistent with FDA’s other user fee programs, FDA will calculate the goal date from the day
after a submission. 12
The GDUFA III commitment letter defines level 1 controlled correspondence as correspondence
submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry:
1.

Requesting information on a specific element of generic drug product development:
a. Before ANDA submission;
b. After a Product-Specific Guidance (PSG) Teleconference if a prospective
applicant or applicant seeks further feedback from FDA;
c. After issuance of a complete response letter (CRL) or tentative approval;
d. After ANDA approval; or

Concerning postapproval submission requirements that are not covered by Center for
Drug Evaluation and Research (CDER) postapproval changes guidance and are not
specific to an ANDA. 13

The GDUFA III commitment letter defines level 2 controlled correspondence as correspondence
that meets the definition of level 1 controlled correspondence and:
10
Level 2 controlled correspondence was called “complex controlled correspondence” in the GDUFA II
commitment letter.

GDUFA III commitment letter at 11. See also the definition of days, which “unless otherwise specified, means
calendar days” (id. at 47).
11

GDUFA III commitment letter at 4. Also, refer to FDA’s guidance for industry Providing Regulatory
Submissions in Electronic Format — Receipt Dates (Feb. 2014) for information on how FDA calculates receipt
dates for regulatory submissions in electronic format, including controlled correspondence. As described in that
guidance, controlled correspondence will be received by the Agency Monday through Friday from 12:00 a.m. to
11:59 p.m. Eastern Standard Time/Eastern Daylight Time, excluding Federal holidays and days when the FDA
office that will review the correspondence is closed. We update guidances periodically. For the most recent version
of a guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fdaguidance-documents.
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GDUFA III commitment letter at 46.
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Involves evaluation of clinical content;

Requests a Covered Product Authorization 14 and review of bioequivalence (BE)
protocols for development and testing that involves human clinical trials for an
ANDA where the reference listed drug (RLD) is subject to a Risk Evaluation and
Mitigation Strategy (REMS) with Elements to Assure Safe Use (ETASU);

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Requests a Covered Product Authorization to obtain sufficient quantities of an
individual covered product subject to a REMS with ETASU when development and
testing does not involve clinical trials;

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Requests evaluations of alternative BE approaches (e.g., pharmacokinetic, in vitro,
clinical); or

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Requires input from another office or center. 15

This guidance provides additional detail and recommendations concerning:

III.

•

What inquiries FDA considers to be controlled correspondence for the purposes of
meeting the Agency’s agreements under the GDUFA III commitment letter

•

What information requestors should include in a controlled correspondence to
facilitate FDA’s consideration of and response to a controlled correspondence

•

What information FDA will provide in its communications to requestors that have
submitted controlled correspondence

•

How requestors can submit requests to clarify ambiguities in FDA’s controlled
correspondence responses and the Agency’s process for responding to those requests
CONTROLLED CORRESPONDENCE

A Covered Product Authorization is a letter from FDA authorizing an eligible product developer to obtain
sufficient quantities of an individual covered product subject to a Risk Evaluation and Mitigation Strategy with
Elements to Assure Safe Use for product development and testing purposes, as described in section 610 of Division
N of the Further Consolidated Appropriations Act, 2020 (21 U.S.C. 355-2), commonly referred to as the
“CREATES Act” (GDUFA III commitment letter at 47). For further information on how to obtain a Covered
Product Authorization, see FDA’s draft guidance for industry, How To Obtain a Covered Product Authorization
(Sep. 2022). When final, this guidance will represent FDA’s current thinking on this topic.
14

GDUFA III commitment letter at 46.
4

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A controlled correspondence can be submitted by or on behalf of a generic drug manufacturer or
related industry before ANDA submission. Under the GDUFA II commitment letter framework,
correspondence seeking regulatory and/or scientific advice after issuance of a CRL or tentative
approval, or after ANDA approval, was considered general correspondence. Under the GDUFA
III commitment letter, these types of correspondence can be submitted as controlled
correspondence. Also, under the GDUFA III commitment letter, a controlled correspondence
can be submitted during an ANDA assessment cycle if an applicant seeks further feedback from
FDA after a PSG Teleconference or seeks a Covered Product Authorization. During an ANDA
assessment cycle, all other correspondence will be considered general correspondence and
should be submitted to the ANDA so that it becomes part of the full administrative record for
that application.
A. Guidance on Inquiries Within the Scope of Controlled Correspondence That
Cannot Be Answered by FDA
1. Controlled Correspondence Related to a Pending Citizen Petition, Petition for Stay of
Action, or Petition for Administrative Reconsideration of Action
If a controlled correspondence is submitted about an issue that relates to one or more pending
citizen petitions, petitions for stay of action, or petitions for administrative reconsideration of
action, FDA intends that the response to the controlled correspondence will explain that we
cannot answer the question posed because the request is about an issue related to a petition and
we will close the controlled correspondence. 16 Once FDA responds to the pending citizen
petition, petition for stay of action, or petition for administrative reconsideration of action, the
requestor can resubmit the controlled correspondence. Requestors can monitor the current status
of the petition at https://www.regulations.gov.
2. Requests Related to Matters Still Under Consideration by the Agency
FDA occasionally receives requests for information about issues that the Agency is considering,
but for which no scientific or regulatory decision has been made or for which there is no clear
scientific consensus. For a request for which controlled correspondence is the appropriate
pathway but the subject is still under consideration at the time of the goal date, FDA will notify
the requestor that the goal date has been missed because the request raises issues about which
FDA has not made a decision. In such instances, the request will remain open until FDA issues a
response.

Under the GDUFA I and GDUFA II commitment letters, if a controlled correspondence was submitted about an
issue that related to one or more pending citizen petitions, petitions for stay of action, or petitions for administrative
reconsideration of action, the time period for responding started on the date FDA responded to the petition (if there
was only one petition) or the last pending petition.

