[Federal Register Volume 81, Number 226 (Wednesday, November 23, 2016)]
[Rules and Regulations]
[Pages 84465-84477]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-28120]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 330

[Docket No. FDA-2016-N-0543]
RIN 0910-AH30


Food and Drug Administration Review and Action on Over-the-
Counter Time and Extent Applications

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is amending 
its nonprescription (over-the-counter or OTC) drug regulations. This 
final rule supplements the time and extent application (TEA) process 
for OTC drugs by establishing timelines and performance metrics for 
FDA's review of non-sunscreen TEAs, as required by the Sunscreen 
Innovation Act (SIA). It also amends the existing TEA process to 
include filing determination and withdrawal provisions to make the TEA 
process more efficient.

DATES: This rule is effective December 23, 2016.

ADDRESSES: For access to the docket to read background documents or the 
electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this final rule, into the ``Search'' box and follow the 
prompts and/or go to the Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kristen Hardin, Center for Drug 
Evaluation and Research (CDER), Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 240-402-4246, 
[email protected].

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Executive Summary
    A. Purpose and Coverage of the Final Rule
    B. Summary of the Major Provisions of the Final Rule

[[Page 84466]]

    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations and Acronyms Commonly Used in This 
Document
III. Background
    A. Need for the Regulation/History of This Rulemaking
    B. Summary of Comments on the Proposed Rule
    C. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Response
    C. Specific Comments on Timelines for FDA Review and Action and 
FDA Response
    D. Specific Comments on the Filing Determination and FDA 
Response
    E. Technical Amendments
VI. Effective Date
VII. Economic Analysis of Impacts
    A. Introduction
    B. Summary
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Reference

I. Executive Summary

A. Purpose and Coverage of the Final Rule

    This final rule implements part of the SIA (Pub. L. 113-195) 
enacted November 26, 2014, by establishing timelines and related 
performance metrics for the review of certain submissions under FDA's 
regulation governing TEAs, which is codified in Sec.  330.14 (21 CFR 
330.14). The TEA regulation sets forth criteria and procedures by which 
OTC drugs initially marketed in the United States after the OTC Drug 
Review began in 1972 and OTC drugs without any U.S. marketing 
experience can be considered in the OTC drug monograph system. Section 
586F(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 
U.S.C. 360fff-6(b)), which was added by the SIA, requires FDA to issue 
regulations providing for the timely and efficient review of 
submissions under the TEA regulation, including establishing: (1) 
Reasonable timelines for reviewing and acting on such submissions for 
non-sunscreen OTC active ingredients and other conditions (non-
sunscreen TEA conditions) and (2) measurable metrics for tracking the 
extent to which such timelines are met.
    FDA is also amending the TEA regulation to make the TEA process 
more efficient and predictable for product sponsors, consumers, and FDA 
by adding filing determination requirements and criteria, and by 
addressing the withdrawal of consideration of TEAs and safety and 
effectiveness data submissions.
    The timelines and metrics in this final rule apply to non-sunscreen 
TEA conditions. FDA is addressing timelines for review of sunscreen 
active ingredients and other related topics regarding sunscreens 
separately, under other provisions of the SIA.

B. Summary of the Major Provisions of the Final Rule

    This final rule implements the SIA requirements for non-sunscreen 
TEAs by establishing timelines for FDA to review and take action on 
non-sunscreen TEA conditions. Timelines are provided for each stage of 
the TEA process and are intended to be reasonable while taking into 
consideration FDA public health priorities and available resources. The 
timelines established by this rule provide sponsors, other interested 
persons, and the public with consistent time frames for expected Agency 
action.
    This rule also implements the SIA requirements for non-sunscreen 
TEAs by establishing measurable metrics that FDA will use for tracking 
the extent to which the timelines set forth in the regulations are met. 
The Agency anticipates that, among other potential benefits, making the 
metrics publicly available will improve transparency by providing 
sponsors, other interested persons, and the public with information 
that will enable them to quickly find out the number of TEAs that have 
been submitted to FDA. Over time, these measurements may also assist 
the Agency with resource planning and use.
    The applicability of these metric and timeline provisions are 
generally limited to non-sunscreen TEAs submitted after the enactment 
of the SIA.
    The final rule also amends the existing TEA regulation to provide 
for FDA to make filing determinations regarding safety and 
effectiveness data submissions for eligible TEA conditions. This 
additional procedural step provides early notification on whether 
submissions are sufficiently complete to permit a substantive review by 
FDA.
    In addition, the rule amends the existing TEA regulation to include 
a provision regarding the withdrawal of consideration of TEAs, and 
safety and effectiveness data submissions. The withdrawal provision 
provides clarity on the status of TEAs, and safety and effectiveness 
data submissions that are no longer being pursued, so that FDA does not 
spend resources on these submissions.
    Finally, the final rule adds certain definitions, and makes minor 
conforming and clarifying changes to the existing TEA regulation.

C. Legal Authority

    This rule is issued under FDA's authority to regulate OTC drug 
products under the FD&C Act (see sections 201, 501, 502, 503, 505, 510, 
586F, and 701(a) of the FD&C Act (21 U.S.C. 321, 351, 352, 353, 355, 
360, 360fff-6, and 371(a))). As stated in the Federal Register of 
January 23, 2002 (67 FR3060), in which the final rule establishing the 
TEA process was published, submission of a new drug application (NDA) 
has been required before marketing a new drug since passage of the FD&C 
Act in 1938 (21 U.S.C. 355). To market a new drug, the drug must first 
be approved under section 505 of the FD&C Act. Section 701(a) of the 
FD&C Act authorizes FDA to issue regulations for the efficient 
enforcement of the FD&C Act. FDA's regulations in part 330 describe the 
conditions for a drug to be considered GRASE and not misbranded. If a 
drug meets each of the conditions contained in part 330, as well as 
each of the conditions contained in any applicable OTC drug monograph, 
and other applicable regulations, it is considered generally recognized 
as safe and effective (GRASE) and not misbranded, and is not required 
by FDA to obtain approval under section 505 of the FD&C Act.
    In addition, section 586F of the FD&C Act requires FDA to issue 
regulations providing for the timely and efficient review of certain 
submissions under the TEA regulation in Sec.  330.14. Section 586F of 
the FD&C Act specifically requires these regulations to include 
timelines and metrics associated with the review of those submissions 
under the TEA regulation. This rule adds timeline and metrics 
provisions that are intended to implement section 586F of the FD&C Act.

D. Costs and Benefits

    We expect that the final rule will make the TEA process more 
efficient and predictable, and improve communication between FDA, 
sponsors, and other interested persons. Sponsors and other interested 
persons may benefit from knowing whether additional data are needed and 
what optimal steps to take to receive a GRASE determination, and we 
will be able to bring resolution to TEA conditions. However, we do not 
know the monetary value of added predictability.
    We expect the rule will create a minimal burden on persons that 
submit

[[Page 84467]]

safety and effectiveness data submissions, primarily when they send a 
letter to request a meeting with us. Thus, we anticipate no increase in 
annual recurring costs for either small or large sponsors or other 
interested persons. We expect the six current sponsors of non-sunscreen 
TEAs covering conditions that have been found eligible to be considered 
for inclusion in the OTC drug monograph system will incur one-time 
costs to read and understand the rule.
    We also estimate sponsors will submit two additional TEAs annually, 
and each of these sponsors will also spend time reading and 
understanding the rule. The present value of the total costs over 10 
years ranges from about $17,000 to $35,000 with a 7 percent discount 
rate and from about $19,000 to $38,000 with a 3 percent discount rate. 
With a discount rate of 7 percent and 3 percent, we estimate that on 
average affected sponsors will incur less than $150 of annualized costs 
per year.

