Enlightenment and Suggestions on the Construction of Information Platform and Processing Mechanism of Drug Shortages in Developed Countries to China

Cui Li,Xing Hua

(School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To study how to improve and perfect the information platform and processing mechanism of drug shortages in China.Methods By searching the relevant policies from official websites of FDA,European Medicines Agency (EMA),Health Canada (HC) and National Health Commission,the good experience of the United States,the European Union and Canada in the construction of information platform and processing mechanism of drug shortages was summarized for reference in China.Results and Conclusion China has initially established the processing mechanism of drug shortages,but the platform construction should be improved,and the information disclosure of drug shortages varies from province to province.We should improve the information platform of drug shortages,strengthen the disclosure and communication of information,enrich the processing tools and measures after the drug shortages occurs,and strengthen the cooperation with relevant associations and other non-governmental departments.

Keywords: drug shortage;construction;information platform;processing mechanism

Across the world,drug shortages often occur.Aiming at the global problem of drug shortages,developed countries led by the United States and Canada have taken corresponding measures.Although the national conditions of developed countries are different and drug regulatory policies have different emphases,they have a high degree of consistency in dealing with drug shortage problems,which generally includes three steps: Reporting drug shortages,information evaluation,and coping with the shortage.Currently,the United States and other developed countries have set up the information platform of drug shortages,which includes various types of websites belonging to official agencies,industry association,and the third-party professional institution.Among them,the platforms of drug shortages in the United States,the European Union and Canada are the most representative and mature ones.These platforms are outstanding in evaluating,sharing,disclosing,and handling drug shortage information.This paper introduces and analyzes the construction of information platform and processing mechanism of drug shortages in the United States,the European Union and Canada,and puts forward some suggestions for improving the information platform and processing mechanism of drug shortages in China.

1 Information platform and processing mechanism of drug shortages in the United States

FDA defines a drug shortage as a period of time when the demand or projected demand for the drug within the United States exceeds the supply of the drug[1].To strengthen the management of drug shortage information,Center for Drug Evaluation&Research (CDER) established a searchable drug shortage information platform (FDA Drug Shortages)on the FDA website[2].The information listed on the platform is the shortage of medical necessities and the non-medical necessities that have been reported many times.CDER’s drug shortage staff (DSS) is responsible for maintaining the platform.The platform is fully functional,with four sections,namely,drug shortage status,suspension of production,treatment category and new and updated information,with retrieval and sorting functions,facilitating the public and healthcare professionals to quickly query the shortage of drugs[3].

1.1 Information collection and reporting of drug shortages in the United States

Section 506C of the “Federal Food Drugs and Cosmetic Act (FD&CA)”,as amended in 2015,requires all manufacturers of prescription drugs to report to the FDA a permanent suspension of production or temporary interruption of production.The FD&CA specifies the reporting time to be six months in advance (or as soon as possible if not),but in any case,it should not be later than five working days after the actual suspension or interruption of production.The act also requires FDA to send noncompliance letters to manufacturers that fail to fulfill their reporting duties under Section 506C and make it public[4].

FDA centers track shortages and supplies of the products they regulate and collect information on drug shortages in a variety of ways.Drug manufacturers/applicants can directly notify DSS of drug discontinuation,supply interruption via the CDER Direct NextGen Portal.Healthcare professionals,professional organizations,the public,and others can report drug shortages by sending e-mail or calling.In addition,the FDA launched its first drug shortages mobile App in 2015 to provide the public with an additional way to report drug shortages to the FDA.The public can also report drug shortages to the American Society of Health System Pharmacists(ASHP) by completing a drug shortage report form.

1.2 Information evaluation and processing of drug shortages in the United States

DSS judges and deals with different situations based on the three aspects of authenticity,clinical necessity and substitutability of drug shortages.Because shortage information is reported from multiple sources,DSS uses information from manufacturers,distributors,and market share data to verify the authenticity of drug shortages after receiving initial notification of potential drug shortages.If there is no shortage of drugs,routine procedures are used to monitor changes in drug supply and demand.If there is a real drug shortage,it is necessary to further determine whether the drug is a medical necessity and whether it comes from an exclusive manufacturer,and to formulate different treatment measures according to different situations (Fig.1).

