FormalPara Key Summary Points

Why carry out this study?

During the recent coronavirus disease 2019 (COVID-19) pandemic, preferences for factors associated with vaccines have been evaluated in Japan and other countries using a conjoint analysis; however, preferences for antiviral drugs have not been fully evaluated to date.

Intangible costs for factors associated with oral antiviral drugs for COVID-19 treatment were investigated in Japan using a conjoint analysis based on an online survey.

What was learned from this study?

Drugs developed by a Japanese company were preferred over those developed by a foreign company, and the difference in intangible costs between them, JPY 5390, was larger than that for changes in the formulation and size of the drug, frequency of administration, dosage, and the number of days until one is no longer infectious.

This study clarified intangible costs for factors associated with oral antiviral drugs in the Japanese population based on the survey in August 2022; the results may change as the number of people who have a history of COVID-19 infection increases and significant progress is made in regard to treatment.

Introduction

In addition to critical factors such as efficacy and safety, studies have recently reported intangible costs for various factors related to disease prevention and treatment. Previous studies indicated the value of convenience for factors associated with medication, such as administration route and dosage, using a conjoint analysis [1, 2], which is an established method to assess consumer preference in market research, and has been increasingly used in medical research [1,2,3,4,5,6,7,8].

During the recent coronavirus disease 2019 (COVID-19) pandemic, preferences for factors associated with the SARS-CoV-2 vaccine have been evaluated in Japan [4, 5] and other countries [6,7,8]. A Japanese study reported that the country where the vaccine was developed was the factor most strongly associated with vaccine preference among other factors, including the location of the clinical trial, risk of adverse side effects, efficacy, and vaccine type [4]. In that study, a domestically developed vaccine was the most preferred compared to vaccines developed in the other four countries. U.S. studies have also reported the preference for a vaccine from the participants’ own country [6, 8].

Preferences for COVID-19 treatments may also depend on various factors. In Japan, three oral antiviral drugs have been approved for patients with COVID-19 symptoms classified as mild (either no respiratory symptoms or cough alone without shortness of breath, and without pneumonia findings) to moderate I (shortness of breath and/or pneumonia findings) [9]. These drugs are molnupiravir (granted Special Approval for Emergency in December 2021) [10], nirmatrelvir/ritonavir (granted Special Approval for Emergency in February 2022) [11], and ensitrelvir (granted Emergency Approval in November 2022) [12]. Effectiveness of these drugs has been reported in real-word settings [13, 14]. However, to the best of our knowledge, preferences for such treatment for COVID-19 have not been fully assessed.

In this study, we investigated the intangible costs for factors associated with oral antiviral drugs for COVID-19 treatment in Japan using a conjoint analysis. Effectiveness, safety, and medical costs were not considered. Here, effectiveness was defined as the disappearance of symptoms, and safety was defined as adverse events.

Methods

Study Design and Participants

This study applied a conjoint analysis to data collected through an online survey (August 23−30, 2022) to estimate intangible costs for factors associated with COVID-19 treatments.

We selected the survey respondents from an online panel managed by INTAGE (Tokyo, Japan). The panel consisted of individuals across Japan who had pre-registered in advance to participate in online surveys. Respondents were limited to those between the ages of 20 and 69. The survey company conducted a process to eliminate low-quality samples.

Through a screening survey, we divided the potential respondents into two groups based on their history of COVID-19 infection: those without and those with (groups 1 and 2, respectively). We planned to include 10,000 and 1000 individuals in groups 1 and 2, respectively. In the screening survey, questionnaires were randomly sent to individuals in the panel to confirm their history of COVID-19 infection. We determined the number of respondents by age–gender bands in each group based on the proportion of those with and those without a history of COVID-19 infection among individuals who responded to the screening survey and the age–gender distribution of the Japanese population. The beginning of the survey contains a statement explaining that individuals willing to answer the questions could withdraw from the survey at any time; those who did so were excluded from the final sample. Consequently, the response rate for all questions in this survey was 100%.

