Cost-effectiveness of providing patients with information on managing mild low-back symptoms. A controlled trial in an occupational health setting

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1 Author s response to reviews Title: Cost-effectiveness of providing patients with information on managing mild low-back symptoms. A controlled trial in an occupational health setting Authors: Jarmo Rantonen (jarmo.rantonen@fimnet.fi;jarmo.rantonen@ttl.fi;jarmorantonen@gmail.com) Jaro Karppinen (jaro.karppinen@ttl.fi) Aki Vehtari (aki.vehtari@aalto.fi) Satu Luoto (satu.luoto@jippii.fi) Eira Viikari-Juntura (eira.viikari-juntura@ttl.fi) Markku Hupli (markku.hupli@eksote.fi) Antti Malmivaara (antti.malmivaara@thl.fi) Simo Taimela (simo.taimela@evalua.fi) Version: 1 Date: 08 Mar 2016 Author s response to reviews: PUBH-D : Cost-effectiveness of providing patients with information on managing mild low-back symptoms. A controlled trial in an occupational health setting Dear Editor, We thank You and the Reviewers for the valuable and constructive comments about our manuscript. We have addressed all the items raised by the reviewers and the editor. You will find below our item-by-item Responses after each comment [in brackets, numbered by the editor and reviewer].

2 You will also find the revised manuscript performed with the changes by MS Office Word 'track changes'. After serious editing, our manuscript has improved a lot. We have made several efforts in order to increase clarity of the manuscript so that it would be easier to read also among colleagues that are not deeply specialized in this field. However, reporting a cost-effectiveness study is never too simple, because of the complexity of data and the management of missing values. We are most thankful for all the comments about our manuscript and we are sure that the manuscript has improved substantially during the process. We hope that our manuscript fulfills your criteria of an article to be published. Sincerely, on behalf of the team, Jarmo Rantonen, MD Editor s Comments EdC1: [Please improve clarity and presentation of the manuscript, and use an appendix if needed.] Response EdC1: We have revised the manuscript largely in terms of clarity and presentation. We have also moved two tables and one figure into appendix. The following reports have been used as general guidelines in our cost-effectiveness reporting: Consolidated Health Economic Evaluation Reporting Standards (CHEERS) [1] and the ISPOR Good research Practices Task Force Report [2]. Reviewer Comments Reviewer #1 general comment: In this study focusing on employees with non-specific, mild Low Back Pain (LBP), three groups were compared: a reference group "no intervention" or natural course (NC), and two intervention subgroups, "booklet" and "combined" (booklet combined with face-to-face oral information). The two intervention groups were issued from a randomized controlled study

3 with two arms. Using the booklet (Back Book) is a validated approach, in the sense that the Back Book is a tool which has been much studied in various contexts. In a previous step, for the same population (mild LBP), the authors concluded that for the self-management of mild LBP, the booklet alone was as effective as the combination "booklet + face-to-face verbal information", for LBP-specific outcomes. The present study adds the cost-effectiveness (CE) dimension, which is an innovative aspect. A positive aspect too is the relatively long follow-up (two years). There are no similar studies for mild LBP, since other studies have focused on chronic LBP. "Costs" in the study are direct costs associated with use of health care resources months after the baseline. The cost-effectiveness analysis took into account also all cause sickness absence for the same period (but this is not very clear). The estimate of the cost of the intervention corresponded to the visit to the occupational health nurse. Clinical effectiveness was measured 24 months after the baseline, and included: physical impairment (Roland-Morris disability questionnaire), intensity of LBP (visual analogue scale); sickness absence for LBP or other cause was available for the 2 years period, based on the administrative payroll system of the employer, but the frame months was used (as for use of health care resources). Response: The design and methods of the study are nicely summarized above. We tried to clarify the presentation of the time period in question for the CE analysis in the methods section. For example, (statistical analyses p ), the cost-effectiveness analysis includes all cause sickness absence from the same period as costs (13 24 months time-frame within the 24 month follow-up period). Sickness absence days from the second follow-up year are the effectiveness part of the cost-effectiveness analysis. Reviewer #1 Comments for the Author (RC= Reviewer Comment (followed by number); Response RC=Author response to the Reviewer Comment (followed by number)) RC1: [Abstract. The presentation of the results in the abstract should be improved; one does not understand what is presented in "results": CE for health care or for sickness absence?] Response RC1: Thank you. We agree that the traditional way of presenting cost-effectiveness results is difficult to understand and we made serious efforts in improving readability of the abstract. RC2: [How to interpret the figures?]

