Abstract

A veterinarian and pet owner survey (Project Jake) examined the use and safety of isoxazoline parasiticides given to dogs. Data were received during August 1-31, 2018 from a total of 2,751 survey responses. Forty-two percent (1,157) reported no flea treatment or adverse events (AE), while 58% (1594) had been treated with some parasiticide for flea control, and of those that received a parasiticide, the majority, or 83% (1,325), received an isooxazoline. When any flea treatment was given, AE were reported for 66.6% of respondents, with no apparent AE noted for 36.1%. Project Jake findings were compared to a retrospective analysis of publicly available Food and Drug Administration (FDA) and European Medicines Agency (EMA) reported AE. The number of total AE reported to FDA and EMA were comparable, although a 7 to 10 times higher occurrence of death and seizures was reported from the EMA or from outside the United States (US). Serious AE responses for death, seizures and neurological effects reported in our survey were higher than the FDA but moderately lower than the EMA reports. These sizable global data sets combined with this pre- and post-parasiticide administration survey indicated that isoxazoline neurotoxicity was not flea- and tick-specific. Post-marketing serious AE were much higher than in Investigational New Drug (IND) submissions. Although the labels have recently been updated, dogs, cats and their caregivers remain impacted by their use. These aggregate data reports support the need for continued cross-species studies and critical review of product labelling by regulatory agencies and manufacturers.


Authors

Palmieri, Valerie;  Dodds, W. Jean;  Morgan, Judy;  Carney, Elizabeth;  Fritsche, Herbert A.;  Jeffrey, Jaclyn;  Bullock, Rowan;  Kimball, Jon P.

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  • pre-publication peer review (FINAL ROUND)
    Decision Letter
    2020/04/25

    25-Apr-2020


    Dear Dr. Dodds:


    It is a pleasure to accept your manuscript entitled "Survey of Canine Use and Safety of Isoxazoline Parasiticides" in its current form for publication in Veterinary Medicine and Science.


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    Associate Editor Comments to Author:


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    Reviewer(s)' Comments to Author:


    Reviewer: 1


    Comments to the Author
    All points rainsed by the reviewers have been sufficiently addressed.

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    Reviewer report
    2020/04/07

    All points rainsed by the reviewers have been sufficiently addressed.

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    Author Response
    2020/04/06

    RESPONSES to REVIEWERS Manuscript ID VMS3-2019 -Oct 0265 R3


    Prof. Gayle Hallowell
    Editor in Chief, Veterinary Medicine and Science gayle.hallowell@nottingham.ac.uk


    Associate Editor Comments to Author:
    Reviewer(s)' Comments to Author:
    Reviewer: 1
    Comments to the Author
    All critical points have been sufficiently addressed. THANK YOU very much!


    Reviewer: 3
    Comments to the Author
    Paper is still repetitive. Editing is needed. The Abstract has been revised slightly for clarity. The Introduction has been rearranged. Paragraph on lines 154-168 has been relocated to lines 191-211 in the R3 manuscript
    You have failed to respond to the questions asked by the reviewers last time. We did address the comments.
    Line 34: (Lines 37-38 in R3) Isoxazolines are five-membered heterocyclic chemical compounds, containing one atom each of oxygen and nitrogen which are located adjacent to one another. This statement appears to have been copied from Wikipedia (https://en.wikipedia.org/wiki/Isoxazoline)
    There are many different compounds with differing effects that are isoxazolines (or isoxazoles - an azole with an oxygen atom next to the nitrogen). For example, some are insecticides, others are antithrombotics, or NSAIDs. In the last review one of your reviewers stated that your statement about having been developed for at least 20 years was incorrect. You have chosen to ignore that and add the reference they provided, which discusses 2014 as the first development of these insecticides. We disagree, but have clarified this section in the R3 Introduction.
    Line 55-58: (Lines 60-63 in R3) In the paper later on you state the manufactures changed warnings on the insert. It appears they did not disregard the reports. We don’t understand the point here? The latest updates for the revised pkg labels are: Nexgard pkg label dated 05/2018, Bravecto pkg label dated 04/2019, Credelio pkg label dated 09/2019, Simparica pkg label dated 06/2019.

    Line 58: (Line 63 in R3) Experts? What are the credentials? As our paper is anonymized by Journal policy, we cannot state more about our panel of experts. This comment by the reviewer seems unprofessional.
    Line 76: (Lines 81-83 in R3) Which social media sites? There is a difference between posting on a news feed and posting on 'XYZ kills dogs'. We described how are survey was distributed. This reviewer has apparently assumed that we were unqualified to conduct an appropriate survey.
    Line 79-81: (Lines 86-87 in R3) This statement already biases your survey. Our article clearly states the principle emphasis of the survey analysis, which was to focus on serious neurotoxic AE. The scope of the survey encompassed the universe of AE reported but our primary analysis for this paper is the neurological AEs that have not been addressed in pkg labeling or marketing materials.
    Lines 82-86: (Lines 85-92 in R3) You did not discuss any of these concerns about bias, you only listed them. How did you come to the conclusion that 'the findings described herein reflect valid concerns?' This is an important part of study design and you fail to recognize this. If one read the paper carefully, these issues of bias are stated and discussed.
    Line 112: (Lines 117-119 in R3) Please reference. I would disagree with this statement in the new social media age- within days of a product release there is a Facebook page stating, 'XYZ killed my dog.' Looking at the reports on many of these pages it is noted that many of these patients have different types of clinical signs which are not expected from an AE (or poisoning) situation. We are not sure about the reviewer’s expectations for AE or ‘poisoning’. The therapies for AE varied to address vomiting, inappetence, diarrhea and a more serious array of signs. Patients may have had a full spectrum of effects, or none.
    Line 136: (Line 142 in R3) Are neurologic effects defined the same across reporting systems? Neurologic AE including tremors, ataxia (incoordination) and seizures, along with many others are standard clinical manifestations.
    Line 168: (Lines 191-211 in R3) Time frame of clinical signs? Different agents have different pharmacokinetics. The survey did not address this and it makes the paper worthless. Your time frame is 3 months afterwards, several of the agents are gone long before this time frame is up. To describe our findings as “worthless” seems unprofessional. Our survey did ask for temporal observations, but few respondents were able to comply by pinpointing the timing – mostly because pet owners are not trained scientists and reporting AE are generally post-event without exact documentation but based on recollection. We did provide temporal findings that could be discerned from the EMA data.
    Line 216: (Lines 229-230 in R3) Time frame of clinical signs not reported. Signs should be seen at peak serum levels. This complaint is repetitive. See reviewer’s 1st comment; also see our previous comments above.



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  • pre-publication peer review (ROUND 3)
    Decision Letter
    2020/03/24

    24-Mar-2020


    Dear Dr. Dodds:


    Manuscript ID VMS3-2019-Oct-0265.R2 entitled "Survey of Canine Use and Safety of Isoxazoline Parasiticides" which you submitted to Veterinary Medicine and Science, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.


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    Once again, thank you for submitting your manuscript to Veterinary Medicine and Science and I look forward to receiving your revision.


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    Prof. Gayle Hallowell
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    Associate Editor Comments to Author:


    Associate Editor
    Comments to the Author:
    (There are no comments.)


    Reviewer(s)' Comments to Author:


    Reviewer: 1


    Comments to the Author
    All critical points have been sufficiently addressed.


    Reviewer: 3


    Comments to the Author
    Paper is still repetitive. Editing is needed.
    You have failed to respond to the questions asked by the reviewers last time.


    Line 34: Isoxazolines are five-membered heterocyclic chemical compounds, containing one atom each of oxygen and nitrogen which are located adjacent to one another. There are many different compounds with differing effects that are isoxazolines (or isoxazoles - an azole with an oxygen atom next to the nitrogen). For example, some are insecticides, others are antithrombotics, or NSAIDs. In the last review one of your reviewers stated that your statement about having been developed for at least 20 years was incorrect. You have chosen to ignore that and add the reference they provided, which discusses 2014 as the first development of these insecticides.


    Line 55-58: In the paper later on you state the manufactures changed warnings on the insert. It appears they did not disregard the reports.


    Line 58: Experts? What are the credentials?


    Line 76: Which social media sites? There is a difference between posting on a news feed and posting on 'XYZ kills dogs'.


    Line 79-81: This statement already biases your survey.


    Lines 82-86: You did not discuss any of these concerns about bias, you only listed them. How did you come to the conclusion that 'the findings described herein reflect valid concerns?' This is an important part of study design and you fail to recognize this.


    Line 112: Please reference. I would disagree with this statement in the new social media age- within days of a product release there is a Facebook page stating, 'XYZ killed my dog.' Looking at the reports on many of these pages it is noted that many of these patients have different types of clinical signs which are not expected from an AE (or poisoning) situation.


    Line 136: Are neurologic effects defined the same across reporting systems?


    Line 168: Time frame of clinical signs? Different agents have different pharmacokinetics. The survey did not address this and it makes the paper worthless. Your time frame is 3 months afterwards, several of the agents are gone long before this time frame is up.


    Line 216: Time frame of clinical signs not reported. Signs should be seen at peak serum levels.

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    Reviewer report
    2020/03/23

    Paper is still repetitive. Editing is needed.
    You have failed to respond to the questions asked by the reviewers last time.

    Line 34: Isoxazolines are five-membered heterocyclic chemical compounds, containing one atom each of oxygen and nitrogen which are located adjacent to one another. There are many different compounds with differing effects that are isoxazolines (or isoxazoles - an azole with an oxygen atom next to the nitrogen). For example, some are insecticides, others are antithrombotics, or NSAIDs. In the last review one of your reviewers stated that your statement about having been developed for at least 20 years was incorrect. You have chosen to ignore that and add the reference they provided, which discusses 2014 as the first development of these insecticides.

    Line 55-58: In the paper later on you state the manufactures changed warnings on the insert. It appears they did not disregard the reports.

    Line 58: Experts? What are the credentials?

    Line 76: Which social media sites? There is a difference between posting on a news feed and posting on 'XYZ kills dogs'.

    Line 79-81: This statement already biases your survey.

    Lines 82-86: You did not discuss any of these concerns about bias, you only listed them. How did you come to the conclusion that 'the findings described herein reflect valid concerns?' This is an important part of study design and you fail to recognize this.

    Line 112: Please reference. I would disagree with this statement in the new social media age- within days of a product release there is a Facebook page stating, 'XYZ killed my dog.' Looking at the reports on many of these pages it is noted that many of these patients have different types of clinical signs which are not expected from an AE (or poisoning) situation.

    Line 136: Are neurologic effects defined the same across reporting systems?

    Line 168: Time frame of clinical signs? Different agents have different pharmacokinetics. The survey did not address this and it makes the paper worthless. Your time frame is 3 months afterwards, several of the agents are gone long before this time frame is up.

