Reviewer's report
Title:Cost-Effectiveness of Sofosbuvir-Based Treatments for Chronic Hepatitis C
Version:2Date:9 February 2015
Reviewer: Sergio Iannazzo
Reviewer's report:
This is an interesting study, focused on a topic that deserves a lot of attention
today: new treatments for Hepatitis C. A new breadth of treatments is becoming
available in these days, and their effectiveness is in some cases impressive, but
all of them are coming to market with important costs to be borne by National
Healthcare Systems (in Europe) or by third-party payers (in the US). This is
motivating the emphasis on health economic assessment in this field. The
current study seems well conducted or at least in line with the current standard of
modelling in this therapeutic area. One major limitation is however the lack of
mention to treatments newer than Sofosbuvir, that have been approved by the
FDA and included in the latest revision of the clinical guidelines for CHC in the
US (AASLD). For this and other reasons detailed here below, I believe that this
paper requires some revision before being considered for publication.
Major Compulsory Revisions
1.Abstract. The description of the comparators tested in the cost-effectiveness
analysis is not clear in the abstract. Please list them out clearly. A sentences like
“different treatment strategies” is too generic and does not inform the readers on
what have been really studied in this analysis
2.Abstract, results section. Please describe (in the methods section, see previous
comment) what is meant by “two-phase treatments”
3.Abstract row 11; Methods first paragraph. Can the authors explain why their
analysis is limited to males only? Further on this point, what is the basis for the
assumption of 45 years initial age of the simulated cohort? Is this based on the
cohort characteristics in anyone of the mentioned RCTs of sofosbuvir? This
would be acceptable but needs to be specified.
4.Background, third paragraph. The authors state that “Recently, sofosbuvir
(brand name Sovaldi) as a new component of interferon-free oral regimen has
been approved by the U.S. Food and Drug Administration (FDA) for treating
CHC.” The approval of sovaldi dates back to December 2013. More than one
year is quite a long time frame in this rapidly evolving therapeutic area. There is
now an assortment of hepatitis C treatments. This includes Viekira Pak
(ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets),
Olysio (simeprevir) and Harvoni (ledipasvir and sofosbuvir), just to mention the
latest approvals. The latest update of the clinical guideline by the AASLD (and
other organizations) has already included all of them
(http://www.hcvguidelines.org). In this context the current analysis presenting a
comparison of Sovaldi with Peginterferon-ribavarin (P/R) appears to be
out-dated. As a consequence the authors need to clarify what was driving the
design of their analysis. Was this driven by the fact that, regardless the
abundance of more effective treatments for CHR, P/R is still regarded as the
standard of care? Or was this simply linked to the available clinical evidence of
the effectiveness of sofosbuvir (i.e. availability of only the comparison with P/R
from RCTs)? This should be discussed and explained in the introduction /aim
and discussion sections (as a clear limitation of the analysis).
5.Methods, second paragraph. The authors declare that all costs were inflated to
2013 dollars. Please add the reference for the relevant price index that was used.
Since we are today in 2015, I believe that a refresh of costs is needed. Please
revise the costs in the analysis using the latest available price index (Q3 2014?).
6.Methods, Sensitivity analysis. The authors declare “In addition to one-way
sensitivity analyses for all variables, we consider the effect of simultaneously
changing all of the parameters values in the same direction.” This type of
analysis is providing just a limited information on the overall stability of the model,
because some parameters can have a positive impact of the ICER (for instance
cost parameters) while others have a negative one (for instance the effectiveness
of the studied drug). Thus while setting all parameters in the same direction their
summed effect may elide one with the other. A standard approach to test the
overall stability of a model is to perform a probabilistic sensitivity analysis, and to
verify the reliability of base case results with cost-effectiveness acceptability
curves. I recommend performing this analysis.
7.Table 7.1 and table 7.2 in Results section. The layout of these 2 tables should
be improved to provide more clarity. More in detail the ICERs in the last column
to the right are calculated with what comparators? Please also specify the
criterion used (i.e. the threshold) to judge one alternative “inefficient”
8.Results, Sensitivity analysis. The section that reports the results of the one-way
sensitivity is poorly detailed. Sentences like “little effect” or “certain parameters
changes” are too generic. The entire section needs to be revised in order to
provide more punctual information. I recommend including some sort of visual
representation of the uncertainty, like for instance tornado diagrams. These can
be included as appendixes.