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B. Guidance on Inquiries Outside the Scope of Controlled Correspondence
1. Requests More Appropriately Addressed Through Other Mechanisms
In certain circumstances, controlled correspondence may not be the optimal mechanism to gain
FDA’s feedback on a topic. For example, topics that are general in nature would be more
appropriately considered as part of the Regulatory Science Initiative, such as the proposed use of
in vitro data to support demonstration of bioequivalence for a class of RLDs for which no
ANDAs have been submitted.
As another example, for certain questions, it may be more appropriate to submit a meeting
request in lieu of submitting a controlled correspondence. The purpose of the controlled
correspondence process is to provide a mechanism for a direct inquiry about FDA’s position with
respect to a particular element of generic drug development and for the Agency’s direct, brief,
and timely response. A controlled correspondence may also be appropriate if the requestor has
clarifying questions or questions that are outside of the scope of a meeting request. In contrast,
one of the meetings described in the GDUFA III commitment letter may be a better forum in
which to seek a dialogue with the Agency about a particular matter for which the controlled
correspondence process is not suitable (e.g., methods of characterization for complex products or
clinically critical BE considerations). FDA recommends that prospective applicants and
applicants refer to the GDUFA III commitment letter and FDA’s guidances for industry for
additional information on GDUFA III meetings. 17 For such questions that are more
appropriately addressed in a meeting, the Agency will notify the requestor of the recommended
alternative pathway and close the controlled correspondence.
2. Exceptions to the Definition of Controlled Correspondence
Historically, FDA has excluded three types of inquiries about generic drug development from
controlled correspondence: (1) requests for recommendations on the appropriate design of BE
studies for a specific drug product; (2) requests for review of BE study protocols; and (3)
requests for meetings to discuss generic drug development. Additional information on these
types of inquiries is provided below.
First, FDA will continue to address PSG requests consistent with the public process described in
the Agency’s guidance for industry Bioequivalence Recommendations for Specific Products
(June 2010) and FDA’s good guidance practices regulation. 18 Under this approach, FDA
publishes BE recommendations in PSGs. The availability of a PSG is announced in the Federal
Register, and public comments are requested for a designated period to ensure they are received

See footnote 4. See, e.g., FDA’s guidances for industry Formal Meetings Between FDA and ANDA Applicants of
Complex Products Under GDUFA (Oct. 2022) and Post Complete Response Letter Clarification Teleconferences
Between FDA and ANDA Applicants Under GDUFA (Oct. 2022).

21 CFR 10.115.
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before the Agency begins work on the final version of the guidance. However, comments can be
submitted on draft or final guidance documents at any time under our good guidance practices.
The PSG process enhances transparency, provides a mechanism for public comment about
recommended BE studies, provides for more efficient use of Agency resources, and follows
FDA’s good guidance practices regulation.
With this public process, FDA can be proactive in developing and publishing guidance for new
drug products without waiting for inquiries about BE methodologies from individual
requestors. 19 FDA anticipates that this process will continue to expedite the availability of BE
methodologies to generic drug manufacturers. However, this process involves time frames that
differ from the goal dates for controlled correspondence, and the Agency has determined that it
would not be appropriate to circumvent this public process by responding to individual
requestors to meet the GDUFA III commitment letter goal dates for controlled correspondence
because we believe public input is important to the development of BE methodologies. The
Agency will continue to consider BE guidance requests in prioritizing PSG development. 20
Second, FDA will continue to generally exclude requests for BE study protocol review from
controlled correspondence and the related goal dates. 21 These include requests for review of
protocols for in vivo BE studies with pharmacokinetic, pharmacodynamic, or comparative
clinical endpoints conducted to support demonstration of bioequivalence for a proposed generic
drug. Historically, FDA has not considered such requests as controlled correspondence because

FDA has committed to continuing to issue PSGs identifying the methodology for generating evidence to support
ANDA approval. For complex products approved in new drug applications (NDAs) on or after October 1, 2022, a
PSG will be issued for 50 percent of such NDA products within 2 years after the date of approval, and for 75 percent
of such NDA products, within 3 years after the date of approval. FDA will continue to develop PSGs for complex
products approved before October 1, 2022, for which no PSG has been published. For non-complex drug products
approved in NDAs on or after October 1, 2022, that contain a new chemical entity (as described in section
505(j)(5)(F)(ii) of the FD&C Act (21 U.S.C. 355(j)(5)(F)(ii))), a PSG will be issued within 2 years after the date of
approval for 90 percent of such products. GDUFA III commitment letter at 23.
19

A complex product generally includes: (1) products with complex active ingredients (e.g., peptides, polymeric
compounds, complex mixtures of active pharmaceutical ingredients, naturally sourced ingredients); complex
formulations (e.g., liposomes, colloids); complex routes of delivery (e.g., locally acting drugs such as dermatological
products, complex ophthalmological products, and otic dosage forms that are formulated as suspensions, emulsions,
or gels); or complex dosage forms (e.g., transdermal systems, metered dose inhalers, extended release injectables);
(2) complex drug-device combination products (e.g., prefilled auto-injector products, metered dose inhalers); and (3)
other products where complexity or uncertainty concerning the approval pathway or possible alternative approach
would benefit from early scientific engagement (GDUFA III commitment letter at 45-46).
Interested parties can submit requests for a PSG to be developed through the CDER Direct NextGen Collaboration
Portal, which can be accessed at https://edm.fda.gov/. In addition, interested parties, including those that fall outside
the scope of entities that can submit controlled correspondence, can submit requests for consideration of alternative
BE approaches to the public docket for PSGs (FDA-2007-D-0369).
20

FDA intends to accept requests for BE study protocol review as controlled correspondence in two circumstances:
(1) as part of a request for a Covered Product Authorization and (2) after issuance of a CRL that identified
deficiencies related to establishing equivalence.

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these requests are more time- and resource-intensive than other requests and often call for
consultation with multiple disciplines within the Office of Generic Drugs (OGD), as well as with
other offices or centers (e.g., the Center for Devices and Radiological Health). Below are
recommended alternatives to submitting a request for BE study protocol review: 22
•

If the request is intended to address a specific question not covered by a PSG, FDA
recommends submitting a controlled correspondence requesting FDA to comment on
the specific question in lieu of submitting a request for BE study protocol review.

•

If the request involves the evaluation of a BE study design that deviates from the BE
study recommended in the PSG, FDA recommends submitting a controlled
correspondence requesting that FDA evaluate the alternative approach in lieu of
submitting a request for BE study protocol review.

•

If the request involves multiple questions or complex issues, FDA recommends
submitting a pre-ANDA meeting 23 request or a controlled correspondence in lieu of
submitting a request for BE study protocol review.

Third, FDA will not treat requests for meetings as controlled correspondence, because, as
described in section III.B.1 of this guidance, such requests serve a different purpose than
controlled correspondence. In addition, meeting requests include different information from the
requestor; materials and information submitted with a controlled correspondence should provide
the Agency with the relevant information on which to base its considerations, while the materials
submitted in support of a meeting request should help the Agency determine whether a meeting
is appropriate. Accordingly, we will treat meeting requests separately.
3. Topics Outside the Scope of Controlled Correspondence
This section provides additional guidance on the types of inquiries that do not fall within the
definition of controlled correspondence. First, during an ANDA assessment cycle, a controlled
correspondence can only be submitted if an applicant seeks further feedback from FDA after a
PSG Teleconference or to seek a Covered Product Authorization. 24 All other correspondence
Requestors that would like to submit a BE study protocol to FDA for review outside the controlled
correspondence process should submit the protocol through the CDER Direct NextGen Collaboration Portal, which
can be accessed at https://edm.fda.gov/.
22

See FDA’s guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products
Under GDUFA (Oct. 2022). We recommend applicants review the guidance and the GDUFA III commitment letter
when evaluating whether the product under development could qualify for a pre-ANDA meeting.
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Consistent with FDA’s historic practices, the Agency has identified limited situations, beyond those described in
the GDUFA III commitment letter, in which we will consider a request for information in a controlled
correspondence related to a specific pending ANDA. For example, the Agency will consider a request for
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submitted during an ANDA assessment cycle will be considered general correspondence and
should be submitted to the ANDA.
Second, inquiries submitted to FDA that are not directly related to generic drug development will
not be considered controlled correspondence for the purposes of GDUFA III. For example,
inquiries requesting information about the administrative practices of OGD, or about
development of a generic drug for which there has never been a U.S.-approved RLD identified in
FDA’s Approved Drug Products with Therapeutic Evaluations (the Orange Book), will not be
considered controlled correspondence. 25
Third, as reflected in the definition of controlled correspondence, a controlled correspondence
should not contain general questions related to product development. Consistent with FDA’s
past and current practices, general or insufficiently detailed questions related to product
development are not appropriate subjects of controlled correspondence. 26 For example, an
inquiry seeking information about general approval standards for a particular product is not an
appropriate subject of a controlled correspondence. Likewise, an inquiry about the acceptability
of an inactive ingredient without providing the proposed level of the inactive ingredient and
information about the RLD, including a specific product strength for the RLD, provides
insufficient detail for the Agency to respond. FDA provides information to stakeholders about
its approval standards and general submission recommendations through FDA regulations and
guidances, and the Agency encourages generic drug manufacturers and related industry to review
this information before submitting controlled correspondence to OGD. The controlled
correspondence process is intended to facilitate, not supplant, the generic drug development
endeavor and the full scientific assessment of an ANDA.
4. Entities Outside the Scope of Controlled Correspondence
The controlled correspondence process is available to generic drug manufacturers and related
industry, or their authorized representatives, that have a question related to a potential or actual
ANDA submission to OGD, because this mechanism exists to facilitate generic drug
development. Other parties (e.g., private citizens, financial firms, or public advocacy groups that
information in a controlled correspondence regarding development of a new strength for a product for which the
submitter is an applicant of a pending ANDA for other strengths. In addition, the Agency will consider a request for
information in a controlled correspondence regarding development of a different package configuration for a
product for which the submitter is an applicant of a pending ANDA for other package configurations. For example,
if an inquiry pertaining to a gel in a metered-dose pump is submitted and there is a pending ANDA for gel in a unitdose package, the controlled correspondence could still be accepted for review.
Requestors can submit a controlled correspondence asking a question about an approved suitability petition and
should provide the docket number for the approved suitability petition because that information is used to confirm
that FDA can accept the controlled correspondence for review.
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Controlled correspondence should not be used to ask FDA to develop a new regulatory policy or to change an
existing policy. However, FDA intends to monitor subjects of controlled correspondence to consider future topics
for developing guidance documents.

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are not directly involved in developing generic drugs) should submit their inquiries related to
generic drugs to the Division of Drug Information. 27
IV.

SUBMITTING A CONTROLLED CORRESPONDENCE
A. How To Submit a Controlled Correspondence

Requestors seeking FDA’s response to a controlled correspondence should submit the
correspondence electronically through the CDER Direct NextGen Collaboration Portal (the
portal), which can be accessed at https://edm.fda.gov. 28 This process will facilitate prompt
consideration of and response to the controlled correspondence by the appropriate discipline
based on assessment timelines identified in the GDUFA III commitment letter. Requestors
should register a corporate email address with the portal. 29 We do not intend to consider portal
submissions that are generated from general, personal accounts as controlled correspondence. If
a requestor would like to obtain a secure email account, the requestor (or its U.S. agent) can
apply for a secure email pathway by contacting [email protected].
FDA strongly discourages submitting controlled correspondence to individual FDA
employees and submitting additional copies of a controlled correspondence in paper form,
by courier, or by facsimile. As described in section V.A of this guidance, FDA intends to
provide requestors notification via the portal on the status of a request soon after it is submitted,
which should provide a requestor adequate assurance that the Agency has received the
communication. The Agency’s response will either state that FDA is considering the request as a
controlled correspondence or provide the basis for not responding to it as a controlled
correspondence, as described in this guidance.
B. Content of a Controlled Correspondence

See contact information for the Division of Drug Information on the second title page of this guidance.

Requestors that are unable to submit a controlled correspondence through the portal can send their controlled
correspondence, as an attachment to an email, to [email protected]. In this situation, requestors should
include the information specified in section IV.B of this guidance. [email protected] is a general OGD
address to which certain submissions related to generic drugs can be submitted. If requestors submit their controlled
correspondence to [email protected] instead of the portal, all communications regarding that controlled
correspondence will be through email and will not be captured in the portal.
28

Requestors can register with the portal at https://edm.fda.gov.
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FDA recommends the cover letter 30 to a controlled correspondence be submitted on corporate
letterhead, be dated within 7 calendar days of submission of the controlled correspondence, and
include the following information:
•

Name, title, address, email, phone number, and entity (e.g., corporate affiliation) of the
person submitting the controlled correspondence. If the controlled correspondence is not
submitted by the generic drug manufacturer or related industry’s authorized
representative, the generic drug manufacturer or related industry’s authorized agent, or
the agent’s authorized representative, located in the United States, then FDA will not
treat the submission as controlled correspondence under the GDUFA III commitment
letter. 31
− If an authorized agent is submitting the controlled correspondence, identify the
company for which you are the authorized agent and include a copy of a letter of
authorization with each controlled correspondence. 32 The letter of authorization
should be on corporate letterhead and dated within 1 year of the date the
controlled correspondence is submitted. FDA intends to provide a response to the
company’s U.S. authorized agent or the agent’s authorized representative, similar
to FDA’s practice when an ANDA is submitted.

•

FDA-assigned controlled correspondence number and submission date of any previous,
related controlled correspondence that was accepted for substantive review and response,
if any, as well as a single copy of that previous controlled correspondence and FDA’s
response, if any.
− For controlled correspondence regarding a CRL, FDA recommends submitting a
copy of the CRL and identifying any other controlled correspondence or meeting
requests related to that CRL.

•

Relevant RLD(s) and/or reference standard(s), 33 as applicable, including application
number, proprietary (brand) name, manufacturer, active ingredient, dosage form, route of
administration, and strength(s).

For more information on preparing cover letters to controlled correspondence, see FDA’s draft guidance for
industry Cover Letter Attachments for Controlled Correspondences and ANDA Submissions (Dec. 2021). When
final, this guidance will represent FDA’s current thinking on this topic.

See the definition of controlled correspondence (“correspondence submitted to the Agency, by or on behalf of a
generic drug manufacturer or related industry”) (GDUFA III commitment letter at 46).

A letter of authorization should be provided by all authorized agents, regardless of whether the prospective
applicant or applicant is located in the United States.
32

33
21 CFR 314.3(b) (“Reference standard is the drug product selected by FDA that an applicant seeking approval of
an ANDA must use in conducting an in vivo bioequivalence study required for approval”).

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Statement that the controlled correspondence is related to either a potential ANDA
submission to OGD, an ANDA that is pending with FDA, an ANDA that received a CRL
and is pending with the applicant, an ANDA that received a tentative approval letter, or
an approved ANDA.
− Provide the ANDA number, including whether the controlled correspondence is
related to a potential ANDA submission to OGD that has already received a preassigned ANDA number.

•

Concise statement describing the controlled correspondence inquiry, including specific
questions to be answered.
− If the controlled correspondence is related to a deficiency identified in a CRL,
include a reference to that specific deficiency.

•

Recommendation for the appropriate FDA review discipline to assess the controlled
correspondence. General information regarding review disciplines is provided in section
IV.D of this guidance.

Requestors should also include, either in the cover letter or as an attachment to the cover letter,
relevant prior research and supporting materials on the specific element of generic drug
development about which the requestor seeks information. In addition, FDA recommends that
all documents be dated.
If FDA determines that the inquiry does not contain the information specified in section IV.B of
this guidance, then FDA will not consider the inquiry to be submitted as controlled
correspondence for purposes of the GDUFA III commitment letter.
C. Additional Recommendations on the Content of Specific Types of Controlled
Correspondence Inquiries
This section provides additional recommendations for the content of specific types of inquiries
submitted as controlled correspondence.
1. Requests Related to Inactive Ingredients
The Agency often receives requests for information pertaining to whether particular inactive
ingredients present at higher levels than the maximums listed in the Agency’s Inactive Ingredient

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Database (IID) are permissible in a generic drug. 34 FDA recommends that a requestor submit for
evaluation no more than three inactive ingredients and no more than three proposed levels for a
drug product in any given controlled correspondence. For example, in any given controlled
correspondence:
•

A requestor can submit (1) a request that proposes three inactive ingredients with one
level each, or (2) a request that proposes one inactive ingredient with three levels.

•

If the drug product is indicated for the adult and pediatric populations, a requestor can
submit (1) a request that proposes one inactive ingredient with one level for three
different dosing ranges (based on body weight or age range specified in the RLD
labeling), or (2) a request that proposes three inactive ingredients with one level for one
dosage range.

If the drug product is indicated for more than one route of administration, requests regarding
inactive ingredients for each route of administration should be submitted in a separate controlled
correspondence.
If a requestor submits a range of levels for an inactive ingredient, the Agency only intends to
review the highest proposed level in that range for that inactive ingredient. In addition,
requestors should only submit the inactive ingredients they wish to be evaluated and their
proposed levels and not the whole formulation.
FDA notes that certain inactive ingredients are composed of multiple subcomponents (e.g.,
flavors). If levels of individual subcomponents are found within limits by the Agency when
reviewed through a controlled correspondence, applicants should be aware that this does not
necessarily mean the whole inactive ingredient will be found to be within acceptable limits
during ANDA assessment. This is because the whole inactive ingredient’s safety profile is
evaluated in the context of the entire drug product formulation during ANDA assessment (and,
as applicable, during assessment of the acceptability of the pertinent drug master file).
Furthermore, when a flavor and/or the subcomponents of a flavor are expressed as ≤ 0.1 percent
(weight/weight) of the total weight of the drug product in a controlled correspondence, the
Agency uses this 0.1 percent (weight/weight) limit as a threshold determination that the flavor
and/or the subcomponents of a flavor are acceptable at the filing stage only. This is because the
amount of a flavor and/or subcomponents of a flavor is reviewed by FDA during ANDA
The IID Update mailbox ([email protected]) can be used to inform FDA of errors in the IID and to ask
questions about IID listings. The GSRS mailbox ([email protected]) can be used for unique ingredient
identifier requests and for questions about the preferred term for an excipient listed in the IID. These types of
communications should not be sent to [email protected]. The IID is available at
https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm. For more information on the IID, see the draft guidance
for industry Using the Inactive Ingredient Database (July 2019). When final, this guidance will represent the
current thinking of FDA.
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assessment when the complete drug product formulation information is available to assessors.
Thus, the Agency’s filing determination does not mean that the proposed amount will ultimately
be found approvable at the ANDA assessment stage.
A requestor should wait for FDA’s response to the controlled correspondence before submitting
a different request for consideration. The Agency believes this is a reasonable limit based on
what can be evaluated for a particular drug product within the GDUFA III commitment letter
goal date time frame. This process also encourages requestors to provide targeted submissions to
the Agency and allows requestors to refine their subsequent formulation proposals based on
FDA’s previous responses.
Such requests should identify the RLD (including the specific drug product strength(s)), the
requestor’s determination of the maximum daily dose of the drug product, and information
supporting this determination (e.g., information from literature searches, drug information
services, approved labeling, pharmacology review of the Summary Basis of Approval for the
RLD). Absent that information, there is no means for FDA to evaluate the safe use of that
inactive ingredient, which depends on many factors, including context of use (e.g., dose, route of
administration, duration of use, and patient population) for the RLD. Although FDA may
provide information regarding an inactive ingredient through a controlled correspondence, FDA
evaluates the ultimate acceptability of an inactive ingredient in the context of a specific proposed
drug product’s formulation during ANDA assessment, when the Agency has the full complement
of data and information in support of ANDA approval to consider.
2. Requests for Formulation Assessment (e.g., Q1/Q2 Sameness)
For certain types of products, FDA’s regulations generally require that proposed products be
qualitatively (Q1) and quantitatively (Q2) the same as the RLD with respect to certain inactive
ingredients. 35 When submitting a controlled correspondence for a Q1/Q2 sameness assessment,
FDA recommends the controlled correspondence include the information about the RLD in the
bulleted list below, which can be found in the Orange Book. Consistent with the Agency’s past
and current practices, FDA does not intend to review proposed formulations for Q1/Q2 sameness
that are not required to be Q1/Q2 the same as the RLD by regulation. Formulations that are not
Q1/Q2 the same as the RLD are permissible for certain products as long as the differences do not
affect the safety or effectiveness of the product. The acceptability of such differences would be
considered in the context of ANDA assessment. It should be noted that Agency policy or
regulation may limit the amount or type of information that FDA can disclose in response to a
request for Q1/Q2 sameness assessment, and that FDA does not intend to provide clarification on
why a formulation is not Q1/Q2 the same as the RLD (see section V.B of this guidance). 36