Fig.1 Flowchart of drug shortage staff (DSS) handling drug shortages

1.3 Information disclosure of drug shortages in the United States

FDA has two ways to disclose information about drug shortages.One is to publish information about drug shortages on its information platform.The other is to publish the annual shortage of drugs in the annual report.The FDA issued its first official annual report in 2013,and it has issued eight annual reports on drug shortages so far.Due to the adoption of appropriate measures,between 2011 and 2016,the number of drugs in shortage dropped sharply,and then increased slightly but the overall situation remained good.The FDA successfully prevents hundreds of drug shortages each year,as shown in Fig.2.

Fig.2 Number of drug shortages in the United States from 2010 to 2020

1.4 Role of various stakeholders in addressing drug shortages in the United States

FDA attaches great importance to multiparty participation in dealing with drug shortages,and provides three ways to solicit opinions from stakeholders: Open meetings,stakeholder hearings and open documents.Industry associations and other stakeholders also play an indispensable role in managing drug shortages.The ASHP made full use of its professional advantages,set up a drug shortage information page on its website to collect and publish drug shortages information.In addition,ASHP also issued the “ASHP Guidelines on Managing Drug Product Shortages”,which clarified the causes and management strategies of drug shortages from the perspective of drug supply[5].

2 Information platform and processing mechanism of drug shortages in the European Union

In the European Union,most drug shortages are addressed at the national level by the competent authorities of the member states.When drug shortages are related to safety or quality issues,or affect more than one member state,the European Medicines Agency (EMA) may be involved in addressing shortages.To ensure consistency in the detection and management of coordinated drug shortages across the EU,the EMA has defined drug shortages clearly and uniformly as an event that occurs when supply at the national level is insufficient to meet demand[6].The EMA has set up a drug shortages web page on its official website to report information on specific drug shortages affecting multiple countries and provide advice to health care professionals and patients.In addition,the official website also provides screening of published drug shortage reports based on release date and update status.

2.1 Information Collection and reporting of drug shortages in the European Union

EU Directives 2001/83/EC Article 23a (2) and 2001/82/EC Article 27a (2) provide that if a medicinal product is temporarily or permanently discontinued on the market in its member states,the marketing authorization holder (MAH) notifies the competent authorities of the member state concerned.Except in exceptional circumstances,notification shall be no later than two months prior to the interruption[7].The MAH shall notify the EMA and the member states concerned if the shortage involves a centrally authorized product.

In 2019,a single point of contact (SPOC)network was established between the EMA and the competent authorities of member states to improve the sharing of information on shortages of important drugs for human use within member states,the EMA and the EU,which regulated their actions to avoid and manage drug shortages.In the first phase of the program,24 member states have shared 52 shortage notifications using the SPOC system.

2.2 Information evaluation and processing of drug shortages in the European Union

The EMA has developed decision trees to help member states assess whether shortages are being dealt with by themselves or at EU level.In response to the drug shortages at the EU level,the Committee for Medicinal Products for Human Use will organize a multidisciplinary team of experts in the industry.The expert panel assessed the criticality of the drug shortages from the two dimensions of therapeutic use and availability of alternatives,and adopted a fiexible approach based on the results of the benefit/risk assessment and the specific situation.

2.3 Information disclosure of drug shortages in the European Union

The European Union uses a variety of methods to publish information on drug shortages.On the one hand,the list of drug shortages is published on the shortages page of the EMA website.The catalogue contains a detailed report on each product in shortage,describing the drug indications,the reasons for the shortage,the scope of the possible impact on member states,the status of the drug shortages and providing clear advice for healthcare professionals and other stakeholders.To date,the EMA has issued a total of 26 reports of drug shortages,of which 19 have been successfully resolved.On the other hand,more effective communication tools such as press releases will also be used for high-impact drug shortages.For shortages that occur only in a single member state,the EMA website also provides a list of national shortage registers for EU and member states of European Economic Area for easy reference.So far,only five member states (Cyprus,Luxembourg,Malta,the Netherlands and Poland) have not registered their national drug shortage registers online.

2.4 Role of various stakeholders in addressing drug shortages in the European Union

The EMA has organized multi-stakeholder workshops to gather stakeholders’ perspectives on addressing the issue of drug availability.The European Federation of Pharmaceutical Industries and Associations (EFPIA) and the European Generic Medicines Association (EGA) led an internal working group to develop principles for coordination and communication between the industry and regulators in response to drug supply disruptions.

3 Information platform and processing mechanism of drug shortages in Canada

Health Canada (HC) defines a drug shortage as a situation in which the MAH of a drug product is unable to meet demand for a drug product[8].A drug shortage includes a temporary or permanent cessation of manufacturing,and the supply of a drug product.In response to the call of the Minister of Health,Industry Canada in 2012 established an open industry website(www.drugshortages.ca) for drug manufacturers to voluntarily post notifications and information about shortages,discontinuities and therapeutic alternatives.Because of the voluntary reporting system,the public and health-care providers are not fully informed about drug shortages and discontinuations.In 2016,HC led negotiations to form the Multi-Stakeholder Working Group to design and establish a new third-party drug shortages website (DrugShortagesCanada.ca).Manufacturers are required to report projected and actual shortages on the website.

The new site has more notification capabilities and mobile applications than ever before,providing email notification for users to receive the latest information.The website provides detailed reports on shortages and suspensions,as well as historical updates,for public comparison.HC has also established the Drug Product Database (DPD),which is updated synchronously daily to publish information on domestic drug approvals[9].DPD identifies the market status of a drug product.If the manufacturer has not marketed the product in Canada for 12 consecutive months,the product status will change from “marketed” to “dormant” to better reflect the market status of the drug product[10].

3.1 Information Collection and reporting of drug shortages in Canada

Section C.01.014.9 (1) of the “Food and Drug Regulations” of Canada provides that if there is an actual or anticipated shortage of the drug,drug manufacturers should be required to report information about drug shortages and discontinuities on third-party websites[11].The regulation specifies the information,timing and timely updates required for mandatory reporting.The information must be published six months in advance of the anticipated shortage or discontinuation of the product or,if not six months in advance,within five working days after the MAH becomes aware of the anticipated or actual shortage and decides to discontinue the product.

In 2012,HC established a Multi-Stakeholder Steering Committee on Drug Shortages (MSSC),comprising industry and healthcare representatives,to work on drug shortages.MSSC has developed the “Protocol for Notification and Communication of Drug Shortages” and formulated a framework for reporting and communicating shortages of drugs by grades.According to the specific characteristics of each drug in shortage,the information on shortages is reported and communicated by grades.Tier 1 is where the manufacturer or importer anticipates that future supply of drugs may not meet expected demand.Tier 2 is where drug shortages that have occurred but will not have a significant impact.Drug shortages that will have a significant impact on the national drug supply and healthcare system (and lack of alternative treatments) are included in tier 3.

3.2 Information evaluation and processing of drug shortages in Canada

In response to drug shortages,HC has adopted a tiered response mechanism,with each level requiring relevant stakeholders to take appropriate actions.The “Protocol for Notification and Communication of Drug Shortages” developed by the MSSC sets out clear expectations for how and when stakeholders across the supply chain will share information about drug shortages.MSSC investigates the reasons for the shortage and takes actions based on the details of the shortage quantity,inventory,shortage time,and scope shared by all stakeholders[12].

3.3 Information disclosure of drug shortages in Canada

Unlike FDA and EMA,which only publish the actual shortage information,Canadian third-party websites publish the shortage information in a wider range,including the expected and actual shortage information.At present,13 709 shortage reports have been published on third-party Canadian websites,405 shortages have been avoided,and a total of 11 813 drug shortage reports have been successfully solved,with a resolution rate of 86.17%[13].

3.4 Role of various stakeholders in addressing drug shortages in Canada

MSSC is responsible for bringing together key players in the pharmaceutical supply chain to communicate,share information and collaborate to address drug shortages.The “Multi-Stakeholder Toolkit” developed by MSSC analyzes the drug supply chain and divides it into four key stages: Drug approval,production,procurement and distribution,and final distribution.It defines the roles and responsibilities of key participants in each stage of the supply chain.It also analyzes the causes of drug shortages at each stage and develops appropriate tools and strategies.The Group Purchasing Organization acts as a third-party organization that negotiates on behalf of buyers and manufacturers,supports collaboration among stakeholders during drug shortages,conducts ongoing market research,develop new drug procurement strategies,such as split award contracts,to prevent drug shortages in advance.The Canadian Association for Pharmacy Distribution Management is responsible for ensuring,among other things,that drugs in shortage are distributed fairly and evenly across the country[14].

4 Information platform and processing mechanism of drug shortages in China

4.1 Construction of drug shortages information platform in China

In China,drug shortages are defined as drugs approved for marketing by China’s drug regulatory authorities,which are clinically necessary and irreplaceable or cannot be completely replaced,and are in short supply or unstable in a certain period of time or in a certain region[15].Although China has established a drug shortage information collection platform,the platform is only accessible to regulators and enterprises,and no public platform has been established.The information collected by the platform is mainly from the monitoring office of medical institutions,which is taken as the only source of reporting shortage information.Although the information is accurate,it lacks sensitivity and timeliness,making it difficult to achieve timely warning.To change the regulatory inconvenience caused by terminal discovery mechanism in medical institutions,China is exploring the establishment of multi-source information collection platform for drug shortages,which will expand the monitoring scope,integrate and share information on key links of drugs.In addition,the National Medical Products Administration (NMPA) has added a module to the drug information collection platform,which collects information on the production,supply and discontinuation reports of drugs in short supply for drug MAH.

4.2 Information Collection and reporting of drug shortages in China

In 2019,the General Office of the State Council issued the “Opinions on Further Better Sustaining Supply and Price Stabilization of Drugs in Shortage”,which stipulated the implementation of the report on shortage and discontinuation[16].In 2020,the newly revised “Measures for Supervision and Administration of Drug Production” made detailed provisions on the scope,time limit and punishment of drugs to be included in discontinued production reports.For the drugs in the list of short-listed drugs in the national implementation suspension report,the MAH shall report to the drug regulatory department of the province,autonomous region,or municipality where it is located six months before the implementation of the production suspension.The drug regulatory department of the municipality directly under the central government shall,when necessary,report to the NMPA[17].At the same time,MAH and drug manufacturers who fail to report production suspensions will be fined between 10 000 yuan and 30 000 yuan.

4.3 Information evaluation and processing of drug shortages in China

For the evaluating and processing shortage information,the National Health Commission organized and formulated the “Technical Guide for Classification and Alternative Use of Drugs in Shortage in Medical Institutions” to guide medical institutions to classify and evaluate the shortage of drugs[18].Medical institutions evaluate and classify the drugs in shortage from the three dimensions of clinical necessity,substitutability,and the severity of the shortage,rank them according to the time of shortage,and take targeted measures according to the evaluation results.Medical institutions can alleviate drug shortages by restricting use,rationally selecting substitutes,and finding other procurement channels to increase the number of purchases.If a drug is in short supply in more than 3 provinces and cannot be resolved within a certain time,the drug will be included in the national shortage drug list or the national key monitoring basic list of clinically necessary and easily in short supply drugs,and the government will solve it.

4.4 Information disclosure of drug shortages in China

For the management of drug shortages,China implements the management system of drug shortages list.At present,the National Health Commission has issued the first batch of national drug shortages list and national key monitoring list of clinical essential drugs prone to shortage.A total of 6 drugs were included in the national drug shortages list and 57 drugs were included in the national key monitoring list of clinical essential drugs prone to shortage.The shortage information in the list only included variety name and dosage form.Each province has established a provincial shortage list according to its own situation,but there are still many problems.

4.4.1 Information disclosure of drug shortages varying from province to province

By searching the official websites of the National Health Commission and the procurement platforms of various provinces,and inquiring about the disclosure of information on drug shortages,it is found that most provinces have released information on drug shortages to the public.In addition,some provinces also regularly release information on drug shortages to medical institutions,drug distribution companies and other units in the province.However,the platforms announced to the public are different,most of which are made by the National Health Commission of the provinces under their jurisdiction,and a few provinces such as Heilongjiang and Shanghai release information on their procurement platforms.For some provinces,the announcement is made in stages or batches,and some provinces such as Liaoning and Shaanxi announce the announcement in quarters.

4.4.2 Contents and standards of information disclosure of drug shortages varying from province to province

Among the provinces that disclose to the public,the content of the information disclosed by each province is also quite different.Most of the shortage information released by most provinces includes basic information such as generic names of drugs,dosage forms,specifications,and manufacturers.In addition,Liaoning Province also announced the reasons for drug shortages,and Sichuan Province announced the procurement types of drug shortages.The information on drug shortages announced by Hunan Province is relatively comprehensive.In addition to the basic information,it also includes the purchase price of the drug,the type of shortage,the starting time of the shortage,and whether there are alternative drugs[19].

4.4.3 A lag in updating information

Although China has issued the list of drug shortages and stipulated the standards of product withdrawal from the list,there is no time limit for daily maintenance and update.Stakeholders often do not know whether a shortage of drugs on the list is still in shortage or has been successfully addressed,or whether there are new shortages.The untimely information update not only brings great inconvenience to the public to get the information of drug shortage,but also brings a certain lag for the government to deal with a sudden drug shortage.

5 Enlightenment and suggestions

5.1 Improving information collection and network communication platform for drug shortages

Although multi-source information collection platform for drug shortages has been established in China,it still needs to be improved.Special departments should be set up to take charge of daily maintenance and management of drug information in shortage.Information on drug registration,production,procurement and use should be collected,and the scope of collection should be expanded from medical institutions to raw material suppliers,drug manufacturers and operators.Based on the collection platform,the information disclosure module of drug shortages is added to facilitate all stakeholders to query the information of shortage of drugs.Platform should take the initiative to release information and should not be limited to release drug name,variety,dosage forms.Some basic information should also be reported such as shortage reason,whether to have alternative drugs,the affected provinces,inventory,drug purchase price and suggestion for health care personnel information.This can make full use of the drug market resources,as well as exchange,and ensure clinical needs.At the same time,the government should learn from various database models in Canada,classifying the status of drugs based on the existing drug database,and distinguishing the types of drugs that are prone to shortage such as approved but unmarketed and discontinued drugs.

5.2 Strengthening information disclosure and communication on drug shortages

In the process of dealing with drug shortages in developed countries such as the United States,the European Union,and Canada,they pay more attention to the communication of drug shortage information between drug manufacturers,health care personnel,patients and other relevant stakeholders.Increasing disclosure and communication of drug shortages not only provides information for regulators and stakeholders in the supply chain to coordinate mitigation measures,but also enables healthcare practitioners and their patients to make timely decisions about the drugs they use.To ensure consistent and effective communication,a unified reporting and public module should be formulated to publicize information for all provinces.At the same time,the public disclosure and communication of shortage information should not be limited to the catalogue list.We can learn from the annual public reporting system of drug shortages in the United States to summarize the experience and deficiencies in dealing with drug shortages.

5.3 Enriching and improving the coping tools and measures after drug shortages

Drug supply involves drug production,circulation,use,supervision and other links.Therefore,the absence of any link is bound to lead to drug shortages[20].Some tools and guidelines for dealing with drug shortages should be developed to analyze the causes of drug shortages from the aspects of drug registration,production,and circulation.Then,corresponding countermeasures should be formulated to prevent drug shortages from the source.Besides,a risk assessment mechanism for drug shortages should be established to conduct benefit/risk assessment based on drug shortage information,and targeted regulatory actions can be taken based on the results.

5.4 Strengthening cooperation with industry associations and other non-governmental sectors

We can learn from international experience to strengthen cooperation with healthcare groups,industry associations and other non-governmental sectors,which will jointly process drug shortages with government regulatory authorities,enterprises and society.Relevant policies shall be issued to clarify the responsibilities and obligations of all stakeholders in the drug supply chain in the process of drug shortage management.Based on the clear responsibilities and obligations,full communication and coordination shall be carried out to make the strategies to solve the problem of drug shortages more effectively.