9.The paper is missing a true discussion, to guide the interpretation of the results
obtained in the context of similar studies published (for the US and/or other
countries) and to discuss the limits of the analysis, with specific reference to the
selection of comparators (see point 4)
Minor Essential Revisions
10.Abstract, row 5. Please specify that the price of $84,000 is applicable to the
US. Alternatively add the setting of the cost-effectiveness analysis (i.e. the US) in
the title.
11.Abstract, row 11. “Treatment-native” should read “treatment-naïve”. Please
correct it trough all the paper (the same spelling error is present in the main text
in some instances)
12.Methods second row of second paragraph. If the analysis is limited just to
males (this has, however, to be explained, see relevant comment among the
major revisions) then “he/she” should read “he”
13.Methods, Health-State Related Quality Adjusted Life Years. The cited sources
(i.e. 6, 20, 22, 23) for utilities appear to be previously published
cost-effectiveness analysis, which, in turn, should have derived them by QoL
studies. Please updated the reference, citing the original QoL study, or
alternatively declare that your model is in line with previously published models
14.Table 7.1 The number of the table and the legend is repeated identically for
two subsequent tables. Please adjust the numbers and the legend.
15.Conclusions, row 18. Please correct spelling error “they did not significantly
impacting
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:Cost-Effectiveness of Sofosbuvir-Based Treatments for Chronic Hepatitis C
Version:2Date:9 February 2015
Reviewer: Sergio Iannazzo
Reviewer's report:
This is an interesting study, focused on a topic that deserves a lot of attention
today: new treatments for Hepatitis C. A new breadth of treatments is becoming
available in these days, and their effectiveness is in some cases impressive, but
all of them are coming to market with important costs to be borne by National
Healthcare Systems (in Europe) or by third-party payers (in the US). This is
motivating the emphasis on health economic assessment in this field. The
current study seems well conducted or at least in line with the current standard of
modelling in this therapeutic area. One major limitation is however the lack of
mention to treatments newer than Sofosbuvir, that have been approved by the
FDA and included in the latest revision of the clinical guidelines for CHC in the
US (AASLD). For this and other reasons detailed here below, I believe that this
paper requires some revision before being considered for publication.
Major Compulsory Revisions
1.Abstract. The description of the comparators tested in the cost-effectiveness
analysis is not clear in the abstract. Please list them out clearly. A sentences like
“different treatment strategies” is too generic and does not inform the readers on
what have been really studied in this analysis
2.Abstract, results section. Please describe (in the methods section, see previous
comment) what is meant by “two-phase treatments”
3.Abstract row 11; Methods first paragraph. Can the authors explain why their
analysis is limited to males only? Further on this point, what is the basis for the
assumption of 45 years initial age of the simulated cohort? Is this based on the
cohort characteristics in anyone of the mentioned RCTs of sofosbuvir? This
would be acceptable but needs to be specified.
4.Background, third paragraph. The authors state that “Recently, sofosbuvir
(brand name Sovaldi) as a new component of interferon-free oral regimen has
been approved by the U.S. Food and Drug Administration (FDA) for treating
CHC.” The approval of sovaldi dates back to December 2013. More than one
year is quite a long time frame in this rapidly evolving therapeutic area. There is
now an assortment of hepatitis C treatments. This includes Viekira Pak
(ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets),
Olysio (simeprevir) and Harvoni (ledipasvir and sofosbuvir), just to mention the
latest approvals. The latest update of the clinical guideline by the AASLD (and
other organizations) has already included all of them
(http://www.hcvguidelines.org). In this context the current analysis presenting a
comparison of Sovaldi with Peginterferon-ribavarin (P/R) appears to be
out-dated. As a consequence the authors need to clarify what was driving the
design of their analysis. Was this driven by the fact that, regardless the
abundance of more effective treatments for CHR, P/R is still regarded as the
standard of care? Or was this simply linked to the available clinical evidence of
the effectiveness of sofosbuvir (i.e. availability of only the comparison with P/R
from RCTs)? This should be discussed and explained in the introduction /aim
and discussion sections (as a clear limitation of the analysis).
5.Methods, second paragraph. The authors declare that all costs were inflated to
2013 dollars. Please add the reference for the relevant price index that was used.
Since we are today in 2015, I believe that a refresh of costs is needed. Please
revise the costs in the analysis using the latest available price index (Q3 2014?).
6.Methods, Sensitivity analysis. The authors declare “In addition to one-way
sensitivity analyses for all variables, we consider the effect of simultaneously
changing all of the parameters values in the same direction.” This type of
analysis is providing just a limited information on the overall stability of the model,
because some parameters can have a positive impact of the ICER (for instance
cost parameters) while others have a negative one (for instance the effectiveness
of the studied drug). Thus while setting all parameters in the same direction their
summed effect may elide one with the other. A standard approach to test the
overall stability of a model is to perform a probabilistic sensitivity analysis, and to
verify the reliability of base case results with cost-effectiveness acceptability
curves. I recommend performing this analysis.
7.Table 7.1 and table 7.2 in Results section. The layout of these 2 tables should
be improved to provide more clarity. More in detail the ICERs in the last column
to the right are calculated with what comparators? Please also specify the
criterion used (i.e. the threshold) to judge one alternative “inefficient”
8.Results, Sensitivity analysis. The section that reports the results of the one-way
sensitivity is poorly detailed. Sentences like “little effect” or “certain parameters
changes” are too generic. The entire section needs to be revised in order to
provide more punctual information. I recommend including some sort of visual
representation of the uncertainty, like for instance tornado diagrams. These can
be included as appendixes.
9.The paper is missing a true discussion, to guide the interpretation of the results
obtained in the context of similar studies published (for the US and/or other
countries) and to discuss the limits of the analysis, with specific reference to the
selection of comparators (see point 4)
Minor Essential Revisions
10.Abstract, row 5. Please specify that the price of $84,000 is applicable to the
US. Alternatively add the setting of the cost-effectiveness analysis (i.e. the US) in
the title.
11.Abstract, row 11. “Treatment-native” should read “treatment-naïve”. Please
correct it trough all the paper (the same spelling error is present in the main text
in some instances)
12.Methods second row of second paragraph. If the analysis is limited just to
males (this has, however, to be explained, see relevant comment among the
major revisions) then “he/she” should read “he”
13.Methods, Health-State Related Quality Adjusted Life Years. The cited sources
(i.e. 6, 20, 22, 23) for utilities appear to be previously published
cost-effectiveness analysis, which, in turn, should have derived them by QoL
studies. Please updated the reference, citing the original QoL study, or
alternatively declare that your model is in line with previously published models
14.Table 7.1 The number of the table and the legend is repeated identically for
two subsequent tables. Please adjust the numbers and the legend.
15.Conclusions, row 18. Please correct spelling error “they did not significantly
impacting
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:Cost-Effectiveness of Sofosbuvir-Based Treatments for Chronic Hepatitis C
Version:2Date:9 February 2015
Reviewer: Sergio Iannazzo
Reviewer's report:
This is an interesting study, focused on a topic that deserves a lot of attention
today: new treatments for Hepatitis C. A new breadth of treatments is becoming
available in these days, and their effectiveness is in some cases impressive, but
all of them are coming to market with important costs to be borne by National
Healthcare Systems (in Europe) or by third-party payers (in the US). This is
motivating the emphasis on health economic assessment in this field. The
current study seems well conducted or at least in line with the current standard of
modelling in this therapeutic area. One major limitation is however the lack of
mention to treatments newer than Sofosbuvir, that have been approved by the
FDA and included in the latest revision of the clinical guidelines for CHC in the
US (AASLD). For this and other reasons detailed here below, I believe that this
paper requires some revision before being considered for publication.
Major Compulsory Revisions
1.Abstract. The description of the comparators tested in the cost-effectiveness
analysis is not clear in the abstract. Please list them out clearly. A sentences like
“different treatment strategies” is too generic and does not inform the readers on
what have been really studied in this analysis
2.Abstract, results section. Please describe (in the methods section, see previous
comment) what is meant by “two-phase treatments”
3.Abstract row 11; Methods first paragraph. Can the authors explain why their
analysis is limited to males only? Further on this point, what is the basis for the
assumption of 45 years initial age of the simulated cohort? Is this based on the
cohort characteristics in anyone of the mentioned RCTs of sofosbuvir? This
would be acceptable but needs to be specified.