21 CFR 314.94(a)(9)(iii-iv).

See e.g., 21 CFR 20.61(a) and (b).
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For products where Q1/Q2 sameness is not required by regulation, FDA’s guidances (e.g., PSGs)
sometimes recommend specific BE approaches that may be suitable when the formulation
components and composition of the proposed generic drug product meet specified criteria for
sameness or for no significant difference relative to that of the reference standard, which
ordinarily is the RLD. 37 In these instances, requestors can submit a controlled correspondence to
ask whether one or more proposed formulation(s) may be suitable for the specific BE approach
recommended in FDA’s guidance, and should include the information about the RLD and
reference standard (if the reference standard is not the RLD) in the bulleted list below.
Consistent with the Agency’s past and current practices, FDA does not intend to review requests
for formulation assessment that are not recommended as part of a BE approach in a guidance. 38
In addition, FDA only intends to opine as to whether it is acceptable for the applicant to use the
requested BE approach based on the proposed formulation and does not intend to comment on
whether the proposed formulation is the same (e.g., Q1/Q2) as the RLD or reference standard.
As described above, the following information should be included in the controlled
correspondence:
•
•
•
•
•
•
•
•
•
•

Application holder
Application number
Proprietary name
Active ingredient
Strength (if a parenteral drug product, specify both the total quantity of drug substance in
the container closure and the concentration of the drug substance)
If a parenteral drug product, specify the fill volume
Dosage form
Route of administration
Approval date
Marketing status (i.e., whether the product is prescription, over-the-counter, or in the
“Discontinued” section of the Orange Book (which includes drug products that have been
withdrawn from the market))

The formulation descriptions should include adequate details, including salt and hydration forms,
purity, grade or type, function, and appropriate units (e.g., amount/milliliter, amount/gram,

For more information on the terms RLD and reference standard, see the guidance for industry Referencing
Approved Drug Products in ANDA Submissions (Oct. 2020).

If FDA has previously reviewed and responded to a proposed alternative BE approach within the scope of a preANDA product development meeting, and FDA’s response indicated that the proposed formulation is not
appropriate for the proposed alternative approach, then the requestor can submit a controlled correspondence for
feedback on the appropriateness of using the proposed alternative approach with an updated formulation.
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percentage weight/weight, percentage weight/volume, percentage volume/volume), as
applicable, of the active ingredients and inactive ingredients in the product. 39
FDA recommends that no more than three proposed formulations of a single drug product be
submitted in one controlled correspondence. Limiting a single controlled correspondence to no
more than three formulation assessment requests allows for FDA’s targeted and timely review of
such requests. In addition, the Agency recommends against submitting a request for formulation
assessment and a separate request for evaluation of a proposed inactive ingredient amount or
concentration at the same time.
If a requestor is seeking formulation assessment for multiple drug products, FDA recommends
that each drug product request be submitted in a separate controlled correspondence. Thus, a
requestor should not seek formulation assessment for generic drugs with different RLDs in a
single controlled correspondence. This includes separate formulation assessment requests for
drug products with multiple strengths, such as parenteral drug products with different fill sizes,
because each strength is a separate drug product. 40
3. Requests Related to Product Quality
In addition to product quality questions related to generic drug development, the Agency often
receives requests for information pertaining to chemistry, manufacturing, and controls for Type
II drug master files for drug substances submitted in support of generic drug applications. FDA
recommends that a requestor include prior research and supporting product quality information
in the controlled correspondence so the Agency can adequately respond to the inquiry. The level
of detail of the supporting product quality information should be appropriate considering the
question(s) being asked. Typically, a submission related to product quality would include, as
applicable, a brief description of the proposed formulation, manufacturing process, containerclosure system, and developmental studies. For example:

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•

An inquiry on stability bracketing/matrixing design should include whether a common
blend is used to make the drug product, proposed product strengths, storage conditions,
and a description of the container-closure system, including any other information to
justify the reduced stability design.

To facilitate consideration of the request, FDA recommends that the inactive ingredient and/or the formulation
information be presented in the format in which it would be submitted in an ANDA. In cases in which a drug
product is supplied as a dose pack, such as a vial containing lyophilized product and a diluent, the requestor should
submit formulation compositions for both the lyophilized product and the diluent.

For parenteral drug products, strength is generally determined by both the total quantity of drug substance in a
container closure and the concentration of the drug substance. Orange Book, 42nd ed. (2022), at xvii; see also 80
FR 6802 at 6816 (February 6, 2015). Therefore, a deviation from the total drug content of the RLD parenteral drug
product or the concentration would constitute a change in strength. The Orange Book Preface explains, however,
that the “strengths of certain parenteral drug products, including contrast agents, may be expressed as a percentage”
(Orange Book, 42nd ed. (2022), at xvii).
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•

A question on size, shape, or other physical attributes of a drug product should be
supported by comparative data of the proposed generic drug and RLD with regard to
product dimensions, volume, images, and other relevant properties.

A detailed description, with relevant prior research and supportive information, in a controlled
correspondence will increase the likelihood that FDA will have sufficient information to provide
a specific response to the inquiry. We also recommend that requestors review FDA’s guidance
for industry Questions and Answers on Quality Related Controlled Correspondence (September
2021) before submitting a controlled correspondence.
4. Requests Related to the Evaluation of the User Interface of a Drug-Device
Combination Product
Requestors can submit controlled correspondence requesting preliminary feedback regarding
differences between the user interface of a proposed generic drug-device combination product as
compared to the user interface of its RLD. These submissions should include comparative
analyses, 41 specific questions about the user interface for the proposed generic combination
product, and three samples each of the proposed generic combination product and the RLD. 42 If
the requestor would like FDA’s feedback on more than one strength, the requestor should
include three samples of each strength (proposed generic and RLD) unless the device user
interfaces of the different strengths are identical except for color scheme and labeling
information. In this case, three samples of one strength (proposed generic and RLD) and one
sample of each of the other strengths are sufficient. If the samples of the generic combination
product are prototypes and do not represent the final, to-be-marketed version, the controlled
correspondence should specify that the samples are prototypes and identify any components
(including device labeling) that have been omitted or are still in development. Questions related
to device performance and specifications are considered product quality questions and should be
submitted in a separate controlled correspondence (see section IV.C.3 of this guidance).
5. Requests Requiring Review by More Than One Discipline

