Drug shortages in China: a cross-sectional study

The World Health Organization (WHO) has considered drug shortages a complex global challenge [1]. There is a lack of a standardized definition of drug shortage globally [2]. According to the WHO, a drug shortage is an insufficiency in the supply of medicines, health products, and vaccines are identified by the health system as essential to meet public health and patient needs [3]. It profoundly impacts patient safety, clinical outcomes, quality control, and healthcare facility management, posing complex challenges for healthcare providers [4]. Drug shortages have prevailed worldwide, affecting high-, middle-, and low-income countries. From 2012 to 2018, shortages of 3,530 pharmaceutical products, including 1,833 different active substances, were reported in France [5]. From 2014 to 2019, 209 drug shortages impacted medications on the WHO Model List of Essential Medicines for Children (EMLc), of which 77 (36.8%) remained unresolved by 2019 in the United States [4]. In 2021,there were 114 drug shortages in the United States [6]; the Dutch Medicines Evaluation Board received 3660 notifications of a lack of 1,835 medicines [7]. Although high-, middle- and low-income countries all deal with shortages, there have been few research studies about the prevalence of shortages in low- and middle-income countries [2]. Drug shortages substantially increased from 2020 to May 2021 due to the COVID-19 pandemic. There were 399 drugs classified as vital unavailable medicines in Colombia until May 2021 [8].

In China, drug shortage was defined as “the shortage of drugs that are clinically necessary, irreplaceable or not completely replaceable, and are in short supply or unstable supply in a certain period of time or in a certain region after being approved by the National Medical Products Administration (NMPA)” [9]. Identifying the characteristics of drug shortages can be beneficial to implementing targeted preventive measures. A qualitative study on drug shortages in Shaanxi Province was conducted in 2016, which indicated that drugs facing shortages were increasing, and essential medicines were mostly involved. The shortage of all 87 identified biologicals and chemicals was reported by tertiary and secondary hospitals in Shaanxi Province [10]. In 2017, a study to characterize the shortage of emergency drugs in China showed that the shortage was very severe. According to the survey, 90.7% of the respondents experienced drug shortages during the previous year. More than half of the physicians (65.7%) reported that drug shortages occurred at least once a month [11]. In 2018, an analysis of 614 hospitals in China showed that the average frequency of drug shortages in general hospitals was 56.1 times per year [12]. A national list of drug shortages involving 58 drugs was also released by National Health Commission of the People’s Republic of China on December 30th, 2020 [13].

The ongoing shortage of drugs has brought negative effects to health care, such as treatment discontinuation due to the unavailability of therapeutic drugs [11]. In particular, the shortage of some emergency medicines may delay treatment and directly threaten patients’ lives [14, 15]. Drug regulatory agencies in various countries attach more and more importance to drug shortages to solve the problem. The Chinese government implemented the national and provincial list management systems for drug shortages, requiring each province to collect, analyse and evaluate the information on drug shortages and formulate the provincial list of drug shortages and list of clinically essential but liable to shortage drugs (hereinafter referred to as “lists of drug shortages”).

Essential medicines were defined by WHO as a class of drugs satisfying the population’s priority healthcare needs and were defined in China as medicines that meet essential medical and health needs, with appropriate dosage forms, reasonable prices, guaranteed supply, and fair access to the public [16, 17]. To ensure public demands, the model and system of essential medicines have been established in China, and the “National Essential Medicine List” (NEML) was formulated through scientific and systematic selection [18]. The latest edition of the NEML was developed in 2018 [19]. The “National Medical Insurance Drug List” (NMIDL) is one of the carriers and manifestations of the basic Chinese medical insurance system. It is used to guide the use and reimbursement of drugs, reduce the burden of medical treatment, and protect the rights and interests of universal health insurance [20]. According to different payment standards, drugs on the list can be divided into category A and category B. Category A drugs are clinically necessary, widely used, and less expensive than other drugs with similar efficacy, while category B drugs refer to drugs that are also clinically necessary and effective but have a higher price than category A. Category A drugs can be reimbursed 100% through universal health insurance. In contrast, category B drugs can be reimbursed at a certain proportion, usually between 70% and 90% depending on local policies and specific drugs. The latest edition of the NMIDL was developed in 2021 [21]. Since 2019, the volume-based drug purchasing policy that aimed to further decrease drug prices by guaranteeing market shares was also implemented in China, and five batches of this kind of purchasing involving 218 drugs had been carried out successfully by June 2021 [22].

However, no comprehensive study was conducted to explore the full picture of drug shortages in China. This study was to collect the lists of drug shortages issued in China from 2018 to 2021 and summarize the characteristics, to provide references for the solution to drug shortages in China.

A total of 408 drugs were involved in the issued provincial lists of drug shortages in China from 2018 to 2021 (Table S1 in Supplementary Material).

In this study, 408 drugs have been in shortage in the last four years in China. Meanwhile, like the United States, France, and other countries [5, 8, 26], China’s drug shortage has shown an upward trend in recent years. It indicated the drug shortage’s severity.

Of the 671 medicines in shortage in Europe, including Belgium, the Netherlands, the United Kingdom, Italy, Germany, Spain, and France from 2010 to 2013, 51% were oral, and 40% were injection, but 52% were injectable, and 40% were oral among 200 essential medicines [27]. In France, injections and oral agents accounted for 47.5% and 43.3% of the 3,530 drugs in shortage during the 7-year period from 2012 to 2018 [5]. In the United States, most drugs affected by shortages from 2014 to 2019 were parenteral (61.2%), followed by oral (25.4%) [4]. Consistent with our findings, the largest proportion of drugs in shortage were injections. The underlying cause of many drug shortages is a lack of profit due to low prices, in which case injections are likelier to be in shortage due to their higher cost than other dosage forms [28].

Drug shortages causes are multifactorial. The drug shortages caused by raw material shortages and production issues have been considered globally [29]. Moreover, the number of hospital patients, as a variable significantly affecting shortage frequency, may indicate that the great demand for drugs will also lead to the emergence of shortages [11]. Low margins, rather than low prices, lack of incentives for high-quality drugs in the generic market, and complexity of drug logistics and regulations further complicate restoring the supply after the market disruptions [28, 30]. As indicated by this study, 3 to 50 manufacturers produced 76.8% (73/95) of the drugs in shortage with a frequency ≥ 5. The lack of manufacturers could not explain the shortage of all drugs. However, some drugs were in shortage and APIs were only produced by fewer than three manufacturers, indicating a potential risk of supply interruption and needed to be closely monitored. To solve this problem, fixed-point productions for some shortages of drugs were conducted in China. The Chinese government invites bids from manufacturers for drugs that are clinically necessary and shortages, and the bid-winning enterprises will conduct fixed-point production. The government-run primary medical and health institutions and public hospitals are required to be equipped with fixed-point production varieties and pay in time according to the contract. At the same time, other medical and health institutions are encouraged to purchase and use designated production varieties. Relevant departments shall monitor the production and supply of designated production enterprises, coordinate and solve existing problems, and ensure stable production and effective supply [31]. Furthermore, regulatory issues such as lack of monitoring systems or policies and unavailability of communication among stakeholders can also affect drug shortages [2]. National and provincial monitoring systems for drug shortages have been established in China since 2016 [32]. However, drug shortage information was mostly reported by medical institutions, and reporting of drug manufacturers was generally insufficient, resulting in the delay of warning for 3 to 6 months [33, 34]. A multi-source information collection platform for drug shortages was launched in November 2021 to realize information interconnection and sharing among drug manufacturers, distributors, and medical institutions; facilitate the joint response to shortages; and improve the sensitivity and timeliness of monitoring and response. It is a national-level platform for monitoring and early warning. Based on this platform, we suggest establishing a shared drug inventory database to place the warning even earlier. Demand issues also causes of drug shortages. Emergency drugs, such as protamine, pralidoxime chloride, and sodium thiosulfate are likely to be in short supply due to low market demand. Yang et al. proposed establishing a reserve system for drug shortages to reserve specific medicines, such as emergency medicines and orphan drugs [10].

Unlike our study, Yang et al. showed that there was no significant difference in the frequency of drug shortages in different regions, but that the number of emergency medicine shortages in eastern regions was significantly higher than the number of shortages in western and central regions [11]. The difference may be because it only investigated the shortages of emergency medicine and the number of drugs in shortage or because the scope of the investigation was significantly narrower than in our study. In general, according to our study, some drugs were in shortage nationwide and others only in several specific provinces. It presented the characteristics of national shortages accompanied by regional shortages in China. This may be related to the differences in disease distribution [35]. Local medicine policies, drug inventory, economic development, and transportation convenience, as well as the pharmaceutical industry, may also influence drug supply. Studies have shown that the drug supply in central China is better than in eastern and western China [36].

In terms of therapeutic properties, nearly all categories of drugs had been reported to be in short supply. The distribution of therapeutic categories for drug shortages in China was similar to other countries such as the United States, Europe and Australia, and was an international public health challenge. In many countries, including China, the cardiovascular system, nervous system, antineoplastic and immunomodulating agents and Anti-infectives for systemic use are among the top categories with the most serious shortage [5, 27, 37]. As the first-line therapy for several cardiovascular diseases, the shortage of antianginals, inotropes, and vasopressors may result in serious health consequences, such as an unsatisfactory effect or increased risk of side effects [38]. An upward trend was also observed in the number of cardiovascular drugs in short supply reported each year in the United States, according to the UUDIS database, from 2017 to 2021 [6]. Ongoing shortages of cardiovascular drugs may have a major impact on public health. Neostigmine, the most commonly used acetylcholinesterase inhibitor in perioperative medicine, was the most common nervous system drug in shortage not only in China but also in the United States [39]. Similarly, pyridostigmine bromide was also in short supply. The shortage of antineoplastic drugs was a particular challenge. There are also shortages of many drugs that played an important role in cancer treatment, such as methotrexate, bleomycin, cytarabine and mitoxantrone. The previous studies reported increased tumor recurrence and impaired survival in cancer patients treated with non-standard therapy during shortages [40]. In addition, there was also a high risk of shortages of blood system drugs such as vitamin K1 and urokinase in China according to this study as well as the previous study [41].

The results of a previous survey of 236 emergency department physicians showed that most respondents agreed that original medicines, injections, essential medicines, medicines without alternative agents, and cheap medicines were more susceptible to shortages than generics, orals, nonessential medicines, medicines with alternative agents and expensive medicines, respectively [11]. In China, 30.4% of essential medicines are in shortage, accounting for 51.0% of the shortage. China had severe essential medicine shortages, consistent with previous surveys in other countries. In a European survey, 30% of drugs with reported shortages were the WHO essential medicines [27]. Shortages of essential medicines have also been reported frequently in some countries in North America, Asia, and South America [42‐44]. Global access to essential medicines remains problematic.

Furthermore, most drugs in shortage were medical insurance drugs in our study. Essential medicines and medical insurance drugs have the characteristics of clinical necessity, safety, effectiveness, reasonable price and guaranteed quality. Therefore, more attention should be paid to these drugs’ shortages. The supply guarantee of such drugs is highly significant to ensure basic medical services for the public.

Consistent with other studies [45], we also found that emergency drugs were likelier to be in short supply. If these drugs are unavailable, the common clinical effect of emergency drug shortages on patients is to delay treatment [11]. Patients may miss the best treatment opportunity and face serious risks if these drugs are unavailable.

This study also found that drug shortage incidence (5.9%) and the VBPL proportion in the drug shortage list (3.4%) were very low, significantly lower than other lists. Therefore, the national procurement pattern of VBPL may effectively decrease drug shortages. This pattern realized the procurement alliance and the inter-provincial adjustment. Its biggest advantage is to ensure the number of transactions and the government will pay a certain percentage of the transaction as the advance payment to guarantee enterprises’ production, so the unit price is low and the total profit of enterprises is sufficient. In the United States, the European Union and some other countries, extensive research has been conducted on mitigation strategies. Many measures have been proposed to cope with drug shortages. In addition to the above measures, risk assessment procedures, national mitigation guidelines, public service obligations on drug suppliers, expediting of drug reviews to restore production, and other measures have good reference significance for the management of drug shortages in China [46‐48].Generally, drug shortages are a global problem that requires international collaboration to develop global mitigation strategies. In high-income countries, almost all categories of drugs have experienced shortages during different periods. In low- and middle-income countries, previous studies mainly focused on the affordability/availability of some essential medicines [2]. Compared to the United States and European countries, less research on drug shortages has been conducted in China. The goal of this study is to comprehensively collect and analyze the national and provincial lists of drug shortages issued in China over the past four years. This will provide references for solving the problem.

Some limitations to this study should be noted. Due to the lack of data in many provinces, there may be some bias in this study. The ATC classifications and manufacturers of the drugs in the list were manually matched. Due to the short implementation time and the absence data from seven provinces, our study was not able to adequately analyze drug shortage trends and assess the effects of new policies or measures. Further research is needed on the causes, trends and effects of intervention.