    Line 216: Time frame of clinical signs not reported. Signs should be seen at peak serum levels.

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    Reviewer report
    2020/03/19

    All critical points have been sufficiently addressed.

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    Author Response
    2020/03/04

    RESPONSES to REVIEWERS Manuscript ID VMS3-2019 -Oct 0265 R2


    Prof. Gayle Hallowell
    Editor in Chief, Veterinary Medicine and Science gayle.hallowell@nottingham.ac.uk


    Associate Editor Comments to Author:


    Associate Editor
    Comments to the Author:
    The reviewers have some additional concerns about the study design and data handling. Please see the following reviewer comments for details.


    Reviewer(s)' Comments to Author:


    Reviewer: 1


    Comments to the Author
    The manuscript can be accepted in its revised form. Great !


    Reviewer: 3 NOTE Lines #s cited here may not be correct as shown, as the reviewers only saw the anonymized version. I’ve highlighted the changed lines in Yellow on the attached R2 manuscript.


    Comments to the Author
    The paper is quite repetitive. ??


    Line 39-40: I believe you are missing an 'as' Correct – added “as” [Line 42 in R2]


    How was the survey distributed? Revised to state “---electronically by email to ---" [Line 75 in R2]
    What are the pitfalls of this type of sampling (please provide references)? New sentences added with references -- see list below added to refs. [Lines 82-84 in R2]
    Evans & Mathur, 2018; Nayak & Narayan, 2019; Rice at al, 2017; Vaske, 2011.


    Line 106: Reference? Reworded instead [Line 100 in R2]


    Line 130: Are neurologic effects defined the same across the reporting platforms? YES What are 'behavior changes?' Not sure what lines the reviewer is referring to here?
    Line 159-160: What are the pharmacokinetics? Lines 152-153 in R2 and Letendre et al, 2014 (Line 165) This sentence refers to the EMA’s data not ours. How to they differ for each substance? We don’t know what the EMA specifically meant. This is the fatal flaw in your questionnaire. We did ask these questions, as Q. 12 and 14 asked about intervals and # of doses for time of onset. You do not ask the onset of adverse events after the dosing of the flea/tick medication as the way the questions are written the onset could be from minutes to 3 months afterwards. We couldn’t determine how many AE responders reported “Unsure” - for time to the event, as the questions were phrased as "How many doses of [selected] did you give before your dog became ill?" and "Approximately how long was it between when you first noticed signs of illness and when you contacted your veterinarian?" Thus, we could not extrapolate our data findings to answer the reviewer here. We have stated this point in Lines 212-213 of R2. Also, we are describing only the oral isoxazoline product responses in Tables 5 & 6, which has been clarified in Lines 222-225 in R2. Several of these products are long gone from the body by 3 months. By not providing a time frame you increase the potential for 'adverse effects' to occur and therefore taint your data with unrelated items. This makes your hypothesis of under-reporting flawed. Figure 1 shows the temporal relationship from time of dose to events – seen in lines 162-163 in R2 --“The most serious AE as stated in the EMA cumulative reports were observed at 0-24 hrs after the first dose, and then again after the second and third doses (Figure 1), which was consistent with the known isoxazoline pharmacokinetics of absorption and elimination following administration of oral chews (Letendre et al, 2014).” Additionally, PK & half-life was also noted in: [Drag et al., Veterinary Parasitology 2014, 201,198–203. DOI: 10.1016/j.vetpar.2014.02.022)]. This information has been added to the revised text (Lines 167-168 in R2).
    Line 204: Time frame? Addressed above with Figure 1 and Lines 161-163 in R2.


    Line 301-302: What are the differences? Added new wording Lines 288-289 in R2 .


    Question 2: Continuous? Presumably so during at risk exposure seasons. Intermittent? Only in temperate climates. Not everyone lives were ectoparasites are found all year round. Correct


    Question 3: I assume shampoo, spray, dip and collars fall under topical. No; we are referring only to topical flea and tick preventives. But our survey referred to and analyzed AEs related to oral/chewable treatments – although it did include questions as to ‘other’ treatments. Topical (non-oral) dosing was excluded from the data analyses.
    We have reviewed the survey responses again and note that 450 respondents say they used a topical treatment, so that is the denominator for the percentages shown below – we have added a simple summary statement to the revised text under Results, (Lines 205-208 in R2).


    Advantage/Advantage II/Advantage Multi 26 5.78%
    Advantix/Advantix II 59 13.11%
    Advocate 13 2.89%
    Frontline/Frontline Plus 102 22.67%
    Kin and kind 19 4.22%
    Revolution 22 4.89%
    Sentinel 23 5.11%
    Seresto collar 36 8.00%
    Trifexis 19 4.22%
    Vectra/Vectra 3D 16 3.56%
    Wondercide 15 3.33%
    More than One Product 45 10.00%
    Other (exclusively) 90 20.00%
    Unsure 5 1.11%


    Question 5: What is an 'adverse effect?' Anything unexpected that affected the dog’s health and well-being


    Question 7 and 13: Missing time frame Questions 10 and 12 of the survey relate to time frame – see more response above.


    Question 36: SAMe is not milk thistle (it does not contain silymarin) Yes, but we meant to include milk thistle & SAMe (i.e. with Denamarin)


    Question 41: What is 'barely' recover? Poor phrase- sorry!


    Question 45: Were any of these performed? Yes, necropsies were listed as performed for 2 cases in response to Q 45. Did any indicate the cause of death? One was listed as a “neurologic cause”; the other was ”not able to be determined”. This information is added on Lines 227-229 in R2.


