The Pharmaceutical Industry at a Glance Changes in Outpatient Care and Outpatient Prescription Drugs Influenced by the COVID-19 Pandemic as Seen in NDB Open Data

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Shinji Tsubakihara, Senior Researcher, Pharmaceutical and Industrial Policy Research Institute

SUMMARY

1. Introduction

COVID-19, an infectious disease caused by the novel coronavirus SARS-Cov-2 that broke out in Wuhan, Hubei Province, China, in December ²⁰¹⁹¹⁾ spread quickly throughout the world, and in Japan, an affected person was confirmed on January 15 of the following year. In 2020 and 2021, the government issued "priority measures to prevent the spread of COVID-19" and "declaration of a state of emergency" (Fig. 1), which led to restrictions on activities by the public, stagnation of business activities in all areas, and the loss of social activities. This had an extremely serious impact on social activities as well. In the medical business, in particular, the increased opportunities for hospitalization and treatment of patients with new coronary infections, inoculation of new coronary vaccines, and devotion to examination of fever patients increased the burden on medical personnel, restricted the provision of normal medical services, and reduced the public's behavior in receiving medical care, resulting in major changes in the nature of medical care provision. In the area of pharmaceutical manufacturing, multiple factors have made it difficult to secure certain pharmaceuticals, including a rapid increase in demand, supply chain disruptions such as suppression of imports of active pharmaceutical ingredients from overseas, withdrawal of generic products, GMP violations, and shipment adjustments associated with these factors. To address this issue, the Ministry of Health, Labour and Welfare (MHLW) has held a "Conference of Parties Concerned with Measures to Ensure Stable Supply of Ethical Drugs" since March 2020 to discuss and implement ^{countermeasures2)}.

This paper examines how the COVID-19 pandemic in 2020 and 2021 changed the volume and type of outpatient care and prescription drugs, using the National Data Base (NDB) open data provided by the Ministry of Health, Labour, and Welfare (MHLW) from FY2015 to FY2021. We report on our analysis of outpatient receipts and outpatient prescription drugs in terms of quantity and quality from FY2015 to FY2021 using the National Data Base (NDB) open data provided by the Ministry of Health, Labor and Welfare.

Survey Methodology

⁽ NDB Open Data ³⁾ From the 2nd (FY2015) to the 8th (FY2021), the number of outpatient receipts by each medical procedure from "A: Basic medical fee 'First/revisit fee_number of calculations by sex and age'", "Prescription drugs (oral/external/injection) 'oral_outpatient (out of hospital)_ quantity by sex and age', 'oral_outpatient (in hospital)_ quantity by sex and age The number of units of oral medication was calculated from "Oral_Outpatient (Outpatient) _Quantity by sex and age" and "Oral_Outpatient (Inpatient) _Quantity by sex and age.

Regression analysis was performed using the statistical analysis software "Stata ver. 14.2".

Results

(1) Changes in the number of outpatient receipts

From the NDB open data, the number of outpatient receipts by practice was graphed from FY 2015 to FY 2021 (Figure 2), and the rate of change in the number of outpatient receipts was calculated from the average value for each of the two years from FY 2018 to FY 2019 and the COVID-19 pandemic period from FY 2020 to FY 2021.

There was no significant change in the number of outpatient receipts from FY 2015 to FY 2019, and the same trend was observed from the perspective of each medical practice, including initial and repeat consultations. However, since FY2020, when the pandemic period began, the number of outpatient receipts has clearly decreased, with a decrease rate of -9.3% compared to the comparative period. The decline in receipts for initial consultations was the largest at -21.9%, while receipts for reexamination fees were down 7.1%, and receipts for outpatient consultation fees, which are calculated for outpatient consultations at facilities with 200 or more beds, were down 8.5%. In contrast, the number of re-examination fee receipts using telephones and other remote communication methods and the number of online medical fee receipts increased by 267.6% and 443.5% respectively during the pandemic period, showing extremely large growth rates, but in terms of volume, the average numbers of receipts were 8,650 thousand/year and 8,762/year, respectively.