II. Table of Abbreviations and Acronyms Commonly Used in This Document

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        Abbreviation/acronym                     What it means
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ANDA................................  Abbreviated New Drug Application.
FDA.................................  Food and Drug Administration.
FD&C Act............................  Federal Food, Drug, and Cosmetic
                                       Act.
GRASE...............................  Generally Recognized as Safe and
                                       Effective.
HHS.................................  U.S. Department of Health and
                                       Human Services.
NDA.................................  New Drug Application.
NOE.................................  Notice of Eligibility.
NPRM................................  Notice of Proposed Rulemaking.
OMB.................................  Office of Management and Budget.
OTC.................................  Over-the-Counter.
PRA.................................  Paperwork Reduction Act.
SIA.................................  Sunscreen Innovation Act of 2014.
TEA.................................  Time and Extent Application.
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III. Background

A. Need for the Regulation/History of This Rulemaking

1. Overview of the OTC Drug Monograph System
    The OTC drug monograph system was established to evaluate the 
safety and effectiveness of all OTC drug products marketed in the 
United States before May 11, 1972, that were not covered by NDAs and 
all OTC drug products covered by ``safety'' NDAs that were marketed in 
the United States before enactment of the 1962 drug amendments to the 
FD&C Act. In 1972, FDA began its OTC Drug Review to evaluate OTC drugs 
by therapeutic categories or classes (e.g., sunscreens, antacids), 
rather than on a product-by-product basis, and to develop 
``conditions'' under which classes of OTC drugs are GRASE and not 
misbranded.
    FDA publishes these conditions in the Federal Register in the form 
of OTC drug monographs, which consist primarily of active ingredients, 
labeling, and other general requirements. Final monographs for OTC 
drugs that are GRASE and not misbranded are codified in part 330. 
Manufacturers of drugs that meet each of the conditions contained in 
part 330, including each of the conditions contained in any applicable 
OTC drug monograph, and other applicable regulations, need not seek FDA 
clearance before marketing.
2. Overview of the TEA Process Prior to This Rulemaking
    Initially, OTC drug conditions not marketed in the United States 
prior to the inception of the OTC Drug Review were not eligible for 
review under the OTC drug monograph process. The TEA process, 
established by regulations finalized in 2002 (Sec.  330.14), expanded 
the scope of the OTC Drug Review. A ``condition,'' for purposes of the 
TEA regulation, is an active ingredient or botanical drug substance (or 
a combination of active ingredients or botanical drug substances), 
dosage form, dosage strength, or route of administration marketed for a 
specific OTC use. The TEA process provides a potential pathway for OTC 
conditions, including new active ingredients or dosage forms that 
previously had no U.S. marketing history or that were marketed in the 
United States after the OTC Drug Review began, to be marketed under an 
OTC drug monograph.
    Active ingredients and other conditions that satisfy the TEA 
eligibility requirements are subject to the same safety, effectiveness, 
and labeling standards that apply to other conditions under the OTC 
monograph process (see Sec.  330.14(g)). The TEA regulation requires 
multistep, notice-and-comment rulemaking procedures before an active 
ingredient or other condition is added to an OTC drug monograph.
    The TEA process begins with the submission of a TEA containing data 
documenting the OTC marketing history of the active ingredient, 
combination of active ingredients, or other condition(s) (e.g., a new 
dosage strength for an active ingredient already included in an OTC 
drug monograph). FDA reviews the application and determines whether the 
sponsor's marketing data establish that the condition or conditions 
have been marketed to a material extent and for a material time, as set 
forth in the TEA regulation's eligibility requirements. If the 
condition is not found eligible, FDA will send a letter to the sponsor 
explaining why the condition was not found acceptable. If the marketing 
data satisfy the TEA regulation's eligibility criteria, FDA publishes a 
notice of eligibility (NOE) in the Federal Register announcing that the 
active ingredient or other condition is being considered for inclusion 
in an OTC drug monograph and calling for submissions of safety and 
efficacy data for the proposed OTC use.
    We note that although a TEA is the application regarding the time 
and extent of marketing, which leads to an eligibility determination 
(resulting in publication of an NOE or a letter of ineligibility), 
references to TEAs or applications (including in the SIA) sometimes 
encompass FDA's review of the condition's eligibility and the GRASE 
determination for the condition. Thus, these references may be used to 
mean the TEA itself, the safety and effectiveness data submission, 
FDA's GRASE determination, associated order or rulemaking actions, or 
all of these. In this rule and preamble, the terms ``TEA'' and ``safety 
and effectiveness data submission'' are used, where appropriate, to 
describe the two distinct submissions under the TEA regulation. 
However, the term ``TEA process'' may be used when referring to one or 
more actions under the TEA regulation.
    If, after FDA reviews the safety and effectiveness data, the Agency 
initially determines that the active ingredient or other condition is 
GRASE, it will publish a notice of proposed rulemaking (NPRM) to 
include the condition in an appropriate OTC drug monograph.
    If the condition is initially determined not to be GRASE, FDA will 
inform the sponsor and other interested persons that submitted data of 
its decision by letter, and will include the letter in the relevant 
public docket (Sec.  330.14(g)(4)). The Agency will also publish a NPRM 
to include the condition in Sec.  310.502 (21 CFR 310.502). The sponsor 
and other interested persons will have an opportunity to submit 
comments and new data on FDA's initial determination and NPRM (Sec.  
330.14(g)(5)). After evaluation of any additional data submitted, FDA 
will either issue a final rule or a new NPRM, if necessary, in the 
Federal Register.

[[Page 84468]]

3. The Sunscreen Innovation Act (SIA)
    In November 2014, Congress passed the SIA to supplement the TEA 
process with regard to both sunscreen and non-sunscreen OTC drug 
products. Section 586F of the FD&C Act was added by the SIA and only 
applies to TEAs for drugs other than nonprescription sunscreen active 
ingredients or combinations of nonprescription sunscreen active 
ingredients (see sections 586 and 586F of the FD&C Act (21 U.S.C. 
360fff and 360fff-6) as amended by the SIA). For FDA review of non-
sunscreen TEA conditions, section 586F includes two main requirements. 
The first requirement (see section 586F(a) of the FD&C Act), which is 
generally outside the scope of this rule, is regarding a framework and 
timelines for review of certain eligible TEA conditions pending before 
the date of enactment of the SIA. The second general requirement (see 
section 586F(b) of the FD&C Act) is that FDA issue a regulation that 
includes: (1) Timelines for review of new non-sunscreen TEA conditions 
(with certain exceptions noted in sections 586F(a)(1) and (3)) and (2) 
measurable metrics for tracking the extent to which the timelines are 
met. Accordingly, FDA published a proposed rule on April 4, 2016, to 
address both timelines and metrics, as required by the SIA.
4. Brief Summary of the Proposed Rule
    As described in the proposed rule ``Food and Drug Administration 
Review and Action on Over-the-Counter Time and Extent Applications'' 
(81 FR 19069, April 4, 2016) (Proposed Rule), FDA had determined that 
with regard to non-sunscreen TEAs, the best way to both address the 
statutory requirements of the SIA and to make certain FDA-initiated 
modifications to the TEA process set forth in Sec.  330.14 was to: (1) 
Propose a new section (Sec.  330.15) that is specific to non-sunscreen 
TEA conditions and establishes the SIA-required timelines and metrics 
and (2) amend Sec.  330.14 with regard to process improvements for TEAs 
for all OTC drugs (such as providing format and content criteria for a 
filing determination and addressing withdrawal of consideration).
    We refer readers to the preamble of the Proposed Rule for 
additional information about the development of the Proposed Rule. The 
Agency requested public comments on the Proposed Rule, and the comment 
period closed June 3, 2016.

B. Summary of Comments on the Proposed Rule

    We received comments from a trade association and several 
individual citizens. The comments were generally supportive. In 
addition to a few general comments, we received comments specific to 
the proposed timeline provision as well as on the format and content of 
the safety and effectiveness submissions.

