Advice of Medicine Shortages in Europe

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Romana Zelko	--	1941	2022-04-02 12:34:37	\|
2	format	Jason Zhu	-90 word(s)	1851	2022-04-06 04:41:30	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijerph19074102

The following recommendations should be considered to handle the issue of drug shortages more effectively in Europe. Since drug shortages do not respect borders and cross-country collaboration would be beneficial for more effective shortage management, a unified European definition and reporting criteria of shortages would be necessary to assure internationally consistent monitoring, reporting, comparisons, responses, and solutions. National authorities across Europe should be aware of shortages through coordinated systems, increasing cross-country transparency, and facilitating solutions in every country. It was a significant step forward in the European Union that in July 2019, the EMA published the “Guidance on detection and notification of shortages of medicinal products for Marketing Authorisation Holders in the Union”. The document contains the effort to facilitate the more uniform reporting and communication of drug shortages and create a harmonization “drug shortage” definition. The document “Good practice guidance for communication to the public on medicines availability issues”contains communication guidelines for the national authorities and the EMA for patients and healthcare professionals.

drug shortage critical medicines risk assessment

1. Introduction

Drug shortages can be defined as when the available or calculated demand for drugs does not sufficiently meet the end-user level demand. The issue affects all stakeholders along the pharmaceutical supply chain, ranging from Marketing Authorization Holders (MAHs) through wholesalers to hospitals, community pharmacies, and patients, posing a serious threat to treatment outcomes ^[1]. Drug shortages are recognized as a global problem, to which local responses are necessary, taking into account regionally diverse factors ^[2]. However, international coordination and common best practices would be beneficial for more effective shortage management. As a starting point, internationally adopted guidelines and definitions would be useful to compare different regions, as currently these are lacking ^[3].

Competent authorities (CAs) have the most crucial role in handling shortages: they must ensure the continued volume of pharmaceutical products, and therefore they should always be aware of any interruptions in the supply of products and take actions to mitigate the impact of drug shortages ^[4]. Competent authorities worldwide took various actions over the past decades to collect, monitor, evaluate, and prevent drug shortages and reduce their impact on the healthcare system ^[5]. In Europe, the responsibility to avoid shortages is shared between authorities, MAHs, and distributors. According to Article 81 of Directive 2001/83, MAHs and the distributors shall ensure appropriate and continued supplies of the medicinal products to pharmacies and hospitals to address the needs of patients ^[6]. The European Association of Hospital Pharmacists (EAHP) started investigating drug shortages in 2012 due to increased reports from its members expressing difficulties in sourcing medicine ^[7]. In the United States (US), President Obama signed the Food and Drug Administration (FDA) Safety Innovation Act in July 2012 ^[8]. The Act mandated manufacturers to inform the FDA of impending shortages to enable early mitigation of the problem. In Australia, the Therapeutic Goods Administration (TGA) dedicated a website to monitoring medicine shortages in May 2014 ^[9]. However, drug shortages remain a global issue, also present in most developed countries, and competent authorities should further improve their shortage management practices, as the substitution or absence of safe and effective therapies can compromise medical procedures, cause errors, and have a serious adverse impact on patient care. This is especially important in the case of drugs included on the World Health Organization (WHO) essential medicine list, as their shortage is more likely to have severe negative impacts on treatment outcomes ^[10].

Drug shortages arise due to several root causes, which can be grouped into economic factors, manufacturing and quality factors, and logistic and regulatory factors ^[2]. Therefore, a diverse set of actions is necessary to effectively address them ^[11].

2. Comparison of Shortage Management in Examined Countries

The analysis clearly shows that the proportion of critical shortages relative to population size is significantly higher in Europe than in other investigated regions of the world. This affects every ATC group under examination, but anti-infective (J) and nervous system (N) drugs show drastically higher critical shortage levels in Europe. The critical shortages of medicines on the WHO Essential Medicine List need to be reduced and prevented in particular. European nations need to adopt a wider range of transparent, unified shortage management countermeasures across countries to address drug shortages. The current forms of countermeasures by country are reported in Table 1 and can be grouped under the six following categories:

Table 1. Countermeasures introduced by countries.

	Compulsory Stockpiling	Measures for Essential Medicines—Legal Definitions	Notification Responsibilitiy—Legal Background	Measures Affecting Wholesalers	Export Bans	Emergency Imports
BE	Full-line wholesalers required to have a range of products in stock for the needs of the given geographic territory/ies ^[12].	Not defined.	Not providing the exact reasons is considered a clear legal violation ^[13].	Full-line wholesalers are assigned besides regular ones with special responsibilities and privileges ^[12]^[14].	Temporarily to medicinal products for which a shortage is notified ^[13].	Based on a doctor’s request wholesalers may temporarily import medicine from the EU, if no substitutes are available in BE, in specific quantities requested by the doctor ^[15].
CH	Delegated to companies at a defined level of stocks in Ordinance ^[16].	Compounds for which there are no or only limited substitutes have been affected by a supply shortage over the previous three years ^[16].	Determined in 531.215.32 Ordinance ^[16].	Managing the strategic level of inventory stock delegated by the federal government in local law ^[16].	Parallel export does not become significant due to high prices ^[17].	Upon application for temporary import submission ^[18].
ES	CA may demand commercialization to grant the suspension, or the revocation of the product ^[19].	Essential if the pharmaceutical gap cannot fully cover or have a high economic impact. Critical if it has no available therapeutic alternatives and has a complex manufacturing process, and/or has only one supplier ^[14].	Spanish Medicine and Products Devices Agency Circular No. 3/2011 ^[20].	All wholesalers are required to deliver within 24 working hours ^[14].	If lack of medicinal products causes a pharmaceutical gap ^[21].	The Spanish Agency of Medicinal Products and Medical Devices can also approve the import of medicines labeled in other languages or with an expiry date shorter than 6 months ^[14].
US	FDA supports MAHs to maintain production ^[22].	If used to treat or prevent a serious disease or condition, and there is no other adequate available source ^[23].	Safety and Innovation Act in 2012 ^[8].	* Not applicable.	* Not applicable.	FDA may allow emergency importation ^[22].
A	National Medical Stockpile maintains the strategic reserve of products ^[24].	Included on Medicines Watch List, has a potential life-threatening or serious impact, or has no potential substitutes ^[25].	Therapeutic Goods (Reportable Medicines) Determination 2018 ^[26].	Wholesalers also have a duty to notify authorities about the expected duration of a discontinuation ^[27].	Only for MAH or designated entity ^[28].	Therapeutic Goods Act has been amended to assist import ^[29].
HU	Products decreed by the minister should be available in the quantity defined therein ^[30].	Not defined.	Act XCV of 2005 on Medicinal Products for Human Use ^[30].	Authorized wholesale distributors shall be required to procure and supply the medicinal products as their authorization for wholesale distribution pertains ^[30].	The active substances decreed by the minister for a period not exceeding one year ^[30].	On the wholesaler’s request “contingent-approval” ^[31] or the physician statement “individual approval of OGYEI” ^[32].

Compulsory stockpiling
Measures for essential medicines
Notification responsibility
Measures affecting wholesalers
Export bans
Emergency imports

3. Compulsory Stockpiling

In Australia, the National Medical Stockpile must maintain “key medicines” to avoid critical shortages of essential drugs ^[33]. A similar system exists in Switzerland, where the government defines medications that are subject to compulsory stockpiling in the appendix to Ordinance and the level of such stock that would satisfy average domestic consumption for three months without any import ^[16].

4. Measures for Essential Medicines

In Spain, the government can demand production and commercialization from MAHs to bridge supply gaps concerning essential products ^[34]. This seems to be an effective measure to cut back shortages, as critical shortages per million people in Spain were significantly the lowest among European countries. The US shortage management system works similarly. In response to the shortage of a medically necessary drug, the FDA can suggest and support establishing a new manufacturing site or even involving a new supplier. If a MAH decides on a voluntary recall, the FDA may conduct risk evaluation and encourage other MAHs to initiate, maintain, or increase production of the drug ^[22]. They can also facilitate the new generic applications that are potential alternatives ^[22]. The regulation also permits hospitals within the same health facility to repackage drugs into smaller units to alleviate drug shortages ^[8]. In Spain, MAHs that stop the distribution of a medicinal product without the authorities’ permission face heavy fines ^[35].

5. Notification Responsibility

In the US, authorities maintain an apparent oversight of shortages. They, therefore, can handle them very effectively—the quantitative analysis clearly reflected that the critical shortages per million people are the lowest in the US. The criteria for products reported in the central systems are strict and well-defined, so authorities can monitor developing shortages from an early stage and address them accordingly ^[36]. For example, MAHs are mandated to inform the FDA of impending shortages six months in advance when they plan to stop producing a single-source or medically necessary (life-supporting, life-sustaining, or intended for use in the prevention or treatment of a debilitating disease or condition, including emergency medical care or during surgery) drug ^[8]. This effectively helps to maintain a low percentage of shortages that turn into critical. The FDA may also oblige the MAHs to conduct periodic risk assessments to address vulnerabilities in its supply chain.

6. Measures Affecting Wholesalers

In Belgium and Spain, some countermeasures specifically target wholesalers, who are obliged to ensure continued and adequate supply. In Spain, all wholesalers are required to deliver within 24 working hours ^[14]. In Belgium, to reduce the cases where shortages arise due to “distribution problems”, distributors were assigned as full-line and regular wholesalers. MAHs are obliged to supply within a shorter period to full-line wholesalers. Full-line distributors are required to deliver emergency shipments in 24 h. They must have a range of specified medicines in stock to supply the needs of defined geographic areas. Moreover, full-line distributors are only allowed to supply strictly determined wholesalers, domestic pharmacies, and hospitals; thereby, parallel export is not permitted ^[12].

7. Export Bans

In Australia, export can only be performed by MAHs or designated distributors acting on behalf of the MAHs, not by most wholesalers like in many European countries ^[28]. This is highly important, as parallel export is usually a key factor in causing shortages, mostly affecting countries with low drug prices compared to international averages. In Spain, authorities (AEMPS) can restrict exportation only to medicinal products without therapeutic equivalents ^[37]. There are serious penalties and fines of up to 1 million euros for distributors who export medicines when this activity has been forbidden.

8. Emergency Imports

When there is no other possibility to resolve a critical shortage as no substitution is available domestically, emergency imports must be performed. The conditions of an emergency import are determined by national laws. In most countries, this is contingent on the approval of the competent authority, such as the FDA in the US, the OGYEI in Hungary, or the Spanish Agency of Medicinal Products and Medical Devices in Spain (see in Table 1). In Belgium, wholesalers may also perform emergency imports from the EU based on a doctor’s request, in the specific quantities necessary for the given treatment ^[15].

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