    Reviewer: 4 See link:
    https://www.sciencedirect.com/journal/veterinary-parasitology/vol/201/issue/3 ; Special Issue: NEXGARD®. Afoxolaner, a new oral insecticide-acaricide to control fleas and ticks in dogs. D. Otranto, et al.


    Comments to the Author

    I am struggling to make sense of the numbers when the authors acknowledge the inherent bias of voluntary reports that weight heavily towards adverse effects. The authors seem to think that they are somewhat immunized from this bias because they included questions to include with or without AE and that 36.1% did not see any AE at all. That ought to tell them something right there. We don’t understand this comment, as the reviewer implies that the reactions noted by most respondents to our survey are of little consequence. The FDA’s first announcement in the fall of 2018 included a warning alert for the potential adverse neurological events associated with these isoxazoline products. Subsequent FDA updates have followed.
    https://www.fda.gov/animal-veterinary/cvm-updates/animal-drug-safety-communication-fda-alerts-pet-owners-and-veterinarians-about-potential-neurologic----


    I believe that ~66.6% of dosed dogs in their survey had AE, but I do not believe that projects to ~60% of dosed dogs having an AE in the normal population. We haven’t said that or even implied it. This type of percentage if real would be intolerable and financially unsustainable for any of the manufacturers. So if they are not real, what value are they? What do they mean? Further, if we do not know how many total doses are given to dogs in the same period as this survey, how are we to put any of this in context? The industry does not reveal how many total doses have been given, although it no doubt is very large. Regardless, our survey findings indicate that more AEs have occurred than the manufacturers have admitted or reported to the FDA. The public is being misinformed about safety concerns, given the extensive marketing efforts by big pharma for these drugs.


    The opening sentence of the Intro state the isoxazoline class have been developed for at least 20 years. No they have not. The Shoop et al. 2014 Veterinary Parasitology paper was the first paper published supporting the launch of a developed member of this class. Thanks; we’ve added it (Line 36 in R2). It included efficacy data in dogs and showed mode of action Afoxolaner. Previous works were experimental one-offs that had little or no relevance to the commercial compounds of today. The earlier reports of compound ‘invention’ and mechanisms laid the groundwork for preclinical studies, and to the special (marketing/science) issue of Vet Parasit., 2014. Added to Lines 42-46 in R2.


    The authors state in the Discussion 'Thus, as a class of drugs, isoxazolines work as intrinsic neurotoxins across species.' No, they do not. Our survey findings disagree. The authors note that they are 'highly potent arthropod-specific'. What part of that do they not understand? The word 'highly' is a relative word not an absolute word. Removed it. See Lines 318-321 in R2. Experimental data on these drugs show there is a large difference between arthropod and mammalian GABA receptors, but not an absolute one. Correct Where the line is crossed in Veterinary Medicine I do not know, but I know (?) the authors have not shown the line being crossed with these survey results nor with the AE results of the regulatory bodies. We respectfully disagree.!


    The Abstract ends by saying 'These survey data support the need for continued cross-species studies and critical review of product labeling by regulatory agencies and manufacturers' which is a great deal tamer than how the Discussion ends which is "We believe that the FDA should consider additional changes to their criteria for AE observation, and define what would be needed for them to reconsider clearance of this class of drugs.' That last phrase is a bomb. It seems to suggest the authors seek removal of the approval of these drugs based on survey results. Wow! Reworded,as it was not intended as has been interpreted here.


    I went back and forth between Major Revision and Reject and settled on Major Revision. I don't want to silence anyone especially if there is a possibility of animals being harmed. Good. But the evidence I have seen is to the contrary and shows that this is a highly efficacious drug with few side effects. Except that our findings indicate that a cohort of pets do suffer AEs. If someone thinks they are not then let them show real convincing data. If the Editor and Authors want the survey results put on the record I would not wish to stop them, but I would ask that the above criticisms be seriously considered. We believe that we have responded to these concerns.



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  • pre-publication peer review (ROUND 2)
    Decision Letter
    2020/02/13

    13-Feb-2020


    Dear Dr. Dodds:


    Manuscript ID VMS3-2019-Oct-0265.R1 entitled "Survey of Canine Use and Safety of Isoxazoline Parasiticides" which you submitted to Veterinary Medicine and Science, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.


    Before submitting your revisions:




    1. Prepare a response to the reviewer comments appended below in point-by-point fashion. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response and indicate the page numbers in the manuscript where you have addressed each comment.




    2. Prepare a revised manuscript (word document), highlighting the changes you’ve made. Save this new document on your computer as you will be asked to upload it during the revision submission process. NOTE: Please be sure to keep in mind reviewer comments and incorporate your responses within the manuscript. There may well be areas where you disagree; for example, you may want to write, "A reviewer suggests that... However, I disagree because...". In any case, please try to address all of the concerns that are raised within the manuscript.




    3. In addition to your revised manuscript with changes highlighted, please also save a “clean” copy where the changes are not marked.




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    3. File Upload: Delete any files that you will be replacing (this includes your old manuscript). Upload your new revised manuscript file with changes highlighted, a “clean” copy of your revised manuscript file, any replacement figures/tables, or any new files. Once this is complete, the list of files in the “My Files” section should ONLY contain the final versions of everything. REMEMBER: figures/tables should be in jpeg, tiff, or eps format. If you haven't done so already, please consider uploading an image of the organism(s) studied in your paper to be considered for online cover and blog publication.