C. General Overview of the Final Rule

    This rule finalizes the Proposed Rule. The following subsections 
give a brief summary of the proposed provisions we are finalizing, 
including a summary of the key changes between the proposed and final 
rules.
1. Applicability (Sec.  330.15(a))
    We proposed that a condition in a TEA submitted under Sec.  330.14 
would be subject to the timelines for FDA review and action except for: 
(1) A sunscreen active ingredient or a combination of sunscreen active 
ingredients, or other conditions for sunscreen ingredients or (2) a 
non-sunscreen active ingredient or combination of non-sunscreen active 
ingredients, and other conditions for such ingredients submitted in a 
TEA under Sec.  330.14 before November 27, 2014, subject to section 
586F(a)(1)(C) of the FD&C Act. The exceptions are based on provisions 
of the SIA, including section 586F(b) of the FD&C Act, which directs 
the Agency to issue regulations establishing timelines for drugs other 
than nonprescription sunscreen active ingredients or combinations of 
nonprescription active ingredients. For additional discussion on the 
development of this provision see the preamble (81 FR 19069 at 19073) 
of the Proposed Rule.
    We are finalizing this provision without change.
2. Timelines for FDA Review and Action (Sec.  330.15(c))
    In accordance with section 586F(b) of the FD&C Act, FDA proposed 
timelines for each of the various stages of the TEA process for 
conditions within the scope of the rule. The proposed timelines for 
each stage take into consideration factors set forth under the SIA. For 
additional discussion on the development of this provision, see the 
preamble (81 FR 19069 at 19073 to 19077) of the Proposed Rule.
    We are finalizing this provision with one clarifying change to 
acknowledge that, with respect to the 90-day timeline for FDA to issue 
a filing determination, a safety and effectiveness data submission can 
be submitted by a person other than the sponsor of the TEA.
3. Metrics (Sec.  330.15(b))
    Section 586F(b) of the FD&C Act requires FDA to establish 
measurable metrics for tracking the extent to which the timelines set 
forth in the regulations are met. We proposed to maintain a publicly 
available posting of metrics for the review of TEAs and safety and 
effectiveness data submissions submitted under Sec.  330.14 that are 
subject to the timelines, and update the posting annually. The proposed 
metrics, when publically posted, should provide sponsors and the public 
with information that will enable them to quickly ascertain the number 
of TEAs that have been submitted to FDA, and the Agency's performance 
in meeting the proposed timelines. For additional discussion on the 
development of this provision, see the preamble (81 FR 19069 at 19077) 
of the Proposed Rule.
    We are finalizing this provision without change.
4. Definitions (Sec.  330.14(a))
    We proposed additional definitions that, in general, are intended 
to clarify the beginning or ending of the timelines for FDA review and 
action. We proposed to add these definitions to Sec.  330.14 instead of 
Sec.  330.15 because Sec.  330.14 describes the TEA process to which 
these definitions apply. For additional discussion on the development 
of this provision, see the preamble (81 FR 19069 at 19077 to 19078) of 
the Proposed Rule.
    We are finalizing this provision with clarifying changes to the 
definition of ``Date of filing'' and ``Safety and effectiveness data 
submission'' to acknowledge that a safety and effectiveness data 
submission can be submitted by a person other than the sponsor of the 
TEA.
5. Filing Determination (Sec.  330.14(j))
    We proposed certain filing determination requirements to help 
improve the content and format of a safety and effectiveness data 
submission. We also proposed timelines related to these proposed new 
requirements and proposed processes that apply whether the submission 
is accepted for filing, refused, or filed over protest. The proposed 
requirement and related timelines were developed, in part, to provide a 
clear pathway for the Agency to indicate when a submission does not 
contain the information necessary for a complete review and what 
additional information is needed. For additional discussion on the 
development of this provision, see the

[[Page 84469]]

preamble (81 FR 19069 at 19078 to 19079) of the Proposed Rule.
    We are finalizing the provision with several changes to the 
Proposed Rule for clarification purposes (for additional details on the 
changes, see section V.E):
     Throughout the provision, we have made clarifying changes 
to acknowledge that a safety and effectiveness data submission can be 
submitted by a person other than the sponsor of the TEA.
     With respect to Sec.  330.14(j)(2), we are clarifying in 
this final rule that data submitted after a submission has been filed 
will be reviewed as part of the proposed rulemaking if there is 
adequate time before the NPRM will publish, or if there is not adequate 
time, the data will be evaluated as comments to the NPRM.
     In Sec.  330.14(j)(3), we are changing the proposed term 
``informal conference'' to ``meeting'' to use consistent terminology 
with the SIA.
     In both Sec.  330.14(j)(2) and (3), we clarify that a copy 
of the notice will be posted to the docket.
     In Sec.  330.14(j)(3), we originally proposed the process 
that a person that submitted a safety and effectiveness data submission 
must follow to request that FDA file a submission over protest. To 
avoid potential ambiguity, we are modifying Sec.  330.14(j)(3) to 
clarify that the submitter cannot request to file over protest without 
first having a meeting with FDA. In addition, this final rule clarifies 
the status of the submission and the TEA condition once FDA has refused 
to file a submission.
6. Withdrawal of Consideration of a TEA or Safety and Effectiveness 
Data Submission (Sec.  330.14(k))
    We proposed to add a withdrawal provision to new Sec.  330.14(k). 
The proposed provision allowed a sponsor to request withdrawal of 
consideration of a TEA or safety and effectiveness data submission. In 
addition, we also proposed (Sec.  330.14(k)(1)(ii)) that inaction by a 
sponsor in certain circumstances may be deemed by FDA as a withdrawal 
of consideration. The proposed Sec.  330.14(k)(2) also included a 
provision that FDA would give notice to the sponsor before deeming the 
submission withdrawn from consideration to give the sponsor an 
opportunity to provide an update and request FDA not withdraw the 
submission. Another proposed provision, Sec.  330.14(k)(3), provided 
that the notice of withdrawal of consideration would be posted to the 
docket. In addition, we proposed in Sec.  330.14(k)(4) that if the TEA 
or safety and effectiveness data submission is deemed withdrawn, the 
timelines under Sec.  330.15(c) and the metrics under Sec.  330.15(b) 
no longer apply. The provisions were proposed in part to enable the 
Agency to better allocate resources by providing a process for the 
Agency to suspend work on TEAs or safety and effectiveness data 
submissions that are no longer being pursued by the sponsor. For 
additional discussion on the development of these provisions see the 
preamble (81 FR 19069 at 19079 to 19080) of the Proposed Rule.
    We are finalizing the provision with several clarifying changes to 
the Proposed Rule (for additional details on the changes, see section 
V.E):
     Throughout the provision, we have made clarifying changes 
to acknowledge that a safety and effectiveness data submission can be 
submitted by a person other than the sponsor of the TEA.
     Under Sec.  330.14(k)(1)(ii), we no longer include that a 
sponsor's failure to act on a submission is a reason for FDA's deeming 
the submission withdrawn because until the sponsor or other interested 
person acts and files a TEA submission or safety and effectiveness data 
submission, there is nothing for FDA to deem withdrawn from 
consideration. For example, once a notice of eligibility is issued, the 
TEA is no longer under consideration and the eligible condition is not 
deemed under consideration until a safety and effectiveness data 
submission is filed.
     We have revised the proposed Sec.  330.14(k)(2) to extend 
the time period to make a request that FDA not deem a submission 
withdrawn from consideration.
     The final rule makes a technical change to proposed Sec.  
330.14(k)(3) to account for the situation in which an NOE for a TEA has 
not been issued and the TEA therefore is not in the public docket.
     The final rule also clarifies in Sec.  330.14(k)(3) that 
if FDA deems a submission withdrawn from consideration, the condition 
still remains eligible for consideration if an NOE was issued, and the 
sponsor or any interested person can pursue consideration of the 
condition in the future by submitting a new safety and effectiveness 
data submission.
7. Minor Changes to Sec.  330.14 for Clarity and Consistency
    We proposed minor changes to Sec.  330.14 for clarity and 
consistency purposes. These changes included adding definitions to 
proposed new paragraph (a). We proposed several minor amendments to 
Sec.  330.14(f) for clarity and for consistency with the OTC monograph 
regulations under Sec.  330.10. We also revised Sec.  330.14(f) to use 
terminology consistent with the new definition in Sec.  330.14(a)(5) 
for ``safety and effectiveness data submission'' when referring to a 
data package submitted for an eligible TEA condition. We also proposed 
to add the word ``feedback'' prior to the word ``letter'' in the first 
sentence of Sec.  330.14(g)(4) to use terminology consistent with the 
proposed new definition for ``feedback letter'' in Sec.  330.14(a)(7). 
For additional discussion on the development of this provision, see the 
preamble (81 FR 19069 at 19080) of the Proposed Rule.
    We are finalizing this provision with changes to Sec.  330.14(f) in 
order to clarify that a safety and effectiveness data submission can be 
submitted by a person other than the sponsor of the TEA.

IV. Legal Authority

    This rule is issued under FDA's authority to regulate OTC drug 
products under the FD&C Act (see sections 201, 501, 502, 503, 505, 510, 
586F, and 701(a) of the FD&C Act). As stated in the Federal Register of 
January 23, 2002, in which the final rule establishing the original TEA 
process was published, submission of an NDA has been required before 
marketing a new drug since passage of the FD&C Act in 1938 (21 U.S.C. 
355). To market a new drug, the drug must first be approved under 
section 505 of the FD&C Act. Section 701(a) of the FD&C Act authorizes 
FDA to issue regulations for the efficient enforcement of the FD&C Act. 
FDA's regulations in part 330 describe the conditions for a drug to be 
considered GRASE and not misbranded. If a drug meets each of the 
conditions contained in part 330, as well as each of the conditions 
contained in any applicable OTC drug monograph, and other applicable 
regulations, it is considered GRASE and not misbranded, and is not 
required by FDA to obtain approval under section 505 of the FD&C Act.
    In addition, section 586F of the FD&C Act requires FDA to issue 
regulations providing for the timely and efficient review of certain 
submissions under the TEA regulation in Sec.  330.14. Section 586F of 
the FD&C Act specifically requires these regulations to include 
timelines and metrics associated with the review of certain submissions 
under the TEA regulation. Therefore, Sec.  330.15 adds timeline and 
metrics provisions that are intended to implement section 586F of the 
FD&C Act.

[[Page 84470]]

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received three comment letters on the Proposed Rule, each 
containing one or more comments on one or more issues. The comments 
were submitted by a trade association and individual consumers. The 
submissions overall support the objectives of the rule. None of the 
comments suggested changes to specific provisions of the Proposed Rule.
    We describe and respond to the comments in sections V.B. through 
V.D. We have numbered each comment to help distinguish between 
different comments. The number assigned to each comment or comment 
topic is purely for organizational purposes and does not signify the 
comment's value or importance or the order in which comments were 
received.

B. Description of General Comments and FDA Response

    (Comment 1) The comments generally support the TEA process, the 
establishment of timelines associated with the general steps in that 
process, and the proposed revisions to the TEA regulation.
    (Response 1) We appreciate the support expressed in the comments 
received. The TEA process is intended to provide a potential pathway 
for OTC conditions, including newer active ingredients that previously 
had no U.S. marketing history or that were marketed in the United 
States after the OTC Drug Review began, to be marketed under an OTC 
drug monograph. The associated timelines and revisions to the TEA 
regulation are intended to implement certain requirements in the SIA 
and to make the TEA process more efficient and predictable.

C. Specific Comments on Timelines for FDA Review and Action and FDA 
Response

    (Comment 2) One comment stated that the explanation for the 
proposed timelines was clear. However, the comment suggested that 
additional changes to the monograph system could further streamline the 
projected TEA timeline.
    (Response 2) This final rule establishes timelines within the 
context of the general OTC monograph process, which involves rulemaking 
to establish general recognition of safety and effectiveness for 
conditions in a monograph. Because this rule is limited to the TEA 
process and not the overall monograph regulatory framework, changes to 
the OTC monograph process that in turn could affect the timelines 
established in this rule are outside the scope of this rulemaking.
    (Comment 3) One comment expressed concern that factors such as the 
format and content of the data submission, the complexity of the data, 
competing Agency priorities, and available Agency resources and 
reasonableness could delay TEA reviews and actions many years beyond 
the established timelines.
    (Response 3) As explained in the preamble to the Proposed Rule, 
section 586F(b) of the FD&C Act provides that the timelines for review 
of non-sunscreen TEA conditions shall: (1) Reflect FDA public health 
priorities (including potential public health benefits of including 
additional drugs in the OTC drug monograph system), (2) take into 
consideration the resources available for carrying out such public 
health priorities and the relevant review processes and procedures, and 
(3) be reasonable, taking into account the required consideration of 
priorities and resources. We accordingly took these factors into 
consideration when establishing timelines. Furthermore, we determined 
that instead of setting multiple timelines for submissions of varying 
content, complexity, and format, it would be more efficient and 
sensible, for each stage of the TEA process, to set one general 
timeline for the review of non-sunscreen TEA conditions that 
accommodates anticipated variation among submissions. Because 
anticipated variation is already accounted for, FDA expects the time 
frames to be achievable in most circumstances.

D. Specific Comments on the Filing Determination and FDA Response

    (Comment 4) With respect to the format and content of submissions, 
one comment seeks FDA guidance on the inclusion of certain information 
from foreign data sources for non-sunscreen active ingredients. The 
comment incorporated a comment that was previously submitted to FDA on 
its draft guidance for industry ``Nonprescription Sunscreen Drug 
Products--Content and Format of Data Submissions To Support a GRASE 
Determination Under the Sunscreen Innovation Act'' \1\ (nonprescription 
sunscreen content and format draft guidance) (Ref. 1).
---------------------------------------------------------------------------

    \1\ When final, this guidance will represent FDA's current 
thinking on this topic.
---------------------------------------------------------------------------

    (Response 4) As explained in the preamble to the Proposed Rule, the 
general advice provided in the nonprescription sunscreen content and 
format draft guidance (Ref. 1) may also be useful to persons preparing 
safety and effectiveness data submissions for non-sunscreen TEAs. The 
comment's request for guidance on the inclusion of certain information 
from foreign data sources in the safety and effectiveness data 
submission is outside the scope of this rulemaking. However, the Agency 
will consider providing additional guidance to address this issue.

E. Technical Amendments

    The revised regulatory text includes technical amendments that we 
have made to the proposed provisions in order to clarify requirements. 
In the following subsections, we summarize the changes that are 
intended to clarify amendments to the relevant provisions.
1. Clarifying That the Sponsor or Other Interested Person Can Submit a 
Safety and Effectiveness Data Submission
    We are finalizing Sec. Sec.  330.14(a), (f), (j), (k), and 
330.15(c)(2) with changes to clarify that a safety and effectiveness 
data submission can be submitted by a person other than the sponsor of 
the TEA.
    In proposed Sec.  330.14(a), we defined the term ``Sponsor'' to 
mean the person that submitted the TEA, and we defined ``Safety and 
effectiveness data submission'' to mean, in part, a data package 
submitted by a sponsor. Generally we expect the person submitting the 
TEA (i.e., the sponsor) will submit a safety and effectiveness data 
submission upon issuance of a NOE. However, upon issuance of the NOE, 
the TEA is no longer under consideration, and the sponsor does not 
necessarily have to be the person that submits the safety and 
effectiveness data submission. Therefore, while we are not changing the 
definition of ``Sponsor,'' we are modifying the definition of ``Safety 
and effectiveness data submission'' to clarify that the submission can 
be submitted by a person other than the sponsor.
    Correspondingly, we are clarifying the proposed definition of 
``Date of filing'' under Sec.  330.14(a) and clarifying the proposed 
Sec. Sec.  330.14(f) and 330.15(c)(2) by removing references to the 
``sponsor'' in order to acknowledge that the safety and effectiveness 
data submission can be submitted by a person other than the sponsor. In 
addition, throughout Sec.  330.14(j) and (k), we have removed 
references to the ``sponsor'' in the context of a safety and 
effectiveness data submission and replaced the term with more general 
terms, such as ``submitter'' or ``person that submitted the safety and 
effectiveness submission,'' in order to acknowledge that the safety and 
effectiveness data submission can be

[[Page 84471]]

submitted by a person other than the sponsor.
2. Filing Determination (Sec.  330.14(j))
    In addition to the changes noted in the previous subsection, we are 
finalizing the provision with several additional changes for 
clarification purposes.
    In Sec.  330.14(j)(2), FDA proposed that the date of filing will 
begin the FDA timelines described in Sec.  330.15(c)(3) and (4). 
Because FDA needs adequate time to review submitted data and the 
timeline for FDA to review and develop a NPRM begins as soon as the 
safety and effectiveness data submission has been filed, we are 
clarifying that data submitted after a submission has been filed will 
be reviewed before issuance of the NPRM if there is adequate time; 
otherwise, the data will be evaluated as comments to the NPRM. We note 
that although other submitted data submissions may be considered under 
the rulemaking process, they will not be subject to a filing 
determination. Furthermore, as with comments submitted after the 
comment period, any data submitted after the comment period for the 
NPRM may not be considered before issuance of the final rule.
    We are also adding language to both Sec.  330.14(j)(2) and (3) to 
clarify that when FDA sends a notice to the person that submitted a 
safety and effectiveness data submission informing that person that the 
submission is filed or filed over protest, a copy of the corresponding 
notice will be posted to the docket. The posting to the docket, which 
is public, provides other interested persons notice that a submission 
is filed and FDA is beginning its review.
    Additionally, in proposed Sec.  330.14(j)(3), we described the 
process for cases in which FDA refuses to file the safety and 
effectiveness data submission. The Proposed Rule provided that the 
sponsor (now submitter) can request an informal conference within 30 
days of FDA notifying the sponsor that it refuses to file the 
submission. We are changing the term ``informal conference'' to 
``meeting'' to be consistent with the SIA. In addition, the proposed 
provision explained that a sponsor's request to file over protest must 
be within 120 days of the meeting with FDA. To avoid potential 
ambiguity, we are modifying Sec.  330.14(j)(3) to clarify that a 
sponsor (now submitter) cannot request to file over protest without 
first meeting with FDA.
    Finally, we are clarifying the status of a safety and effectiveness 
data submission that FDA has refused to file by including at the end of 
Sec.  330.14(j)(3) that if FDA refuses to file a safety and 
effectiveness data submission and the submission is not filed over 
protest, then the submission is no longer deemed under consideration. 
If the original submitter or other interested person wishes to pursue 
consideration of an eligible condition at some point in the future, a 
new safety and effectiveness data submission must be submitted.
3. Withdrawal of Consideration of a TEA or Safety and Effectiveness 
Data Submission (Sec.  330.14(k))
    We are finalizing the provision with several clarifying changes.
    We no longer include failure to act on a submission as a reason 
that FDA may deem the submission to be withdrawn from consideration, as 
was proposed under Sec.  330.14(k)(1)(ii). In the preamble to the 
Proposed Rule, we explained there have been past instances when a NOE 
was issued but the sponsor never submitted safety and effectiveness 
data and the TEA condition remained unresolved. We proposed that a 
failure to act on a submission, which could include a sponsor's failure 
to file a safety and effectiveness data submission for a TEA-eligible 
condition, is one reason for FDA to deem the submission withdrawn from 
consideration and that, for purposes of the provision, this could 
include deeming a TEA-eligible condition withdrawn from consideration. 
However, in such a scenario when a condition is found eligible and 
there has not been a safety and effectiveness data submission, there is 
no action for FDA to take. Once a NOE is issued, the TEA is no longer 
under consideration. Also, since the sponsor or any other interested 
person is not obligated or under an established deadline for submitting 
a safety and effectiveness data submission, we do not consider the TEA-
eligible condition to be under consideration until such a submission is 
filed. As a result, a sponsor's failure to act on a submission will not 
result in the need for FDA to deem a submission or other aspect of the 
TEA process withdrawn from consideration, and inclusion of this 
provision is not necessary.
    We also proposed in Sec.  330.14(k)(1)(ii) that FDA may deem a 
submission to be withdrawn from consideration due to the sponsor's 
failure to respond to communications from FDA. This provision remains, 
and we note the reference to ``communications'' encompasses the notice 
of withdrawal under Sec.  330.14(k)(2) and any preceding communication 
from FDA that the sponsor failed to respond to.
    In Sec.  330.14(k)(2), we proposed that FDA will notify the sponsor 
of a submission that FDA intends to deem withdrawn under Sec.  
330.14(k)(1)(ii), and that the sponsor will then have 30 days from the 
date of the notice to request that FDA not withdraw consideration of 
the TEA or safety and effectiveness data submission. We are changing 
the time provided to request that FDA not withdraw consideration from 
30 days to 90 days.
    We are also further revising proposed Sec.  330.14(k)(3), in which 
FDA proposed that a notice of withdrawal will be posted to the docket 
when FDA deems a submission withdrawn from consideration. We are 
including a clarification that when a condition has been found 
eligible, even if the safety and effectiveness data submission is 
withdrawn, not only does the NOE remain in the public docket but the 
condition remains eligible for consideration, so that the condition can 
still be considered in the future if a new safety and effectiveness 
data submission is received. In addition, we are adding an exception to 
the notice of withdrawal being posted to the docket. Specifically, when 
a TEA submission is withdrawn from consideration before the issuance of 
an NOE, the notice of withdrawal will not be posted to the public 
docket and will only be sent to the sponsor because in such an instance 
the TEA, itself, is not on public display.
    Finally, although not a change to the Proposed Rule, we note as we 
discussed in the preamble to the Proposed Rule, that if a sponsor 
requests withdrawal of consideration of its TEA or safety and 
effectiveness data submission, FDA generally intends to stop its 
review. However, although FDA may withdraw consideration of a TEA or 
safety and effectiveness determination, we may determine not to 
withdraw or not to stop review in some cases. For example, if FDA has 
already issued a NPRM that tentatively determines that the active 
ingredient or other condition is GRASE for an OTC use or is not GRASE 
for an OTC use, FDA may continue the rulemaking and proceed to issue a 
final rule.

VI. Effective Date

    The SIA requires that the final rule be published not less than 30 
calendar days before the effective date of the regulation. 
Consequently, this final rule will become effective 30 calendar days 
after the date of the rule's publication in the Federal Register.
    Beginning on that date, the timelines and metrics set forth in this 
regulation will apply to the review of non-sunscreen TEAs, and safety 
and

[[Page 84472]]

effectiveness data submissions to which this regulation is applicable, 
and any amended provisions of Sec.  330.14 will apply to the TEA 
process under that regulation.

VII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct us to assess all costs 
and benefits of available regulatory alternatives and, when regulation 
is necessary, to select regulatory approaches that maximize net 
benefits (including potential economic, environmental, public health 
and safety, and other advantages; distributive impacts; and equity). We 
have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. We believe that this final rule 
is not a significant regulatory action as defined by Executive Order 
12866.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because this final rule does not impose significant new 
economic burdens on any entity, we certify that the final rule will not 
have a significant economic impact on a substantial number of small 
entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated costs and benefits, before issuing ``any rule that includes 
any Federal mandate that may result in the expenditure by State, local, 
and tribal governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation) in any one 
year.'' The current threshold after adjustment for inflation is $146 
million, using the most current (2015) Implicit Price Deflator for the 
Gross Domestic Product. This final rule would not result in an 
expenditure in any year that meets or exceeds this amount.
    In table 1, we provide the Regulatory Information Service Center/
Office of Information and Regulatory Affairs Consolidated Information 
System accounting information.
[GRAPHIC] [TIFF OMITTED] TR23NO16.004


[[Page 84473]]



