Reviewer ’s report  
 
Title:  Comparative cost -effectiveness of cabozantinib as second -line therapy for patients with 
advanced hepatocellular carcinoma in Germany and the United States  
 
Version: 0 Date: 08 Mar 2020  
 
Reviewer: Sitanshu Sekhar Kar  
 
Reviewer's report:  
 
Thank you for the opportunity to review this article.  
Review and Comments: 'Comparative cost -effectiveness of cabozantinib as second -line therapy 
for patients with advanced hepatocellular carcinoma in Germany and the United States'  
 
1. Despite the increase d survival outcome in clinical trial, the present cost -effectiveness 
study predicts that the Cabozantinib intervention, as systemic therapy for advanced 
hepatocellular carcinoma, is not cost -effective even at 3 times GDP per capita threshold in both 
German y and United States. Cost -effectiveness may be achieved only at the threshold of 6 - or 9-
times GDP per capita in Germany whereas there are very less or no possibility for Cabozantinib 
intervention to be cost -effective in United States even at 6 - or 9- times GDP per capita threshold.  
 
2. The definition of the target population, intervention, model cycle, the time horizon has 
been clearly mentioned and the parameters used for clinical effectiveness, cost and utilities are 
optimal and respective to the Germany  and US health care settings. Robustness of the model is 
validated through univariant and probabilistic sensitivity analyses and the results of sensitivity 
analysis are presented and well -explained.  
 
 
However, there are few clarifications required on the fo llowing comments:  
1. Please provide a brief description about Best Supportive Care and give justification on 
choosing the same as a comparator in the model.  
 
2. It is well justified through the Chi -squared test that there are no significant Cabozantinib -
induced adverse events. However, minimal influence of adverse events on QALY and ICER is 
shown through sensitivity analysis (Ref. Table 5, Page no 17). Whether, is there a difference in 
frequencies or cost for management of the adverse events in the intervent ion and comparator 
scenario? Please provide information on the same (Ref. Table 2 Page no 13).  
 
Thank you,  
 
Sincerely,  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary co ntrols?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included  as confidential comments 
to the editor s, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  Comparative cost -effectiveness of cabozantinib as second -line therapy for patients with 
advanced hepatocellular carcinoma in Germany and the United States  
 
Version: 0 Date: 08 Mar 2020  
 
Reviewer: Sitanshu Sekhar Kar  
 
Reviewer's report:  
 
Thank you for the opportunity to review this article.  
Review and Comments: 'Comparative cost -effectiveness of cabozantinib as second -line therapy 
for patients with advanced hepatocellular carcinoma in Germany and the United States'  
 
1. Despite the increase d survival outcome in clinical trial, the present cost -effectiveness 
study predicts that the Cabozantinib intervention, as systemic therapy for advanced 
hepatocellular carcinoma, is not cost -effective even at 3 times GDP per capita threshold in both 
German y and United States. Cost -effectiveness may be achieved only at the threshold of 6 - or 9-
times GDP per capita in Germany whereas there are very less or no possibility for Cabozantinib 
intervention to be cost -effective in United States even at 6 - or 9- times GDP per capita threshold.  
 
2. The definition of the target population, intervention, model cycle, the time horizon has 
been clearly mentioned and the parameters used for clinical effectiveness, cost and utilities are 
optimal and respective to the Germany  and US health care settings. Robustness of the model is 
validated through univariant and probabilistic sensitivity analyses and the results of sensitivity 
analysis are presented and well -explained.  
 
 
However, there are few clarifications required on the fo llowing comments:  
1. Please provide a brief description about Best Supportive Care and give justification on 
choosing the same as a comparator in the model.  
 
2. It is well justified through the Chi -squared test that there are no significant Cabozantinib -
induced adverse events. However, minimal influence of adverse events on QALY and ICER is 
shown through sensitivity analysis (Ref. Table 5, Page no 17). Whether, is there a difference in 
frequencies or cost for management of the adverse events in the intervent ion and comparator 
scenario? Please provide information on the same (Ref. Table 2 Page no 13).  
 
Thank you,  
 
Sincerely,  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary co ntrols?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included  as confidential comments 
to the editor s, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  Comparative cost -effectiveness of cabozantinib as second -line therapy for patients with 
advanced hepatocellular carcinoma in Germany and the United States  
 
Version: 0 Date: 08 Mar 2020  
 
Reviewer: Sitanshu Sekhar Kar  
 
Reviewer's report:  
 
Thank you for the opportunity to review this article.  
Review and Comments: 'Comparative cost -effectiveness of cabozantinib as second -line therapy 
for patients with advanced hepatocellular carcinoma in Germany and the United States'  
 
1. Despite the increase d survival outcome in clinical trial, the present cost -effectiveness 
study predicts that the Cabozantinib intervention, as systemic therapy for advanced 
hepatocellular carcinoma, is not cost -effective even at 3 times GDP per capita threshold in both 
German y and United States. Cost -effectiveness may be achieved only at the threshold of 6 - or 9-
times GDP per capita in Germany whereas there are very less or no possibility for Cabozantinib 
intervention to be cost -effective in United States even at 6 - or 9- times GDP per capita threshold.  
 
2. The definition of the target population, intervention, model cycle, the time horizon has 
been clearly mentioned and the parameters used for clinical effectiveness, cost and utilities are 
optimal and respective to the Germany  and US health care settings. Robustness of the model is 
validated through univariant and probabilistic sensitivity analyses and the results of sensitivity 
analysis are presented and well -explained.  
 
 
However, there are few clarifications required on the fo llowing comments:  
1. Please provide a brief description about Best Supportive Care and give justification on 
choosing the same as a comparator in the model.  
 
2. It is well justified through the Chi -squared test that there are no significant Cabozantinib -
induced adverse events. However, minimal influence of adverse events on QALY and ICER is 
shown through sensitivity analysis (Ref. Table 5, Page no 17). Whether, is there a difference in 
frequencies or cost for management of the adverse events in the intervent ion and comparator 
scenario? Please provide information on the same (Ref. Table 2 Page no 13).  
 
Thank you,  
 
Sincerely,  
 
 
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary co ntrols?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to asses s any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, funding, or salary from an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares  in an organisation t hat may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents  relating to the content of the  
manuscript?  
 
4. Have you recei ved reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have  no competing interests' 
below. If your reply is yes to any, please give details below.  
 
I declare that I have no competing interests  
 
I agree to the open peer  review policy of the journal. I understan d that my name will be included 
on my report to the authors and, if the manuscript is accepted f or publication, my named report 
including any attachments I upload will be posted on the website along with the author s' 
responses. I agree for my report to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included  as confidential comments 
to the editor s, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant