Author's response to reviews Title: Cost-Effectiveness of 2+1 Dosing of 13-Valent and 10-Valent Pneumococcal Conjugate Vaccines in Canada Authors: Stephanie R Earnshaw (searnshaw@rti.org) Cheryl L McDade (cmcdade@rti.org) Giovanni Zanotti (giovanni.zanotti@pfizer.com) Raymond A Farkouh (rfarkouh@pfizer.com) David Strutton (david.strutton@pfizer.com) Version: 2 Date: 30 March 2012 Author's response to reviews: see over
Peer Review Report BMC Infectious Disease Cost-effectiveness of 2+1 Dosing of 13-Valent and 10-Valent Pneumococcal Conjugate Vaccines in Canada Dear Dr. Principi: MS: 6377847266173214 Thank you for the reviewer / editorial comments in response to our manuscript entitled Costeffectiveness of 2+1 Dosing of 13-Valent and 10-Valent Pneumococcal Conjugate Vaccines in Canada. We thank the reviewers for their constructive feedback which has helped add clarity and has significantly improved the quality/presentation of the manuscript. We believe that we have satisfactorily addressed the comments within the manuscript text. Please find below our responses to each comment (in italics). We have submitted a revised manuscript after incorporating the changes. In this submission, we have submitted eight Microsoft Word documents: Earnshaw Vaccine Manuscript 30March2012 with Highlights(Sent).docx: manuscript with highlighted changes Earnshaw Vaccine Manuscript 30March2012(Sent).docx a clean version of the manuscript Earnshaw Vaccine Appendix 30March2012(Sent).docx a clean version of the appendix. Earnshaw Figure 1 Model Structure 30March2012(Sent).jpg a clean version of Figure 1 Earnshaw Figure 2 Breakeven Analysis 30March2012(Sent).jpg a clean version of Figure 2 Earnshaw Figure 3a Change in PCV7 Serotype Coverage Over Time 30March2012(Sent).jpg a clean version of Figure 3a Earnshaw Figure 3b Serotypes-Coverage for All Pneumococcal Vaccines Over Time 30March2012(Sent).jpg a clean version of Figure 3b Earnshaw Figure 4 Sensitivity Analysis Results 30March2012(Sent).jpg a new, clean version of Figure 4 Please feel free to contact me if you have further questions. We look forward to hearing from you. Sincerely,
Stephanie Earnshaw Reviewer's Comments Reviewer 1: Kristina Bryant Reviewer's report: Major Compulsory Revisions Earnshaw and colleagues compare the cost-effectiveness of a 2+1 dosing schedule of PCV13 to PCV10. This sort of analysis is important and can help inform vaccine policy decisions. Response: thanks However, when all of the authors are employed by or paid the pharmaceutical company that owns the product favored by the analysis, is important to avoid even the hint of bias. On page 11, the authors state that PCV10 is less immunogenic than PCV across the 7 common serotypes. In fact, using WHO defined criteria, PCV10 was non-inferior to PCV7 for serotypes 4, 9V, 14, 18C and 19F. Lower antibody responses were seen for serotypes 6B and 23F. This misrepresentation detracts from the manuscript and the important conclusions it draws. Response: We have clarified this statement in the Direct Effects section. There is also a tendency to emphasize potential disadvantages of PCV10, such as inconsistent effects on pneumococcal carriage, while conversely emphasizing potential advantages of PCV13. The authors make generous assumptions in estimating the indirect effects of PCV13 that may be valid but are not sufficiently supported by the data provided. The authors do acknowledge in the limitations that indirect effects of PCV13 have not been proved. Response: We acknowledge the reviewer s point here. A recent study by the Centers for Disease Control was recently presented at the 8 th International Symposium on Pneumococci & Pneumococcal Diseases. In this study, the CDC reports that PCV13- type IPD is declining among adults (i.e.,nonvaccinated individuals) in the US. (Moore M, Link-Gelles R, Farley M, Schaffner W, Thomas A, Reingold A, Harrison L, Lexau C, Zansky S, Petit S, Gershman K, Scherzinger K, Juni B, Beall B, Whitney C. Impact of 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease, United States, 2010-11. Presented at 8 th International Symposium on Pneumococci & Pneumococcal Diseases. 13March2012.) As a result of this new evidence, we have updated the text in the 1 st paragraph of the Direct Effect section and the 7 th paragraph in the Discussion section. The authors acknowledge that their results are somewhat different than those reported by investigators who based their analysis on pneumococcal epidemiology from Alberta.
One is left to wonder if Quebec data was used because it supported the hypothesis that PCV13 is always dominant vs PCV10. Given regional differences in the epidemiology of pneumococcal vaccine, it should be noted that this analysis is may or may overestimate or underestimate cost-effectiveness for the nation as a whole. Response: We see the reviewers point here. We used the Quebec data because it represents the most recently available epidemiology data. Since the introduction of PCV7, there has been a dramatic drop in disease and PCV7-typed disease. As a result, our guess is that ensuring that we are using the most recent epidemiology data is perhaps more important than ensuring that region specific data are used. Comparing the incidence of IPD that we could use between the different sources, we find that the incidence derived from the Quebec data is actually lower than the IPD incidence reported as being used by Chuck et al (2010) and Morrow et al (2009). Also, looking at Figure 3a, we see that the incidence of PCV7 serotypes are similar between all Canada (i.e., Bettinger et al data), Quebec, and Alberda (Kellner et al data) where the more recent data are available for Quebec than the other regions. We updated the text in the 1 st paragraph in the Incidence section and the 3 rd paragraph of the Discussion section to note this. Reviewer 2: Maurizio de Martino Reviewer's report: This is a very good paper, well written, with an excellent study design. Results are clearly reported and well discussed. I think that the paper can be accepted, provided some minor changes: 1. avoid the term "patients" (as in methods in the abstract or at page 8...). Children are healthy when they are vaccinated; Response: great point! We have revised the text throughout the manuscript to replace the word patient. 2. erase at page 7, line 5, the comma between PNE and hospitalized; Response: great catch! We have deleted the comma. 3. the authors must decide: or Streptococcus pneumoniae or S. pneumoniae, always throughout the text; Response: great point! We have revised the text throughout the manuscript. 4. the authors must discuss more deeply the bias of the acquisition cost of PCV10 which was not available. Response: We have updated text in the last paragraph in the Discussion section. We also performed additional sensitivity analyses around the impact of changes in results when changing the cost per dose of PCV10 while holding the cost per dose of PCV13 constant. We have updated the text in the last paragraph in the Base-case Results section. Reviewer 3: Paolo Bonanni Reviewer's report:
The manuscript deals with a very interesting and up-to-date subject. The methods are well described, and the discussion and conclusions sound reasonable. Most limitations are recognized, and the overall writing of the article is very good. Response: thank you very much. Discretionary Revisions A clear limitation regards the fact that the data on serotype coverage for IPD for PCV10 and PCV13 were obtained by a personal communication. Since the Authors report that such communication was made on March 21, 2011, it is difficult to understand why such data are still unpublished, at least in some official document if not in a scientific journal. Correctly, the Authors also used other sources of data for serotype coverage, but since the baseline results make reference to such personal communication, the possibility to cite a published source would be beneficial for the article. Were those data finally published? Response: The reviewer has a great point. There is a manuscript that has been developed, but it is currently under review with a journal. In the meantime, we have updated the citation with a reference to a public presentation of these data. Minor Essential Revisions Another point to clarify regards what is illustrated also in Figure 2, i.e. the data (reported at page 18) on the possibility that Assuming a total per-dose cost of PCV10 of $94.10 (acquisition and administration) and considering a threshold incremental cost per QALY of $50,000, the cost per dose for PCV13 could be as high as $737.11 for PCV13 to remain cost-effective, when both direct and indirect effects were considered. Since these data seem to me to be contradictory with what reported in the Discussion section (page 23) where it is stated that When including indirect effects, our model was not sensitive to PCV13 price variation; PCV13 remained a cost-saving option even if PCV13 was twice the price of PCV10, I would ask the Authors to explain better this apparent contradiction. Response: These statements are actually not contradictory. The first statement says that when a cost of $94.10 per dose for PCV10 is assumed, the cost of PCV13 could be as high as $737.11 per dose and PCV13 would be cost-effective (i.e., incremental cost per QALY=$50,000). At a cost per dose that is approximately twice the cost of PCV10 ($197.72 or 110% increase in PCV10 cost per dose), PCV13 and PCV10 are cost neutral. As a result, the cost per dose for PCV13 can change a lot from the assumed parity with PCV10 and still be cost-effective. We have updated the text in the Result section to clarify the cost per dose and the percent increase in cost per dose of PCV13 when cost neutrality occurs. Other two points, always regarding the pricing issue, would make the manuscript look more balanced. The first is a further sensitivity analysis where the price of PCV10 might be made lower than that fixed as invariable ($94.10), vis-à-vis the lower coverage afforded by the 10-valent versus the 13-valent vaccine (and the consequent possibility that the producer of PCV10 might decide to offer it at a lower price). Response: Great point. We performed this analysis and added the results to the 4 th paragraph in the Results-Base Case Analysis section.
The other point regards the possibility that, given the fact that indirect effects of the new conjugate vaccines are not demonstrated in a definitive way, it would be better, in my opinion, to draw a baseline scenario where neither PCV13 nor PCV10 have an indirect effect, leaving all the other possibilities presented in the manuscript as sensitivity analyses. Response: We acknowledge the reviewer s point here. A recent study by the Centers for Disease Control was recently presented at the 8 th International Symposium on Pneumococci & Pneumococcal Diseases. In this study, the CDC reports that PCV13- type IPD is declining among adults (i.e.,nonvaccinated individuals) in the US. (Moore M, Link-Gelles R, Farley M, Schaffner W, Thomas A, Reingold A, Harrison L, Lexau C, Zansky S, Petit S, Gershman K, Scherzinger K, Juni B, Beall B, Whitney C. Impact of 13-valent pneumococcal conjugate vaccine on invasive pneumococcal disease, United States, 2010-11. Presented at 8 th International Symposium on Pneumococci & Pneumococcal Diseases. 13March2012). As a result of this new evidence, we feel that assuming indirect effects for PCV13 is appropriate. We have updated the text in the 1 st paragraph of the Direct Effect section and the 7 th paragraph in the Discussion section to present this new evidence. Do note we do also present a base case analysis in which we assume direct effects only. Let us know if we should address this differently. Table 6 seems very long and crowded. If possible, an alternative way of presenting these crucial data for the article should be explored. Response: Great point! We have updated Table 6 to be presented as a figure. This is now inserted as Figure 4.