4 Response RC2: The corrections in the abstract (see Response RC1) indicate more clearly the purpose of the CE figures. RC3: [Before giving results for cost-effectiveness, indicate whether the intervention(s) reduced heath care costs and physical impairment.] Response RC3: We suggest that the cost-effectiveness (CE) results should be presented first because that was the primary objective of our manuscript. We have clarified our presentation of the results. RC4: [And also: It seems odd that negative figures indicate savings. ] Response RC4: Yes, we agree that the traditional way of presenting ICER in the CE analyses is at first against one s intuition in case of savings. Thus we have simplified the presentation of the results, especially in the abstract, where we now talk about savings rather than negative costs. Negative figures in the avoided SA days have been replaced with positive across the manuscript. The negative (differential) costs are due to the method of cost-effectiveness analysis, as analyzed by incremental cost-effectiveness ratio ICER. When the costs of two interventions are compared, the difference between two interventions appear negative if the new intervention is less costly (costs are lower) than the old intervention (costs are higher). We wanted to keep this way of presenting the results in the body of manuscript, since this is the recommended way of reporting. RC5: [Answers to the previous questions can be (at least partly) found in the text, but the abstract could be improved in order to bring a clear message. ] Response RC5: Checked as requested. RC6: [Background, study design and population Two references (15 and 23) and the flow chart (figure 1) are given in order to describe the study design. The paragraph on study design gives also some information. However, it is difficult to have a global view, partly because the last paragraphs in "background" are difficult to understand without reading those dealing with "study design". ] Response RC6: We have clarified the last paragraph in the section Background. RC7: [Anyway, it would be useful to have more information on the years and the timing of the study, and on the history of the various studies (two RCTs for two types of LBP?) issued from the cohort. ] Response RC7: We have included more information about the study in the following sections: Background and Methods.

5 RC8: [The title of reference 23, published in 2012, indicates a 4-years follow-up. But the followup of the present study is only two years, why not a longer follow-up? "] Response RC8: Clinical effectiveness data and cost data are available only in two years. Therefore, we decided to show the two year follow-up figures also concerning sickness absence (SA). SA data is available up to 4 years, but if it were reported further than 2 years that might cause confusion among the readers. RC9: [In the present study we assessed the clinical effectiveness and cost-effectiveness " (page 3, line 106). For clinical effectiveness, there might be an overlap with the results presented in reference 15, which seem to be also on clinical effectiveness. ] Response RC9: Missing values have been imputed in both reports, but with different methods. Therefore, concerning the intervention groups Booklet and Combined, there might be an overlap with the clinical effectiveness results. In the reference 15, the method was the last observation carried forward (LOCF), whereas in this paper the missing values were generated in a more sophisticated and modern, multiple imputation method. RC10: [In addition, the sentence line ( the feasibility natural course of LBP ) is not clear. ] Response RC10: Corrected. RC11: [Cost of the intervention In Methods it is indicated that the estimate for the cost was 20 euros, corresponding to the extra time consumed for the verbal patient information in the Occupational Service. Is it the same for the two arms of the intervention? Does it takes into account the time spend by the nurse, or also the time spend by the employee, if he or she was not productive for this period of time? This must be clarified. This is relevant too concerning the external validity of the results, and the feasability in countries other than Finland.] Response RC11: The 20 cost indicates the extra time consumed per participant by the OH nurse for the verbal patient information in the Combined group. As explained in the Methods (line 261), we did not include any indirect costs (e.g. productivity losses when employees were not productive when visiting the OH nurse) in the cost-effectiveness analysis. RC12: [Sensitivity analysis A paragraph page 10 is devoted to sensitivity analysis for costeffectiveness analysis. Details on the method are given, but it would be useful to explain first why a sensitivity analysis was performed, which were the objectives. ]

