Reviewer’s report
Title: 
Evaluating Cost Per Remission and Cost of Serious Adverse Events of
Advanced Therapies for Ulcerative Colitis
Version: 
0 
Date: 
11 Apr 2022
Reviewer: 
Amanda Tatro
Reviewer's report:
Thank you for the opportunity to review. 
Congratulations to the authors for this analysis taking a more comprehensive
approach to understanding the financial impact of the selection of different
targeted therapies for UC. 
Please see below the comments by section. 
Methods
Ttofacitinib is described as 2 regimens. Would be more accurate to describe it as
a single regimen in induction and 2 in maintenance
Ustekinumab induction - note single dose as all others have frequency. Appears
as an omission when it is a description of a single dose
No Vedo SC data? It is included in the referenced NMA and appears as an
omission here
Ratione for inclusion of different defintions of repsonse/remission is included but
no comment is included regarding the different time points for assessment on
induction and maintenance. Would be useful, particularly for the induction to
include a comment on the rationale for inclusion of the width of the range.
Alternatively, include a comment in the discussion on the lack of standardization
and any impact the authors think could have resulted.
Would appreciate a statement regarding how different study types, eg, re-
randomization and treat straight through were handled. Understand this is
addressed in greater detail in the referenced NMA, but I find the differences in
study types relevant and would appreciate some summary statement be included
here as well. Later statement regarding costs per maintenance remission suggests
that treat-straight-through were evaluated as re-randomization (eg, denominator
of induction responders) but this is not stated in the NNT methods section and it
would be useful to include here to allow clarity for other sections.
Table 1 - recommend adding the induction regimen assumed in the footnotes as
the rows list only the maintenance dosing 
NNH - for the costs of the different SAE/SI, it would be helpful to understand
what types of costs compose the costs included, eg, direct costs, inpatient care,
medication cost, etc. I would also recommend avoid the phrase healthcare
sector's costs. This suggests some understanding of who bares the costs - this is a
fraught question in many systems, esp those where patients bare more of the
costs. 
Costs per SAE reference for use of vedolizuamb as the comparator appears to be
incorrect. Think it should be to 5 not 15. Struggling a bit with this as ref 5 notes
no difference in rates - "All treatments were similar to vedolizumab 300 mg
Q8W with regard to rates of serious adverse events and serious infections, with
no significant differences observed." Think this is a question of significance vs
lowest number but this manuscript needs to note the difference rather than
reading as though it is significantly different 
Site of care - what was defined as the base case? 
Results
Page 9, line 47 - costs of SAE and SI for Vedolizumab were only lowest because
it was held as the reference. This reads as though there were none. Need to
rephrase to make this more clear. As is, could be read to say there were no costs
due to SAE or SI in vedolizumab treated patients when it should be that it was
the reference and the SAE or SI costs of other therapies were considered as in
excess or less than those of vedolizumab
Figure 1 key - need to reorder colors and definitions based on order of
appearance in image above, eg, non responder, induction responder, maintenance
responder, no SAE, SAE
Conclusions
Conclusions statements regarding cost offsets from avoidance of impact of
disease outcomes - authors may want to consider referencing literature on this
topic, either pharmacoeconomic assessments or association of improved
outcomes with avoidance of disease related morbidity, eg, ACT or other
references associating maintenance endoscopy and outcome
Last paragraph on page 12 - 1) how does this study differ from the previously
presented poster - reads as though many of the references are the same though
the manuscript reviewed here includes more recently available agents and some
additional newer references on the older agents - would be ideal to include some
wording here to clarify, 2) sentences 1 and 2 sound redundant - please review
and see if sentence 2 is necessary - if so, please reword to make it clearer what is
added with this sentence
Page 13 description of the network meta-analysis as strong - please provide
some rationale for the use of this word. I am reviewing as a clinical reader not an
expert in NMA. There may be statistical justification for use of this word but
given the differences in study designs and time points of assessment, and the
availability of only a single head-to-head trial to check the assessment against
(with differences in endpoint definitions impacting that comparison), it seems it
is as strong as is possible but not clear why this word is justified. 
Publons Reviewer Recognition
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find the details of processing in Publons’ privacy policy
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Yes
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, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that 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 received 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.
Yes. I am employed by and hold shares of Roche/Genentech who was
developing a therapy for Ulcerative Colitis that would have competed with the
therapies described herein. The trials were unsuccessful and that therapy is not
moving forward for review and approval. 
