Impact of Pharmacist Educational Intervention on Costs of Medication with Improved Clinical Outcomes for Diabetic Patients in Various Tertiary Care Hospitals in Malaysia: A Randomized Controlled Trial

Comments 1: Title

•          I recommend to put the clinical outcomes also into the title.

•          It would be good to make clear that the education is for the patients by the pharmacists in the abstract and throughout the document.

Response 1: Thank you for your valuable feedback. We agree with your suggestion and have accordingly revised the title. The updated title, along with the changes, has been highlighted in red for your reference.

Comments 2: Abstract

•          I am not familiar with the currency 'RM'. Please write it out the first time.

•          There were two public hospitals how were patient numbers included for intervention and control group distributed over these locations? Evenly?

•          From the abstract I do not understand the results on treatment expenses for differences between the group. What costs were taken into account? Only medication costs - was medication then stopped in the intervention group? Costs on additional counselling?

Response 2: Agree. We have, accordingly, changed and modified. Please refer to the updated abstract. The changes made are highlighted in red.

Comments 3: Introduction

•          The introduction may be rewritten to better introduce the research question by a logical flow: e.g. disease frequency and meaning for patient lives, costs for society, health professionals impact in general and pharmacists' impact on patient understanding of disease. Please be clear on what the relation of lifestyle modification is on treatment costs and outcomes.

Please state why cost-effectiveness in medication treatment is so meaningful (being more adherent means more dispenses and more costs for drug treatment!). It seems that it is more important to use medication and lifestyle improvement effectively to prevent complications and hospital admissions? The paragraph to this might be written more clearly to what costs are spent on prevention, on treatment of the disease and on treatment of complications-costs on medication used and costs for services provided.

Please also give some information on the specific situation in Malaysia. In European countries type 2 diabetes patients would be treated in primary care and only for severe complications in hospitals.

Objective:

•          In the introduction it is stressed that collaborative care from several healthcare practitioners is needed. It is not clear why then this study focusses on an intervention from pharmacists -what does 'governed' mean?

•          The objective is on a 'correlation' do you mean 'association'? And why not estimate the effect of an intervention by using regression analysis?

•          Please state the outcomes specifically in the objective: what clinical outcomes are taken into account? What treatment costs are included (see above: drugs and intervention costs)?

Response 3:

Thank you for your valuable comments and insightful suggestions. We greatly appreciate your time and effort in reviewing our manuscript.

As per your recommendations, we have made significant revisions to the Introduction and Objective sections to enhance clarity and logical flow. Major changes have been incorporated to better introduce the research question, highlight the role of pharmacists in diabetes management, clarify cost-effectiveness considerations, and specify the clinical outcomes and treatment costs included in the study. Additionally, we have provided relevant details on the healthcare system in Malaysia for better context.

All the requested changes have been made and are highlighted in red for your reference. Please refer to the updated file for the revised version..

Comments 4: Methodology

• From the objective a prospective follow-up study is expected, however in the methods the study is described as an RCT. If this is true, then effect measures should be aimed at, not only associations.
• Sample size was powered on comparison of blood glucose levels. However, from the title and the objective it was not clear that this was the main outcome (see comments above). Sample size should be calculated on an absolute difference between the groups (being clinically relevant), not a percentage.
• What measures are compared between the study arms? Means at follow-up? Recommended is to perform a regression analysis, where the follow-up measures are adjusted on patient level for the baseline levels, so that you in fact compare the changes in blood glucose levels between baseline and follow up per patient and within the groups.

(This is referred to in the methods section 2.2- however, I do not understand how you can adjust for baseline observations by an ANOVA. It is said that 'changes relative to baseline observations' were calculated. I propose not to use relative but absolute measures - and from table 3.2 in the results it can be seen that absolute values were taken and differences between follow up and baseline were calculated - this is nice and should be clearly described in the methods.)

• The first paragraph should be on study design. Please use a different paragraph to describe the settings (hospitals, pharmacists etc), patient inclusion with criteria and then sample size. (Now from paragraph 2.5 it becomes clear that patients had to provide written consent - however this should be clearly described in a paragraphs in patient inclusion.) Please be clear on inclusion criteria for patients and informed consent. Please state how you included patients for intervention and control groups within the two settings.
• I miss a paragraph on the intervention. Please describe what the 'educational intervention form pharmacists' meant: was there a protocol, were the pharmacists trained, how many pharmacists provided the intervention?

Please also describe what standard care in Malaysia means with regard to the outcome measures and pharmacist engagement.

• More importantly: as the patients were randomized within the settings, how did you prevent that the control group also got the intervention?

Were patients blinded? Pharmacists could not be blinded - but were other healthcare providers (e.g. those who assessed clinical parameters)?

• Here it becomes clear that only medication costs are calculated from the price list. However, From better adherence, I would expect costs to increase. Thus this outcome measure is not clear to me in relation to the objective. And why are not additional costs for the intervention taken into account? Why aren't complications measured with their costs and compared between the groups?
• The validation of the data collection form is extensively described. It was used by healthcare professionals, obviously additionally to routine data assessment. Were the professionals filling the form blinded for the group status of the patients? Was it online? Were data collected during routine measurements prospectively or at the end of the study from files? (This becomes more clear from paragraph 2.5-but should be explained in a paragraph on data collection and data management - before describing the analysis).
• See earlier comments on the statistical analysis. For an RCT regression analysis is recommended to not only test for differences but to estimate effects.

Response 4:   

Thank you for your detailed and insightful comments. We have carefully incorporated all the suggested revisions into the Methodology section to enhance clarity and accuracy. The study design, sample size calculation, intervention details, patient inclusion criteria, data collection methods, and statistical analysis have been revised accordingly. Additionally, we have addressed concerns regarding effect estimation, cost analysis, and blinding procedures.