B. Summary

1. Baseline Conditions
    We regulate nonprescription drug products under two primary 
pathways: (1) The NDA process, described in 21 CFR part 314 or (2) the 
nonprescription (over-the-counter or OTC) drug monograph process, 
described in part 330. There are important differences between these 
two pathways. Under the NDA process, the sponsor of an application must 
submit to us nonclinical and clinical data that support the safety and 
effectiveness of its drug product, and we must review and approve the 
application before the sponsor can market such product. By contrast, 
OTC drug monographs are regulations describing conditions (Sec.  330.14 
defines ``condition'' as an active ingredient or botanical drug 
substance (or combination of both), dosage form, dosage strength, or 
route of administration marketed for a particular specific OTC use) 
that certain OTC drugs (such as antacids) must meet to be considered 
GRASE and not misbranded. In contrast with the application pathway, 
once a sponsor or other interested person submits safety and 
effectiveness data to amend a monograph (which is posted to a public 
docket), the data are public. Drug products that comply with an 
applicable OTC drug monograph and other applicable regulations may be 
marketed without an NDA.
    Initially, active ingredients and other conditions that were not 
marketed in the United States before the inception of the OTC Drug 
Review in 1972 were not eligible for review under the OTC drug 
monograph process. However, the TEA process, established by regulations 
finalized in 2002 (Sec.  330.14), expanded the scope of this OTC drug 
review. The TEA process offers a pathway for OTC conditions to be 
marketed under an OTC drug monograph. OTC conditions can include newer 
active ingredients that previously had no U.S. marketing history, or 
that were marketed in the United States after the OTC drug review 
began. Active ingredients and other conditions that satisfy the TEA 
eligibility requirements are subject to the same safety, effectiveness, 
and labeling standards that apply to other conditions under the OTC 
monograph process.
    The TEA process requires multistep, notice-and-comment rulemaking 
procedures before a new active ingredient or other condition is added 
to an OTC drug monograph. After determining that an active ingredient 
or other condition is eligible for consideration under the OTC 
monograph process, we issue a notice in the Federal Register announcing 
the TEA determination and requesting safety and effectiveness data for 
the proposed OTC use. Next, after reviewing data submitted to the 
docket, we issue a NPRM to either include the condition in the 
appropriate OTC drug monograph or, if the condition is initially 
determined not to be GRASE for OTC use, include it in Sec.  310.502, 
which would require the sponsor to seek approval under the NDA pathway 
to market the condition. NPRMs regarding GRASE determinations allow for 
public comments and for sponsors and other interested persons to submit 
additional data for safety and effectiveness. If a monograph is 
amended, by publishing a final rule, an OTC condition that complies 
with the OTC monograph and the general requirements for OTC drugs may 
be marketed in the United States without an NDA (examples of other 
general requirements include requirements to comply with Current Good 
Manufacturing Practice, to register and list products, to use drug 
facts labeling).
    Although our multistep TEA process allows sponsors and other 
interested persons to learn about the progress of our review of a 
submission (for example, when an NOE is issued, and if a feedback 
letter is issued), there are no established timelines to review 
submissions or for data to be submitted. The lack of timelines can 
create unpredictability for interested persons because they may lack 
key information. For example, they may not know: (1) Whether the safety 
and effectiveness data submitted is sufficient or in the right format 
for us to conduct a substantive review; (2) when they need to submit 
new information; or (3) when to expect our determinations regarding 
eligibility or other feedback. The unpredictability in the process 
could result in interested persons not performing a required action 
within reasonable time for our review, performing unnecessary actions 
(examples of unnecessary actions may include collecting unnecessary or 
inadequate data, performing tests or studies that do not contribute to 
data needed by us to make a GRASE determination), or creating 
unnecessary effort for us and for them. Without specific timelines, 
persons that submit safety and effectiveness data submissions may not 
know whether their initial data submissions were insufficient to 
review, whether their data submissions were sufficient and are under 
review, or whether we require additional information. In addition, 
without specific timelines, we don't know whether interested persons 
intend to submit additional data or whether they do not intend to 
pursue a TEA condition any further.
2. Purpose of This Rule
    This rule complies with certain mandates of the SIA enacted in 
November 2014. In particular, the final rule establishes timelines and 
metrics for review of TEAs for non-sunscreen OTC drug products. 
Specific timelines applicable to non-sunscreen TEA conditions will be 
added in a new Sec.  330.15. The first timeline is to issue an NOE or 
post a letter of ineligibility to the TEA docket within 180 days of 
submission of a TEA. The second timeline is to issue a filing 
determination within 90 days of receipt of a complete safety and 
effectiveness data submission once the submitter has confirmed that it 
considers the submission to be complete. If we initially determine the 
active ingredient or other condition not to be GRASE, we will inform 
sponsors and other interested persons who submitted data within 730 
days from the date of filing as defined in Sec.  330.14(a). The next 
timeline is to issue a NPRM within 1,095 days from the date of filing. 
Lastly, we will issue a final rule regarding GRASE status within 912 
days of the closing of the docket of the proposed rulemaking.
    The final rule will also amend the existing Sec.  330.14 by: (1) 
Setting forth clear filing determination requirements with regard to 
the content and format of safety and effectiveness data submissions for 
TEAs and (2) addressing withdrawal of consideration of a TEA or safety 
and effectiveness data submission. These amendments will apply to all 
TEAs, and their goal is to provide early notification on whether the 
submissions meet the filing requirements and to provide more clarity 
regarding withdrawal of TEA-related submissions. The amendments in this 
final rule are intended to provide us with feedback from sponsors or 
other interested persons on whether they intend to actively pursue 
their submissions, and specify that we may withdraw consideration of a 
TEA or safety and effectiveness data submission in certain 
circumstances (such as at a submitter's request). Finally, this final 
rule also adds definitions and makes clarifying changes to the TEA 
regulation in Sec.  330.14.
    The clarifications and establishment of timelines for the TEA 
process seek to dissipate uncertainties that may have prevented 
interested persons from submitting all the necessary data for us

[[Page 84474]]

to make final GRASE determinations to existing TEA conditions that have 
been found to be eligible to be considered for inclusion in the OTC 
drug monograph system. Since the TEA review process became effective in 
2002 (67 FR 3060 at 3074), we have received six TEAs for non-sunscreen 
active ingredients, including applications for dandruff, laxative, 
gingivitis, and acne products. Of these six, the sponsors for three of 
the TEAs have subsequently requested that the Agency withdraw 
consideration of the conditions that were found eligible for 
consideration.
3. Benefits
    We lack data to quantify the potential benefits of this final rule. 
With this final rule, we expect the timelines and data submission 
clarifications will make the TEA process, including establishing a new 
OTC drug monograph, more efficient and predictable, and improve 
communication between us and sponsors or other interested persons. 
Sponsors and other interested persons may benefit from knowing whether 
additional data are needed and what optimal steps to take to receive a 
GRASE determination, and we will be able to bring resolution to TEA 
conditions. However, we do not know the monetary value of added 
predictability.
4. Costs
    We expect this final rule will create a minimal burden on sponsors 
and other interested persons from the possible cost associated with 
sending a meeting request letter to us in the event that we refuse to 
file a safety and effectiveness data submission and the submitter wants 
to meet with us to discuss the decision, or the possible cost of 
calling or writing us to request that we do not withdraw consideration 
of a submission under Sec.  330.14(k)(2). Therefore, we anticipate no 
increase in annual recurring costs for either small or large sponsors 
or other interested persons.
    We expect the six current sponsors will spend time reading and 
understanding the final rule; we estimate this task will take from 
about 6.5 hours to 13 hours. With an hourly wage rate of $133 including 
100 percent overhead, each sponsor will incur one-time costs ranging 
from about $865 to $1,730. This cost range is an overestimate because 
most sponsors are already familiar with the rule if they read the 
Proposed Rule. We also estimate that we will receive 2 additional TEAs 
annually, and thus during a 10-year horizon we estimate potentially 20 
additional applicants will spend the time to read and understand the 
final rule. This cost is also an overestimate because we assume that 
future sponsors will be different from sponsors who already have read 
and understood the rule. The present value of the total costs over 10 
years ranges from about $17,000 to $35,000 with a 7 percent discount 
rate and from about $19,000 to $38,000 with a 3 percent discount rate. 
With a discount rate of 7 percent and 3 percent, we estimate that on 
average, sponsors will incur less than $150 of annualized costs per 
year.
5. Impact on Small Entities
    The Regulatory Flexibility Act requires a Regulatory Flexibility 
Analysis unless the Agency can certify that the final rule will have no 
significant impact on a substantial number of small entities. The final 
rule will affect few entities. Moreover, we estimate one-time costs 
under $2,000 per entity, costs well below 0.01 percent of annual 
revenues for the smallest entities; thus we certify that the final rule 
will not have a significant economic impact on a substantial number of 
small entities.
    This is the full economic analysis.

VIII. Analysis of Environmental Impact

    We have determined under 21 CFR 25.31(a) that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the 
information collection provisions are shown below with an estimate of 
the annual reporting burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Additional Criteria and Procedures for Classifying Over-the-
Counter Drugs as Generally Recognized as Safe and Effective and Not 
Misbranded--OMB Control No. 0910-0688--Revision.
    Description: The final rule amends FDA's TEA regulations to 
establish timelines and performance metrics for FDA's review of non-
sunscreen TEAs and safety and effectiveness data submissions, as 
required by the SIA. FDA is making other changes to make the TEA 
process more efficient. Accordingly, FDA is revising the information 
collection currently approved under OMB control number 0910-0688 
consistent with the regulations.
    FDA has OMB approval (control number 0910-0688) for the information 
collection in Sec.  330.14, which specifies additional criteria and 
procedures by which OTC drugs that were initially marketed in the 
United States after the OTC Drug Review began and OTC drugs without any 
U.S. marketing experience may become eligible for consideration in the 
OTC drug monograph system.
    The final rule amends the TEA regulations in Sec.  330.14 to make 
the process more efficient and to make conforming and clarifying 
changes. Section 330.14(j) clarifies the requirements on content and 
format criteria for a safety and effectiveness data submission, and 
provides procedures for FDA's review of the submissions and 
determination of whether a submission is sufficiently complete to 
permit a substantive review. Section 330.14(j)(3) describes the process 
for cases in which FDA refuses to file the safety and effectiveness 
data submission. Under Sec.  330.14(j)(3), if FDA refuses to file the 
submission, the Agency will notify the submitter in writing, state the 
reason(s) for the refusal, and provide 30 days in which to submit a 
written request for a meeting with the Agency about whether the Agency 
should file the submission. A written request for a meeting is not 
already approved under OMB control number 0910-0688. We estimate that 
approximately one person that submits a safety and effectiveness data 
submission (``Number of Respondents'' in table 2, row 1) will annually 
submit to FDA approximately one request for a meeting (``Total Annual 
Responses'' in table 2, row 1), and preparing and submitting each 
request will take approximately 1 hour (``Average Burden per Response'' 
in table 2, row 1).
    Under Sec.  330.14(j)(4)(iii), the safety and effectiveness data 
submission must contain a signed statement that the submission 
represents a complete safety and effectiveness data submission and that 
the submission includes all the safety and effectiveness data and 
information available to the submitter at the time of the submission, 
whether positive or negative. A signed statement is not already 
approved under OMB control number 0910-0688. We estimate that 
approximately two persons (``Number of Respondents'' in table 2, row 2) 
will annually submit to FDA approximately two signed statements as