For more information on how to conduct analyses of the proposed user interface for a generic drug-device
combination product when compared to the user interface of the RLD, see FDA’s draft guidance for industry
Comparative Analyses and Related Comparative Use Human Factors Studies for a Drug-Device Combination
Product Submitted in an ANDA (Jan. 2017). When final, this guidance will represent FDA’s current thinking on this
topic.
41

Product samples should be sent to:
Office of Research and Standards
Office of Generic Drugs
U.S. Food and Drug Administration
10903 New Hampshire Avenue
Building 75, Room 4723
Silver Spring, MD 20993
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If a requestor seeks information related to separate elements of generic drug development or
postapproval submission requirements that require review by more than one discipline, which are
identified in section IV.D of this guidance (e.g., information on a proposed formulation and
proposed product labeling), FDA recommends that the requestor submit separate requests
regarding the product. 43 This process will facilitate our timely review and response.
6. Considerations for Specific Types of Level 1 Controlled Correspondence
Below are additional recommendations regarding specific types of inquiries submitted as level 1
controlled correspondence.
a. Controlled correspondence submitted after a PSG teleconference
When a new or revised PSG is published and an applicant or prospective applicant has already
commenced an in vivo BE study (i.e., the study protocol has been signed by the study sponsor
and/or the contract research organization), the applicant or prospective applicant can request a
PSG Teleconference to obtain FDA’s feedback on the potential impact of the new or revised
PSG on its development program. 44 If the applicant or prospective applicant seeks further
feedback from FDA after the PSG Teleconference, they can request a Pre-Submission PSG
Meeting or a Post-Submission PSG meeting, or they can submit a controlled correspondence. 45
FDA recommends that requestors do not submit a controlled correspondence and a request for a
Pre-Submission PSG Meeting or a Post-Submission PSG meeting at the same time. 46
b. Controlled correspondence submitted after issuance of a CRL or tentative
approval
FDA intends to respond to controlled correspondence seeking regulatory and/or scientific advice
after the issuance of a CRL for an ANDA and after the issuance of a CRL for a supplement as
long as the CRL for the ANDA or supplement was issued on or after October 1, 2022. If the
CRL was issued before October 1, 2022, the correspondence should be submitted as general
correspondence. A controlled correspondence submitted after issuance of a CRL should not be
used to submit proposed responses to deficiencies identified in the CRL to FDA for review.

Requests requiring review by more than one discipline can be submitted concurrently. As discussed in section
IV.B of this guidance, FDA recommends that a controlled correspondence include the submission date of any other,
related controlled correspondence that was accepted for substantive review and response.

GDUFA III commitment letter at 24.

Id.

FDA may deny a Pre- or Post-Submission PSG Meeting if the inquiry would be more appropriately resolved
through a controlled correspondence. FDA may grant a Pre- or Post-Submission PSG meeting after such a
controlled correspondence if FDA determines that any issues remain unresolved or would be more appropriately
resolved in a meeting (GDUFA III commitment letter at 25).
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FDA will also respond to controlled correspondence submitted on or after October 1, 2022, after
issuance of a tentative approval.
c. Requests submitted after ANDA approval and concerning postapproval
submission requirements
FDA will respond to controlled correspondence submitted on or after October 1, 2022, that
contains questions about a specific approved ANDA. 47 FDA will also respond to controlled
correspondence submitted on or after October 1, 2022, seeking information on postapproval
submission requirements that are not covered by CDER guidance on postapproval changes and
are not specific to an ANDA (i.e., the requirements impact more than one ANDA owned by the
application holder). 48 Such controlled correspondence includes, but is not limited to, specific
questions related to a product site transfer and specific questions related to modernizing a
manufacturing facility (e.g., expanding an existing production line or constructing a new
building within an existing manufacturing facility) that impact more than one ANDA. FDA
recommends submitting questions concerning postapproval submission requirements in a
separate controlled correspondence from other questions (e.g., a question about post-approval
manufacturing requirements should be submitted in a separate controlled correspondence from a
question about a quality deficiency identified in a CRL).
7. Considerations for Level 2 Controlled Correspondence
Below are additional recommendations regarding inquiries submitted as level 2 controlled
correspondence.
a. Requests that involve evaluation of clinical content
Consistent with FDA’s past and current practices, FDA will continue to consider controlled
correspondence that requires evaluation of clinical content (and is therefore level 2 controlled
correspondence) to include requests that require input from OGD’s Office of Safety and Clinical
Evaluation and OGD’s Office of Research and Standards Clinical Safety and Human Subject
Research Team. As further described in section IV.C.7.d of this guidance, FDA will also
consider controlled correspondence that requires input from other offices and centers outside of
OGD (e.g., the Center for Devices and Radiological Health), including about the evaluation of
clinical content, to be level 2 controlled correspondence. The evaluation of clinical content
includes, but is not limited to, clear, specific questions related to the planning of a BE study with
comparative clinical endpoints and questions related to adverse events that occur during the
conduct of a BE study.
b. Requests for a Covered Product Authorization
47

GDUFA III commitment letter at 11 and 46.

GDUFA III commitment letter at 46.
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FDA will consider requests for a Covered Product Authorization, including the review of BE
protocols for development and testing that involve human clinical trials for an ANDA if the RLD
is subject to a REMS with ETASU to be level 2 controlled correspondence. 49 FDA will also
consider requests for a Covered Product Authorization to obtain sufficient quantities of an
individual covered product subject to a REMS with ETASU to be level 2 controlled
correspondence when development and testing does not involve clinical trials. 50
FDA has issued guidance on how to obtain a Covered Product Authorization. This draft guidance
for industry How To Obtain a Covered Product Authorization (Sep. 2022) explains how to
submit a request for a CPA and what to include in the request. 51
c. Requests for evaluation of alternative BE approaches
FDA will consider requests to evaluate alternative BE approaches (e.g., pharmacokinetic, in
vitro, comparative clinical endpoints) for drug products for which a PSG is available to industry
to be level 2 controlled correspondence. In addition, FDA will consider requests to use an
alternate reference product in a BE study, or otherwise use an alternative BE approach, when
there is no market availability of the reference standard and the RLD, and there are no approved
generic drugs referencing the same listed drug, to be level 2 controlled correspondence. 52
d. Requests that require input from another office or center
FDA will consider requests that require the review discipline to obtain input from another office
or center to be level 2 controlled correspondence. For example, if OGD’s Office of Research
and Standards has to consult OGD’s Office of Bioequivalence or OPQ’s Office of Lifecycle
Drug Products has to consult OPQ’s Office of Biotechnology Products on a request, that would
constitute a level 2 controlled correspondence. As another example, if the controlled
correspondence includes questions about the device constituent part of a drug-device
combination product, and those questions require input from another office (e.g., OGD’s Office
of Safety and Clinical Evaluation or the Office of Surveillance and Epidemiology) or center, then
that would constitute a level 2 controlled correspondence. During substantive review of the

GDUFA commitment letter at 46.