    4. Review and submit: please be sure to double-check everything carefully so that your manuscript can be processed as quickly as possible.




    Deadlines:
    Because we are trying to facilitate timely publication of manuscripts submitted to Veterinary Medicine and Science,your revised manuscript should be uploaded as soon as possible. If it is not possible for you to submit your revision in 2 months, we may have to consider your paper as a new submission. If you feel that you will be unable to submit your revision within the time allowed please contact me to discuss the possibility of extending the revision time.


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    Once again, thank you for submitting your manuscript to Veterinary Medicine and Science and I look forward to receiving your revision.


    Sincerely,
    Prof. Gayle Hallowell
    Editor in Chief, Veterinary Medicine and Science
    gayle.hallowell@nottingham.ac.uk


    Associate Editor Comments to Author:


    Associate Editor
    Comments to the Author:
    The reviewers have some additional concerns about the study design and data handling. Please see the following reviewer comments for details.


    Reviewer(s)' Comments to Author:


    Reviewer: 1


    Comments to the Author
    The mansucript can be accepted in its revised form.


    Reviewer: 3


    Comments to the Author
    The paper is quite repetitive.


    Line 39-40: I believe you are missing an 'as'


    How was the survey distributed? What are the pitfalls of this type of sampling (please provide references)?


    Line 106: Reference?


    Line 130: Are neurologic effects defined the same across the reporting platforms? What are 'behavior changes?'


    Line 159-160: What are the pharmacokinetics? How to they differ for each substance? This is the fatal flaw in your questionnaire. You do not ask the onset of adverse events after the dosing of the flea/tick medication. The way the questions are written the onset could be from minutes to 3 months afterwards. Several of these products are long gone from the body by 3 months. By not providing a time frame you increase the potential for 'adverse effects' to occur and therefore taint your data with unrelated items. This makes your hypothesis of under-reporting flawed.


    Line 204: Time frame?


    Line 301-302: What are the differences?


    Question 2: Continuous? Intermittent? Not everyone lives were ectoparasites are found all year round.


    Question 3: I assume shampoo, spray, dip and collars fall under topical.


    Question 5: What is an 'adverse effect?'


    Question 7 and 13: Missing time frame


    Question 36: SAMe is not milk thistle (it does not contain silymarin)


    Question 41: What is 'barely' recover?


    Question 45: Were any of these performed? Did any indicate the cause of death?


    Reviewer: 4


    Comments to the Author
    I am struggling to make sense of the numbers when the authors acknowledge the inherent bias of voluntary reports that weight heavily towards adverse effects. The authors seem to think that they are somewhat immunized from this bias because they included questions to include with or without AE and that 36.1% did not see any AE at all. That ought to tell them something right there. I believe that ~60% of dosed dogs in their survey had AE, but I do not believe that projects to ~60% of dosed dogs having an AE in the normal population. This type of percentage if real would be intolerable and financially unsustainable for any of the manufacturers. So if they are not real, what value are they? What do they mean? Further, if we do not know how many total doses are given to dogs in the same period as this survey, how are we to put any of this in context?


    The opening sentence of the Intro state the isoxazoline class have been developed for at least 20 years. No they have not. The Shoop et al. 2014 Veterinary Parasitology paper was the first paper published supporting the launch of a developed member of this class. It included efficacy data in dogs and showed mode of action Afoxolaner. Previous works were experimental one-offs that had little or no relevance to the commercial compounds of today.


    The authors state in the Discussion 'Thus, as a class of drugs, isoxazolines work as intrinsic neurotoxins across species.' No, they do not. The authors note that they are 'highly potent arthropod-specific'. What part of that do they not understand? The word 'highly' is a relative word not an absolute word. Experimental data on these drugs show there is a large difference between arthropod and mammalian GABA receptors, but not an absolute one. Where the line is crossed in Veterinary Medicine I do not know, but I know the authors have not shown the line being crossed with these survey results nor with the AE results of the regulatory bodies.


    The Abstract ends by saying 'These survey data support the need for continued cross-species studies and critical review of product labeling by regulatory agencies and manfacturers' which is a great deal tamer than how the Discussion ends which is "We believe that the FDA should consider additional changes to their criteria for AE observation, and define what would be needed for them to reconsider clearance of this class of drugs.' That last phrase is a bomb. It seems to suggest the authors seek removal of the approval of these drugs based on survey results. Wow!


    I went back and forth between Major Revision and Reject and settled on Major Revision. I don't want to silence anyone especially if there is a possibility of animals being harmed. But the evidence I have seen is to the contrary and shows that this is a highly efficacious drug with few side effects. If someone thinks they are not then let them show real convincing data. If the Editor and Authors want the survey results put on the record I would not wish to stop them, but I would ask that the above criticisms be seriously considered.

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    Reviewer report
    2020/02/11

    I am struggling to make sense of the numbers when the authors acknowledge the inherent bias of voluntary reports that weight heavily towards adverse effects. The authors seem to think that they are somewhat immunized from this bias because they included questions to include with or without AE and that 36.1% did not see any AE at all. That ought to tell them something right there. I believe that ~60% of dosed dogs in their survey had AE, but I do not believe that projects to ~60% of dosed dogs having an AE in the normal population. This type of percentage if real would be intolerable and financially unsustainable for any of the manufacturers. So if they are not real, what value are they? What do they mean? Further, if we do not know how many total doses are given to dogs in the same period as this survey, how are we to put any of this in context?