I have worked on molecules earlier in
the pipeline but these are all at Ph 2 or earlier and will not gain or lose from the
publication of this manuscript.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Evaluating Cost Per Remission and Cost of Serious Adverse Events of
Advanced Therapies for Ulcerative Colitis
Version: 
0 
Date: 
11 Apr 2022
Reviewer: 
Amanda Tatro
Reviewer's report:
Thank you for the opportunity to review. 
Congratulations to the authors for this analysis taking a more comprehensive
approach to understanding the financial impact of the selection of different
targeted therapies for UC. 
Please see below the comments by section. 
Methods
Ttofacitinib is described as 2 regimens. Would be more accurate to describe it as
a single regimen in induction and 2 in maintenance
Ustekinumab induction - note single dose as all others have frequency. Appears
as an omission when it is a description of a single dose
No Vedo SC data? It is included in the referenced NMA and appears as an
omission here
Ratione for inclusion of different defintions of repsonse/remission is included but
no comment is included regarding the different time points for assessment on
induction and maintenance. Would be useful, particularly for the induction to
include a comment on the rationale for inclusion of the width of the range.
Alternatively, include a comment in the discussion on the lack of standardization
and any impact the authors think could have resulted.
Would appreciate a statement regarding how different study types, eg, re-
randomization and treat straight through were handled. Understand this is
addressed in greater detail in the referenced NMA, but I find the differences in
study types relevant and would appreciate some summary statement be included
here as well. Later statement regarding costs per maintenance remission suggests
that treat-straight-through were evaluated as re-randomization (eg, denominator
of induction responders) but this is not stated in the NNT methods section and it
would be useful to include here to allow clarity for other sections.
Table 1 - recommend adding the induction regimen assumed in the footnotes as
the rows list only the maintenance dosing 
NNH - for the costs of the different SAE/SI, it would be helpful to understand
what types of costs compose the costs included, eg, direct costs, inpatient care,
medication cost, etc. I would also recommend avoid the phrase healthcare
sector's costs. This suggests some understanding of who bares the costs - this is a
fraught question in many systems, esp those where patients bare more of the
costs. 
Costs per SAE reference for use of vedolizuamb as the comparator appears to be
incorrect. Think it should be to 5 not 15. Struggling a bit with this as ref 5 notes
no difference in rates - "All treatments were similar to vedolizumab 300 mg
Q8W with regard to rates of serious adverse events and serious infections, with
no significant differences observed." Think this is a question of significance vs
lowest number but this manuscript needs to note the difference rather than
reading as though it is significantly different 
Site of care - what was defined as the base case? 
Results
Page 9, line 47 - costs of SAE and SI for Vedolizumab were only lowest because
it was held as the reference. This reads as though there were none. Need to
rephrase to make this more clear. As is, could be read to say there were no costs
due to SAE or SI in vedolizumab treated patients when it should be that it was
the reference and the SAE or SI costs of other therapies were considered as in
excess or less than those of vedolizumab
Figure 1 key - need to reorder colors and definitions based on order of
appearance in image above, eg, non responder, induction responder, maintenance
responder, no SAE, SAE
Conclusions
Conclusions statements regarding cost offsets from avoidance of impact of
disease outcomes - authors may want to consider referencing literature on this
topic, either pharmacoeconomic assessments or association of improved
outcomes with avoidance of disease related morbidity, eg, ACT or other
references associating maintenance endoscopy and outcome
Last paragraph on page 12 - 1) how does this study differ from the previously
presented poster - reads as though many of the references are the same though
the manuscript reviewed here includes more recently available agents and some
additional newer references on the older agents - would be ideal to include some
wording here to clarify, 2) sentences 1 and 2 sound redundant - please review
and see if sentence 2 is necessary - if so, please reword to make it clearer what is
added with this sentence
Page 13 description of the network meta-analysis as strong - please provide
some rationale for the use of this word. I am reviewing as a clinical reader not an
expert in NMA. There may be statistical justification for use of this word but
given the differences in study designs and time points of assessment, and the
availability of only a single head-to-head trial to check the assessment against
(with differences in endpoint definitions impacting that comparison), it seems it
is as strong as is possible but not clear why this word is justified. 
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
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, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that 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 received 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.
Yes. I am employed by and hold shares of Roche/Genentech who was
developing a therapy for Ulcerative Colitis that would have competed with the
therapies described herein. The trials were unsuccessful and that therapy is not
moving forward for review and approval. 