All changes have been made in the revised version and are highlighted in red for your reference. Please refer to the updated file.

Comments 5: Results

• Please describe the results without an opinion (e.g. 'only 299 diabetics succeeded') - opinions are for the discussion.
• Do not describe the analysis anymore - that was part of the methods.
• I miss information on the intervention: who performed it how many persons at what location, how often was it performed, how long did it last, what did it include (oral, written, online information, calls etc), was it tailored and so on.
• Table 3.4 shows the costs taken into account. It should have been described earlier on what drugs costs were estimated, I hadn't expected costs on NSAIDs (please write out first time) or vitamins. It should also have been described in the methods that costs were calculated on diabetic co-morbidities and diabetic complications and what sort of costs were taken into account. It is not clear to me why costs on diabetic co-morbidities should change after an intervention.
• From the results on page 11 it can be learned that the intervention was not education only but also treatment changes and changes in vitamines. This was not clear from the introduction, objective or methods.
• It would be better to merge tables 3.5 and 3.6.

Table 3.4 could be part of the baseline table 3.1

When performing regression analysis, there could be one table for the baseline parameters and one for the effect measures.

Response 5:   

Thank you for your valuable feedback. We have carefully incorporated all the suggested revisions into the Results section. The text has been refined to present findings objectively, without opinions or repeated analysis descriptions. Additional details on the intervention have been included for clarity. Cost estimations, intervention components, and related changes have been properly described in the Methods section. Furthermore, tables have been adjusted as per your recommendations for better readability.

All changes have been made in the revised version and are highlighted in red for your reference. Please refer to the updated file.

Comments 6: Discussion

• As stated before, the pharmacists contribution to the outcomes reported didn't become clear. Outcomes reported were not on costs only, please also name the clinical outcomes.
• Lifestyle modifications are here reported as intervention outcomes, indirectly measured by less drug utilization. However, this may also be due to non-adherence. As commented above, please be clear on the outcome measures chosen and discuss here the limitations of these choices.
• I miss a discussion of the strengths and limitations of this study.
• Please do not repeat the results but focus on the main outcomes, answering the research question-and placing this study within the context of what is already known. Comparison with other findings should be earlier in the discussion-being more specific on the effects of the interventions, the latter described more extensively.

Response 6:   

Thank you for your insightful comments. We have incorporated all suggested revisions into the Discussion section. The role of pharmacists, clinical outcomes, and the impact of lifestyle modifications have been clearly addressed. Additionally, we have included a discussion on the strengths and limitations of the study. The section now focuses on interpreting key findings in the context of existing literature rather than repeating results.

All changes have been made in the revised version and are highlighted in red for your reference. Please refer to the updated file.

4. Response to Comments on the Quality of English Language

Point 1:

Response 1:   As per Respected Reviewer (The English is fine and does not require any improvement.)

5. Additional clarifications

With due respect, we sincerely appreciate your valuable feedback. We would like to clarify that our study was a Randomized Controlled Trial (RCT), and the primary objective was to evaluate the impact of pharmacist intervention on medication costs alongside improved clinical outcomes. The reduction in drug usage was an expected outcome of improved disease management.

We politely feel that Regression Analysis was not necessary, as it was not aligned with our study’s main objective. We sincerely apologize for any misunderstanding and kindly request your consideration on this matter.

Comments 1: This paragraph can be moved above. (Introduction part)

Response 1: Thank you for your valuable feedback. Changes were made as per the recommendations, and the paragraph was moved up, rephrased, and highlighted in red.

 Comments 2: Introduction and Methdology part

Please provide any specific inclusion/exclusion criteria like uncontrolled hyperglycemia, hyperglycemic emergencies (DKA, HHS), diabetes type 1.

- Please determine the "blinding status of the study".

Please explain these interventions by pharmacists.

Please calculate and report costs by USD, rather than RM.

Please define "primary" and "secondary" outcomes of the study.

Please define these diabetic complications.

Response 2: Agree. Thank you for your valuable suggestions. We have incorporated all the requested changes into the Introduction and Methodology sections. Specific inclusion/exclusion criteria such as uncontrolled hyperglycemia, hyperglycemic emergencies (DKA, HHS), and diabetes type 1 have been clearly defined. The blinding status of the study has also been clarified. We have elaborated on the pharmacist interventions, provided costs in USD instead of RM, and defined both primary and secondary outcomes, along with the details of diabetic complications.

All changes have been made in the revised version and are highlighted in red for your reference. Please refer to the updated file.

Comments 3: Result

Few changes suggested in Table Specifically in Table 3.2, 3.4, and 3.5.

Response 3:

Thank you for your valuable comments and insightful suggestions. We greatly appreciate your time and effort in reviewing our manuscript.

As per your recommendations, we have made changes.

All the requested changes have been made and are highlighted in red for your reference. Please refer to the updated file for the revised version.  

Comments 4: Discussion

• A few lines need to be deleted, and a few references need to be added.

Response 4:   

Thank you for your detailed and insightful comments. We have carefully incorporated all the suggested revisions into the Discussion section to enhance clarity and accuracy.

All changes have been made in the revised version and are highlighted in red for your reference. Please refer to the updated file.

Comments 1: The manuscript reference format should be revised according to the journal style.

Additional clarifications

Thank you for your thoughtful recommendation. We understand the importance of using graphs to present results in a more accessible format. However, as the main objective of our study was to evaluate the impact of pharmacist intervention on medication costs alongside improved clinical outcomes, and given that the focus was on clinical and cost measures, we feel that the use of graphs may not be necessary for our analysis.

We kindly request your understanding and hope that the current presentation of the results is sufficient for clarity.

Please refer to the revised version, where we have highlighted all changes in red.