6 Response RC12: We have explained the sensitivity analysis more deeply in the manuscript (see lines and ). Sensitivity analysis has been performed in order to assess the uncertainty of various inputs in the cost-effectiveness analysis. RC13: [Anyway, the result on sensitivity analyses are too much difficult to understand (could be given as an appendix?). ] Response RC13: Sensitivity analyses are essential parts of the critical evaluation of CEA and they are expected to be performed according to the guidelines [1, 2]. In our opinion, sensitivity analyses should be presented in the Results. We have clarified the Results section concerning the sensitivity analysis. RC14: [Use of health care The use of health care resources seems very high in the Natural Course subgroup. Some of the resources are specific of the context of the country, for example Occupational Health Services do not exist (or are not organized the same way) in other countries. ] Response RC14: Occupational health services play a major part of the Primary health care system among employees in Finland. Therefore, all professional visits under the OH category are comparable with the general or primary health care as well as the private health care visits. We have clarified the description of health care services in the Methods section. RC15: [A total of 65 visits to "other professional" in alternative care in the Natural Course subgroup (and 32 in the booklet group) seems much, maybe specific of the country too. This is to discuss since it has to do with how far the results could be generalized to other countries. ] Response RC15: The visits to other professional in alternative care include visits for instance to massager, acupuncture specialist or chiropractor etc. We have explained the content of other professional in alternative care in the Methods section and discussed the issue also in the Discussion-section. RC16: [Results, comment to tables 2 Not sure that the paragraph "use of HC resources" reflects correctly the main results in table 2. ] Response RC16: The paragraph use of HC resources reflects correctly the main results in the Additional File 1 in the appendix (previous Table 2). Please, see also Response RC17. RC17: [The data given in table 2 suggest a large variability in health care resource usage, with globally more health care resource usage in the "Natural Course" subgroup. Between "combined" and "booklet" one main difference is 21 days in an inpatient rehabilitation center in the combined group (for how many subjects?). Since some other types of health

7 care are also relatively high in the combined group, this leads to a mean cost higher in this group than in the booklet group (due to how many subjects?). In fact, an answer to that question is given at the top of page 16 in the discussion ("a single inpatient episode of only one person"), but it should be indicated earlier, in "results". ] Response RC17: Our data shows that Natural Course (NC) group members used health care resources more than the average intervention group member. This data has been generated by several individuals. However, some high cost health care use still incurred but just because of only one individual in the NC group, resulting in higher total costs in that group. We believe that the section Discussion is the best part of the manuscript to interpret the purpose and reliability of these results and Results section is for simply presentation of the results. The costs concerning the inpatient rehabilitation center days in the group NC have already been explained in Discussion. RC18: [In table 2 it would be useful to have the number of subjects in each group. ] Response RC18: We have inserted the number of subjects in each group also into the units/group and total cost/group columns. Please, see Additional File 1 (previous Table 2). RC19: ["Total cost" is not informative, since it depends from the size of the group. ] Response RC19: As in the Additional File 1 (previous Table 2) is presented, both intervention groups include the same number of subjects. Total costs in between the intervention groups are therefore easily compared if necessary. Although NC group is smaller than the intervention groups, the total costs of the NC group were higher. RC20: [Instead, it might be interesting to have the number of subjects with at least one unit of this type in the group. ] Response RC20: Although interesting, the number of subjects with at least one unit of this type in the group would be quite hard to understand in the same frequency table with the cost-results. RC21: [Check the consistency in table 2: OHs in the title versus OH in the table, SD or STD in the table. ] Response RC21: Checked and corrected. RC22: [Check also the figure for mean cost in the "booklet" group, 77 in the text, 73 in tables 2 and 3. ] Response RC22: Checked. The mean cost for the Booklet group is 73 in the Additonal file 1 (previous table 2) and also 73 according to complete case analysis in the table

8 2 (previous table 4). The same cost has been reported as 73 also in the text in the paragraph Use of HC resources. RC23: [Results, cost-effectiveness analyses The part dealing with table 3 is too much difficult to understand for readers who are not specialists (no explanation on what is ICER Is it for sickness absence?). If these results are important, more explanations are needed, an alternative is to have them in appendix. ] Response RC23: We have clarified the Results section concerning the cost-effectiveness analysis and the terms (like ICER) have been explained more deeply in Methods. We have presented our cost-effectiveness results by following the corresponding guidelines [1, 2]. The importance of missing value management has been emphasized in the literature. Additional File 2 (previous Table 3) shows both the original (non-imputed) and imputed results of the cost-effectiveness parameters in this study. From our perspective, these results are highly important concerning the interpretation of robustness of the results. Previous Table 3 (now Additional File 2) has been moved into appendix. RC24: [Table 4 is relatively easy to read, and could be used as a basis for presenting simple results on cost-effectiveness. ] Response RC24: Table 4 presents only the costs and effects separately. For the joint analysis of cost-effectiveness we need specialized methods and advanced statistics that have been introduced in the paragraph Statistical analyses. These results have been presented in the previous Table 3 (now Additional File 2), Figures 2 3 in the manuscript and Additional File 3 (previous Figure 4). RC25: [However, the figures (or additional figures) should be given taking into account the size of the group: number of sickness absence days divided by the number of subjects in the group ] Response RC25: The mean numbers of sickness absence in all study groups and the results of group comparisons are already presented in the Table 2 (previous Table 4). The number of subjects in each group, both in the main and complete case analyses, are presented in the footnotes 1 and 2. RC26: [Discussion, "combined" compared to "booklet" The paragraph page 15, lines , is difficult to understand. Employees in the "combined" groups had probably more opportunities to discuss with occupational nurses, and possibly more information about potential medical services specific for low back pain, leading to an increase in health care in the period considered in the study. If this is a plausible explanation it should be indicated. ]