    The opening sentence of the Intro state the isoxazoline class have been developed for at least 20 years. No they have not. The Shoop et al. 2014 Veterinary Parasitology paper was the first paper published supporting the launch of a developed member of this class. It included efficacy data in dogs and showed mode of action Afoxolaner. Previous works were experimental one-offs that had little or no relevance to the commercial compounds of today.

    The authors state in the Discussion 'Thus, as a class of drugs, isoxazolines work as intrinsic neurotoxins across species.' No, they do not. The authors note that they are 'highly potent arthropod-specific'. What part of that do they not understand? The word 'highly' is a relative word not an absolute word. Experimental data on these drugs show there is a large difference between arthropod and mammalian GABA receptors, but not an absolute one. Where the line is crossed in Veterinary Medicine I do not know, but I know the authors have not shown the line being crossed with these survey results nor with the AE results of the regulatory bodies.

    The Abstract ends by saying 'These survey data support the need for continued cross-species studies and critical review of product labeling by regulatory agencies and manfacturers' which is a great deal tamer than how the Discussion ends which is "We believe that the FDA should consider additional changes to their criteria for AE observation, and define what would be needed for them to reconsider clearance of this class of drugs.' That last phrase is a bomb. It seems to suggest the authors seek removal of the approval of these drugs based on survey results. Wow!

    I went back and forth between Major Revision and Reject and settled on Major Revision. I don't want to silence anyone especially if there is a possibility of animals being harmed. But the evidence I have seen is to the contrary and shows that this is a highly efficacious drug with few side effects. If someone thinks they are not then let them show real convincing data. If the Editor and Authors want the survey results put on the record I would not wish to stop them, but I would ask that the above criticisms be seriously considered.

    Reviewed by
    Cite this review
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    Reviewer report
    2020/02/08

    The paper is quite repetitive.

    Line 39-40: I believe you are missing an 'as'

    How was the survey distributed? What are the pitfalls of this type of sampling (please provide references)?

    Line 106: Reference?

    Line 130: Are neurologic effects defined the same across the reporting platforms? What are 'behavior changes?'

    Line 159-160: What are the pharmacokinetics? How to they differ for each substance? This is the fatal flaw in your questionnaire. You do not ask the onset of adverse events after the dosing of the flea/tick medication. The way the questions are written the onset could be from minutes to 3 months afterwards. Several of these products are long gone from the body by 3 months. By not providing a time frame you increase the potential for 'adverse effects' to occur and therefore taint your data with unrelated items. This makes your hypothesis of under-reporting flawed.

    Line 204: Time frame?

    Line 301-302: What are the differences?

    Question 2: Continuous? Intermittent? Not everyone lives were ectoparasites are found all year round.

    Question 3: I assume shampoo, spray, dip and collars fall under topical.

    Question 5: What is an 'adverse effect?'

    Question 7 and 13: Missing time frame

    Question 36: SAMe is not milk thistle (it does not contain silymarin)

    Question 41: What is 'barely' recover?

    Question 45: Were any of these performed? Did any indicate the cause of death?

    Reviewed by
    Cite this review
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    Reviewer report
    2020/01/14

    The mansucript can be accepted in its revised form.

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    Author Response
    2019/12/24

    Response to Reviewer’s Comments for Manuscript ID VMS3-2019-Oct -0265
    The authors thank the reviewers for their helpful comments and are responding below:
    Reviewer #1
    1. The Introduction (page 2, lines 32-48) has been expanded as suggested and the cited references are included. The Gaens et al paper from 2019 had not been published when we prepared our Manuscript, so thank you for including it.
    2. We concur about the mode of action of isooxazoline class of compounds, and that for most pets these drugs are safe. The role of the MDR1 efflux carrier potentially acting at the blood-brain barrier, as well as the potential role of isoxazolines in causing excessive bleeding (Quan et al. J Med Chem 42:2760-2773, 1999) from their known antithrombotic effect (inhibitors of Factor Xa), and hemolysis from their red blood cell membrane lipid bilayer affinity have been included (page 2, lines 38-41).

    3. We had provided the Survey Questionnaire to the Journal along with the Manuscript and have now made it part of the revision (See Attachment). We have also specified in more detail the collection of the EMA and FDA pharmacovigilance data (page 4, lines 80-83; 85-86).
    4. We recognize this likelihood, but 36.1% of the survey respondents indicated that they did not see any AE and another 8.2% were unsure (page 1, lines 4-5; page 3, 76-78; page 5, 111-113).
    5. We have explained why data on Spinosad were included. Spinosad was listed in both the FDA and EMA reports, so we decided that we should not selectively exclude it from their reports. (page 5, lines 121-122).
    6.We are unaware beyond the manufacturer’s advertising and marketing materials how many of the products have been sold. Further, neither the FDA nor EMA address the total doses or treatments given in their data, and the package inserts do not delineate how many animals were treated and how many has serious AE. Presumably, like pet vaccines with their real, albeit rare AEs, they are in the millions, if not more. These comments have been included (page 4, lines 97-101).
    7. We chose to focus just on the dog rather than include cats (page 3, lines 75-76).
    8. The active compounds have now been listed by their PubChem formulas as footnotes to Tables 1 and 2.


    Reviewer #2
    We believe that our revised manuscript has addressed the comments of this reviewer and disagree that our paper lacks scientific rigor. We have added additional references as suggested. We also have added two-tailed Z-test statistical differences between the severe AE in the Project Jake Survey with those reported by the FDA and EMA reports (See Table below; all were highly significant at Z <0.00001). The statisticians in our group have stated from the outset that in depth statistical analyses cannot be applied to this type of survey (page 4, lines 90-93; pages 9 &10, 232-238).


    Severe Reaction Z-test for difference in two proportions (two tailed) P-value
    Bravecto NexGard Simparica
    Survey vs EMA Survey vs FDA Survey vs EMA Survey vs FDA Survey vs EMA Survey vs FDA
    Death < .00001 < .00001 < .00001 < .00001 < .00001 < .00001
    Seizures/Convulsions < .00001 < .00001 < .00001 < .00001 < .00001 < .00001
    Ataxia/Instability/Imbalance < .00001 < .00001 < .00001 < .00001 < .00001 < .00001



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  • pre-publication peer review (ROUND 1)
    Decision Letter
    2019/12/08

    08-Dec-2019


    Dear Dr. Dodds:


    Manuscript ID VMS3-2019-Oct-0265 entitled "Survey of Canine Use and Safety of Isoxazoline Parasiticides" which you submitted to Veterinary Medicine and Science, has been reviewed. Some revisions to your manuscript have been recommended. Therefore, I invite you to respond to the comments appended below and revise your manuscript.


    Before submitting your revisions:




    1. Prepare a response to the reviewer comments appended below in point-by-point fashion. In order to expedite the processing of the revised manuscript, please be as specific as possible in your response and indicate the page numbers in the manuscript where you have addressed each comment.




    2. Prepare a revised manuscript (word document), highlighting the changes you’ve made in track changes. Save this new document on your computer as you will be asked to upload it during the revision submission process. Please ensure that the changes and comments on your revised manuscript (word document) are anonymised. To do this, in Microsoft Word, select ‘inspect document’. From there, a dialogue box should open called ‘Document Inspector’. Inspect ‘document properties and personal information’ and remove all personal information saved within the document. NOTE: Please be sure to keep in mind reviewer comments and incorporate your responses within the manuscript. There may well be areas where you disagree; for example, you may want to write, "A reviewer suggests that... However, I disagree because...". In any case, please try to address all of the concerns that are raised within the manuscript.




    3. In addition to your revised manuscript with changes highlighted, please also save a “clean” copy where the changes are not marked.




    To submit your revised manuscript:



    1. Log in by clicking on the link below


    PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm.


    https://mc.manuscriptcentral.com/vetmedsci?URL_MASK=63e6c28e5c4f472fb08eaccde1105a1d


    OR


    Log into https://mc.manuscriptcentral.com/vetmedsci and click on Author Center. Under author resources, use the button “Click here to submit a revision”. PLEASE DO NOT SUBMIT YOUR REVISIONS AS A NEW MANUSCRIPT.




    1. Follow the on-screen instructions. First you will be asked to provide your “Response to Decision Letter”—this is the response to reviewer comments that you prepared earlier.




    2. Click through the next few screens to verify that all previously provided information is correct.




    3. File Upload: Delete any files that you will be replacing (this includes your old manuscript). Upload your new revised manuscript file with changes highlighted, a “clean” copy of your revised manuscript file, any replacement figures/tables, or any new files. Once this is complete, the list of files in the “My Files” section should ONLY contain the final versions of everything. REMEMBER: figures/tables should be in jpeg, tiff, or eps format. If you haven't done so already, please consider uploading an image of the organism(s) studied in your paper to be considered for online cover and blog publication.




    4. Review and submit: please be sure to double-check everything carefully so that your manuscript can be processed as quickly as possible.




    Deadlines:
    Because we are trying to facilitate timely publication of manuscripts submitted to Veterinary Medicine and Science,your revised manuscript should be uploaded as soon as possible. If it is not possible for you to submit your revision in 2 months, we may have to consider your paper as a new submission. If you feel that you will be unable to submit your revision within the time allowed please contact me to discuss the possibility of extending the revision time.


    If you feel that your paper could benefit from English language polishing, you may wish to consider having your paper professionally edited for English language by a service such as Wiley’s at http://wileyeditingservices.com. Please note that while this service will greatly improve the readability of your paper, it does not guarantee acceptance of your paper by the journal.


    Once again, thank you for submitting your manuscript to Veterinary Medicine and Science and I look forward to receiving your revision.


    Sincerely,
    Prof. Gayle Hallowell
    Editor in Chief, Veterinary Medicine and Science
    gayle.hallowell@nottingham.ac.uk


    Associate Editor Comments to Author:


    Associate Editor
    Comments to the Author:
    Thank you for submitting your manuscript to Veterinary Medicine and Science. As you can see from the comments attached, the reviewers have recommended revisions to your manuscript. If the manuscript can be revised to satisfy these concerns, we would be willing to reevaluate it.


    Reviewer(s)' Comments to Author:


    Reviewer: 1


    Comments to the Author
    The authors provide data from a veterinarian and pet owner survey examining the use and safety of isoxazoline parasiticides given to dogs and compare this data with the official FDA and EMA adverse event recording. Although the manuscript provides interesting and important information to the field, there are some concerns that have to be addressed.




    1. The introduction into the topic is sparse. Only three papers are cited and discussed. There are some more paper that are obligatory to be mentioned, including: Garcia-Reynaga et al. (2013) Chem Res Toxicol 26:514-516, Nakata et al. (2017) Mol Pharmacol 92:546-555, Ozoe et al. (2010) Biochem Biophys Res Commun 391:744–749, Zhao and Casida (2014) J Agric Food Chem 62:1019-24. Furthermore, there is a case report describing neurological toxicity in a dog that received fluralaner (Gaens et al. (2019) BMC Vet Res 15:283) that has to be mentioned and discussed.




    2. The point is that based on their mode of action as negative allosteric modulators of parasite GABA-gated chloride channels, isoxazoline drugs have at least the theoretical potential to provoke convulsive effects on vertebrate GABA receptors which structurally belong to the same receptor class of Cys-loop receptors. Selectivity for the first against the other has not convincingly be shown so that excitatory adverse events in dogs and cats might have a mechanistic explanation. Nevertheless, isoxazoline drugs are safe in the vast majority of the patients. Factors that might predispose patient for such kind of adverse events are currently unknown, however, a role of the MDR1 efflux carrier at the blood-brain barrier has been discussed.




    3. At the beginning of the discussion it is outlined how the survey was designed. Here, in addition the original questionair should be provided as supplementary material. Furthermore, it is neccesary to provide more details for data collection of the EMA and FDA pharmacovigilance cases. A major concern is that all official PV cases are evaluated by a specific protocoll and end up in a classification level. Unfortunately, this is neither mentioned nor discussed here.




    4. A serious bias of the survey is that participation is more likely when severe adverse events occur in a dog and it can be speculated that the feedback is as more frequent as more severe the AE occured.




    5. It is not finally clear why spinosad was included in the mauscript. All would be more concise when the focus would only be on the isoxazolin drugs.




    6. If available the number of sold products should be included and related to the number of AE cases reported here as this might help to better estimate how freuquent these AE really are.




    7. Why only dogs were included. Isoxazoline drugs are also used in cats.




    8. Include the active compounds in Table 1




    Reviewer: 2


    Comments to the Author
    This paper pulled FDA and EMA AE reports to compare to own research results. This data is useful in a comprehensive review of isoxazoline AE reports, but has not been presented in a manner that is analysed or reported appropriately for this. The paper is lacking in description of survey methods, statistical analysis, appropriate literature citation (many multi-centric studies from USA/EU omitted), appropriate AE reporting methods, and interpretation. Inflammatory language/opinions should be removed from the paper or restricted to the discussion section.
    Overall, I appreciate the efforts to promote safer product use and hold pharmaceutical companies to a high standard of care, but this paper lacks in scientific rigor to do that.

    Decision letter by
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    Reviewer report
    2019/12/03

    This paper pulled FDA and EMA AE reports to compare to own research results. This data is useful in a comprehensive review of isoxazoline AE reports, but has not been presented in a manner that is analysed or reported appropriately for this. The paper is lacking in description of survey methods, statistical analysis, appropriate literature citation (many multi-centric studies from USA/EU omitted), appropriate AE reporting methods, and interpretation. Inflammatory language/opinions should be removed from the paper or restricted to the discussion section.
    Overall, I appreciate the efforts to promote safer product use and hold pharmaceutical companies to a high standard of care, but this paper lacks in scientific rigor to do that.

    Reviewed by
    Cite this review
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    Reviewer report
    2019/11/14

    The authors provide data from a veterinarian and pet owner survey examining the use and safety of isoxazoline parasiticides given to dogs and compare this data with the official FDA and EMA adverse event recording. Although the manuscript provides interesting and important information to the field, there are some concerns that have to be addressed.

    1. The introduction into the topic is sparse. Only three papers are cited and discussed. There are some more paper that are obligatory to be mentioned, including: Garcia-Reynaga et al. (2013) Chem Res Toxicol 26:514-516, Nakata et al. (2017) Mol Pharmacol 92:546-555, Ozoe et al. (2010) Biochem Biophys Res Commun 391:744–749, Zhao and Casida (2014) J Agric Food Chem 62:1019-24. Furthermore, there is a case report describing neurological toxicity in a dog that received fluralaner (Gaens et al. (2019) BMC Vet Res 15:283) that has to be mentioned and discussed.

    2. The point is that based on their mode of action as negative allosteric modulators of parasite GABA-gated chloride channels, isoxazoline drugs have at least the theoretical potential to provoke convulsive effects on vertebrate GABA receptors which structurally belong to the same receptor class of Cys-loop receptors. Selectivity for the first against the other has not convincingly be shown so that excitatory adverse events in dogs and cats might have a mechanistic explanation. Nevertheless, isoxazoline drugs are safe in the vast majority of the patients. Factors that might predispose patient for such kind of adverse events are currently unknown, however, a role of the MDR1 efflux carrier at the blood-brain barrier has been discussed.

    3. At the beginning of the discussion it is outlined how the survey was designed. Here, in addition the original questionair should be provided as supplementary material. Furthermore, it is neccesary to provide more details for data collection of the EMA and FDA pharmacovigilance cases. A major concern is that all official PV cases are evaluated by a specific protocoll and end up in a classification level. Unfortunately, this is neither mentioned nor discussed here.

    4. A serious bias of the survey is that participation is more likely when severe adverse events occur in a dog and it can be speculated that the feedback is as more frequent as more severe the AE occured.

    5. It is not finally clear why spinosad was included in the mauscript. All would be more concise when the focus would only be on the isoxazolin drugs.

    6. If available the number of sold products should be included and related to the number of AE cases reported here as this might help to better estimate how freuquent these AE really are.

    7. Why only dogs were included. Isoxazoline drugs are also used in cats.

    8. Include the active compounds in Table 1

    Reviewed by
    Cite this review
    Endorsed by
    Ongoing discussion (0 comments - click to toggle)
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