Survey of potentially inappropriate prescriptions for common cold symptoms in Japan: A cross-sectional study.

BACKGROUND: Common cold is among the main reasons patients visit a medical facility. However, few studies have investigated whether prescriptions for common cold in Japan comply with domestic and international evidence.
OBJECTIVE: To determine whether prescriptions for common cold complied with domestic and international evidence.
METHODS: This cross-sectional study was conducted between October 22, 2020, and January 16, 2021. Patients with cold symptoms who visited the two dispensing pharmacies and met the eligibility criteria were interviewed. MAIN OUTCOME MEASURE: The pharmacists at each store and a physician classified the patients into two groups: the potentially inappropriate prescribing group and the appropriate prescribing group.
RESULTS: Of the 150 selected patients, 14 were excluded and 136 were included in the analysis. Males accounted for 44.9% of the total study population, and the median patient age was 34 years (interquartile range [IQR], 27-42). The prevalence rates of potentially inappropriate prescriptions and appropriate prescriptions were 89.0% and 11.0%, respectively and the median drug costs were 602.0 yen (IQR, 479.7-839.2) [$5.2 (IQR, 4.2-7.3)] and 406.7 yen (IQR, 194.5-537.2) [$3.5 (IQR, 1.7-4.7)], respectively. The most common potentially inappropriate prescriptions were the prescription of oral cephem antibacterial agents to patients who did not have symptoms of bacterial infections (50.4%) and β2 stimulants to those who did not have respiratory symptoms due to underlying disease or history (33.9%).
CONCLUSIONS: Approximately 90% of prescriptions for common cold symptoms in the area were potentially inappropriate. Our findings could contribute to the monitoring of the use of medicines for the treatment of common cold symptoms.

Introduction

Common cold symptoms are one of the main reasons patients visit a medical facility both internationally and in Japan [1, 2]. In the past, physicians mainly prescribed antimicrobial agents for common cold symptoms. Numerous studies have reported the actual practice of prescribing antimicrobial agents [3, 4] and the harmful effects of consumption of these antimicrobial agents by patients with common cold symptoms [5, 6]. According to the reports published in the United States, antimicrobials should not be prescribed for common cold as much as possible owing to drug resistance (more than 2 million antibiotic-resistant diseases are reported each year), the financial burden on the patient and healthcare system (approximately 50% of antimicrobial prescriptions are unnecessary, totaling to medical expenses of more than $3 billion annually), and side effects (5%–25% of patients who use antimicrobials experience adverse events) [7]. In Japan, approximately 60% of outpatients with common cold symptoms were prescribed antimicrobials in 2005 [3], which led to the establishment of the government-led Action Plan to address antimicrobial resistance in 2016.

Several drugs intended to treat common cold symptoms in adults have been useful in relieving symptoms. However, their efficacy is limited [8], and their benefits and disadvantages should be considered. Previous studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs) and first-generation antihistamines may be inappropriate for older patients and should not be prescribed frequently for common cold symptoms in this population [9]. However, there is a lack of evidence on whether physicians’ prescriptions for common cold in Japan comply with the domestic and international evidence [10]. Therefore, we planned to conduct a study by examining prescriptions for common cold in Japan and conducting interviews with patients.

We aimed to investigate whether prescriptions for common cold at two dispensing pharmacies in Izumo City, Shimane Prefecture, Japan, comply with the domestic and international evidence and assess the appropriateness of the prescriptions from these pharmacies.

Materials and methods

Study design

This cross-sectional study was conducted for approximately 3 months, from October 22, 2020, to January 16, 2021. Two pharmacists from each of the two dispensing pharmacies in Izumo City conducted in-depth interviews with patients who had been prescribed medication to relieve cold symptoms.

Study protocol

The study researchers were four experienced pharmacists and one physician who was an expert in primary care. The pharmacists collected the data directly, and the physician set the definition of common cold and the classification criteria for the two groups, namely, potentially inappropriate and appropriate prescribing groups, using data from previous studies based on domestic and international evidence (S1 Appendix) [11, 12]. Next, a questionnaire was prepared for collecting data from the patients, which included the following variables: patient sex and age, doctor’s diagnosis and explanation of common cold, type of symptoms during the visit, duration of symptoms, presence of allergies, history, and current status of smoking, type of prescribed medication, and drug cost (S2 Appendix).

A flowchart of the patient selection process is shown in Fig 1. The patients visited a hospital or clinic, received a prescription, and then visited the pharmacy to pick up the medication. Next, the pharmacist assessed whether the patient met the inclusion criteria using the questionnaire (S2 Appendix) and confirmed the patients’ symptoms and details of the prescribed medication (the content of the questionnaire was based on the patients’ subjective opinions) (n = 150). The physician, who was not the prescribing physician, excluded patients who met the exclusion criteria, after which two pharmacists and a physician classified the patients with prescriptions into two groups: the potentially inappropriate prescribing group and the appropriate prescribing group (S1 Appendix) (N = 136).

Fig 1

Flowchart of the patient selection process.

Definitions

The term “potentially inappropriate prescribing” in this study refers to prescribing of medicines for which there is no clear evidence or indication or that are not suitable for the patient’s symptoms or are contraindicated or administered in inappropriate doses, all of which indicate that the disadvantages of prescribing are likely to outweigh the benefits [11, 12]. “Appropriate prescription” refers to prescribing drugs suitable for the patient’s symptoms where the benefits of prescribing for the patient’s condition are likely to outweigh the disadvantages for various reasons and the prescription is based on clear evidence and indications. The two pharmacists and the primary care expert physician made these judgments using the classification criteria developed in previous studies (S1 Appendix). The term “common cold symptoms” refers to one or more common cold symptoms, namely, acute low-grade fever, headache, cough symptoms, nasal congestion symptoms, and sore throat symptoms [1, 13]. ※ S1 Appendix includes reference [14-33].

Inclusion criteria

In this study, we included adult patients aged 20–80 years who reported that they had one or more typical symptoms of common cold, namely, low-grade fever, headache, cough, nasal congestion, and sore throat symptoms [1, 13] and that these symptoms were comparable to those they had previously. Prescriptions were included only for drugs intended to relieve cold symptoms (drugs included in S1 Appendix). We also ensured that the medications prescribed to the patients were their own medications.

Exclusion criteria

Patients with underlying diseases and those who were pregnant or breastfeeding were excluded. Since there is not enough scientific evidence for Chinese herbal medicines, also called “Kampo medicines,” prescriptions containing Kampo medicines were excluded from this study. Kampo medicine is a combination of herbal medicines made from a number of plants and minerals originally developed in China. It was introduced in Japan and developed into a unique treatment method in Japan. Through thousands of years of experience, the effects of various combinations of herbal medicines have been confirmed.

Patients who regularly took medicines other than those to relieve cold symptoms were also excluded to reduce the impact or interaction of other medicines on the results of our study. Patients with incomplete data, such as incomplete interviews, and patients who were judged by the prescribing physician or the physician involved in the study as not having evident symptoms of common cold were excluded from the study.

Outcome measures

The primary outcome was the frequency of "potentially inappropriate prescription " and "appropriate prescription." Other outcomes included the cost of each prescription drug (Japanese yen was converted to US dollars based on the exchange rate of 114.92 yen per 1 US dollar on December 29, 2021) in "potentially inappropriate prescriptions" and "appropriate prescriptions," types of symptomatic and antimicrobial drugs prescribed, and types of prescription drugs used for classifying prescriptions into the potentially inappropriate prescribing group based on patient interviews and prescription drug evidence.

Statistical analyses

We used standard descriptive statistics to calculate the number, percentage, median, and IQR (interquartile range). All statistical analyses were performed using JMP®, Version 15. SAS Institute Inc., Cary, NC, 1989–2021.

Ethics approval

The present study was conducted after obtaining approval from the Ethics Committee of the Shimane University School of Medicine (No. 20200622–2. Approval date: October 19, 2020). The included patients provided informed consent to participate in this study.

Results

Sample characteristics

The study included 150 patients with symptoms such as fever, headache, cough, nasal congestion, sore throat without underlying disease. Among them, 14 were excluded because the physician, who was not the prescribing physician, judged that the patients did not have cold symptoms, or the interview was incomplete (Fig 1). Patient characteristics are presented in Table 1. The median patient age was 34 years (interquartile range [IQR], 27–42), and the median duration of common cold symptoms was 2 days (IQR, 1.0–4.8). For 89.7% of the patients, the physician described the symptoms as “cold, upper respiratory tract infection, pharyngitis, and swollen tonsils.” Of all the patients, 18.4% had some kind of allergy, and 11.0% were smokers with median pack-years of 7.5% (IQR, 5–16).

Table 1

Background characteristics of patients (n = 136).

Male sex, No (%)		61 (44.9)
Age, median (IQR), y		34 (27–42)
Days of cold symptoms (IQR), d		2.0 (IQR 1.0–4.8)
Patients who received any explanation from a doctor, No (%) (Ex. common cold, upper respiratory tract inflammation, sore pharyngitis, swollen tonsils)		122 (89.7)
Any allergies, No (%)		25 (18.4)
Smoking	n (%) Pack-years, median (IQR)	15 (11.0) 7.5 (5–16)

IQR, interquartile range.

Patients’ symptoms

Table 2 shows the details of the patients’ symptoms. The most common symptom reported by the patients was sore throat (63.2%), followed by cough (52.2%), runny nose (46.3%), phlegm (41.9%), nasal congestion (36.8%), lethargy (35.3%), headache (30.1%), fever (28.7%), painful swallowing (26.5%), sneezing (18.4%), and abdominal pain (1.5%). The median body temperature of the patients who had a fever was 37.4°C (IQR, 37.1–38.0).

Table 2

Patients’ symptoms.

	n	%
Sore throat	86	63.2
Cough	71	52.2
Runny nose	63	46.3
Phlegm	57	41.9
Nasal congestion	50	36.8
Lethargy	48	35.3
Headache	41	30.1
Fever	39	28.7
	37.4°C	(IQR 37.1–38.0)
Painful swallowing	36	26.5
Sneezing	25	18.4
Abdominal pain	2	1.5
Others	17	12.5

IQR, interquartile range.

Details of prescriptions

Among all the prescriptions (n = 136), the most commonly prescribed symptomatic medications were H1 receptor antagonists (chlorpheniramine maleate, bepotastine; 41.9%), followed by expectorants (carbocysteine, bromhexine, ambroxol; 41.2%), NSAIDs (diclofenac, thiaramide, loxoprofen; 40.0%), β2-stimulants (mainly tulobuterol patches, terbutaline; 36.0%) and decalinium chloride lozenges (indicated for sore throat in Japan; 36.0%), non-narcotic antitussives (dimethorphan, dextromethorphan, tipepidine; 22.1%), tranexamic acid (indicated for sore throat in Japan; 19.9%), acetaminophen (18.4%), multi-ingredient cold medication (non-pyrine cold remedy combination granules, pyrazolone antipyretic analgesic anti-inflammatory combination granules; 7.4%), and leukotriene receptor antagonists (pranlukast, montelukast; 3.7%). Regarding antimicrobial agents, 44.9% of all prescriptions contained oral cephem (cefcapene pivoxil, cefdinir), 25.0% contained new quinolones (galenoxacin, levofloxacin), 9.5% contained macrolides (azithromycin, clarithromycin), and 2.2% contained penicillin (amoxicillin) (Table 3).

Table 3

Details of prescription drugs (n = 136).

	Breakdown of all prescriptions		Breakdown of potentially inappropriate prescription drugs for each drug prescribed.		Percentage of potentially inappropriate prescriptions drugs for each drug in the total potentially inappropriate prescriptions (n = 121).
	n	%	n	%	%
Symptomatic medicine
H1 receptor antagonist	57	41.9	0	0	0
Expectorant drug	56	41.2	0	0	0
NSAIDs	53	40.0	6	11.3	5.0
β2-stimulant	49	36.0	41	83.7	33.9
Decalinium chloride (cough drop)	49	36.0	0	0	0
Non-narcotic antitussive	30	22.1	0	0	0
Tranexamic acid	27	19.9	0	0	0
Acetaminophen	25	18.4	0	0	0
Multi-ingredient cold medication	10	7.4	0	0	0
#Non-pyrine cold remedy combination granules, Pyrazolone antipyretic analgesic anti-inflammatory　 combination granules
Leukotriene receptor antagonist	5	3.7	0	0	0
Others	13	9.4	3	23.1	2.5
Antibacterial drugs
Cephem (Oral)	61	44.9	61	100	50.4
New quinolone	34	25.0	34	100	28.1
Macrolide	13	9.5	12	92.3	10.0
Penicillin	3	2.2	0	0	0
Cephem (Nasal spray)	1	0.7	0	0	0

NSAID, non-steroidal anti-inflammatory drug.

Note: Active ingredients in 1 g of Non-pyrine cold remedy combination granules (salicylamide, 270 mg; acetaminophen, 150 mg; caffeine anhydrous, 60 mg; promethazine methylene disalicylate, 13.5 mg); active ingredients in 1 g of Pyrazolone antipyretic analgesic anti-inflammatory combination granules (isopropylantipyrine, 150 mg; acetaminophen, 250 mg; allyl isopropylacetylurea, 60 mg; caffeine anhydrous, 50 mg).

Details of potentially inappropriate prescription

The breakdown of potentially inappropriate prescription drugs in terms of each prescribed drug is shown in Table 3. β2 stimulants (83.7%), followed by NSAIDs (11.3%), had the highest percentage among symptomatic medicines. Among the antimicrobial agents, oral cephems and new quinolones had the highest rates (100%), followed by macrolides (92.3%).

The percentage of each potentially inappropriate drug in the total number of potentially inappropriate prescriptions is shown in Table 3. β2 stimulants (33.9%), followed by NSAIDs (5.0%), had the highest percentage among symptomatic medicines. Among antimicrobial agents, oral cephem had the highest percentage (50.4%), followed by new quinolones (28.1%) and macrolides (10.0%).

There were two contraindicated doses (for patients with a history of β2-stimulant hypersensitivity), and the pharmacist posed questions regarding the prescription. There were no dosage errors.

Rates of potentially inappropriate prescription and medication costs

When the prescriptions were classified using the classification criteria (S1 Appendix), 11.0% (n = 15) fell under the appropriate prescription group and 89.0% (n = 121) under the potentially inappropriate prescription group (Fig 2). The median total cost of the prescribed drugs was 593.6 yen (IQR, 470–795.6) [$5.2 (IQR, 4.1–6.9)]. In particular, the median cost of drugs in the potentially inappropriate prescription group was 602.0 yen (IQR, 479.7–839.2) [$5.2 (IQR, 4.2–7.3)], and the median cost of drugs in the appropriate prescription group was 406.7 yen (IQR, 194.5–537.2) [$3.5 (IQR, 1.7–4.7)].

Fig 2

Classification of prescriptions based on criteria.

Discussion

This study suggests that approximately 90% of the prescriptions for common cold symptoms in this area are inappropriate and that antimicrobials and symptomatic drugs, such as β2-stimulants, which are not suitable for the respiratory symptoms in the absence of underlying disease or history, maybe inappropriately prescribed. This is the first cross-sectional study in Japan to investigate whether prescriptions for common cold comply with domestic and international evidence.

The rationale for classification as the potentially inappropriate prescribing group

Oral cephem antibiotic, β2-stimulants, and new quinolone antibacterials were the top three drugs used in classifying prescriptions into the potentially inappropriate prescribing group, based on patient interviews and prescribed drugs and prescription drug evidence. The rationale for classifying prescriptions of oral cephem antibiotics as potentially inappropriate is as follows: antimicrobial agents are not beneficial for common cold symptoms, and their side effects are notable [15]. In the case of suspected streptococcal infection, penicillin is recommended as the first choice because of its proven efficacy and safety, narrow spectrum, and low cost [31]. The rationale for classifying prescriptions containing β2-stimulants as potentially inappropriate is as follows: β2-stimulants are useful in patients with a history of cough, asthma, chronic obstructive pulmonary disease (COPD), and other diseases [27]. However, there is no clear benefit of these drugs for acute bronchitis and acute cough in adults, and side effects such as tremor and neurological symptoms may occur [28]. The tulobuterol patch, which was mainly used in this study, is approved for use only in Japan and Korea, and there is insufficient evidence in terms of its efficacy and safety [29]. Considering this information, we concluded that it is reasonable to consider a prescription for β2-stimulants for patients without underlying diseases such as asthma or COPD and with strongly suspected findings for acute cold symptoms as potentially inappropriate. The rationale for judging new quinolones as inappropriate is as follows. New quinolones are considered inappropriate as they are ineffective against viruses which cause common cold. The risk of aortic aneurysm and aortic dissection by inducing collagen degradation has been reported for some new quinolones [32]. Given the magnitude of the risk of adverse effects, it is unlikely that they need to be administered to patients with acute cold symptoms.

Factors responsible for prescriptions of potentially inappropriate drugs

Based on previous studies, four major factors may be involved in the prescriptions becoming potentially inappropriate: The first factor is that patients may be seeking medications from doctors [34]. The Japanese healthcare system provides easy access to higher medical institutions and clinics. Due to the low cost of medical care in Japan, patients may be inclined to receive some kind of medication and feel relieved [35]. The second factor may be the physician’s attitude toward consultation. For example, doctors intend to satisfy patients by prescribing them medications [36] and quickly end the consultation [37]; their prescribing patterns are fixed to some extent according to the age and sex of the patient [38]. The third factor is the lack of evidence on physicians’ standard of care for the treatment of common cold. In Japan, despite the publication of national guidelines in 2016 regarding the appropriate use of antimicrobials, there was no significant change in the trend of antimicrobial use among outpatients with acute upper respiratory tract infection before and after the publication [39]. In this study, the percentage of antimicrobials in prescriptions (83%) was higher than that reported in previous studies (60%) [3]. Furthermore, third-generation oral cephem antibacterial agents were used in approximately 50% of the prescriptions for common cold symptoms, followed by new quinolone and macrolide antibacterials, and the proportion of prescriptions was approximately the same as that in previous studies [3]. This information suggests that there is insufficient awareness regarding the need to refrain from prescribing unnecessary antimicrobials for common cold symptoms. Fourth, there is a lack of primary care education for physicians. It is common for Japanese primary care physicians to specialize in organ-specific treatment and start private practices, taking on the role of primary care providers in their respective regions [40]. In Japan, many physicians start their own clinical practice without undergoing any special training for minor illnesses [41]. Therefore, it is possible that many physicians in this region also routinely prescribe the same drugs that they prescribe for organ-specific treatment. However, it is unlikely that any single solution will alter the prescribing habits of physicians [42]. Cultural factors may also be involved in addressing this problem, and steps other than continuing medical and patient education are necessary.

Pharmacists’ views on potentially inappropriate prescription

In Japan, the importance of the pharmacists’ intervention in prescribing has been highlighted in recent years [43]. Pharmacists in Japan are proactive in making inquiries regarding the "safety and dosage volume" of drugs [43]. In contrast, in cases where there is a possibility of inappropriate prescribing but the pharmacist is unsure about making an inquiry, the pharmacist often does not make an inquiry, taking the prescribing physician’s intentions into consideration. One of the reasons underlying this is that a certain number of physicians consider the pharmacist’s frequent inquiries to be bothersome, and pharmacists, who place importance on a good relationship with the local physician, are hesitant to make such inquiries. Such psychological barriers between pharmacists and doctors may be detrimental to patients. This is an issue that needs to be gradually addressed in the future.

Considerations for drug costs

The median cost of drugs for potentially inappropriate prescriptions and appropriate prescriptions were 602.0 yen (IQR, 479.7–839.2) [$5.2 (IQR, 4.2–7.3)] and 406.7 yen (IQR, 194.5–537.2) [$3.5 (IQR, 1.7–4.7)], respectively. As shown in the previous study, "Japan’s universal health insurance system covers all prescription drugs generally; therefore, patient co-payments are minimal, and this is a factor that contributes towards doctors prescribing drugs easily” [44, 45]. This makes it easier for doctors to prescribe unnecessary drugs leading to a higher cost of drugs. As part of the Choosing Wisely Campaign, it is generally recommended that patients ask their doctors the following five questions [46]. (1) Do I really need this test or procedure? (2) What are the risks? (3) Are there simpler, safer options? (4) What happens if I do not do anything? (5) What are the costs? Patients must be aware of their own "treatment" by referring to the above questions to promote the appropriate use of medicines in Japan. It is necessary to incorporate education and measures that consider the interactive opinions of the medical professionals and patients.

Limitations

This study had several limitations. First, the sample size was small, and the survey was limited to hospitals and clinics in Izumo City; therefore, there may have been strong influences of the characteristics of doctors in the area, such as biases in prescribing. Second, because the survey was conducted in a dispensing pharmacy, the actual conversations between the doctors and patients in the clinic, patients’ physical findings, and information in their medical records were not captured. Third, the study excluded prescriptions of Kampo medicines. Since Kampo medicines are often prescribed for common cold symptoms in Japan, the results of this study do not fully reflect the actual situation of prescriptions for common cold symptoms in Japan. Fourth, the criteria used to classify prescriptions were not complete. Several previous overseas studies have evaluated the efficacy of cold medicines; however, the efficacy of many of these medicines is unclear, which may have led to the misclassification of the prescriptions. Fifth, there may have been influences of changes in the epidemiology of common cold caused by the novel coronaviruses. Fortunately, however, during the study period (October 2020 to January 2021), we had the lowest incidence of coronavirus disease in Japan, with the lowest positivity rate in polymerase chain reaction (S3 Appendix). Therefore, although we believe that the impact of the epidemiological changes caused by the new coronavirus infection in this study was quite limited, we cannot deny the possibility of its impact on the study. Sixth, the details regarding the prescribing physician were not investigated in this study as the Ethics Committee stipulates that “the content that identifies the prescribing physician (specialty, affiliation, and the number of individuals) must not be added to the content of the interview because it may cause disadvantages to the prescribing physician.” We believe that the prescribing physician’s details are important factors and further research is needed. Lastly, this study was limited to adult patients with no underlying medical conditions. The content of prescriptions for common cold patients is likely to be affected by the presence or absence of underlying diseases and the age of the patients. Therefore, the results of this study may not fully reflect the current status of prescribing for common cold symptoms in Japan.

Conclusion

Approximately 90% of the prescriptions for common cold symptoms in this local area were potentially inappropriate, and antimicrobials and symptomatic drugs such as β2-stimulants, which are not suitable for the patients’ respiratory symptoms in the absence of underlying diseases or history, may be inappropriately prescribed. This finding is expected to help promote the appropriate use of medicines for common cold symptoms and improve the quality of medical care. However, this was a pilot study at the regional level, and it is necessary to conduct a nationwide survey in the future.

Classification criteria.

(XLSX)

Click here for additional data file.

Patient information sheet.

(DOCX)

Click here for additional data file.

Number of people newly infected with SARS-CoV-2 in Izumo city.

(PPTX)

Click here for additional data file.

6 Dec 2021

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Reviewer #1: I find the manuscript to be well written, informative and concise. The paper presents novel findings based on analysis of patient interviews and prescriptions, which will be of interest to the readers.

Reviewer #2: The authors report an evaluation of the appropriateness of prescriptions for the common cold. The authors interviewed 136 patients presented to a pharmacy in Japan and evaluated the appropriateness and costs associated with the prescriptions provided.

Comments

1. Line 37 – remove word “Even”

2. Line 42 – Remove “on the contrary” as the statement implies similarity (60% vs 50%) and not “contrary”

3. Line 56 – suggest rephrase objectives statement. What is meant by “to determine the actual status of prescriptions” is unclear. Suggest state that the objective was to assess the appropriateness of prescriptions

4. S1 Appendix: The appendix provides a summary of the evidence used for the authors to adjudicate the prescriptions. However, the way the authors used this evidence summary to adjudicate the prescriptions is a bit opaque. It is not clear to me how each prescription was classified. Can the authors add another column clarifying which medications were appropriate or inappropriate based on the criteria used? For example; amoxicillin described as first line for GAS pharyngitis. How did the authors adjudicate amoxicillin or penicillin prescriptions for patients with pharyngitis without swab confirmation of GAS? I did not see a section for swab results on the interview form.

5. Please clarify what Cephem is? I am not familiar with this from North America. In the appendix listed as a nasal spray but in the manuscript it is treated as a systemic antibiotic. If a topical spray I suggest separating out from the systemic antimicrobials

6. Can the authors clarify what proportion of “inappropriate prescriptions” were for incorrect dose and which were unnecessary?

7. Line 126: I am not familiar with “Kampo medicine”, can the authors briefly explain this exclusion?

8. Line 142: I am not sure why the primary outcome was only presented descriptively and the secondary outcome was analyzed with a statistical test. With 136 participants it is a missed opportunity to not evaluate for predictors of inappropriate prescribing from the data collected. I recommend the authors perform bivariate and multivariable analysis evaluating predictors for inappropriate prescriptions.

9. I was surprised the authors did not capture whether a throat swab (rapid antigen or culture) was done for GAS. Is this common practice in primary care in Japan? Given how common sore throat as a complaint was I am not clear how antibiotic prescriptions were adjudicated without this information. Were all antibiotics assumed to be inappropriate? This relates back to point 4.

10. Line 200: Are these percentages of antibacterial agents the percent of all prescriptions? Percent of antimicrobials? Or percent of patients?

11. As above comment if Cephem is not a systemic antibiotic consider separating this out from the other antibiotics

12. Table 3 lists the percent of prescriptions. Can you add the percent inappropriate to this table? For example 41.9% of prescriptions were H1 blockers (or is it 41.9% of patients received H1 blocker?)…what percent of those 57 H1 blockers were inappropriate?

13. Can you convert Yen to US dollars in brackets?

14. Table 4: Suggest combine with table 3 and include numbers (not just percentages). How many prescriptions, what percent of total, and what number and percent were inappropriate

15. As per point 8 suggest include a statistical evaluation of predictors of inappropriateness

16. Line 260: clarify if Cephem is topical or systemic

17. Line 261: “Penicillin is recommended as the first choice…” how was this factored into the study? It is not clear how penicillin was adjudicated in this study (appropriate or inappropriate?)

18. Line 273: The provided reason for classifying quinolones as inappropriate is not accurate. Quinolones are inappropriate because they have no effect on viruses which cause the common cold. You have listed 1 rare but important side effect of that medication class.

19. Line 280: I don’t understand the separation of sections titled “Factors leading…” and “Factors responsible…” The authors discuss one potential aspect leading to inappropriate prescribing (medical education). I agree this may be a factor but there is a whole behavioral science literature of the many complex reasons for inappropriate prescribing – perceived patient expectations, fear, habit, etc. Many reasons beyond education and knowledge base. While this may be beyond the scope of this manuscript to discuss in detail these are important to briefly discuss as the solutions to this complex problem will involve much more than modifying medical education or continuing medical education as we know these interventions, while important, have overall limited impact on behavior change and quality improvement.

20. Line 291: The authors summarize literature on drivers of inappropriate drugs but missed an opportunity in this study to contribute to that literature. As per point 8 and 15 above I suggest you add that evaluation.

21. Line 321: Suggest add to limitations that the findings are limited to adults without underlying medical comorbidities (as per study inclusion criteria)

**********

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Submitted filename: Reviewers Comments.docx

Click here for additional data file.

21 Jan 2022

January 13, 2022

Dear PLOSONE Editor:

Thank you for giving us the opportunity to revise the manuscript. The constructive suggestions and feedback provided by the Reviewer have enabled us to substantially improve the quality of our paper. We have provided a point-by-point response to the Reviewer’s suggestions. The changes have been indicated in a yellow highlight in the revised manuscript.

Regarding open data, we have indicated that the data from this study are available upon request. This is because our study was approved by the Ethics Committee of the Shimane University School of Medicine (No. 20200622-2. Approval date: October 19, 2020), as a pilot study to investigate the inappropriateness of prescribing by doctors in Japan. Before launching the study, the open publication of this information was moderately restricted by the IRB because these are potentially sensitive information for the prescribing doctors, and public disclosure of this data could have a strong impact on the management of the private clinics and practice. We believe, therefore, that this study is important and should be used as a foundation to expand future research on inappropriate prescribing that may be prevalent throughout Japan.

Once again, thank you for your thorough and supportive peer review.

On behalf of all the authors, yours sincerely,

Corresponding author

Takashi Watari, MD, MHQS, MCTM, Ph.D

Shimane University Hospital, General Medicine Center, Shimane, Japan

89-1, Enya-cho, Izumo shi, Shimane, 693-8501, Japan

e-mail: wataritari@gmail.com; Phone: +81-853-20-2005; Fax: +81-853-20-2375

Reviewer

1. Method

I would suggest adding more in the Statistical analyses section on the statistical methods used for deriving results described in the results section (including ones included in the Tables). For example, currently there is no mention on IQRs in the statistical analyses section – please add an explanation on this.

Response:

We appreciate and agree with the reviewer’s comment. The following changes have been made in the revised manuscript:

Changes (Method_Statistical Analyses)

P7, L148

Background: We used standard descriptive statistics to calculate the number, percentage, median, and IQR (interquartile range). All statistical analyses were performed using JMP®, Version 15. SAS Institute Inc., Cary, NC, 1989–2021.

Reviewer

2. Results

How many physicians have prescribed the drugs in this time? What are the specialties of the doctors who prescribed it? What percentage of prescribing physicians belong to a hospital or clinic? Please add their characteristics if possible.

Response

Thank you for your valuable questions. As mentioned, we postulated that the specialty and affiliation of the prescribing physician is a very important factor in considering the results of this study. However, the Ethical Review Committee of the Shimane University School of Medicine (Approval No. 20200622-2, Approval date: October 19, 2020) has issued an order to the effect that "the content that identifies the prescribing physician (the prescribing physician's specialty, affiliation, and number of prescribers) must not be added to the content of the interview as it may be disadvantageous for the prescribing physician. Therefore, we cannot include the prescribing physicians’ specialty, affiliation, and number of prescribers since we have not interviewed them for these points. This information has been added to the Limitations section.

Addition (Discussion_ Limitation)

P18, L347 to P19, L359 (marked_manuscript)

Limitaion: Sixth, the details regarding the prescribing physician were not investigated in this study as the Ethics Committee of the Shimane University School of Medicine (No. 20200622-2. Approval date: October 19, 2020) stipulates that "the content that identifies the prescribing physician (specialty, affiliation, and the number of individuals) must not be added to the content of the interview because it may cause disadvantages to the prescribing physician.” We believe that the prescribing physician's specialty, affiliation, and the number of individuals are important factors while considering the results of this study. Therefore, further research is needed.

Reviewer

3.Discussion

1)Four issues on the part of physicians have been pointed out as factors in inappropriate prescribing (Cephem antibacterials, β2-stimulants, and new quinolone antibacterials). What about the role of pharmacists, such as their intervention against inappropriate prescriptions? For example, in Japan, as a countermeasure against polypharmacy, a pharmaceutical management fee has been newly established as a dispensing fee, and pharmacists are encouraged to propose drug reduction.

Since there is no pharmacist's view for inappropriate prescribing in this document, please add their perspective.

Response

Thank you for your valuable comment. As pointed out, a statement regarding the pharmacist's perspective was not included in the manuscript. Therefore, the following statement has been added to the revised manuscript:

Addition (Discussion_ Pharmacists' views on potentially inappropriate prescription)

P17, L306

In Japan, the importance of the pharmacists' intervention in prescribing has been highlighted in recent years [43]. Pharmacists in Japan are proactive in making inquiries regarding the "safety and dosage volume" [43]. In contrast, in cases where there is a possibility of inappropriate prescribing but the pharmacist is unsure about making an inquiry, the pharmacist often does not make an inquiry, taking the prescribing physician's intentions into consideration. One of the reasons underlying this is that a certain number of physicians consider the pharmacist's frequent inquiries to be bothersome, and pharmacists, who place importance on a good relationship with the local physician, are hesitant to make such inquiries. Such psychological barriers between pharmacists and doctors may be detrimental to patients. This is an issue that needs to be gradually addressed in the future.

Reviewer

3.Discussion

2)It has been shown that medication costs are higher in the inappropriate prescription

group, but this point was not good enough explained, though there are some words about Japanese healthcare system in the “Discussion”

Response

Thank you for bringing this matter to our attention. We have added the following information as suggested:

Changes (Discussion_ Considerations for drug costs)

P17, L322 (marked_manuscript)

As shown in the previous study, "Japan's universal health insurance system covers all prescription drugs without restrictions; therefore, patient co-payments are minimal, and this is a factor that causes doctors to prescribe drugs easily”［44,45］, making it easier for doctors to prescribe unnecessary drugs leading to a higher cost of drugs.

Reviewer

3.Discussion

3)It was described the first factor is that patients may be seeking medications from doctors in this document. However, some authors interviewed the patients actually. Did they confirm this factor? What was the patients' view?

From the perspective of “Choosing Wisely”, how do the authors think about the health literacy education for patients?

Response

Thank you for your insightful comment. In this study, we did not check whether the patients requested their doctors to prescribe medications as we did not include it in the survey items. Therefore, we do not know what the patients' exact intentions were behind seeking prescriptions.

In Australia, the following CWs are being promoted among the patients and the public in a campaign called "Ask Your Doctor Five Questions"(Michiko Yamamoto, Activities of Choosing Wisely and Role of Pharmacists, Yakugaku Zasshi. 2019;139(4):551-556.). (1) Is this test or procedure necessary for me? (2) What risks or side effects does it have? (3) Is there a simpler and safer option? (4) What will happen if I do not take the treatment? (5) How much does it cost? (5) How much will it cost and will my health insurance cover it?

It is necessary for patients to be aware of their own "treatment" by referring to the above questions to promote the appropriate use of medicines in Japan. It is necessary to incorporate education and measures that take into account the interactive opinions of the medical professionals and patients.

――――――――――――――――――――――――――――――

Reviewer

1. Line 37 – remove word “Even”

Response

Thank you for bringing this error to our attention. We have made the following change accordingly.

Changes (Introduction)

P2(marked_manuscript):”Even” has been removed.

Reviewer

2. Line 42 – Remove “on the contrary” as the statement implies similarity (60% vs 50%) and not “contrary”

Response

Thank you for bringing this error to our attention. We have made the following change accordingly.

Changes (Introduction)

P2 (marked_manuscript): ” On the contrary” has been removed.

Reviewer

3. Line 56 – suggest rephrase objectives statement. What is meant by “to determine the actual status of prescriptions” is unclear. Suggest state that the objective was to assess the appropriateness of prescriptions

Response

Thank you for your valuable suggestion. We have rephrased the sentence accordingly.

Changes (Introduction)

P3, L59 (marked_manuscript): assess the appropriateness of prescriptions

Reviewer

4. S1 Appendix: The appendix provides a summary of the evidence used for the authors to adjudicate the prescriptions. However, the way the authors used this evidence summary to adjudicate the prescriptions is a bit opaque. It is not clear to me how each prescription was classified. Can the authors add another column clarifying which medications were appropriate or inappropriate based on the criteria used? For example; amoxicillin described as first line for GAS pharyngitis. How did the authors adjudicate amoxicillin or penicillin prescriptions for patients with pharyngitis without swab confirmation of GAS? I did not see a section for swab results on the interview form.

Response

Thank you for bringing this matter to our attention. As you indicated, we have added the rationale for the classification of the prescription in the column G of “appendix1___classification_criteria”

The decision to prescribe amoxicillin is described below. In primary care settings in Japan, the GAS pharyngeal swab is often omitted; the patient's risk of streptococcal infection is assessed based on the Center criteria, and if the risk is high, amoxicillin is generally prescribed without the GAS pharyngeal swab. In this case, when the pharmacist interviewed the patient, it was confirmed that the patient had been told by the physician that there was a high possibility of pharyngitis or streptococcal infection (appendix 2 item (13)) and if the patient has symptoms such as fever and sore throat and amoxicillin is prescribed, it is considered an appropriate prescription. This information has been described in the column G (penicillin) of “appendix1___classification_criteria”.

Addition (Judgement)

Column G (appendix1___classification_criteria)

Reviewer

5. Please clarify what Cephem is? I am not familiar with this from North America. In the appendix listed as a nasal spray but in the manuscript it is treated as a systemic antibiotic. If a topical spray I suggest separating out from the systemic antimicrobials

Response

Thank you for bringing this matter to our attention. We have added the following information to the revised manuscript as suggested.

Changes (marked_manuscript)

→ Oral chem

Reviewer

6. Can the authors clarify what proportion of “inappropriate prescriptions” were for incorrect dose and which were unnecessary?

Response

Thank you for bringing this matter to our attention. There were no prescriptions with incorrect dosage and administration. However, a prescription was provided to a patient with a history of hypersensitivity to β2 stimulants (which is a contraindication)" (n=2). This information has been added to the Results section.

When medications are prescribed despite a lack of symptoms, we did not generally judge them as unnecessary (potentially inappropriate prescriptions), considering the possibility that the prescribing physician was anticipating future symptoms based on the patient's progress. We judged the appropriateness of the prescription drug based on the overall risk of side effects of the prescription drug and the patient's background.

Changes (marked_manuscript)

P.13, L225 (Results_ Details of Inappropriate Prescription)

There were two contraindicated doses (for patients with a history of β2-stimulant hypersensitivity), and the pharmacist posed questions regarding the prescription. There were no dosage errors．

Reviewer

7. Line 126: I am not familiar with “Kampo medicine”, can the authors briefly explain this exclusion?

Response

Thank you for bringing this matter to our attention. Chinese herbal medicines (Kampo medicines) are a combination of herbal medicines made from a number of plants and minerals. Originally developed in China, it was introduced in Japan and developed into a unique treatment method in Japan. Through thousands of years of experience, the effects of various combinations of herbal medicines have been confirmed. However, Kampo medicines contain thousands of compounds, and it is rarely clear which ingredients exert what effects. In addition, Kampo medicines were excluded from our study as little Western medical evidence is available.

Changes (Method_ Exclusion Criteria)

P6, L124 (marked_manuscript)

Since there is not enough scientific evidence for Chinese herbal medicines, also called “Kampo medicines”, prescriptions containing Kampo medicines were excluded from this study. Kampo medicine is a combination of herbal medicines made from a number of plants and minerals. Originally developed in China, it was introduced in Japan and developed into a unique treatment method in Japan. Through thousands of years of experience, the effects of various combinations of herbal medicines have been confirmed.

Reviewer

8. Line 142: I am not sure why the primary outcome was only presented descriptively and the secondary outcome was analyzed with a statistical test. With 136 participants it is a missed opportunity to not evaluate for predictors of inappropriate prescribing from the data collected. I recommend the authors perform bivariate and multivariable analysis evaluating predictors for inappropriate prescriptions.

Response

We thank the reviewers for their suggestions. The authors apologize for the lack of explanation, and at the same time, the authors agree with the opinion. Our current study was conducted as a challenging pilot study. Our most significant limitation was that we could not collect information on prescribing doctors and clinics from the IRB approval stage of the study, making causal inferences and comparative studies difficult. Therefore, primary outcomes were documented as descriptive instead of statistically analyzing a small sample size. In addition, the statistical analysis of the comparison of monetary values, which was different, has been deleted.

We appreciate your pertinent and constructive feedback.

Deletions (marked_manuscript)

P7, (Method_ Statistical Analyses)

Wilcoxon's rank-sum test was used to compare the median values of the quantitative data between the two groups. All statistically significant differences were defined at p-value <0.05.

P14, (Results_ Rates of Inappropriate Prescription and Medication Costs)

showing a statistically significant difference in the median values of the two groups (p < 0.001).

Reviewer

9. I was surprised the authors did not capture whether a throat swab (rapid antigen or culture) was done for GAS. Is this common practice in primary care in Japan? Given how common sore throat as a complaint was I am not clear how antibiotic prescriptions were adjudicated without this information. Were all antibiotics assumed to be inappropriate? This relates back to point 4.

Response

Thank you very much for your valuable remarks. In primary care settings in Japan, the GAS pharyngeal swab is often omitted; the patient's risk of streptococcal infection is assessed based on the Center criteria, and if the risk is high, amoxicillin is generally prescribed without the GAS pharyngeal swab. In this case, when the pharmacist interviewed the patient, it was confirmed that the patient had been told by the physician that there was a high possibility of pharyngitis or streptococcal infection (appendix 2 item (13)) and if the patient has symptoms such as fever and sore throat and amoxicillin is prescribed, it is considered an appropriate prescription.

Reviewer

10. Line 200: Are these percentages of antibacterial agents the percent of all prescriptions? Percent of antimicrobials? Or percent of patients?

Response

Thank you for your questions. The relevant section describes the percentage of all prescriptions. We have changed the description in the revised manuscript as follows:

Changes (Results_ Details of Prescriptions)

P10, L199 (marked_manuscript)

Regarding antimicrobial agents, 44.9% of all prescriptions contained oral cephem (cefcapene pivoxil, cefdinir), 25.0% contained new quinolones (galenoxacin, levofloxacin), 9.5% contained macrolides (azithromycin, clarithromycin), and 2.2% contained Penicillin (amoxicillin) (Table 3).

Reviewer

11. As above comment if Cephem is not a systemic antibiotic consider separating this out from the other antibiotics

Response

Thank you for your valuable suggestion. We have separated the descriptions regarding Cephem to ensure that oral and topical sprays can be distinguished.

Changes (marked_manuscript)

→ oral cephem

Reviewer

12. Table 3 lists the percent of prescriptions. Can you add the percent inappropriate to this table? For example 41.9% of prescriptions were H1 blockers (or is it 41.9% of patients received H1 blocker?)…what percent of those 57 H1 blockers were inappropriate?

Response

Thank you for bringing this matter to our attention. The percent inappropriateness has been added to Table 3 (Breakdown of potentially inappropriate prescription drugs for each drug prescribed).

Changes (marked_manuscript)

P11-12 (Result_ Table 3. Details of prescription drugs (n = 136))

Reviewer

13.Can you convert Yen to US dollars in brackets?

Response

Thank you for bringing this matter to our attention. We have added the following information to the revised manuscript as suggested.

Changes (marked_manuscript)

P1, L20-21: 602.0 yen (IQR, 479.7–839.2)［$5.2 (IQR, 4.2–7.3) and 406.7 yen (IQR, 194.5–537.2) [$3.5 (IQR,1.7–4.7)],

P13, L232-: The median total cost of the prescribed drugs was 593.6 yen (IQR, 470–795.6)［$5.2 (IQR, 4.1–6.9). In particular, the median cost of drugs in the inappropriate prescription group was 602.0 yen (IQR, 479.7–839.2)［$5.2 (IQR, 4.2–7.3), and the median cost of drugs in the appropriate prescription group was 406.7 yen (IQR, 194.5–537.2) [$3.5 (IQR,1.7–4.7)]

P17, L320-352: The median drug costs of inappropriate prescriptions and appropriate were 602.0 yen (IQR, 479.7–839.2)［$5.2 (IQR, 4.2–7.3) and 406.7 yen (IQR, 194.5–537.2) [$3.5 (IQR,1.7–4.7)]

Reviewer

14. Table 4: Suggest combine with table 3 and include numbers (not just percentages). How many prescriptions, what percent of total, and what number and percent were inappropriate

Response

Thank you for your valuable suggestion. The number of prescriptions for each drug, overall percentage, number of inappropriate prescriptions, and percentage has been added to Table 3.

Changes (marked_manuscript)

P11-12 (Result_ Table 3. Details of prescription drugs (n = 136))

Reviewer

15. As per point 8 suggest include a statistical evaluation of predictors of inappropriateness

Response

Thank you for your pertinent comments. As you mentioned, it is crucial to conduct multivariate analysis to evaluate predictors of inappropriate prescribing. However, due to the socio-ethical background of this study, we were not able to incorporate the essential physician and clinic characteristics as factors from the beginning. To the best of our knowledge, no previous survey has been conducted on the actual status of prescription medications, including symptomatic medications, for cold symptoms. Therefore, we conducted a pilot study on the actual status of prescription drugs in a limited area and with limited sample size. Next, based on the results of this study, we are considering conducting another survey on a national scale to evaluate predictors and conduct a multivariate analysis.

Reviewer

16. Line 260: clarify if Cephem is topical or systemic

Response

Thank you for your valuable suggestion. We have clarified whether the Cepham used was oral or nasal spray in the manuscript.

Changes (marked_manuscript)

P12, Table 3: Cephem (Oral)

P12, Table 3: Cephem (Nasal spray)

Reviewer

17. Line 261: “Penicillin is recommended as the first choice…” how was this factored into the study? It is not clear how penicillin was adjudicated in this study (appropriate or inappropriate?)

Response

Thank you for bringing this matter to our attention. We confirmed during the interview that the patients had symptoms such as fever and sore throat, and the doctor explained that the patient had pharyngitis or streptococcal infection (appendix 2 item (13)). If amoxicillin was prescribed at that time, it was determined as an appropriate prescription.

Reviewer

18. Line 273: The provided reason for classifying quinolones as inappropriate is not accurate. Quinolones are inappropriate because they have no effect on viruses which cause the common cold. You have listed 1 rare but important side effect of that medication class.

Response

Thank you for your valuable suggestion. We have stated that quinolone antibacterials are inappropriate as they are ineffective against viruses that cause common colds.

Changes (Discussion_ The Rationale for Classification as the Potentially Inappropriate Prescribing Group)

P15, L266 (marked_manuscript)

New quinolones are considered inappropriate as they are ineffective against viruses which cause the common cold.

Reviewer

19. Line 280: I don’t understand the separation of sections titled “Factors leading…” and “Factors responsible…” The authors discuss one potential aspect leading to inappropriate prescribing (medical education). I agree this may be a factor but there is a whole behavioral science literature of the many complex reasons for inappropriate prescribing – perceived patient expectations, fear, habit, etc. Many reasons beyond education and knowledge base. While this may be beyond the scope of this manuscript to discuss in detail these are important to briefly discuss as the solutions to this complex problem will involve much more than modifying medical education or continuing medical education as we know these interventions, while important, have overall limited impact on behavior change and quality improvement.

Response

Thank you for bringing this matter to our attention. “Factors leading... " and "Factors responsible... " have been merged in the revised manuscript. We have also added the following sentence to the revised manuscript:

Changes (Discussion_ Factors Responsible for Prescriptions of Potentially Inappropriate Drugs)

P16, L301 (marked_manuscript)

However, it is unlikely that any single solution will alter the prescribing habits of physicians [42]. Cultural factors may also be involved in addressing this problem, and steps other than continuing medical and patient education are necessary.

Reviewer

20. Line 291: The authors summarize literature on drivers of inappropriate drugs but missed an opportunity in this study to contribute to that literature. As per point 8 and 15 above I suggest you add that evaluation.

Response

Thank you for your valuable comment. As you mentioned, it is crucial to conduct multivariate analysis to evaluate predictors of inappropriate prescribing. However, due to the socio-ethical background of this study, we were not able to incorporate the essential physician and clinic characteristics as factors from the beginning. To the best of our knowledge, no previous survey has been conducted on the actual status of prescription medications, including symptomatic medications, for cold symptoms. Therefore, we conducted a pilot study on the actual status of prescription drugs in a limited area and with limited sample size. Next, based on the results of this study, it is extremely important to conduct another survey on a nationwide scale, evaluate predictors, and conduct multivariate analysis.

Reviewer

21. Line 321: Suggest add to limitations that the findings are limited to adults without underlying medical comorbidities (as per study inclusion criteria)

Response

Thank you for your suggestion. The following information has been added to the Limitation section:

Addition (Discussion_ Limitaion)

P19, L355 (marked_manuscript)

Lastly, this study was limited to adult patients with no underlying medical conditions. The content of prescriptions for common cold patients is likely to be affected by the presence or absence of underlying diseases and the age of the patients. Therefore, the results of this study may not fully reflect the current status of prescribing for common cold symptoms in Japan.

----------------------------------------------------------------------------------------------------------

We would like to express our sincere gratitude for your constructive feedback on our paper. We sincerely hope that the revised manuscript is suitable for publication.

Submitted filename: response_to_reviewer_T.W.docx

Click here for additional data file.

16 Feb 2022

Submitted filename: Reviewers comments 2_2022.2.10.docx

Click here for additional data file.

4 Mar 2022

March 4, 2022

Dear PLOS ONE Editor:

Thank you for giving us the opportunity to revise our manuscript. The constructive suggestions and feedback provided by the Reviewer have enabled us to substantially improve the quality of our paper. We have provided a point-by-point response to the Reviewer’s suggestions. The revised portions have been indicated in green highlight in the revised manuscript.

Once again, thank you for your thorough and supportive peer review.

On behalf of all the authors,

Yours sincerely,

Corresponding author

Takashi Watari, MD, MHQS, MCTM, Ph.D

Shimane University Hospital, General Medicine Center, Shimane, Japan

89-1, Enya-cho, Izumo shi, Shimane, 693-8501, Japan

e-mail: wataritari@gmail.com; Phone: +81-853-20-2005; Fax: +81-853-20-2375

Reviewer

2. Results

How many physicians have prescribed the drugs in this time? What are the specialties of the doctors who prescribed it? What percentage of prescribing physicians belong to a hospital or clinic? Please add their characteristics if possible.

Response

Addition (Discussion_ Limitation)

P18, L347 to P19, L359 (marked_manuscript)

Dear author

Your comment has been addressed, but please make it more briefly and more compact.

Response:

We appreciate and agree with the reviewers’ comment. The following changes have been made in the revised manuscript:

Change (Discussion_ Limitation)

Page 19, Lines 362 to 367 (marked_manuscript)

Limitation: Sixth, the details regarding the prescribing physician were not investigated in this study as the Ethics Committee stipulates that "the content that identifies the prescribing physician (specialty, affiliation, and the number of individuals) must not be added to the content of the interview because it may cause disadvantages to the prescribing physician.” We believe that the prescribing physician's details are important factors and further research is needed.

Reviewer

Reviewer

3.Discussion

2) It has been shown that medication costs are higher in the inappropriate prescription

group, but this point was not good enough explained, though there are some words about Japanese healthcare system in the “Discussion”

Response

Discussion_ Considerations for drug costs)

P17, L322 (marked_manuscript)

Dear author

I don't think the following explanation adequately describes the actual situation in Japan.　"Japan's universal health insurance system covers all prescription drugs without restrictions.”

For example, there is the Diagnosis Procedure Combination (DPC), and there is a system for polypharmacy, which provides reimbursement for the dispensing of drugs by reducing the number of drugs. Therefore, how about "Japan's universal health insurance system covers all prescription drugs generally.” ?

Response

We appreciate and agree with the reviewers’ comment. The following changes have been made in the revised manuscript:

Addition (Discussion_ Considerations for drug costs)

Page 18, Line 331 (marked_manuscript)

Considerations for drug costs: Japan's universal health insurance system covers all prescription drugs generally.

Reviewer

Reviewer

3.Discussion

3)It was described the first factor is that patients may be seeking medications from doctors in this document. However, some authors interviewed the patients actually. Did they confirm this factor? What was the patients' view?

From the perspective of “Choosing Wisely”, how do the authors think about the health literacy education for patients?

Response

Dear author

How about the following references as citations of Choosing Wisely?

�  Consumer Reports

https://www.consumerreports.org/doctors/questions-to-ask-your-doctor/

or

�  Muscat DM, et al. Evaluation of the Choosing Wisely Australia 5 Questions resource and a shared decision-making preparation video: protocol for an online experiment. BMJ Open 2019;9:e033126

https://bmjopen.bmj.com/content/9/11/e033126

Response

We appreciate and agree with the reviewers’ comment. The following changes have been made in the revised manuscript:

Addition (Discussion_ Considerations for drug costs)

Page 18, Line 334 to 341 (marked_manuscript)

Considerations for drug costs: As part of the Choosing Wisely campaign, it is generally recommended that patients ask their doctors the following five questions [46]. (1) Do I really need this test or procedure? (2) What are the risks? (3) Are there simpler, safer options? (4) What happens if I do not do anything? (5) What are the costs? Patients must be aware of their own "treatment" by referring to the above questions to promote the appropriate use of medicines in Japan. It is necessary to incorporate education and measures that consider the interactive opinions of the medical professionals and patients.

Reviewer

Finally, after reading the submitted paper more precisely again, I would like to mention an additional point.

The design of this study is a cross sectional study, and thus, it seems inappropriate to refer to this study as a prospective observational study. The reason is as follows; it is cross sectional because they looked at the prevalence of whether or not there had been an inappropriate prescription, where the survey lasted for 3 months – but in fact, the study participants were not followed for 3 months. It is recommended that the authors consult an epidemiologist.

Response

We appreciate and agree with the reviewers’ comment. The following changes have been made in the revised manuscript:

Changes (marked_manuscript)

Page 1, Line 2: A Cross-Sectional Study

Page 1, Line 28: cross-sectional study

Page 4, Line 82: cross-sectional study

Page 14-15, Line 251-252: cross-sectional study

Submitted filename: response_to_reviewer_.docx

Click here for additional data file.

10 Mar 2022

Survey of potentially inappropriate prescriptions for common cold symptoms in Japan: A cross-sectional study

PONE-D-21-33168R2

Dear Dr. Watari,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Masaki Mogi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

No further comment.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

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Reviewer #1: (No Response)

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Reviewer #1: Yes

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Reviewer #1: The changes made by the authors are well noted. It is appreciated that the comments and suggestions have been incorporated into the revised version.

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Reviewer #1: No

15 Mar 2022

PONE-D-21-33168R2

Survey of potentially inappropriate prescriptions for common cold symptoms in Japan: A cross-sectional study

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