9 Response RC26: We have clarified the paragraph concerning the lines The structure of the follow-up visits and the time spent in the visits were comparable in both intervention groups. OH nurse conducted all the intervention and follow-up visits and she was advised to keep the visit structure identical regardless of the intervention group. The only difference between Combined and Booklet visits was in the intervention visit: the Combined group received both the booklet and a verbal review of the contents of the booklet whereas the Booklet group received only the booklet. The whole idea of the patient information with the Back Book was to encourage self-care and avoid unnecessary use of health care services. Therefore we consider the proposed mechanism as unlikely explanation for our findings. RC27: [Discussion, external validity A paragraph in discussion must focus on whether the results can be extrapolated to other countries, and how similar interventions could be developed. ] Response RC27: We have added a few lines in the paragraph concerning the generalizability of the results (lines ). RC28: [Other The large number of acronyms in the text leads to difficulties for reading the text. ] Response RC28: We were able to reduce the number of acronyms and have explained the meaning of acronyms more thoroughly in the whole manuscript. We have also added a separate list of acronyms in the end of the manuscript. We tend to disagree about the overuse of acronyms, since they help in meeting the word limit/space constraints and may also help the reader by making the text more concise. However, if the editor prefers us to write out the acronyms we are of course ready to do that, too. RC29: [General comment: The results are interesting and innovative, but there is a lack of clarity in this paper, it is difficult to understand what has been done, for example whether the results are only on cost-effectiveness (cost-effectiveness for health care resource usage, or also for other dimensions?), or if other outcomes (such as physical impairment) are also considered independently of costs. ] Response RC29: We have made a serious effort in clarifying the focus and presentation of the study (e.g. lines and ) in the revised manuscript. Thank you for pointing this out, we believe that readability of our manuscript has improved a lot. RC30: [Clinical effectiveness, which is indicated in the background, should appear as a specific part of the study. ]

10 Response RC30: Kindly, see also Response RC28. Clinical effectiveness results are already shown under a specific title other health outcomes (see lines ). RC31: [A reader who is not a specialist is lost reading so many sophisticated results. This is frustrating since at least a part of the basic results seems not so complicated, and suggest that comparisons are not easy, partly due to large variability between subjects. All that is common sense and should not be omitted. ] Response RC31: We agree and have clarified our manuscript in all sections. We have moved two tables and the cost-effectiveness acceptability curves (CEAC) into the appendix. Generally, reporting cost-effectiveness analysis (CEA) in three study groups (two randomized interventions vs. control) is quite challenging while following the general guidelines for CEA reporting [1, 2]. We believe that we have controlled also the missing values of the study well by conducting two separate CEAs, generated four cost-effectiveness planes (two of them were presented) and controlled the uncertainty in both analyses according to the guidelines [1, 2]. RC32: [A presentation more accessible for the reader should be feasible, keeping in appendix details (including figures 2 to 4) which may be interesting for specialists.] Response RC32: Kindly, see also Response RC30. We have moved two tables (previous Tables 3 and 4) and previous Figure 4 to the appendix-section. Reviewer #2 Comments for the Author: [Accepted without revision. ] 1. Husereau D, Drummond M, Petrou S, Carswell C, Moher D, Greenberg D, Augustovski F, Briggs AH, Mauskopf J, Loder E et al: Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. BMC Med 2013, 11: Ramsey SD, Willke RJ, Glick H, Reed SD, Augustovski F, Jonsson B, Briggs A, Sullivan SD: Cost-effectiveness analysis alongside clinical trials II-An ISPOR Good Research Practices Task Force report. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research 2015, 18(2):