[[Page 84475]]

described previously (``Total Annual Responses'' in table 2, row 2), 
and that preparing and submitting each signed statement will take 
approximately one hour (``Average Burden per Response'' in table 2, row 
2).
    Under Sec.  330.14(k)(1), FDA, in response to a written request, 
may withdraw consideration of a TEA submitted under Sec.  330.14(c) or 
a safety and effectiveness data submission submitted under Sec.  
330.14(f). A request that FDA withdraw consideration of a TEA or safety 
and effectiveness data submission is not already approved under OMB 
control number 0910-0688. We estimate that approximately one person 
that submitted a safety and effectiveness data submission (``Number of 
Respondents'' in table 2, row 3) will annually submit to FDA 
approximately one request (``Total Annual Responses'' in table 2, row 
3), and that preparing and submitting each request will take 
approximately 1 hour (Average Burden per Response'' in table 2, row 3).
    Under Sec.  330.14(k)(2), a person that submitted the submission 
may request that FDA not withdraw consideration of a TEA or safety and 
effectiveness data submission. A request for FDA to not deem its 
submission withdrawn from consideration is not already approved under 
OMB control number 0910-0688. We estimate that approximately one person 
that submitted a TEA or safety and effectiveness data submission 
(``Number of Respondents'' in table 2, row 4) will annually submit to 
FDA approximately one request (``Total Annual Responses'' in table 2, 
row 4), and that preparing and submitting each request will take 
approximately two hours (``Average Burden per Response'' in table 2, 
row 4).
    FDA estimates the burden of this information collection as follows:

                                 Table 2--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                        Average
         21 CFR Section              Number of     responses per   Total annual     burden per      Total hours
                                    respondents     respondent       responses       response
----------------------------------------------------------------------------------------------------------------
330.14(j)(3)--Request for a                    1               1               1               1               1
 meeting on FDA's refusal to
 file...........................
330.14(j)(4)(iii)--Signed                      2               1               2               1               2
 statement that the submission
 is complete....................
330.14(k)(1)--Request for FDA to               1               1               1               1               1
 withdraw consideration of a TEA
 or safety and effectiveness
 data submission................
330.14(k)(2)--Request for FDA to               1               1               1               2               2
 not deem its submission
 withdrawn from consideration...
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............               6
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information collection provisions of this final rule have been 
submitted to the OMB for review, as required by section 3507(d) of the 
PRA. FDA will publish a subsequent notice in the Federal Register 
announcing OMB's decision to approve, modify, or disapprove the 
information collection provisions in this final rule. An Agency may not 
conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB 
control number.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. Section 4(a) of the Executive order 
requires agencies to ``construe . . . a Federal statute to preempt 
State law only where the statute contains an express preemption 
provision or there is some other clear evidence that the Congress 
intended preemption of State law, or where the exercise of State 
authority conflicts with the exercise of Federal authority under the 
Federal statute.'' The sole statutory provision giving preemptive 
effect to the final rule is section 751 of the FD&C Act (21 U.S.C. 
379r). We have complied with all of the applicable requirements under 
the Executive order and have determined that the preemptive effects of 
this rule are consistent with Executive Order 13132.

XI. Reference

    The following reference is on display in the Division of Dockets 
Management (see ADDRESSES) and is available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; it is also 
available electronically at https://www.regulations.gov. FDA has 
verified the Web site address, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

    1. FDA, Draft Guidance for Industry, ``Nonprescription Sunscreen 
Drug Products: Content and Format of Data Submissions To Support a 
GRASE Determination Under the Sunscreen Innovation Act,'' November 
2015, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM473772.pdf.

List of Subjects in 21 CFR Part 330

    Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
330 is amended as follows:

PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY 
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED

0
1. The authority citation for part 330 is revised to read as follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360fff-6, 
371.


0
2. Section 330.14 is amended as follows:
0
a. Redesignate paragraph (a) as introductory text, revise the newly 
redesignated introductory text, and add new paragraph (a);
0
b. Revise paragraphs (f) heading and introductory text and (g)(4); and
0
c. Add paragraphs (j) and (k).
    The revisions and additions read as follows:


Sec.  330.14  Additional criteria and procedures for classifying OTC 
drugs as generally recognized as safe and effective and not misbranded.

    This section sets forth additional criteria and procedures by which 
over-the-counter (OTC) drugs initially marketed in the United States 
after the OTC drug review began in 1972 and OTC drugs without any U.S. 
marketing experience can be considered in the OTC drug monograph 
system. This

[[Page 84476]]

section also addresses conditions regulated as a cosmetic or dietary 
supplement in a foreign country that would be regulated as OTC drugs in 
the United States. Section 330.15 sets forth timelines for FDA review 
and action.
    (a) Definitions. The definitions and interpretations contained in 
section 201 of the Federal Food, Drug, and Cosmetic Act and the 
following definitions of terms apply to this section and to Sec.  
330.15.
    (1) Botanical drug substance means a drug substance derived from 
one or more plants, algae, or macroscopic fungi, but does not include a 
highly purified or chemically modified substance derived from such a 
source.
    (2) Condition means an active ingredient or botanical drug 
substance (or a combination of active ingredients or botanical drug 
substances), dosage form, dosage strength, or route of administration, 
marketed for a specific OTC use, except as excluded in paragraph (b)(2) 
of this section.
    (3) Date of filing means the date of the notice from FDA stating 
that FDA has made a threshold determination that the safety and 
effectiveness data submission is sufficiently complete to permit a 
substantive review; or, if the submission is filed over protest in 
accordance with paragraph (j)(3) of this section, the date of filing is 
the date of the notice from FDA stating that FDA has filed the 
submission over protest (this date will be no later than 30 days after 
the request that FDA file the submission over protest).
    (4) Feedback letter means a letter issued by the agency in 
accordance with paragraph (g)(4) of this section that informs the 
sponsor and other interested persons who have submitted data under 
paragraph (f) of this section that a condition is initially determined 
not to be generally recognized as safe and effective (GRASE).
    (5) Safety and effectiveness data submission means a data package 
submitted by a sponsor or other interested person that includes safety 
and effectiveness data and information under paragraph (f) of this 
section and that is represented by the submitter as being a complete 
submission.
    (6) Sponsor means the person that submitted a time and extent 
application (TEA) under paragraph (c) of this section.
    (7) Time and extent application (TEA) means a submission by a 
sponsor under paragraph (c) of this section, which will be evaluated by 
the agency to determine eligibility of a condition for consideration in 
the OTC drug monograph system.
* * * * *
    (f) Safety and effectiveness data submission. The notice of 
eligibility will request a safety and effectiveness data submission 
that includes published and unpublished data to demonstrate the safety 
and effectiveness of the condition for its intended OTC use(s), as well 
as the submission of any other relevant data and views. These data will 
be submitted to a docket established in the Division of Dockets 
Management and will be publicly available for viewing at that office, 
except data deemed confidential under 18 U.S.C. 1905, 5 U.S.C. 552(b), 
or 21 U.S.C. 331(j). Data considered confidential under these 
provisions must be clearly identified. Any proposed compendial 
standards for the condition will not be considered confidential. The 
safety and effectiveness data submission must be sufficiently complete 
to be filed by the agency under paragraph (j)(2) of this section. 
Safety and effectiveness data and other information submitted under 
this paragraph are subject to the requirements in Sec.  330.10(c), (e), 
and (f). The safety and effectiveness data submission must include the 
following:
* * * * *
    (g) * * *
    (4) If the condition is initially determined not to be GRASE for 
OTC use in the United States, the agency will inform the sponsor and 
other interested persons who have submitted data of its determination 
by feedback letter, a copy of which will be placed on public display in 
the docket established in the Division of Dockets Management. The 
agency will publish a notice of proposed rulemaking to include the 
condition in Sec.  310.502 of this chapter.
* * * * *
    (j) Filing determination. (1) After FDA receives a safety and 
effectiveness data submission, the agency will determine whether the 
submission may be filed. The filing of a submission means that FDA has 
made a threshold determination that the submission is sufficiently 
complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraph (j)(4) of 
this section for refusing to file the safety and effectiveness data 
submission apply, the agency will file the submission and notify the 
submitter in writing. FDA will post a copy of the notice to the docket. 
The date of filing begins the FDA timelines described in Sec.  
330.15(c)(3) and (4). Data submitted after the date of filing will be 
considered before the issuance of a notice of proposed rulemaking if 
there is adequate time for review; otherwise, the data will be 
considered as comments to the proposed rule after issuance of a notice 
of proposed rulemaking.
    (3) If FDA refuses to file the safety and effectiveness data 
submission, the agency will notify the submitter in writing and state 
the reason(s) under paragraph (j)(4) of this section for the refusal. 
The submitter may request in writing, within 30 days of the date of the 
agency's notification, a meeting with the agency about whether the 
agency should file the submission, and FDA will convene the meeting 
within 30 days of the request. If, within 120 days after the meeting, 
the submitter requests that FDA file the submission (with or without 
correcting the deficiencies), the agency will file the safety and 
effectiveness data submission over protest under paragraph (j)(2) of 
this section, notify the submitter in writing and post a copy to the 
docket, and review the submission as filed. The submitter must have a 
meeting before requesting that FDA file the submission over protest but 
need not resubmit a copy of a safety and effectiveness data submission 
that is filed over protest. A safety and effectiveness data submission 
and the corresponding TEA-eligible condition are both not deemed under 
consideration if FDA refuses to file the safety and effectiveness data 
submission, and it is not filed over protest; the condition remains 
eligible for consideration and the sponsor or any interested person can 
pursue consideration of the condition in the future by submitting a new 
safety and effectiveness data submission.
    (4) FDA may refuse to file a safety and effectiveness data 
submission if any of the following applies:
    (i) The submission is incomplete because it does not contain 
information required under paragraph (f) of this section. If the 
submission does not contain required information because such 
information or data are not relevant to the condition, the submission 
must clearly identify and provide an explanation for the omission.
    (ii) The submission is not organized or formatted in a manner to 
enable the agency to readily determine whether it is sufficiently 
complete to permit a substantive review.
    (iii) The submission does not contain a signed statement that the 
submission represents a complete safety and effectiveness data 
submission and that the submission includes all the safety and 
effectiveness data and information available to the submitter at the 
time of the submission, whether positive or negative.
    (iv) The submission does not contain an analysis and summary of the 
data and other supporting information,

