[Federal Register Volume 84, Number 131 (Tuesday, July 9, 2019)]
[Notices]
[Pages 32749-32751]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-14528]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2019-N-2281]


Incorporating Alternative Approaches in Clinical Investigations 
for New Animal Drugs; Public Meeting; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public meeting; request for comment.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
announcing a public meeting entitled ``Incorporating Alternative 
Approaches in Clinical Investigations for New Animal Drugs.'' This 
public meeting and request for comments is intended to support FDA 
guidance development as required by the Animal Drug and Animal Generic 
Drug User Fee Amendments of 2018. The topics to be discussed will 
inform the development of guidance to assist sponsors in incorporating 
complex adaptive and other novel investigation designs, data from 
foreign countries, real world evidence (including ongoing surveillance 
activities, observational studies, and registry data), biomarkers, and 
surrogate endpoints into proposed clinical investigation protocols and 
applications for new animal drugs under the Federal Food, Drug, and 
Cosmetic Act (FD&C Act). FDA is seeking comments from stakeholders, 
including representatives of regulated industry, consumer groups, 
academia, veterinarians, and food producers.

DATES: The public meeting will be held on July 16, 2019, from 8:30 a.m. 
to 5 p.m. Submit either electronic or written comments on this public 
meeting by August 17, 2019.

ADDRESSES: The public meeting will be held at Johns Hopkins 
University--Montgomery County, Gilchrist Hall, 9601 Medical Center Dr., 
Rockville, MD 20850. Free parking is available on site.
    You may submit comments as follows. Please note that late, untimely 
filed comments will not be considered. Electronic comments must be 
submitted on or before August 17, 2019. The https://www.regulations.gov 
electronic filing system will accept comments until 11:59 p.m. Eastern 
Time at the end of August 17, 2019. Comments received by mail/hand 
delivery/courier (for written/paper submissions) will be considered 
timely if they are postmarked or the delivery service acceptance 
receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2019-N-2281 for ``Incorporating Alternative Approaches in Clinical 
Investigations for New Animal Drugs.'' Received comments, those filed 
in a timely manner (see ADDRESSES), will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9

[[Page 32750]]

a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: 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 document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Susan Storey, Center for Veterinary 
Medicine, Food and Drug Administration, 7500 Standish Pl., HFV-131, 
Rockville, MD 20855, 240-402-0578, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing a public meeting entitled ``Incorporating 
Alternative Approaches in Clinical Investigations for New Animal 
Drugs.'' This public meeting and request for comment is intended to 
support FDA guidance development as required under section 305 of the 
Animal Drug and Animal Generic Drug User Fee Amendments of 2018 (Pub. 
L. 115-234). Section 305 directs FDA to develop guidance to address 
several alternative approaches in clinical investigations for new 
animal drugs, including incorporating complex adaptive and other novel 
investigation designs, data from foreign countries, real world evidence 
(including ongoing surveillance activities, observational studies, and 
registry data), biomarkers, and surrogate endpoints into proposed 
clinical investigation protocols and applications for new animal drugs 
under sections 512 and 571 of the FD&C Act (21 U.S.C. 360b, 360ccc). 
Section 305 also directs FDA to conduct a public meeting to allow the 
Agency to gather input from stakeholders, including representatives of 
regulated industry, consumer groups, academia, veterinarians, and food 
producers before developing the guidance.

II. Topics for Discussion at the Public Meeting

    The purpose of this public meeting is to facilitate discussion and 
obtain input from stakeholders about the use of complex adaptive and 
other novel investigation designs, data from foreign countries, real 
world evidence, and biomarkers and surrogate endpoints in drug 
development and regulatory decision making.
    The meeting is expected to include four sessions that focus on the 
following topics: (1) Complex adaptive and other novel investigation 
designs; (2) data from foreign countries; (3) real world evidence; and, 
(4) biomarkers and surrogate endpoints. Within each session and 
following all sessions there will be an opportunity for public comment. 
To facilitate the development of guidance on these topics, please 
consider the following questions. When responding please identify the 
topic and question in your response.

Topic 1: Complex Adaptive and Other Novel Investigation Designs

    1. In September 2018, FDA published draft Guidance for Industry: 
Adaptive Designs for Clinical Trials of Drugs and Biologics, which 
applies to human drugs and biologics (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/adaptive-design-clinical-trials-drugs-and-biologics). How should these apply to study designs 
for animal drugs? What are the potential study adaptation features that 
could be applied to animal drug investigations? What are the challenges 
and possible solutions to apply these adaptations to studies for animal 
drugs? To what type of studies for animal drugs would these study 
designs be most applicable?
    2. How does complex adaptive design differ from adaptive design? 
What constitutes other novel investigation designs? What examples are 
directly applicable to animal drug development?
    3. Are there partnerships that can be formed between FDA and the 
regulated industry, academia, or other groups to facilitate the 
development or use of these novel investigational designs for animal 
drug development? What strategic work is needed to enable the regulated 
industry to make full use of these novel investigational designs for 
animal drug development? What methods are needed, such as the use of 
simulations or modeling, to facilitate the use of these novel 
investigational designs for animal drug development?

Topic 2: Data From Foreign Countries

    For the purposes of this meeting, FDA considers data from foreign 
countries to be data from investigations or studies conducted outside 
the United States (U.S.). FDA can accept data from studies conducted 
outside the United States to support a new animal drug application, 
provided the applicant demonstrates that the data are adequate under 
applicable standards to support approval (section 569B of the FD&C Act; 
21 U.S.C. 360bbb-8b). FDA also accepts data from studies conducted 
outside the United States to support a food additive petition for a 
food additive intended for use in animal food, when provided by the 
petitioner (section 409(k)(1) of the FD&C Act; 21 U.S.C. 348(k)(1)). 
While the regulatory standards for approval differ between animal drugs 
and animal food additives, data from foreign countries can be used to 
support either approval if the data meet the appropriate regulatory 
standards.
    1. What challenges and potential solutions do you have in meeting 
the requirements of substantial evidence of effectiveness, as defined 
in 21 CFR 514.4, when using data from foreign countries for an animal 
drug?
    2. Typically in the United States, when we wish to show a test drug 
is no worse than an active control, that active control is an approved 
animal drug in the United States. A non-inferiority analysis is used to 
statistically demonstrate this relationship. In studies conducted 
outside the United States, an active control may be used that is not 
approved for that use in the United States. In the absence of a U.S. 
approval for the active control, FDA cannot interpret non-inferiority 
to the unapproved active control. What challenges exist in utilizing 
these studies? What criteria should FDA use to accept a study where the 
active control is not approved in the United

[[Page 32751]]

States? What are potential options or solutions to enable FDA to use 
these studies?
    3. What challenges exist in demonstrating that data from foreign 
countries were generated under conditions representative of typical 
conditions in the United States for an animal drug or food additive? 
What are potential solutions to these challenges?
    4. What challenges exist in designing studies for an animal drug or 
food additive to meet the approval requirements of different 
jurisdictions? What are possible solutions to these challenges?
    5. What challenges exist in study conduct and the collection and 
interpretability of data from foreign countries (both manual and 
electronic) that may influence study quality and data integrity to 
support the approval of an animal drug or food additive? What are 
possible solutions to these challenges?
    6. What other challenges have you encountered and what potential 
solutions would you propose with regard to providing data from foreign 
countries to FDA?

Topic 3: Real World Evidence

    There is significant activity within FDA aimed at clarifying how to 
determine if real-world data (RWD) are sufficient to generate real-
world evidence (RWE) that could be used for regulatory decision making 
by the Agency. In August 2017, FDA published a guidance document 
entitled, ``Guidance for Industry and Food and Drug Administration 
Staff: Use of Real-World Evidence to Support Regulatory Decision-Making 
for Medical Devices'' (available at https://www.fda.gov/media/99447/download) and, in accordance with the 21st Century Cures Act (Pub. L. 
114-255), released a draft framework entitled ``Framework for FDA's 
Real-World Evidence Program'' (available at https://www.fda.gov/media/120060/download) in December 2018 for human drug and biological 
products.
    1. How should FDA define RWE for making regulatory decisions for 
animal drugs? What sources of RWD should FDA consider to generate RWE 
for animal drugs?
    2. What challenges exist for the use of RWE for animal drug 
approvals? What are possible solutions to these challenges?
    3. In what contexts might RWD/RWE be used to generate clinical 
evidence for regulatory decision making for animal drugs?
    4. What factors should FDA consider when evaluating RWE for animal 
drugs?

Topic 4: Biomarkers and Surrogate Endpoints

    Biomarkers have long been a part of veterinary medicine. Examples 
include routine tests such as body temperature, heart rate, complete 
blood cell count and clinical chemistry, radiographs, and intraocular 
pressure. Numerous technological advancements have greatly increased 
the number of available biomarkers while reducing their cost. 
Unfortunately, many potential biomarkers are not validated for their 
use and interpretation in clinical investigations. FDA's Center for 
Drug Evaluation and Research (CDER) has a formal Biomarker 
Qualification Program, related guidance, and affiliated consortia to 
support the development and use of biomarkers in regulatory decision 
making for human drugs (https://www.fda.gov/drugs/drug-development-tool-qualification-programs/cder-biomarker-qualification-program). FDA 
is seeking stakeholder feedback on how to best support the 
identification and development of new biomarkers for new animal drug 
applications and on ways to better incorporate biomarkers and surrogate 
endpoints into animal drug development.
    1. What are the expectations of sponsors, researchers, 
veterinarians, and producers for the use of biomarkers in the context 
of animal drug regulation and how might biomarkers be used in addition 
to surrogate endpoints in the design and conduct of clinical studies?
    2. Biomarkers are commonly used for diagnosing disease to enroll 
patients, sample size estimations, and pilot/proof-of-concept studies. 
What information should be provided to FDA to support their use in 
these contexts (e.g., analytical validation, clinical validation, 
establishing clinical utility, companion diagnostics etc.)?
    3. What are the major challenges in translating potential 
biomarkers and/or surrogate endpoints into practical tools in clinical 
trials? What are possible solutions to these challenges?
    4. How do we determine the evidentiary criteria for evaluating 
biomarker use?
    5. Should FDA's Center for Veterinary Medicine develop a biomarker 
qualification program like CDER's? Would such a program be beneficial, 
and is it something that stakeholders (e.g., drug sponsors) would use? 
Are there other approaches to the development and acceptance of 
biomarkers for animal drugs?

III. Information About the Public Meeting

    Additional information about the public meeting is available on our 
website at https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/public-meeting-incorporating-alternative-approaches-clinical-investigations-new-animal-drugs. If time and space permit, onsite 
registration on the day of the public meeting will be provided 
beginning at 8 a.m. We will post a notice on the above website no later 
than July 12 as to whether onsite registration is available.
    Streaming Webcast of the Public Meeting: This public meeting will 
also be webcast. Registration for the webcast is required. Information 
to register for the webcast is available at https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/public-meeting-incorporating-alternative-approaches-clinical-investigations-new-animal-drugs. You 
can register for the webcast up until the time of the meeting.
    If you have never attended a Connect Pro event before, test your 
connection at https://collaboration.fda.gov/common/help/en/support/meeting_test.htm. For a quick overview of the Connect Pro program, 
visit https://www.adobe.com/go/connectpro_overview. FDA has verified 
the website addresses in this document, as of the date this document 
publishes in the Federal Register, but websites are subject to change 
over time.
    Transcripts: Please be advised that as soon as a transcript of the 
public meeting is available, it will be accessible at https://www.regulations.gov. It may be viewed at the Dockets Management Staff 
(see ADDRESSES). A link to the transcript will also be available at 
https://www.fda.gov/animal-veterinary/workshops-conferences-meetings/public-meeting-incorporating-alternative-approaches-clinical-investigations-new-animal-drugs.

    Dated: July 2, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-14528 Filed 7-8-19; 8:45 am]
 BILLING CODE 4164-01-P