4.Background, third paragraph. The authors state that “Recently, sofosbuvir
(brand name Sovaldi) as a new component of interferon-free oral regimen has
been approved by the U.S. Food and Drug Administration (FDA) for treating
CHC.” The approval of sovaldi dates back to December 2013. More than one
year is quite a long time frame in this rapidly evolving therapeutic area. There is
now an assortment of hepatitis C treatments. This includes Viekira Pak
(ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets),
Olysio (simeprevir) and Harvoni (ledipasvir and sofosbuvir), just to mention the
latest approvals. The latest update of the clinical guideline by the AASLD (and
other organizations) has already included all of them
(http://www.hcvguidelines.org). In this context the current analysis presenting a
comparison of Sovaldi with Peginterferon-ribavarin (P/R) appears to be
out-dated. As a consequence the authors need to clarify what was driving the
design of their analysis. Was this driven by the fact that, regardless the
abundance of more effective treatments for CHR, P/R is still regarded as the
standard of care? Or was this simply linked to the available clinical evidence of
the effectiveness of sofosbuvir (i.e. availability of only the comparison with P/R
from RCTs)? This should be discussed and explained in the introduction /aim
and discussion sections (as a clear limitation of the analysis).
5.Methods, second paragraph. The authors declare that all costs were inflated to
2013 dollars. Please add the reference for the relevant price index that was used.
Since we are today in 2015, I believe that a refresh of costs is needed. Please
revise the costs in the analysis using the latest available price index (Q3 2014?).
6.Methods, Sensitivity analysis. The authors declare “In addition to one-way
sensitivity analyses for all variables, we consider the effect of simultaneously
changing all of the parameters values in the same direction.” This type of
analysis is providing just a limited information on the overall stability of the model,
because some parameters can have a positive impact of the ICER (for instance
cost parameters) while others have a negative one (for instance the effectiveness
of the studied drug). Thus while setting all parameters in the same direction their
summed effect may elide one with the other. A standard approach to test the
overall stability of a model is to perform a probabilistic sensitivity analysis, and to
verify the reliability of base case results with cost-effectiveness acceptability
curves. I recommend performing this analysis.
7.Table 7.1 and table 7.2 in Results section. The layout of these 2 tables should
be improved to provide more clarity. More in detail the ICERs in the last column
to the right are calculated with what comparators? Please also specify the
criterion used (i.e. the threshold) to judge one alternative “inefficient”
8.Results, Sensitivity analysis. The section that reports the results of the one-way
sensitivity is poorly detailed. Sentences like “little effect” or “certain parameters
changes” are too generic. The entire section needs to be revised in order to
provide more punctual information. I recommend including some sort of visual
representation of the uncertainty, like for instance tornado diagrams. These can
be included as appendixes.
9.The paper is missing a true discussion, to guide the interpretation of the results
obtained in the context of similar studies published (for the US and/or other
countries) and to discuss the limits of the analysis, with specific reference to the
selection of comparators (see point 4)
Minor Essential Revisions
10.Abstract, row 5. Please specify that the price of $84,000 is applicable to the
US. Alternatively add the setting of the cost-effectiveness analysis (i.e. the US) in
the title.
11.Abstract, row 11. “Treatment-native” should read “treatment-naïve”. Please
correct it trough all the paper (the same spelling error is present in the main text
in some instances)
12.Methods second row of second paragraph. If the analysis is limited just to
males (this has, however, to be explained, see relevant comment among the
major revisions) then “he/she” should read “he”
13.Methods, Health-State Related Quality Adjusted Life Years. The cited sources
(i.e. 6, 20, 22, 23) for utilities appear to be previously published
cost-effectiveness analysis, which, in turn, should have derived them by QoL
studies. Please updated the reference, citing the original QoL study, or
alternatively declare that your model is in line with previously published models
14.Table 7.1 The number of the table and the legend is repeated identically for
two subsequent tables. Please adjust the numbers and the legend.
15.Conclusions, row 18. Please correct spelling error “they did not significantly
impacting
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests:
I declare that I have no competing interests
assistant