Id.

When final, this guidance will represent FDA’s current thinking on this topic.

Section 505(j)(2)(A)(iv) of the FD&C Act requires ANDA applicants to include information showing that their
proposed new drug is bioequivalent to a previously approved “listed drug.” Listed drugs are those that have been
approved for safety and effectiveness under section 505(c) of the FD&C Act or approved under section 505(j) of the
FD&C Act (section 505(j)(7) of the FD&C Act; 21 CFR 314.3). Given the potential for bioequivalence
inconsistencies that may result from differences between a non-U.S.-approved product and the U.S. RLD, the
Agency generally does not accept bioequivalence studies based on a non-U.S.-approved product to show that a drug
is bioequivalent to the U.S. RLD.
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controlled correspondence, FDA might determine that input from another office or center is
required and change the classification of the controlled correspondence from level 1 to level 2.
D. Controlled Correspondence Review Disciplines
This section provides additional information on the different disciplines that might review and
respond to a controlled correspondence. In addition, this section provides examples of the types
of inquiries each discipline reviews. The Agency anticipates that this information will assist
requestors in recommending the appropriate discipline to review a particular controlled
correspondence. These descriptions are not intended to be exhaustive, and FDA has the
discretion to determine which discipline should review and respond to a controlled
correspondence.
1. OGD’s Office of Bioequivalence
The Office of Bioequivalence reviews correspondence containing inquiries related to the
planning of BE studies. The Office of Bioequivalence also reviews questions related to the
maximum daily exposure of an inactive ingredient. In addition, the Office of Bioequivalence
reviews controlled correspondence when applicants want to add an additional strength to their
approved product line and request feedback on whether they need to conduct the studies
recommended in the PSG for the additional strength.
2. OGD’s Office of Research and Standards
The Office of Research and Standards reviews correspondence about alternative BE approaches
to those recommended in a PSG and questions related to the use of modeling and simulation
methods. The Office of Research and Standards also reviews controlled correspondence
submitted before ANDA submission that contains questions about complex products, 53 including
questions on formulation sameness (e.g., Q1/Q2 sameness) for complex products. In addition,
the Office of Research and Standards reviews questions submitted before ANDA submission
about the user interface of drug-device combination products.
3. OGD’s Office of Safety and Clinical Evaluation
The Office of Safety and Clinical Evaluation reviews correspondence containing questions on
the maximum daily dose, thresholds for extractable and leachable studies, and requests for
Covered Product Authorizations, including those involving review of BE protocols for
development and testing that involves human clinical trials for drug products subject to a REMS
with ETASU. The Office of Safety and Clinical Evaluation also reviews correspondence sent to
the Agency after issuance of a CRL or after ANDA approval that contains questions on the user
interface of a drug-device combination product.

See footnote 19 for the definition of complex product.
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4. OGD’s Office of Regulatory Operations, Division of Filing Review
The Division of Filing Review reviews correspondence containing inquiries regarding Q1/Q2
sameness and inquiries that involve the review of the amount per dosage unit or percent
composition of inactive ingredients by reference to the FDA’s Inactive Ingredient Database.
5. OGD’s Office of Regulatory Operations, Division of Labeling Review
The Division of Labeling Review reviews correspondence regarding submission requirements
when the ANDA packaging configuration differs from the RLD’s and appropriate labeling
differences.
6. OGD’s Office of Generic Drug Policy
The Office of Generic Drug Policy, which includes the Division of Orange Book Publication and
Regulatory Assessment, reviews correspondence regarding RLD designation or certain reference
standard selection questions.
7. Office of Pharmaceutical Quality
The Office of Pharmaceutical Quality (OPQ) reviews correspondence containing inquiries
regarding chemistry, manufacturing, and controls, including product quality microbiology for
generic drugs. In addition, OPQ reviews inquiries related to Type II drug master files for drug
substances submitted in support of generic drug applications.
As listed below, OPQ contains subdisciplines that respond to various types of controlled
correspondence:
•
•
•
•
•

The Office of Lifecycle Drug Products responds to correspondence containing inquiries
related to formulation, specifications, container-closure, and stability.
The Office of New Drug Products, Division of Lifecycle Active Pharmaceutical
Ingredient, responds to correspondence containing inquiries related to starting materials,
polymorphs, and drug substance manufacturing processes.
The Office of New Drug Products, Division of Biopharmaceutics, responds to
correspondence containing inquiries related to dissolution testing, dissolution methods,
and in vitro-in vivo correlation.
The Office of Pharmaceutical Manufacturing Assessment, Division of Microbiology
Assessment, responds to correspondence containing inquiries related to sterile
processing, bacterial endotoxin limits, and antimicrobial testing.
The Office of Pharmaceutical Manufacturing Assessment, Division of Pharmaceutical
Manufacturing, responds to correspondence containing inquiries such as those related to
blend uniformity, excess fill volumes, facility information submission recommendations,
and current good manufacturing practice requirements.
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Consistent with the recommendation in section IV.C.5 of this guidance, requestors with inquiries
related to generic drug development or postapproval submission requirements for more than one
OPQ subdiscipline should generally submit the inquiries for each specific subdiscipline in
separate controlled correspondence to facilitate a timely and complete response, with the
following exception: for controlled correspondence related to a CRL, requestors should submit
inquiries for OPQ in a single controlled correspondence.
V.

FDA’S COMMUNICATIONS TO REQUESTORS AND REQUESTS TO
CLARIFY AMBIGUITIES IN FDA’S CONTROLLED CORRESPONDENCE
RESPONSE
A. Communications Related to Initial Submissions

For inquiries submitted through the portal, FDA will provide the following information to a
requestor through the portal regarding receipt and consideration of the inquiry. 54
Upon receipt of a submission, FDA will evaluate whether the submission will be considered a
controlled correspondence for the purposes of the GDUFA III commitment letter. FDA will then
send the requestor one of two emails that can be accessed through the portal: (1) an email
confirming acceptance of the submission as a controlled correspondence, which will include an
FDA-assigned controlled correspondence number; 55 or (2) an email informing the requestor
either that the Agency does not consider the submission a controlled correspondence and the
basis for that decision or that FDA lacks adequate information to make this determination. In
most instances, we anticipate confirming acceptance of the submission within 7 calendar days, 56
and the communication will contain a receipt date 57 that the requestor can use to calculate the
goal date. If a requestor resubmits a request for information that addresses any problem that
FDA identified with a previous request, the Agency will consider this to be a new controlled
correspondence and process it as such.
If FDA determines, during substantive review of the inquiry, that the inquiry lacks sufficient
information, it can either close the controlled correspondence at that time or contact the requestor
for additional information through the portal. If the Agency decides to close the controlled
For inquiries submitted to [email protected], FDA’s communications regarding the controlled
correspondence will be sent to the email address from which the controlled correspondence originated.
54

OGD recommends that the requestor refer to the controlled correspondence using the FDA-assigned controlled
correspondence number in the cover letter of any related ANDA submissions and include a copy of the
correspondence.
55

If you do not receive confirmation from FDA within 7 calendar days, please contact [email protected].