[[Page 84477]]

organized by clinical or nonclinical area, such as clinical efficacy 
data, clinical safety data, clinical pharmacology, adverse event 
reports, animal toxicology, chemistry data, and compendial status.
    (v) The submission does not contain a supporting document 
summarizing the strategy used for literature searches, including search 
terms, sources, dates accessed, and years reviewed.
    (vi) The submission does not contain a reference list of supporting 
information, such as published literature, unpublished information, 
abstracts and case reports, and a copy of the supporting information.
    (vii) The submission includes data or information relevant for 
making a GRASE determination marked as confidential without a statement 
that the information may be released to the public.
    (viii) The submission does not contain a complete environmental 
assessment under Sec.  25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec.  25.30 or Sec.  25.31 of 
this chapter.
    (ix) The submission does not contain a statement for each 
nonclinical laboratory study that the study was conducted in compliance 
with the requirements set forth in part 58 of this chapter, or, if it 
was not conducted in compliance with part 58 of this chapter, a brief 
statement of the reason for the noncompliance.
    (x) The submission does not contain a statement for each clinical 
investigation involving human subjects that the investigation was 
conducted in compliance with the institutional review board regulations 
in part 56 of this chapter, or was not subject to those regulations, 
and that the investigation was conducted in compliance with the 
informed consent regulations in part 50 of this chapter.
    (xi) The submission does not include financial certification or 
disclosure statements, or both, as required by part 54 of this chapter, 
accompanying any clinical data submitted.
    (k) Withdrawal of consideration. (1) Notwithstanding paragraph (g) 
of this section, FDA may withdraw consideration of a TEA submission or 
a safety and effectiveness data submission if:
    (i) The person that submitted the submission requests that its 
submission be withdrawn from consideration; or
    (ii) FDA deems the submission to be withdrawn from consideration 
due to the submitter's failure to respond to communications from FDA.
    (2) Before FDA deems a submission withdrawn under paragraph 
(k)(1)(ii) of this section, FDA will notify the person that submitted 
the submission. If, within 90 days from the date of the notice from 
FDA, the submitter requests that FDA not withdraw consideration of the 
submission, FDA will not deem the submission to be withdrawn.
    (3) If FDA withdraws consideration of a submission under paragraph 
(k)(1) of this section, FDA will post a notice of withdrawal to the 
docket, except in the case of a TEA submission that is withdrawn from 
consideration before issuance of a notice of eligibility, in which 
case, the notice of withdrawal will only be provided to the sponsor. 
Information that has been posted to the public docket for the condition 
at the time of the withdrawal (such as a notice of eligibility or a 
safety and effectiveness data submission that has been accepted for 
filing and posted to the docket) will remain in the public docket. If 
the condition has been found eligible through issuance of a notice of 
eligibility, the condition remains eligible for consideration and the 
sponsor or any interested person can pursue consideration of the 
condition in the future by submitting a new safety and effectiveness 
data submission.
    (4) If FDA withdraws consideration of a submission under paragraph 
(k)(1) of this section, the timelines under Sec.  330.15(c) will no 
longer apply as of the date of withdrawal, and the submission will not 
be included in the metrics under Sec.  330.15(b).

0
3. Add Sec.  330.15 to subpart B to read as follows:


Sec.  330.15  Timelines for FDA review and action on time and extent 
applications and safety and effectiveness data submissions.

    (a) Applicability. This section applies to the review of a 
condition in a time and extent application (TEA) submitted under Sec.  
330.14 for consideration in the over-the-counter (OTC) drug monograph 
system. This section does not apply to:
    (1) A sunscreen active ingredient or combination of sunscreen 
active ingredients, and other conditions for such ingredients; or
    (2) A non-sunscreen active ingredient or combination of non-
sunscreen active ingredients, and other conditions for such ingredients 
submitted in a TEA under Sec.  330.14 before November 27, 2014, subject 
to section 586F(a)(1)(C) of the Federal Food, Drug, and Cosmetic Act.
    (b) Metrics. FDA will maintain and update annually, a publicly 
available posting of metrics for the review of TEAs and safety and 
effectiveness data submissions that are subject to the timelines in 
this section. The posting will contain the following information for 
tracking the extent to which the timelines set forth in paragraph (c) 
of this section were met during the previous calendar year.
    (1) Number and percent of eligibility notices or ineligibility 
letters issued within 180 days of submission of a TEA;
    (2) Number and percent of filing determinations issued within 90 
days of submission of a safety and effectiveness data submission;
    (3) If applicable, number and percent of feedback letters issued 
within 730 days from the date of filing;
    (4) Number and percent of notices for proposed rulemaking issued 
within 1,095 days from the date of filing;
    (5) Number and percent of final rules issued within 912 days of 
closing of the docket of the proposed rulemaking; and
    (6) Total number of TEAs submitted under Sec.  330.14.
    (c) Timelines for FDA review and action. FDA will review and take 
an action within the following timelines:
    (1) Within 180 days of submission of a TEA under Sec.  330.14(c), 
FDA will issue a notice of eligibility or post to the docket a letter 
of ineligibility, in accordance with Sec.  330.14(d) and (e).
    (2) Within 90 days of submission of a safety and effectiveness data 
submission, in accordance with Sec.  330.14(j), FDA will issue a filing 
determination. The date of filing begins the FDA timelines in 
paragraphs (c)(3) and (4) of this section.
    (3) Within 730 days from the date of filing, if the condition is 
initially determined not to be GRASE for OTC use in the United States, 
FDA will inform the sponsor and other interested persons who have 
submitted data of its determination by feedback letter in accordance 
with Sec.  330.14(g)(4).
    (4) Within 1,095 days from the date of filing of a safety and 
effectiveness data submission, FDA will issue a notice of proposed 
rulemaking to either:
    (i) Include the condition in an appropriate OTC monograph(s), 
either by amending an existing monograph(s) or establishing a new 
monograph(s), if necessary; or
    (ii) Include the condition in Sec.  310.502 of this chapter.
    (5) Within 912 days of the closing of the docket of the proposed 
rulemaking under paragraph (c)(4) of this section, FDA will issue a 
final rule.

    Dated: November 17, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-28120 Filed 11-22-16; 8:45 am]
 BILLING CODE 4164-01-P