[Federal Register Volume 83, Number 101 (Thursday, May 24, 2018)]
[Notices]
[Pages 24122-24124]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2018-11132]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2018-N-1558]


Food and Drug Administration's Evaluation of Approaches To 
Demonstrate Effectiveness of Heartworm Preventatives for Dogs; Request 
for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; request for comments.

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SUMMARY: The Food and Drug Administration (FDA or we) is evaluating its 
current thinking regarding the design of studies intended to generate 
data to support substantial evidence of effectiveness for 
investigational new animal drugs intended for the prevention of 
heartworm disease in dogs. We are specifically requesting public input 
on possible alternative approaches for evaluating such products or 
information to assist in the potential development of alternative 
recommended study designs.

DATES: Submit either electronic or written comments on the proposed 
method by August 22, 2018.

ADDRESSES: 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 22, 2018. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of August 22, 2018. 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.''

[[Page 24123]]

    Instructions: All submissions received must include the Docket No. 
FDA-2018-N-1558 for ``FDA's Evaluation of Approaches to Demonstrate 
Effectiveness of Heartworm Preventatives for Dogs.'' 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 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.fda.gov/regulatoryinformation/dockets/default.htm.
    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.
    Submit written requests for single copies of the proposed method to 
the Policy and Regulations Staff (HFV-6), Center for Veterinary 
Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20855. Send one self-addressed adhesive label to assist that office 
in processing your requests. Persons with access to the internet may 
obtain the draft guidance at either https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052417.pdf or https://www.regulations.gov.

FOR FURTHER INFORMATION CONTACT: Steven Fleischer, Center for 
Veterinary Medicine (HFV-110), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 240-402-0809, 
[email protected].

SUPPLEMENTARY INFORMATION: FDA is evaluating its current thinking 
regarding the design of studies intended to generate data to support 
substantial evidence of effectiveness for investigational new animal 
drugs intended for the prevention of heartworm disease in dogs.
    An application for a new animal drug shall include ``evidence to 
establish safety and effectiveness'' (21 CFR 514.1(b)(8)). 
Additionally, ``an application may be refused unless it includes 
substantial evidence of the effectiveness of the new animal drug as 
defined in 514.4 [21 CFR 514.4]'' (21 CFR 514.1(b)(8)(ii)). Regarding 
studies, under 21 CFR 514.4(b)(3)(i) substantial evidence of the 
effectiveness of a new animal drug for each intended use and associated 
conditions of use shall consist of a sufficient number of current 
adequate and well-controlled studies of sufficient quality and 
persuasiveness to permit qualified experts:
     To determine that the parameters selected for measurement 
and the measured responses reliably reflect the effectiveness of the 
new animal drug;
     To determine that the results obtained are likely to be 
repeatable, and that valid inferences can be drawn to the target animal 
population [(independent substantiation and inferential value)]; and
     To conclude that the new animal drug is effective for the 
intended use at the dose or dose range and associated conditions of use 
prescribed, recommended, or suggested in the proposed labeling.
    The current recommended approach to demonstrating substantial 
evidence of effectiveness of an investigational new animal drug 
intended for the prevention of heartworm disease is for sponsors to 
conduct two laboratory dose confirmation studies and one multi-site 
field safety and effectiveness study under the principles of Good 
Clinical Practice (GCP) as described in Guidance for Industry #85, 
``Good Clinical Practice (VICH GL9).'' \1\ The laboratory dose 
confirmation studies are experimentally-induced infection studies, each 
conducted at different laboratory facilities, led by independent 
investigators and using recent isolates of Dirofilaria immitis from two 
separate United States geographic locations. The field effectiveness 
study is a multi-site study conducted with investigators in various 
geographical regions of the continental United States with endemic 
heartworm disease that evaluates the use of the investigational new 
animal drug in client-owned animals.
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    \1\ https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052417.pdf.
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    Both study types have strengths and limitations. Strengths of the 
laboratory studies includes the use of a negative control group, which 
provides direct evidence of the effect of the new animal drug and that 
results are not due to the impact of other treatments or external 
influences on disease transmission and progression. In addition, 
laboratory studies allow for appropriate classification of exposure due 
to contemporaneous experimental infection of the same number of 
infectious D. immitis larvae to control and investigational new animal 
drug-administered groups and the appropriate classification of outcome 
due to performance of an adult worm count post mortem. The worm count 
allows for qualitative and quantitative evaluation of outcome by 
determining the presence of adult worms as well as the determination of 
the individual worm burden in each dog. One significant limitation of 
the laboratory studies is the evaluation of only two isolates. Although 
each isolate should be from a different geographic area in the United 
States, under laboratory conditions the isolates may not accurately 
represent the current diversity of D. immitis in the United States and 
may not account for variable susceptibility in the isolates in the 
field. From a substantial evidence of effectiveness standpoint, this 
condition limits the inferential value of the two studies because the 
use of the laboratory isolates may over- or under-represent the 
relative susceptibility of other isolates in the field to the 
investigational new animal drug. Additionally, the small number of 
animals used in the study limits confidence in the interpretation of 
effectiveness results.
    The strength of the field study is that the study evaluates the 
investigational new animal drug under actual conditions of use and with 
the current