57
As noted above, FDA will calculate the goal date from the day after a submission (GDUFA III commitment letter
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correspondence, it will notify the requestor through the portal of that decision and the basis for
that decision. If FDA contacts the requestor for additional information, the goal date for that
controlled correspondence will be extended by the amount of time that the Agency’s request for
additional information is outstanding with the requestor.
After substantive review of the request for information in the controlled correspondence, FDA
will respond in written form via an email that can be accessed in the portal. FDA will only send
a response to the person who originally submitted the controlled correspondence. The length and
content of FDA’s response will depend on the nature of the inquiry submitted. We intend that
the comments we provide in response to a controlled correspondence will be comprehensive as
of the date of the response. We note that comments in the response represent our thinking on a
topic at that time and that our thinking may evolve in the future.
FDA will not respond to status requests regarding pending controlled correspondence before the
goal date. If the Agency does not respond to the controlled correspondence by the goal date,
FDA will send an acknowledgement to the requestor with notification that the request is still
under consideration.
B. Clarification of the Controlled Correspondence Response
FDA will respond to requests to clarify ambiguities in the Agency’s controlled correspondence
response, and such requests might be treated differently than follow-up questions. As defined in
the GDUFA III commitment letter, ambiguity in the controlled correspondence response “means
the controlled correspondence response or a critical portion of it merits further clarification.” 58
All requests for clarification of a controlled correspondence should be included in a single
submission to FDA. The request for clarification should be submitted within 7 calendar days of
issuance of FDA’s controlled correspondence response. 59 Requests for clarification received
after 7 calendar days from issuance of the controlled correspondence response will be considered
a new controlled correspondence.
Requestors seeking clarification of ambiguities in FDA’s controlled correspondence response
should submit the request electronically through the portal, which can be accessed at
https://edm.fda.gov. 60 The request should be submitted under the same event ID for the original
58

GDUFA III commitment letter at 45.

The Agency believes that 7 calendar days provides a requestor sufficient time to review FDA’s controlled
correspondence response and identify any portion of the response the requestor believes is ambiguous. This process
also ensures that requestors submit clarification requests for controlled correspondence that have recently been
reviewed and responded to by the Agency.
59

Requestors that are unable to submit a request for clarification through the portal can send their request, as an
attachment to an email, to [email protected]. In this situation, requestors should include the information
specified in section V.B of this guidance. For inquiries submitted to [email protected], FDA’s
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controlled correspondence submission. The cover letter for the request to clarify ambiguities in
the controlled correspondence response should include the following information:
•

Name, title, address, email, phone number, and entity (e.g., corporate affiliation) of the
person submitting the request for clarification. If the request for clarification is not
submitted by the generic drug manufacturer or related industry’s authorized
representative, the generic drug manufacturer or related industry’s authorized agent, or
the agent’s authorized representative, located in the United States, then FDA will not
treat the request for clarification as subject to the GDUFA III commitment letter.
− Where possible, the request for clarification should be submitted by the person
who originally submitted the controlled correspondence on which clarification is
sought. If this is not possible, FDA will accept the request from an alternate,
authorized representative of the generic drug manufacturer or related industry, its
authorized agent, or the agent’s authorized representative, located in the United
States.
− If an authorized agent is submitting the request, identify the company for which
you are the authorized agent and include a copy of a letter of authorization. 61 The
letter of authorization should be on corporate letterhead and dated within 1 year of
the date the request for clarification is submitted. FDA intends to provide a
response to the company’s U.S. authorized agent or the agent’s authorized
representative, similar to FDA’s practice when an ANDA is submitted.

•

FDA-assigned controlled correspondence number, submission date of the controlled
correspondence on which the requestor is seeking clarification, a copy of that controlled
correspondence, and FDA’s response to the controlled correspondence.

•

Clarifying questions and the corresponding section(s) of FDA’s controlled
correspondence response on which the requestor is seeking clarification.

The scope of the clarifying questions should be limited to the content of FDA’s controlled
correspondence response. Any requests to review follow-up questions, or new or additional
information, will be considered a new controlled correspondence. In these instances, we
recommend that the requestor submit a new controlled correspondence through the portal and
include the FDA-assigned controlled correspondence number of the previous inquiry to facilitate
FDA’s review and response. This process ensures that the question is tracked and that all
requestors are treated equitably.
communications regarding the request for clarification will be sent to the email address from which the request
originated.
61
A letter of authorization should be provided by all authorized agents, regardless of whether the prospective
applicant or applicant is located in the United States.

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As agreed to in the GDUFA III commitment letter, FDA will review and respond to 90 percent
of requests to clarify ambiguities in the controlled correspondence response within 21 calendar
days of the Agency’s receipt of the request. 62 If FDA determines that the request does not
contain the information specified in the bulleted list in this section, the request will not be
considered to be received for purposes of the GDUFA III commitment letter.
After reviewing the request for clarification, FDA, at its discretion, will either call the requestor
or respond in written form via an email that can be accessed in the portal. FDA’s response will
either clarify the ambiguity in the controlled correspondence response or state that, in FDA’s
judgment, the controlled correspondence response does not merit further clarification. Any
subsequent inquiries regarding FDA’s response to a controlled correspondence or FDA’s
response to a request for clarification of ambiguities should be submitted in a new controlled
correspondence.

GDUFA III commitment letter at 11. FDA will calculate the goal date from the day after a submission (GDUFA
III commitment letter at 4). For the purpose of meeting this commitment, requests to clarify ambiguities in FDA’s
controlled correspondence response will be received by the Agency Monday through Friday from 12:00 a.m. to
11:59 p.m. Eastern Standard Time/Eastern Daylight Time, excluding Federal holidays and days when the FDA
office that will review the clarification request is closed.
62

File Type	application/pdf
File Title	Controlled Correspondence Related to Generic Drug Development
Subject	Controlled Correspondence Related to Generic Drug Development
Author	FDA/CDER
File Modified	2022-12-21
File Created	2022-12-20