Next, we analyzed the number of first-visit receipts, which showed a particularly large rate of decrease, by age group (Figure 3). The age group with the largest decrease rate during the pandemic period was the 0-9 year olds (-41.0%), indicating that the behavior of first medical examinations was greatly suppressed among newborns and children. The next largest reductions were seen in the 10-19, 30-39, and 60-69 age groups, with a reduction rate of approximately 20%.

(2) Changes in outpatient prescription medications

The oral drugs prescribed in outpatient clinics were analyzed based on changes in unit quantities from 2015 to 2021 (Figure 4).In the NDB open data, the quantity of prescribed drugs is expressed in units, with the unit being "tablet, capsule, round, package, bag, sheet, bottle, g, mL," and the quantity of each oral drug being calculated as the smallest unit. In this analysis, the unit quantity of each oral drug in total or in each drug category was tabulated.

Figure 4 shows the trend in unit quantities of outpatient oral prescription drugs, categorized by out-of-hospital and in-hospital prescriptions. The total number of units increased by 2.6% for the average COVID-19 pandemic period of FY 2020-2021 compared to the average for FY 2018-2019, while the number of units of out-of-hospital prescription internal medications increased by 5.1%. The volume of out-of-hospital prescription medications has increased over time since FY 2015, and this trend continued during the pandemic period. In contrast, the number of in-hospital prescription units continued to decline, with the average rate of decline during the pandemic period being -10.1%.

Although the number of outpatient receipts was decreasing, the volume of outpatient in-hospital prescriptions was increasing. To confirm the details of this trend, we analyzed the unit volume of in-hospital prescriptions by major drug classifications (Figure 5). The average percentage change during the pandemic period from the FY 2018-2019 average for the major drug classes was 0.9% for central nervous system drugs, 7.8% for circulatory system drugs, -30.9% for respiratory system drugs, 6.0% for digestive system drugs, 11.2% for tonic drugs, 7.3% for other metabolic drugs, 10.7% for oncology drugs, 10.7% for allergy Allergic drugs -0.4%, Antibiotics -25.1%, Chemotherapeutics (for infectious diseases) -11.6%. The fluctuations in each category of drugs varied, with the largest increases in tonic drugs and oncology drugs, followed by 6-8% increases in drugs used for lifestyle-related diseases, such as drugs for the circulatory system, drugs for the digestive system, and other metabolic drugs, including diabetes drugs. In contrast, respiratory drugs and antibiotics showed a marked decrease.

Figures 6-12 show a close examination of each drug category. Among CNS drugs (Figure 6), "other CNS drugs" including Alzheimer's drugs and neuropathic pain drugs increased by 7.2% and epileptic drugs by 5.0%, while "antipyretic analgesics and anti-inflammatory drugs," for which demand increased during the pandemic, increased by only 2.0%. The drug group that changed significantly was "common cold remedies," with a decrease rate of -54.8%.

Among drugs for the circulatory organs (Figure 7), 13.7% were "hyperlipidemic agents" such as statins, 10.6% were "arrhythmic agents" such as beta blockers, 7.1% were "vasodilators" mainly Ca channel blockers, 7.0% were "diuretics" such as K-retaining agents and thiazides, and 5.0% were "antihypertensives" represented by renin-angiotensin antihypertensive agents. The increase rate of "antihypertensives," such as K-retaining and thiazides, was 7.1%, 7.0%, and 5.8%, respectively.

In respiratory drugs (Fig. 8), there was a decrease in all drug groups, with a particularly marked decrease in "antitussives" and "antitussive castorants," which were reduced by half during the pandemic period. The decrease in "castor agents" and "bronchodilators" was about 20%.

Among drugs for digestive organs (Figure 9), "hemostatic agents" such as loperamide and "intestinal preparations" such as lactobacillus preparations increased by 7.4%, followed by "laxatives, enemas", "antacids" and "peptic ulcer agents" such as PPIs.

Other metabolic drugs (Figure 10) accounted for about 70% of the total, with "diabetes drugs" and "gout drugs" accounting for about 70% of the total, and these lifestyle-related disease drugs showed an increase of about 9%.

Protein amino acid preparations" accounted for most of the nourishing drugs (Figure 11), and drugs in this family have been increasing over time since FY2015, with an average increase of 11.2% during the pandemic period.

Among oncology drugs (Figure 12), "other oncology drugs" showed a high rate of increase at 14.1%. The main reasons were the increase in the number of hormone receptor antagonists for breast and prostate cancer in this drug group and the growth of tyrosine kinase inhibitors and Janus kinase inhibitors. The launch of anti-cancer agents with new mechanisms, such as PARP inhibitors and CDK4/6 inhibitors, around the pandemic period was also thought to have had an impact.

Infectious disease drugs (Figure 13) showed a large overall decrease, but the increase or decrease varied by category. The categories with the largest decreases were "synthetic antibacterial agents" (-41.4%), in which the majority of quinolones were used, "mainly acts on Gram-positive and Gram-negative bacteria" (-32.8%), in which the majority of cephalosporin antibiotics were used, and "mainly acts on Gram-positive bacteria and mycoplasma" (-32.4%), in which the majority of macrolide antibiotics were used, mainly affecting Gram-positive bacteria and mycoplasma" (-32.4%).

(3) Regression analysis between pandemic and outpatient care and outpatient prescription drugs

Regression analysis was conducted to test whether the volume of outpatient prescription oral drugs, the number of outpatient receipts, and the volume of prescriptions per outpatient receipt during the COVID-19 pandemic changed due to the pandemic, even controlling for trends from 2015 to 2021 (robust estimation).

Table 1 presents the results. Regression analysis with the explained variable as the logarithm of the number of outpatient prescription drug units and the explanatory variables as year dummies (linear year dummy between FY 2015 and FY 2021) and corona dummies (0 or 1, 1 being FY 2020 and FY 2021) shows a positive trend, although not significant (0.7% annual increase, p = 0.182), Controlling for trend, the impact of the pandemic was not significant (1% increase, p=0.704). Similarly, analysis of outpatient receipts (log) showed a non-significant but negative trend (down 0.5% per year, p=0.166), and controlling for this trend, the impact of the pandemic was significantly negative (p=0.019), indicating an 8.9% annual decrease in outpatient receipts. Furthermore, there was a significant positive trend for the number of outpatient prescription drug units (log) per outpatient visit, increasing by 1.3% per year (p=0.014), indicating that even controlling for this trend, the COVID-19 pandemic significantly expanded the volume of prescriptions per outpatient visit by 10% per year (p=0 .003). Similarly, the results were significant when the analysis was restricted to re-examination receipts (including telephone care) (p=0.001).

Thus, although the number of outpatient visits decreased substantially during the COVID-19 pandemic, the results suggest that in many cases, physicians responded by expanding the volume of prescriptions per outpatient visit, so that the availability of drugs to patients did not decrease.

Summary and Discussion

(1) Outpatient care

During the COVID-19 pandemic period in 2020 and 2021, there was a clear decrease in the number of outpatient visits, with the largest decrease during the pandemic period relative to the FY 2018-2019 average being -21.9% for first-visit receipts, with a particularly large decrease in first-visit visits for pediatric patients. Receipts for reexamination fees decreased by -7.1%, and receipts for outpatient consultation fees, which are calculated for outpatient consultations at facilities with 200 or more beds, decreased by -8.5%. The reasons for the large decrease in receipts for initial consultations were as follows: (1) An increase in refraining from consultations for acute illnesses, (2) A decrease in acute illnesses due to other viral infections such as influenza, (3) A limited number of "outpatient medical institutions for fever treatment" that accepted fever patients, as they had to be designated by applying to become such institutions, (4) An increase in self-medication using OTC drugs, and (5) A decrease in the number of outpatient medical institutions for fever treatment. (4) Self-medication using OTC drugs increased (5) Patients were unable to receive medical examinations because they had been in close contact with others.

The number of re-examination fees using telecommunication methods such as telephone without face-to-face consultation increased to 267.6%, and the number of online medical fee receipts increased to 443.5%. However, online medical care receipts averaged 8,700 times/year during the pandemic period, and only 0.001% of all outpatient consultations were counted on the receipts, which was extremely small, probably because many medical institutions did not have an environment in place (Table 2).

It is unavoidable that face-to-face medical care declines during a pandemic. Particularly in telemedicine for initial consultations, physicians are often unable to examine basic vital signs and obtain sufficient information necessary for diagnosis, such as information on the patient's underlying disease, making it difficult to accurately examine and diagnose the patient's symptoms. Since patients must be able to correctly communicate their symptoms and vital data to their physicians, it is assumed that the use of telemedicine will be difficult for elderly patients and pediatric patients. However, it is very likely that in the near future, not only in a pandemic environment, but also with the aging of the population, the decline in population, and the uneven distribution of physicians and medical institutions, there will be regions where telemedicine, including initial consultations, will become essential, and an environment in which data-driven remote ambulatory care can be realized must be established.

(2) Outpatient prescription drugs

During the two-year COVID-19 pandemic period, a decrease in the number of outpatient receipts was observed, while the volume of outpatient prescription medications showed an increase of 2.6% over the FY 2018-2019 average. Prescription volume per receipt had been trending upward prior to the pandemic period, but the results of the regression analysis suggest that this was due to an approximately 10% increase in prescription volume during the pandemic period, even controlling for trend. Outpatient prescriptions increased by 5.1% and in-hospital prescriptions decreased by -10.1%. The reasons for the increase in outpatient prescriptions can be attributed to (1) an increase in long-term prescriptions due to behavioral restrictions such as the declaration of a state of emergency or a decrease in outpatient visits due to the pandemic itself, (2) worsening of symptoms and laboratory values due to lack of exercise and dietary changes caused by behavioral restrictions such as the declaration of a state of ^emergency4), (3) exacerbation of underlying disease triggered by ^COVID-195), etc., can be inferred from each report. In particular, "cardiovascular drugs" such as vasodilators and hyperlipidemia drugs, "other metabolic drugs" such as diabetes drugs and gout medications, and "gastrointestinal drugs" showed an increase of 6-7%. Lifestyle drugs tend to be administered for a long period of time because their symptoms are often stable, and this tendency is considered to have become stronger during the COVID-19 pandemic period.

Oncology drugs increased by approximately 10%. Among these, "other oncology drugs," which consist mostly of hormone-based oncology drugs and new types of oncology drugs such as tyrosine kinase inhibitors, showed a large increase of about 14%. Hormonal oncology drugs require continuous administration to suppress hormone-dependent tumors, and the trend toward long-term administration of these drugs may be interpreted as a result of the decrease in the number of patient visits. Cytotoxic oncology drugs may have been switched to drugs with new mechanisms of action from the viewpoints of safety and efficacy, considering the decrease in the number of patients receiving medical care.

Protein amino acid preparations, which account for the majority of "tonic" drugs, showed an increase of approximately 11%. In recent years, amino acid preparations, including over-the-counter supplements, have been increasingly used to prevent sarcopenia in the elderly, and it is possible that the declaration of a state of emergency and other events led to an increase in prescriptions to control the severity of muscle loss due to decreased physical activity in the elderly.

Thus, even during the emergency phase of the COVID-19 pandemic, physicians adjusted the amount of drugs they prescribed, and at the same time, pharmaceutical companies fulfilled their responsibility for stable supply by responding to the increased demand during the emergency phase.

In contrast, despite the COVID-19 pandemic, prescriptions of "respiratory drugs" such as cough suppressants and antitussives and "antibiotics" decreased significantly from the previous pandemic period. This study shows that the demand for medicines for non-communicable diseases (NCDs), such as chronic diseases and malignant diseases, and communicable diseases varies greatly depending on the environment. The study was also influenced by the absence of influenza virus epidemics ^worldwide6) through the COVID-19 pandemic period, behavioral restrictions on containment, crowding, and closeness to prevent mass infection, which suppressed cluster infections other than COVID-19, and behavioral changes in infection prevention by the public, including masks and disinfection.

Although the medium- to long-term trend of the COVID-19 pandemic was unknown, the severity of the disease decreased due to the effects of vaccines, group immunization, and the Omicron strain becoming the mainstream, and in May 2023, the Infectious Diseases Control Law classification of the new coronavirus was moved from a category 2 infectious disease to a category 5 infectious disease with milder measures to be implemented by the government and local authorities ^7). The voluntary restraint of going out of the house for persons who were positive for the new coronavirus and those who had been in close contact with the virus was no longer required, and social activities, such as human flow and contact within and outside of Japan, were restored to normal. However, with it, the spread of influenza virus, adenovirus, and group A streptococcus, which had subsided during the COVID-19 pandemic period, was observed. ⁸⁾ In 2023, the influenza epidemic began in September, earlier than usual, causing a rapid increase in demand for antitussives, castor oil, and anti-influenza drugs. Many of the long-listed essential drugs such as cough suppressants, castor oil, and antibiotics, whose prescription volume declined significantly during COVID-19, are low-priced items with small profit margins. In addition, the procurement of APIs for these long-listed products is mostly dependent on overseas suppliers, and the contracts for their purchase volume are on an annual basis. We believe that a structural supply shortage may have occurred as a result.

The supply shortage of respiratory drugs in the medical field has reached a serious stage, and in November, the government approved a cabinet decision on the "Subsidy for Supporting Stable Pharmaceutical Supply " ⁹⁾ to subsidize the equipment and labor costs necessary to increase production of medically necessary drugs under conditions of supply uncertainty. In order to respond to the rapid increase in demand for medicines due to the spread of infectious diseases, it is an urgent issue to establish a system for the systematic stockpiling and research and development of Medical Countermeasures (MCM) ^{10) that} does not rely solely on emergency measures (note: stockpiling of anti-influenza drugs began in 2005). (Note: stockpiling system for anti-influenza drugs started in 2005).

Recently, there are fears of a re-emergence of COVID-19 caused by a new JN.1 ^strain11) in Japan and abroad. It is hoped that the government, companies, and academic societies will work together to establish a crisis management system for infectious diseases from normal times, and that a system will be quickly established to ensure a stable supply of necessary drugs to medical facilities.

Conclusion

In this paper, using NDB open data, we quantitatively analyzed changes in outpatient care and outpatient prescription drugs that occurred during the COVID-19 pandemic. We hope that this information will be helpful in predicting changes in medical services in the event of future environmental changes caused by the spread of infectious diseases. Although we would have liked to conduct a deeper analysis of the COVID-19 impact in this study, there were limitations to the analysis with the current NDB open data, such as the lack of disease-by-disease receipt data. We feel that there are still issues that need to be addressed before COVID-19 can be used for impact analysis, including the introduction of new drugs and policy changes, and we hope that NDB Open Data will continue to evolve in the future.

Acknowledgments

We would like to thank Professor Sadao Nagaoka, Professor Emeritus of Hitotsubashi University, and Professor Junichi Nishimura of Gakushuin University for their invaluable guidance and advice in the statistical analysis of this report. We would like to express our deepest gratitude to them.

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