[[Page 24124]]

enzootic status and genetic factors affecting the disease in each 
location, thereby providing better inferential value than the 
laboratory study. Limitations of the field study are that the exposure 
to infective D. immitis larvae is assumed, but uncertain, and, in cases 
of dogs with positive antigen tests, the actual timing of the exposure 
is unknown. Additionally, the relatively short duration of the field 
study in relationship to the heartworm life cycle and testing 
limitations may not adequately evaluate the entire dosing period of the 
investigational new animal drug. Assurance that individual dogs were 
exposed to D. immitis larvae during the critical first few months of 
the study is lacking, which complicates interpretation of a negative 
antigen test at the end of the study. If the study is started during a 
time of low transmission, such as in winter, exposure is even more 
uncertain. Because of the delay in the ability to detect an adult 
heartworm infection, it is impossible to tell with certainty if 
infections detected between 4 and 8 months after study initiation were 
pre-existing infections or due to lack of effectiveness of the 
preventative. Obtaining false negative and false positive antigen test 
results are possible and, because worm counts are not performed, the 
false results may result in the misclassification of outcome for 
individual dogs.
    In recognition of the limitations of the current recommended 
laboratory and field effectiveness studies for heartworm preventatives 
for use in dogs, we are interested in evaluating alternative approaches 
to these study designs that would mitigate the limitations of such 
studies while ensuring that the studies generate data to support 
substantial evidence of effectiveness as defined in 21 CFR 514.4.
    Currently, there are gaps in knowledge and understanding that 
prevent us from fully evaluating alternative approaches to meeting the 
substantial evidence of effectiveness standard. To address these gaps, 
we are seeking public comment regarding the following questions:
    Population level effectiveness endpoint. The design and evaluation 
of effectiveness studies rely on an understanding of the appropriate 
outcome measure. In seeking to design alternative study approaches, we 
would like to determine a population level effectiveness endpoint that 
could be used to design future studies. Currently we do not have a 
defined level of performance that heartworm preventatives are expected 
to meet when applied to the entire United States canine population. 
Determining a population level endpoint would allow us to explore the 
suitability and feasibility of alternative study designs for the 
evaluation of effectiveness for heartworm preventatives. Factors that 
may contribute to a heartworm preventative's effectiveness include the 
inherent potency of the drug, differences in heartworm susceptibility, 
and owner compliance.
    1. Assuming that a product was administered according to labeled 
directions, what would be an acceptable rate of failure of an approved 
heartworm preventative in the overall United States canine population 
to which it is administered?
    2. What would be the maximum acceptable rate of failure in a high-
risk population?
    3. Alternatively, if you do not have a numerical estimate, what 
recommendations do you have for determining what an acceptable rate of 
failure should be?
    Exposure to infective D. immitis larvae. For humane reasons, field 
studies are not conducted with a negative control group that would 
reflect the study population's level of exposure to heartworm 
infection. Therefore, it is necessary to have other measures to ensure 
that the level of exposure to infective D. immitis larvae experienced 
in the study is sufficient to adequately test the effectiveness of the 
investigational new animal drug. Please provide comment on other 
methods that could reliably be used to ensure adequate exposure of dogs 
enrolled in a field study. Consider the following points:
    4. Can available tests be used to determine an individual dog's 
exposure to infective larvae? What are the sensitivity and specificity 
of those tests in this application? How would the level of sensitivity 
and specificity of these tests impact the reliable assessment of rate 
of failure in the population?
    5. Does the use of a heartworm preventative, even if only partially 
effective, have an impact on the results of these tests?
    6. Could methods that consider a wider area (as opposed to an 
individual animal) such as mosquito testing, forecasting, or modeling 
be reliably used to determine the likely exposure to infective larvae 
of dogs at a specific study site? What information would be needed to 
create the methods or to verify the validity of the methods? What are 
the limitations to such an approach?
    Outcome Assessment. Accurate assessment of the outcome endpoint 
(heartworm infection) is essential for field studies where necropsy 
worm counts will not be performed.
    7. What are the most reliable ways of properly classifying the 
outcome in a non-terminal study?
    8. Are there critical pieces of information supporting substantial 
evidence of effectiveness that can only be gained from a well-
controlled laboratory study? Are there elements that could be added to 
a field study that would partially address those data gaps?
    Other.
    9. Are there laboratory study designs other than the traditional 
dose confirmation study that provide additional information or include 
a model that is more representative of real world exposure? For 
example, the use of live mosquitoes to induce infection rather than the 
mechanical injection of larvae.
    10. How might differences in the route of administration, dosing 
frequency, or pharmacokinetic factors impact effectiveness? How might 
studies be designed to incorporate these factors? For example, a drug 
that demonstrates an early peak, with minimal to no drug levels in the 
dog for the remainder of the dosing interval versus a product with 
continuous drug levels in the dog for the entire dosing interval?

    Dated: May 21, 2018.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2018-11132 Filed 5-23-18; 8:45 am]
 BILLING CODE 4164-01-P