Survey Methods

All respondents were asked for background information (see Table S1 in the electronic supplementary material for the questions), specifically, demographic information, SARS-CoV-2 vaccination status, presence of family members aged ≥ 65 years living with them, presence of diseases or symptoms that are considered risk factors for severe COVID-19, and the degree of feeling at risk of being infected with COVID-19. Additionally, respondents in group 2 were asked about their experiences with COVID-19 infection, including the time of infection and its severity based on symptoms and treatments (Table S1 in the electronic supplementary material).

At the beginning of the survey for the conjoint analysis, respondents were presented with the following situation to set the context for their choice: “You are infected with COVID-19 and are being treated with a drug. Your symptoms are currently mild. The symptoms will disappear after five days of taking the drug.” They were then asked to choose their preferred oral drug treatment from two options as follows, “Which of the following two oral treatment drugs would you choose? It is assumed that the effectiveness such as the disappearance of symptoms and the availability of these two drugs in treating your symptoms will be the same.” They were given 20 different combinations with two options (the combination of treatment options is called a “choice task”; see Fig. 1A for an example of a choice task question) and were required to choose one option each time. Each option consisted of one level of the six attributes: the company that developed the drug (Japanese or foreign), formulation and size of the drug, frequency of administration per day, number of tablets/capsules per dose, number of days until one is no longer infectious to others (day of treatment initiation is considered day one), and out-of-pocket expenses (Fig. 1B). The attributes and levels were determined based on the clinical experience of the medical expert authors, referring to the characteristics of actual oral antiviral drugs (i.e., molnupiravir, nirmatrelvir/ritonavir, and ensitrelvir). It should be noted that we set the amount of out-of-pocket expenses for COVID-19 oral drug treatment to be rather high because the appropriate amount could not be determined due to a lack of previous studies. Twenty-five options were selected from 1152 possible combinations based on an orthogonal design.

Fig. 1
figure 1

An example of choice task questions in the discrete choice experience survey (A) and attributes and levels for each attribute in the survey (B). The size of the capsule (large), tablet (large), and tablet (small) refer to molnupiravir, nirmatrelvir/ritonavir, and ensitrelvir, respectively. JPY, Japanese yen ($1.00 corresponded to approximately JPY 133.19 as of February 2023)

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In addition, the respondents were asked about the factors that they required for COVID-19 drugs besides eliminating COVID-19 symptoms. They were asked to choose, in order from first to third, from among six factor options as well as the options “none of them” and “do not want to answer” (Table S1 in the electronic supplementary material).

Statistical Analysis

We tabulated the responses for background information for each group.

The utility and intangible costs of each level for each attribute in the population were estimated as the main result. The utility (mean and 95% confidence intervals) of each level for each attribute was estimated based on the survey results from groups 1 and 2. The responses of each individual were weighted based on the percentage of individuals who had a history of COVID-19 infection in the screening survey in each age–gender band. We used a fixed effect model for logistic regression for the analysis. Utility was assumed to be equivalent among respondents in this model. The utility of each level was calculated by considering the utility of the level with the highest preference for each attribute to be zero. The intangible cost was calculated by comparing the utility of each level for each attribute to the utility of the monetary attribute (out-of-pocket expenses).

As a subgroup analysis, the utility and intangible costs were estimated for groups 1 and 2 as well as for subgroups based on a combination of their history of COVID-19 infection and the presence of risk factors for severe COVID-19. We selected these factors for the subgroup analysis because we thought they were most likely to cause the differences among various factors, including age, gender, and comorbidities.

Moreover, intangible costs for the population were estimated for hypothetical drugs by referring to the formulations, sizes, and dosages of the following available drugs: ensitrelvir, molnupiravir, and nirmatrelvir/ritonavir (labeled Drug A, Drug B, and Drug C, respectively).

We used SAS v.9.4 and Microsoft Excel 2016 for data analysis.

Ethics Statement

This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects by the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare [15] and the checklist of good research practices for conjoint analysis by the ISPOR [3]. The study was approved by the Ethics Committee of the Research Institute of Healthcare Data Science (RI2022003) and registered with the University Hospital Medical Information Network Clinical Trial Registry (UMIN000048518). Informed consent was obtained online from all respondents.

Results

Respondents

We collected responses from 11,303 respondents (10,272 in group 1 and 1031 in group 2). The mean age of the respondents was 46.7 years in group 1 and 41.3 years in group 2 (see Table 1 for distribution by demographic groups). Table S2 in the electronic supplementary material shows the distribution of the residential areas of the respondents.

Table 1 Distribution of respondents by age and gender
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In both groups, approximately 65% of all respondents reported not having any of the listed risk factors of diseases or symptoms for severe COVID-19 (Table 2). Including age (≥ 65 years) as one of the factors, 36.6% (3521 of 9614 respondents) of respondents in group 1 and 31.2% (296 of 948 respondents) in group 2 had a risk factor. It should be noted that, for respondents who answered “not sure/cannot remember” or “do not want to answer” to the question about the presence of risk factors of diseases or symptoms and were < 64 years old, whether they had the risk factor could not be determined. Therefore, they were excluded from the sub-analysis based on a combination of their history of COVID-19 infection and the presence of risk factors for severe COVID-19.

Table 2 Percentage of respondents with risk factors for severe COVID-19 (answer to Q8: “Please choose any of the following options, including diseases, symptoms, and treatments that apply to you.”)
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In group 2, 79.2% of respondents were infected with COVID-19 in January 2022 or later (Table S3 in the electronic supplementary material). A total of 8.1% of respondents had no symptoms and 83.0% had mild symptoms [with symptoms (fever, respiratory symptoms, fatigue, etc.) but without pneumonia]. Table S2 in the electronic supplementary material shows additional results regarding respondents’ history of COVID-19 infection.

Utility of Factors Associated with Oral Drugs for COVID-19 Treatment Based on Conjoint Analysis

The utility of each level for each attribute for the population was estimated as shown in Fig. 2, and intangible costs were calculated as shown in Table 3. Among the attributes, whether the company developing the drug was Japanese or foreign showed the largest difference between levels: the intangible cost for the foreign company to the Japanese company was JPY 5390 (Table 3; $1.00 corresponded to approximately JPY 133.19 as of February 2023). The attribute with the second largest difference between levels was the number of days until one is no longer infectious, for which 8 to 2 days was JPY 3067, and for which 5 to 2 days was JPY 1337. The intangible cost of higher frequency of administration, thrice per day to once per day (JPY 1517), was greater than that of more tablets/capsules per dose, which is four tablets/capsules per dose to one tablet/capsule per dose (JPY 410). For the same formulation, the intangible cost was lower for small sizes than for large sizes. For similar-sized tablets and capsules, the intangible cost was lower for tablets than capsules.

Fig. 2
figure 2

Utility of each variable for the population. The label for each column represents the level for the following attributes: 1 company developing the drug, 2 formulation and size, 3 frequency of administration per day, 4 number of tablets/capsules per dose, 5 number of days until one is no longer infectious to others (treatment initiation day is considered day 1), 6 and out-of-pocket expenses

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Table 3 Utility and intangible cost of each level for each attribute for the population
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In a subgroup analysis, although a similar tendency was found in groups 1 and 2, differences in intangible costs between levels were smaller in group 2 than in group 1 for the foreign company to the Japanese company and the number of days until one is no longer infectious to others (Table 4). A similar tendency of preferences was also found in the subgroups based on the combination of infection experience and the presence of risk factors for severe COVID-19 (Table 5). Nevertheless, intangible costs were relatively lower in groups with the presence of risk factors for severe COVID-19 for attributes other than the attribute of the company developing the drug.

Table 4 Utility and intangible cost of each level for each attribute for the subgroups by history of COVID-19 infection
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Table 5 Intangible cost of each level for each attribute for the subgroups by history of infection and presence of risk factors for severe COVID-19
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When comparing the estimated intangible costs among the assumed drugs, the difference between Drug A, which had the lowest cost, and Drug B or C was more than JPY 7000 (Table 6).

Table 6 Comparison of estimated intangible costs among assumed drugs
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Expectations for COVID-19 Treatments Based on the Survey

Among the six options, “no transmission of the virus to family members or others nearby” was most frequently selected as the most expected factor for COVID-19 treatment in both groups (36.8% in group 1 and 36.1% in group 2). This was followed by “no sequelae after infection” (36.5% and 33.5%, respectively) and “no restrictions on medications or foods that can be taken together” (11.1% and 10.6%, respectively; Fig. 3). The top two most frequently selected options for the second expected factor were also the same between the groups (Fig. 3).

Fig. 3
figure 3

Elements expected from COVID-19 treatments other than the effect of eliminating the symptoms (answer to Q10: “Oral treatments for COVID-19 are effective in eliminating the symptoms in the infected person. In addition to this effect, what do you expect from the treatments? For each of the following options, please select the first to third most preferred answers.”) A group 1 (n = 10,272), B group 2 (n = 1031)

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Discussion

This study estimated intangible costs for factors associated with oral antiviral drugs for COVID-19 treatment in the Japanese population. Drugs developed by the Japanese company were preferred over those developed by the foreign company, and the difference in intangible costs between levels was the largest among attributes. The next largest difference was in the number of days until one is no longer infectious. Regarding the formulation and size of the drug, the intangible cost was lower for small compared to large for the same formulation and for tablets compared to capsules of similar sizes. A similar tendency was indicated regardless of history of COVID-19 infection as well as the presence of risk factors for severe COVID-19.

We did not specify the country of the “foreign company” in the survey because we intended to identify the difference between Japanese and non-Japanese companies, not between countries. Therefore, it is unclear which country the respondents assumed the “foreign company” to be located in when answering the question. Although the vaccines and the oral treatments for COVID-19 used in Japan were developed by U.S. or U.K. companies at the time of the survey, the respondents may not have necessarily known this; even if they did, they may not necessarily have assumed that the “foreign company” was located in one of those countries.

This study suggested that, for oral drugs for COVID-19 treatment in the Japanese population, whether the drugs were developed by a Japanese company is important. A preference for domestically developed products was also reported for SARS-CoV-2 vaccines in a Japanese study conducted between February and March 2021 [4]. In that study, certain countries, namely, Japan, the U.S., China, the U.K., and Russia, were indicated in the “country of development” attribute; the vaccine developed in Japan was the most preferred, followed by the vaccine developed in the U.S., and then the U.K., China, and Russia, even though the vaccine developed in Japan was not yet available. The difference in countries was the factor most strongly associated with preference, among other factors, including the location of the clinical trial, risk of adverse side effects, efficacy, and vaccine type. A higher preference for a vaccine developed in a company in the participants’ own country was also reported in U.S. studies; the impact compared with efficacy was different between studies—which was similar [6] or higher [8]—but the impact compared with a lower frequency of adverse events was higher in both studies [6, 8]. A preference for domestically manufactured products over imported ones was reported for the influenza vaccine in China, but the most important factors were effectiveness and safety. Notably, that study did not mention specific countries for “imported vaccines” [16]. Higher preferences for domestic products have also been reported among Japanese consumers for various food products [17,18,19,20], even in recent years. The magnitude of preference was reported to be higher in Japan than in other countries, including Thailand for rice [17] and China for pork [19]. Some studies reported that preference for domestic food seemed to be associated with the reliability of safety and quality [19, 20]. The preference for domestic products has also been referred to as “domestic or home-country bias,” which is related to consumer ethnocentrism [21]. These reasons may also be related to the preferences for drugs developed in the participants’ own country in this study.

Awareness of the countries where drugs were developed seems to have increased during the COVID-19 pandemic in Japan. This may also contribute to the preference for Japanese companies developing the drug. The names and locations of companies developing and/or manufacturing drugs were probably less attractive to Japanese patients. Nevertheless, they may have attracted attention during the pandemic when vaccines were recognized by the name of the company, and the news media reported on companies developing drugs and vaccines focused on Japanese or foreign ones. Moreover, concerns were raised about the number of vaccines secured and the time taken to import them. Information on the status of vaccine development and efforts to secure vaccines in Japan has been made available on the website of the Japanese Ministry of Health, Labour and Welfare [22]. Increased awareness of the companies themselves and their locations where drugs were developed may influence the preferences of the Japanese population.

Among the options for expected factors for COVID-19 treatments, “no transmission of the virus to family members or others nearby” was shown to have the highest priority in the survey as well as in the conjoint analysis, which seems to be consistent with the lower intangible costs for fewer days until they are no longer infectious in the conjoint analysis. The higher priority of this option, rather than its effects on one’s own sequelae or no restrictions on medications or foods that can be taken together, may be due to Japanese national characteristics—that is, concern for what others think or prioritizing harmony with others.

Regarding the formulation and size, lower intangible costs for small compared to large seemed reasonable. The lower intangible costs of tablets compared to capsules were similar to those in a previous study on preferences for influenza antivirals in Japanese pediatric patients [2].

Given the similarity of intangible costs across subgroups, the preferences reported in this study appear robust and independent of history of COVID-19 infection or being at higher risk for severe COVID-19. The lack of difference in intangible costs between respondents with and without a history of infection may be related to the fact that, in this survey, more than 90% of respondents with a history of infection had no or mild symptoms. Considering this, most of the respondents may not be taking any treatment for COVID-19 other than treatments for symptoms, such as antipyretics. This may be related to the lack of noticeable differences between respondents with and those without a history of infection. Nevertheless, lower intangible costs for some factors, including the foreign company and a greater number of days until one is no longer infectious, in respondents with a history of infection may suggest that people who had experienced infection felt less burdened by an increase in out-of-pocket expenses for the treatment.

The difference in the estimated intangible costs between the assumed drugs was over JPY 7000. Notably, the cost of ensitrelvir, molnupiravir, and nirmatrelvir/ritonavir was JPY 7407.40 per tablet (JPY 51,851.80 per course) [23], JPY 2357.80 per capsule (JPY 94,312.00 per course) [24], and JPY 19,805.50 per pack (99,027.50 JPY per course) [23].

This study has several limitations. First, an online survey was conducted for panels of individuals who had previously registered as members to participate in online surveys. Although the respondents were gathered from across the country, they may not be representative of the entire Japanese population. In addition, older adults aged ≥ 70 years were not included in this study. Considering that older adults, who have comorbidities and co-medications, may have a willingness to pay higher costs, resulting in higher intangible costs, the results of this study may be conservative. Notably, the age and gender proportions of the respondents were matched to the age and gender distribution of the Japanese population between the ages of 20 and 69. Moreover, in regards to the distribution of time and severity of COVID-19 among respondents in group 2, they did not necessarily represent Japanese people who had a history of infection. Second, this study was conducted in Japan, and the results may be different in other countries. In addition, the results were based on a survey conducted in August 2022; they may change as the number of people who have a history of COVID-19 infection increases and significant progress is made in regard to treatment. Considering possible differences in results due to such differences in survey settings, it is desirable to discuss the results obtained in this study compared to other studies. However, we could not find any studies on preferences and intangible costs associated with COVID-19 treatment either inside or outside the country. Third, although the scenario of the conjoint survey was explained as the efficacy of the two drugs being the same, there was no mention of their safety. In addition, the assumed treatment effects of the drugs may have differed among respondents. Such factors, which were not clearly stated, may influence preferences for other attributes without being noticed. In particular, because the attribute of the company developing the drug (Japanese or foreign) was not quantitative unlike the other attributes, the respondents may have perceived it differently. For example, respondents with a high preference for safety may have perceived drugs developed by Japanese companies as safe, leading to lower intangible costs for the “Japanese company” relative to the “foreign company” as a proxy for safety. Fourth, we did not include an opt-out option in the choice task, which was because we expected all respondents to choose one of the treatment options based on the situation presented to set the context for their choice. Notably, individuals willing to answer the question were allowed to withdraw from the survey at any time. Finally, the reliability of the data obtained in this study depended on whether the respondents adequately understood the questions and whether they answered the questions appropriately and truthfully.

Conclusions

This study estimated the intangible costs of factors associated with oral antiviral drugs for COVID-19 treatment in the Japanese population using a conjoint analysis conducted in August 2022. The intangible cost for the foreign company to the Japanese company was higher than that for changes in the formulation and size of the drug, frequency of administration, dosage, and number of days until one is no longer infectious. The second largest difference in intangible costs between levels was shown for the number of days until one is no longer infectious to others.