I have worked on molecules earlier in
the pipeline but these are all at Ph 2 or earlier and will not gain or lose from the
publication of this manuscript.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Evaluating Cost Per Remission and Cost of Serious Adverse Events of
Advanced Therapies for Ulcerative Colitis
Version: 
0 
Date: 
11 Apr 2022
Reviewer: 
Amanda Tatro
Reviewer's report:
Thank you for the opportunity to review. 
Congratulations to the authors for this analysis taking a more comprehensive
approach to understanding the financial impact of the selection of different
targeted therapies for UC. 
Please see below the comments by section. 
Methods
Ttofacitinib is described as 2 regimens. Would be more accurate to describe it as
a single regimen in induction and 2 in maintenance
Ustekinumab induction - note single dose as all others have frequency. Appears
as an omission when it is a description of a single dose
No Vedo SC data? It is included in the referenced NMA and appears as an
omission here
Ratione for inclusion of different defintions of repsonse/remission is included but
no comment is included regarding the different time points for assessment on
induction and maintenance. Would be useful, particularly for the induction to
include a comment on the rationale for inclusion of the width of the range.
Alternatively, include a comment in the discussion on the lack of standardization
and any impact the authors think could have resulted.
Would appreciate a statement regarding how different study types, eg, re-
randomization and treat straight through were handled. Understand this is
addressed in greater detail in the referenced NMA, but I find the differences in
study types relevant and would appreciate some summary statement be included
here as well. Later statement regarding costs per maintenance remission suggests
that treat-straight-through were evaluated as re-randomization (eg, denominator
of induction responders) but this is not stated in the NNT methods section and it
would be useful to include here to allow clarity for other sections.
Table 1 - recommend adding the induction regimen assumed in the footnotes as
the rows list only the maintenance dosing 
NNH - for the costs of the different SAE/SI, it would be helpful to understand
what types of costs compose the costs included, eg, direct costs, inpatient care,
medication cost, etc. I would also recommend avoid the phrase healthcare
sector's costs. This suggests some understanding of who bares the costs - this is a
fraught question in many systems, esp those where patients bare more of the
costs. 
Costs per SAE reference for use of vedolizuamb as the comparator appears to be
incorrect. Think it should be to 5 not 15. Struggling a bit with this as ref 5 notes
no difference in rates - "All treatments were similar to vedolizumab 300 mg
Q8W with regard to rates of serious adverse events and serious infections, with
no significant differences observed." Think this is a question of significance vs
lowest number but this manuscript needs to note the difference rather than
reading as though it is significantly different 
Site of care - what was defined as the base case? 
Results
Page 9, line 47 - costs of SAE and SI for Vedolizumab were only lowest because
it was held as the reference. This reads as though there were none. Need to
rephrase to make this more clear. As is, could be read to say there were no costs
due to SAE or SI in vedolizumab treated patients when it should be that it was
the reference and the SAE or SI costs of other therapies were considered as in
excess or less than those of vedolizumab
Figure 1 key - need to reorder colors and definitions based on order of
appearance in image above, eg, non responder, induction responder, maintenance
responder, no SAE, SAE
Conclusions
Conclusions statements regarding cost offsets from avoidance of impact of
disease outcomes - authors may want to consider referencing literature on this
topic, either pharmacoeconomic assessments or association of improved
outcomes with avoidance of disease related morbidity, eg, ACT or other
references associating maintenance endoscopy and outcome
Last paragraph on page 12 - 1) how does this study differ from the previously
presented poster - reads as though many of the references are the same though
the manuscript reviewed here includes more recently available agents and some
additional newer references on the older agents - would be ideal to include some
wording here to clarify, 2) sentences 1 and 2 sound redundant - please review
and see if sentence 2 is necessary - if so, please reword to make it clearer what is
added with this sentence
Page 13 description of the network meta-analysis as strong - please provide
some rationale for the use of this word. I am reviewing as a clinical reader not an
expert in NMA. There may be statistical justification for use of this word but
given the differences in study designs and time points of assessment, and the
availability of only a single head-to-head trial to check the assessment against
(with differences in endpoint definitions impacting that comparison), it seems it
is as strong as is possible but not clear why this word is justified. 
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
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, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that 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 received 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.
Yes. I am employed by and hold shares of Roche/Genentech who was
developing a therapy for Ulcerative Colitis that would have competed with the
therapies described herein. The trials were unsuccessful and that therapy is not
moving forward for review and approval. 
I have worked on molecules earlier in
the pipeline but these are all at Ph 2 or earlier and will not gain or lose from the
publication of this manuscript.
Reviewer Publication Consent.
 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
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant