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Drug shortages may compromise patient safety: Results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists
Accepted Manuscript Title: Drug shortages may compromise patient safety: results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists Authors: Andr´e Said, Ralf Goebel, Matthias Ganso, Petra Zagermann-Muncke, Martin Schulz PII: DOI: Reference:
S0168-8510(18)30466-4 https://doi.org/10.1016/j.healthpol.2018.09.005 HEAP 3974
To appear in:
Health Policy
Received date: Revised date: Accepted date:
23-5-2018 19-7-2018 6-9-2018
Please cite this article as: Said A, Goebel R, Ganso M, Zagermann-Muncke P, Schulz M, Drug shortages may compromise patient safety: results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists, Health policy (2018), https://doi.org/10.1016/j.healthpol.2018.09.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Drug shortages may compromise patient safety: results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists
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André Saida,*, Ralf Goebela, Matthias Gansoa, Petra Zagermann-Munckea, b, Martin Schulza
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Author’s details:
[email protected]
Ralf Goebela, RPh, PhD
[email protected]
Matthias Gansoa, RPh, PhD
[email protected]
Petra Zagermann-Munckea, b, RPh, PhD
[email protected]
Prof. Martin Schulza, RPh, PhD, FFIP, FESCP
[email protected]
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Author affiliations: a
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André Saida,*, RPh, PhD
Drug Commission of German Pharmacists (AMK),
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Department of Medicine; ABDA – Federal Union of German Associations of Pharmacists,
b
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Unter den Linden 19–23, 10117 Berlin, Germany ABDATA Pharma-Daten-Service, Avoxa – Mediengruppe Deutscher Apotheker GmbH,
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Apothekerhaus Eschborn,
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Carl-Mannich-Straße 26, 65760 Eschborn, Germany
*Corresponding author: Dr. André Said, Drug Commission of German Pharmacists (AMK), Department of Medicine; ABDA – Federal Union of German Associations of Pharmacists, Unter den Linden 19–23, 10117 Berlin, Germany;
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Phone: +49 30 40004-552, -514; Email: [email protected]
Submission statement: The authors certify that the data in the manuscript are original and the
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manuscript is not under consideration elsewhere. All authors contributed significantly to the publication and have read and approved the manuscript as well as its submission to Health
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Policy.
Highlights
Drug shortages represent a constant challenge for pharmacists in everyday practice.
Community and hospital pharmacists confirmed negative consequences for patient
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treatment.
Pharmacists attempt to counteract imminent or current shortages to ensure patient
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safety.
Pharmacists seek for early, comprehensive and valid information on drug shortages.
Germany now implements mandatory reporting obligations on shortages of specific
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drugs.
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Abstract
Drug shortages are a complex problem and of growing concern. To evaluate implications of drug shortages in terms of outpatient and inpatient safety, the Drug Commission of German Pharmacists surveyed its two nationwide reference pharmacy networks: 865 community and 54 hospital pharmacies.
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Participants were asked to complete a six-question online survey, covering relevance and challenges of drug shortages in everyday practice as well as consequences for patient safety. Answers were given in the context of the last three months prior to the survey. In total, 482 community (56%) and 36 hospital pharmacies (67%) participated. Occurrence of drug shortages were confirmed by 88.6% of community and 80.6% of hospital
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pharmacies. Thus, for example, a substitute was dispensed more than 15 times (60.7% of
community, 44.8% of hospital pharmacies) during the 3-month-period. Comparing community
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and hospital pharmacies, differences in the incidence or severity of consequences for patient safety were apparent. Community pharmacies mainly confirmed adverse effects on patients’ medication adherence (60.4%) and treatment discontinuation (25.8%). A delay or deny of a
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life-saving treatment (39.4%) was largely reported by hospital pharmacies. Medication errors
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were reported by 20.1% of the community and 21.2% of the hospital pharmacies, respectively.
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adequate treatment for patients.
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Taken together, sustainable solutions are needed to counteract drug shortages and to ensure
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Keywords Drug shortages . Pharmacy . Drug Commission of German Pharmacists . Patient
Introduction
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safety . Germany . Survey
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A rising number of studies on drug shortages have been published in the recent years, highlighting its growing issue of concern on health and wellbeing of patients (1–6). So far, there is no universally accepted definition on medicine or drug shortages. Acknowledging the
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increasing number of shortages and stock-outs of medicines and vaccines, the WHO proposed draft definitions on a global level in 2016 (7). According to the German Federal Institute for Drugs and Medical Devices (“Bundesinstitut für Arzneimittel und Medizinprodukte”, BfArM), the term delivery shortage (“Lieferengpass”) equals drug shortages in the context of this publication and refers to an interruption in the normal volume of supply lasting more than two 3
weeks, or a significant increase in demand which cannot be adequately met (8). Moreover, when appropriate drug treatment is compromised due to the non-availability of therapeutic alternatives,
a
delivery
or
drug
shortage
translates
into
a
treatment
shortage
(“Versorgungsengpass”).
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Hence, drug shortages cause serious issues related to patient care and pose challenges for healthcare professionals (9–13). The duty of pharmacists is to ensure a continuous and adequate treatment for patients. Problems underlying drug shortages with negative effects on patient
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safety, as viewed from a pharmacists’ perspective, therefore determines a critical aspect to understand the current situation and the arising implications of shortages in pharmacy practice.
AMK) represents
an
independent
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Deutschen Apotheker”,
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In this context, the Drug Commission of German Pharmacists (“Arzneimittelkommission der national
institution
of
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pharmacovigilance (14). The AMK is organised within the ABDA - Federal Union of German
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Associations of Pharmacists (“ABDA - Bundesvereinigung Deutscher Apothekerverbände e.
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V.”), which is the umbrella organization of all pharmacists and community pharmacies in Germany. The AMK collects, assesses and evaluates risks of medicinal products, reported by
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German pharmacies, as defined by § 63 of the German Medicinal Products Act (“Arzneimittelgesetz”, AMG). The AMK records and processes each individual case report and
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forwards it to the competent authorities, enhancing information flow within and towards healthcare professionals. The documentation of adverse events or compromised patient safety due to drug shortages is an important tool to illustrate the current concerns. However, the well-
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known limitation of a spontaneous reporting system is the distinct underreporting, making it virtually impossible to generate comprehensive data on the current implications of drug shortages in pharmacies (15). To overcome those restrictions, the AMK has established a nationwide network of reference pharmacies. In case of specific questions in the context of pharmacovigilance, the AMK is able 4
to launch a survey to get access to comprehensive data on the topic of interest. With respect to the possible issues caused by drug shortages in pharmacy practice, the AMK carried out a survey to elucidate the relevance and issues of drug shortages from the perspective of both, community and hospital pharmacists. The aim of the survey was to determine similarities and/or differences in respective consequences of inpatient and outpatient safety. In addition, specific
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countermeasures taken by community and hospital pharmacies were enquired. To the best of our knowledge, this is the first study to provide comparative data on drug shortages in German
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community and hospital pharmacies on a nationwide level. Materials and methods
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The AMK reference pharmacy network
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The network of reference community pharmacies was first established in 1978 and constitutes
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an effective tool for AMK-initiated pharmacovigilance surveys. The network of reference
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hospital pharmacies was established in 2013. Reference pharmacies are appointed by the 17 State Chambers of Pharmacists and thus, are distributed throughout Germany. For the
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nomination as a reference pharmacy some quality criteria apply: The community or hospital pharmacy has to verify an established quality management system, a high commitment in the
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areas of education and advanced vocational training as well as an affinity for digital
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correspondence (email, Internet). The AMK network comprises pharmacies of various sizes (in terms of both staff and turnover) and geographical locations (urban, rural, peripheral and border regions). For 2017, the ABDA listed overall 19,748 community and 379 hospital pharmacies
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in Germany. With 865 community and 54 hospital pharmacies at the time of the survey, the AMK reference network comprised about 4.4% of all community and 14.3% of all hospital pharmacies in Germany (16). Upon appointment, the selected reference pharmacy is asked to accept the terms of the agreement to participate in surveys initiated by the AMK. However, pharmacies have the option of not responding to selected questions or complete surveys. 5
Available characteristics of the AMK community and hospital reference pharmacies are provided in Supplementary material 1. Online Survey A survey was developed using the Survey Monkey online tool (Dublin, Ireland). The questions
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were compiled, evaluated and reviewed by the AMK (Supplementary material 2). An email was sent to all reference pharmacies with a brief preamble on the topic of drug shortages and a link
inviting them to participate in the six-questions-survey. The survey was launched on October
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24, 2016 and concluded on December 5, 2016, with an additional email to community pharmacies on November 4, 2016 to encourage participation. No personal identifying
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information was collected.
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Domains of interest
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The survey focused on the occurrence and frequency of drug shortages and the proportion of
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treatment shortages (drug shortage with no therapeutic alternative available), possible
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consequences for patient safety, and countermeasures taken by pharmacists to remedy drug shortages. In addition, the following topics were addressed: the sources of information on drug
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shortages as well as an explicit example of drugs, whose shortage had a negative impact on patient safety. The participants were asked to answer in the context of the last three months
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prior to the survey. All answers given are based on reference pharmacies’ estimations and judgements. All questions were multiple choice, except for the exemplarily mentioned drugs subjected to shortages in the past. For some questions, multiple answers were allowed and/or
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additional free text answers were possible. Statistical Analyses Descriptive statistics were compiled for each question. The data were resumed into two datasets, for community pharmacies and hospital pharmacies, respectively, and analysed using Microsoft Office Excel 2016 (Microsoft, Redmond, WA, USA). 6
Results Relevant number of drug shortages reported by pharmacies In total, 482 community pharmacies and 36 hospital pharmacies participated in the survey (response rates of 56% and 67%, respectively). Nearly 90% of the community pharmacies and over 80% of the hospital pharmacies confirmed that they had experienced drug shortages at
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least once in the last three months which had (or could have had) consequences for the patients’ health. More than 20% even stated that this had happened more than 15 times during that period
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(Table 1, A). However, not every drug shortage has critical implications for patients. Things get particularly problematic when delivery shortages translate to treatment shortages, where
appropriate drug treatment is compromised due to the non-availability of therapeutic
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alternatives. Indeed, the vast majority of community pharmacists (81.4%) and hospital
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pharmacists (91.0%) defined up to 25% of drug shortages as treatment shortages (Table 1, B).
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Around 15% of community pharmacies and 6% of hospital pharmacies estimated that the
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adequate drug supply as under threat.
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proportion of treatment shortages was even higher. Only 3% of pharmacists did not yet see
Challenges for pharmacists and consequences for patients
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Pharmacies were additionally asked about direct consequences of drug shortages. Predefined
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answers included safety-related observations, such as medication errors or discontinuations, whereas individual free text answers were also possible (Table 2). Typical consequences for the patients depended on whether drug shortages occurred in community or hospital
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pharmacies. Most pharmacists admitted to having given patients less suitable drugs (54.9% of community and 72.7% of hospital pharmacies) or dosage forms (56.1% of community and 63.6 % of hospital pharmacies) as a result of shortages. While at 20.1% and 21.2%, the incidence of medication errors reported by community and hospital pharmacies, respectively, was nearidentical, 39.4% of hospital pharmacists believed that the shortage either denied patients a life7
saving treatment or at least delayed it, compared to 15.0% of community pharmacists. In contrast, at 25.8%, the rate of discontinuation reported by community pharmacies was far higher than the 6.1% described by hospital pharmacies. Moreover, 60.4% of community pharmacists vs. 18.2% of hospital pharmacists asserted that the use of substitute drugs had adverse effects
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on medication adherence. With regard to additional free text answers (n=75 of community pharmacies, n=7 of hospital
pharmacies), an increased risk of documentation errors or of incorrect conversion of dosages
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was reported in isolated cases (n=3), as was a significant increase in the time and costs associated with obtaining medications (n=7). Some pharmacists also lamented the increase in
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patient anxiety associated with supply shortages (n=13), which could in some cases lead to
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complete loss of confidence in the supplying pharmacy despite the increased time and effort
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expended by pharmacists (n=3). In total, only ten pharmacies reported having observed no
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negative consequences.
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Countermeasures
Pharmacists were asked to specify how often they had resorted to a predefined selection of
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logistic, pharmaceutical and pharmacotherapeutic solutions listed in the survey (Table 3).
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Community pharmacies (60.7%) and hospital pharmacies (44.8%) had dispensed a substitute for the originally prescribed drug, covered by a rebate contract. Hence, a (bio-)equivalent product in terms of the international non-proprietary name (INN), formulation and dosage,
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more than 15 times in the last three months. Approximately half of the reference pharmacies stated that they had contacted other pharmacies (including subsidiaries) to enquire about the availability of medicines due to shortages up to 10 times within three months. Logistical measures play an important role for pharmacies. Nearly all community pharmacies (98.5%) stated that they had occasionally obtained drugs from pharmaceutical companies instead of their wholesaler. All hospital pharmacies also confirmed that they had made direct purchases from 8
alternative pharmaceutical companies in order to remedy a shortage. Approximately 90% of hospital and 48% of community pharmacies also imported medicinal products on at least one occasion in accordance with § 73 (3) of the AMG. Dispensing pharmacies tried to counteract supply shortages by preparing extemporaneous products (compounding). Hence, 48.2% of hospital and 16.9% of community pharmacies reported having prepared up to four products
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during the specified period. In addition, 42.6% of community and 42.9% of hospital pharmacies
alike consulted the prescribing physician for an alternative prescriptions. Nearly all community
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(94.8%) and all hospital pharmacies stated that they had increased their stockpiles to prevent shortages at least once during the specified period.
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Systemic anti-infectives are often affected by shortages
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Pharmacies which stated that they had been affected by drug shortages were asked to provide a
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specific example of a drug, where the shortage had a negative impact on patient safety. In total,
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360 community pharmacies and 26 hospital pharmacies complied (Figure 1). Here, systemic
hospital pharmacies.
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anti-infectives accounted for a significant proportion of drug shortages in both, community and
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Drugs most commonly reported by community pharmacies were beta-blockers (metoprolol),
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with a total of 130 mentions. In addition, there were 35 reports of metamizole (dipyrone), which made it the most commonly cited analgesic, and, together with fluspirilene (n=11), quetiapine (n=3) and St. John’s Wort (n=6), formed the bulk of CNS active substances. Community
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pharmacies also mentioned 28 times anti-diabetic drugs, especially liraglutide (n=9), dapagliflozin (n=9) and empagliflozin (n=4).” Other drug classes included chemotherapy drugs such as melphalan (n=2), thyroid hormones (levothyroxine, n=4), platelet aggregation inhibitors such as ticagrelor (n=7), urological drugs
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(solifenacin, n=4) or drugs against obstructive airway diseases (salmeterol/fluticasone, n=10, salbutamol (albuterol), and vilanterol). Beside systemic anti-infectives such as piperacillin/tazobactam (n=39), daptomycin, streptomycin, or sultamicillin, hospital pharmacies mainly mentioned electrolyte solutions
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(potassium chloride, n=3), haematological agents (n=2), chemotherapy drugs such as melphalan or oxaliplatin, and thyroid hormones (levothyroxine, n=4).. Other drug classes
included gynaecological drugs, neuromuscular blocking agents (mivacurium, n=2), opioid
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anaesthetics (remifentanil, n=2), antiparasitic drugs (metronidazole), and antidotes such as 4dimethyl-aminophenol (4-DMAP) or calcium folinate.
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Pharmacies keep up to date
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Community and hospital pharmacies use reports issued by the Federal Authorities (BfArM,
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www.bfarm.de: 29.1% and 36.4%, Paul-Ehrlich Institute (PEI), www.pei.de: 39.4% and 30.3%
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of community and hospital pharmacies, respectively). The website of the European Medicines
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Agency (EMA, www.ema.europa.eu) seems far less known or relevant. Only 5.5 % of community and 15.2% of hospital pharmacies resort to the latter when searching for information
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on drug shortages. The vast majority of community pharmacists use information from pharmaceutical wholesalers (94.0%), pharmaceutical companies (84.5%), or the pharmacy
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press (53.6%). For hospital pharmacies, information from wholesalers (24.2%) and the pharmacy press (33.3%) plays a less prominent role than that supplied by pharmaceutical companies. All hospital pharmacies stated that they obtained information on drug shortages
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directly from manufacturers. Further sources of information cited (n=26 and n=14 of community and hospital pharmacies, respectively) included colleagues from other pharmacies (n=9), purchasing communities (n=6), medical sales representatives (n=2), and even social media (n=2).
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Discussion Findings from the survey This survey of AMK reference pharmacies was conducted to provide details of the current challenges of drug shortages in everyday pharmacy practice from the perspective of both,
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community and hospital pharmacies. The provided insights into current implications of inpatient and outpatient safety, together with the countermeasures taken by pharmacists, are
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valuable data to understand the current limitations in German drug supply.
While measures such as drug imports, purchasing directly from (alternative) pharmaceutical
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companies, phone calls to prescribers for alternative prescription, preparation of
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extemporaneous products (compounding) or larger stockpiles can assure drug supply for
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individual patients, they involve considerable time and effort (18, 19). Higher financial costs
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should also be taken into account. Moreover, drug substitution, usually with alternative therapeutics made by other manufacturers, requires a high level of professional expertise, inter-
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professional cooperation and intensive patient counselling (20, 21). For instance, the import of medicinal products according to § 73 (3) AMG requires an order received from individual
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persons in a small quantity and is only allowed, when no drug for the therapeutic indication in
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question, which is identical in terms of the active substance and comparable in terms of the strength, is available in Germany. Recordings taken by pharmacists comprise e.g. the name and batch number of the imported drug, the name and address of the prescribing physician as well
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as the patient, and also special instructions for the use of the imported drug, given to the patient for safety reasons. This survey shows that medication errors, treatment discontinuations or delaying of vital treatments due to drug shortages are far from uncommon. Pharmacists frequently confirmed their occurrence at least once within the period of three months prior to the survey. Although 11
the setup of a multiple-choice questionnaire did not quantify the total number of negative effects, it allows a direct comparison of implications of drug shortages for outpatient and inpatient safety. Here, a discontinuation of treatment most likely refers to the non-availability of a therapeutic alternative, independent of the medical indication. A delay or denial of a life-
anti-cancer drugs, and thus has the most significant impact on patient safety.
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saving treatment implies a shortage of a live-saving medication, e.g. emergency medicine or
Differences in the incidence of life-threatening drug shortages and in patient medication
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adherence, attributed to the use of substitutes, may be explained by the characteristics of hospital and community settings. The illnesses of inpatients tend to be more serious and
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associated with a higher likelihood of complications. However, the hospital setting also means
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that the use of drug substitutes can be supervised by qualified healthcare personnel.
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The number of negative consequences, given in this study largely relied on pharmacists’
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estimations and predictions rather than measured facts or data. However, pharmacists in
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Germany are obliged to report risks of medicinal products and (potential) negative implications for patient safety via the spontaneous reporting system. As an independent national institution
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of pharmacovigilance, the AMK records and processes each individual case report and forwards it to the competent authorities. However, reports referring explicitly to consequences of drug
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shortages are currently underrepresented. Considering the pharmacists’ examples of a drug prone to shortages, with potential (negative)
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consequences for patient safety, differences between community and hospital pharmacies in the therapeutic indications of the drugs concerned were expected. In fact, a number of drug classes are known to be prone to shortages (17). But for the survey, only systemic anti-infectives accounted for a significant proportion of drug shortages in both settings. However, in community pharmacies, systemic anti-infectives were less likely to be antibiotics, with vaccines against infectious diseases (n=57) accounting for 85% of the total. 12
Moreover, it cannot be said with certainty whether the above mentioned examples indeed met the criteria of the BfArM. The German definition of a drug shortage comprises an interruption in the normal volume of supply lasting more than two weeks, or a significant increase in demand which cannot be adequately met. In May 2017, only six of all the active substances mentioned by pharmacies were explicitly listed in the BfArM report on current drug shortages: 4-DMAP,
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calcium folinate, levothyroxine, melphalan, piperacillin/tazobactam and remifentanil. In contrast, 49 of the 57 vaccines mentioned in the survey were also listed in the April 2017 and
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past drug shortage reports of the PEI.
The BfArM has published reports on its website on current shortages of medicines for human
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use in Germany since 2013. However, the majority of pharmacists use information from
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pharmaceutical wholesalers, pharmaceutical companies or the pharmacy press. At the time of
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the survey, the reports provided by BfArM relied solely on information voluntarily submitted
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by marketing authorization holders. The federal authority had no further information regarding the supply status of the listed drugs, and no way of verifying the accuracy of the data. In
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addition, the only drug shortages recorded at the time were those for which information was specifically requested by the healthcare community. These included prescription drugs
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predominantly used for the treatment of severe to life-threatening diseases, and for which no
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alternative therapeutics are available. The PEI issues reports on shortages of human vaccines. Alternative therapeutics are listed when available and otherwise, recommendations are issued by the Standing Committee on Vaccination at the Robert Koch Institute (RKI).
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General reflections to improve the situation The reasons for drug shortages are manifold and usually due to manufacturing problems, pricing or recalls; they can also be demand-related (22). Processes such as drug development, approval, production and distribution are all subject to high quality standards. Shortages often result from quality deficiencies or (serious) industrial accidents in production facilities. Where product 13
recalls mandated by the authorities come into play, e.g. due to deficiencies in the abovementioned processes, it also becomes necessary to assess the potential impact of these measures on patient care. In the absence of alternative therapeutics and as long as there are no immediate risks to patients, abrupt market withdrawals might be avoided in order to prevent serious
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treatment shortages. Drug shortages are especially noticeable when only a few manufacturers are in charge of the
global supply of the agents concerned (23). The pricing of new and older drugs is also held
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responsible. When early assessments fail to reveal an additional benefit, marketing
authorization holders (MAH) sometimes take new drugs off the German market (“opt-out”). In
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contrast, older drugs (no longer under patent protection) are subject to constant pricing
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pressures. As a result, production and sale in Europe is no longer attractive for the manufacturer,
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which can give rise to new monopoly situations resulting from license sales worldwide.
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in Germany and throughout Europe.
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Problems with manufacturers who have a monopoly are thus quick to impact the care of patients
Thus, a stimulation in decision making, attributed to drug shortages, is urgently needed. In order
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to prevent drug shortages and ensure a consistent supply of medicines, current measures should be expanded and adapted, and controls integrated into the processes involved. This requires the
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cooperation of the full spectrum of professionals, institutions, organisations and agencies involved in the healthcare system both at the national and international levels (24–26).
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In fact, in Europe several networks are currently addressing supply problems to patient safety. In the framework of the COST Action CA15105, 26 EU member states aim to achieve clarity on disruption causes, to simulate decision making and to reflect on best coping practices (27). In addition, a joint supply chain actors’ statement on information and medicinal products shortages was recently published by the Pharmaceutical Group of the European Union (PGEU)
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and other European stakeholders, representing manufacturers of medicinal products, parallel distributors and pharmaceutical wholesalers (28). In Germany, on the occasion of the German Pharma Dialogue, it was therefore agreed to dedicate a “Jour Fixe” to drug delivery and shortages attended by the Federal Authorities and
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healthcare professionals, with the participation of the AMK. This “Jour Fixe” has been monitoring and assessing the supply situation since the third quarter of 2016 (29).
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In the course of the activities, a list of relevant drugs potentially sensitive to shortages was
acquired and might be helpful in ensuring their specific and continued supply in the future. These include prescription drugs or drug combinations whose supply is relevant to the entire
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population (usually no orphan drugs), as well as active substances at high risk of shortage. The
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latter are supply-relevant medicinal products for which only one marketing authorization
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holder, only one manufacturer with final clearance or only one active substance manufacturer
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is available. Thus, drugs at high risk of shortage are subject to particularly close regulatory
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monitoring. The current lists of supply-relevant active substances and those at high risk of shortage have been available on the homepage of the BfArM website since early May 2017
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(30). Both lists are subject to monitoring, regular updates and further development by the
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federal authorities with respect to the supply situation. The system, whereby shortage reports by the pharmaceutical industry are voluntary, should be supplemented by mandatory reporting obligations, as confirmed by the outcomes of our survey.
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Pursuant to the German “Care Provision Strengthening Act”, federal authorities will be given the opportunity to request information on sales and prescription volumes straight from pharmaceutical manufacturers. Hospital pharmacies will be able to order appropriate quantities of imported drugs in order to improve acute patient care. Pharmaceutical companies are required to inform hospitals as soon as they become aware of shortages of prescription drugs intended for inpatient care. 15
Since early May 2017 and regardless of mandatory drug shortage reporting in hospitals, as recommended by the “Jour Fixe”, the BfArM now requires marketing authorization holders to report drug shortages involving active substances whose supply has been subject to shortages in the past. This obligation likewise applies to supply-relevant drugs for which three or fewer MAH, manufacturers with final clearance or active substance manufacturers are registered in
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the German Federal Drug Information system.
The extent to which the new reporting requirements will achieve timely reporting of delivery
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and supply shortages or even prevent them remains to be seen. While the AMK welcomes the
obligation to report, it also encourages the prompt, comprehensive and transparent notification of community pharmacies with regard to foreseeable short- and longer-term drug shortages on
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the national and international level.
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Limitations
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The response rates of 56% and 67%, respectively, increase the potential risk of bias,
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overestimating the impact of drug shortages on patient safety. Selected answers such as the estimated number of treatment shortages may be subject to distortion, as they were mostly based
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on subjective impressions. Therefore, scientific caution is advised when interpreting the results. The AMK network of reference pharmacies comprises, however, a large number of pharmacies
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of various sizes and geographical locations. In addition and compared to other surveys, the response rate and the number of participating pharmacies were high (31–34).
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Since the survey was conducted a month-long, it might be a difference if a pharmacist completed the survey at the beginning or end of the time frame, due to the dynamic nature of drug shortages. However, instead of narrowing the observation period, participants were asked to answer in the context of the last three months prior to the survey, allowing a comprehensive analysis of trends and differences between pharmacies and care settings.
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Conclusion This study is the first to provide comparative figures on the effect of drug shortages from the perspective of both, German community and hospital pharmacies. This survey shows that
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pharmacists depend on early, comprehensive and valid information on the respective matter to initiate specific countermeasures and may specify best coping practices. The question remains
if e.g. the recently introduced mandatory reporting obligations for MAH or an intensified
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monitoring by the federal authorities in Germany, can pave the way to ensure consistent drug
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supply for patients in future.
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Funding: This research did not receive any specific grant from funding agencies in the public,
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Declarations of interest: none
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commercial, or not-for-profit sectors
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Acknowledgments: We thank all AMK reference pharmacies who participated in this survey.
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9. Costelloe EM, Guinane M, Nugent F, Halley O, Parsons C. An audit of drug shortages in a community pharmacy practice. Ir J Med Sci 2015; 184(2):435–40. DOI: 10.1007/s11845-014-1139-7
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11. Mazer-Amirshahi M, Pourmand A, Singer S, Pines JM, van den Anker, John. Critical drug shortages: implications for emergency medicine. Acad Emerg Med 2014; 21(6):704–11. DOI: 10.1111/acem.12389 12. Furlow B. Persistent drug shortages jeopardise patient safety in the USA. Lancet Respir Med 2015; 3(3):182–3. DOI: 10.1016/S2213-2600(15)00053-3 13. Wörmann B, Lüftner D. Arzneimittelengpässe am Beispiel der Hämatologie und Onkologie: Mit Übersicht zur Situation in anderen Fachgebieten [Drug shortages: the example of hematology and oncology]. Berlin, February 2017. https://www.dgho.de/publikationen/schriftenreihen/arzneimittelengpaesse/band-9. (last accessed: April 30, 2018) 18
14. Ganso M, Goebel R, Melhorn S, Schrenk D, Schulz M. Lipidpneumonie durch Lipid-haltige Nasensprays und -tropfen. Laryngorhinootologie 2016; 95(8):534–9. DOI: 10.1055/s-0042-108445 15. Hazell L, Shakir SAW. Under-reporting of adverse drug reactions: A systematic review. Drug Saf 2006; 29(5):385–96. 16. Bundesvereinigung Deutscher Apothekerverbände e. V., ABDA (Federal Union of German Associations of Pharmacists). Figures Data Facts 2018; 2018. Available from: URL: https://www.abda.de/fileadmin/assets/ZDF/ZDF_2018/ABDA_ZDF_2018_Brosch.pdf (last accessed: July 12, 2018).
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17. Ventola CL. The Drug Shortage Crisis in the United States: Causes, Impact, and Management Strategies. P & T 2011; 36(11):740–57.
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18. Weerdt E de, Rijdt T de, Simoens S, Casteels M, Huys I. Time spent by Belgian hospital pharmacists on supply disruptions and drug shortages: An exploratory study. PLoS One 2017; 12(3):e0174556. DOI: 10.1371/journal.pone.0174556
19. Weerdt E de, Simoens S, Casteels M, Huys I. Time Investment in Drug Supply Problems by Flemish Community Pharmacies. Front Pharmacol 2017; 8:568. DOI: 10.3389/fphar.2017.00568
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20. van Mil JW, Westerlund T, Brown L, Chen TF, Henman M, Hersberger K et al. Medical care and drug-related problems: Do doctors and pharmacists speak the same language? Int J Clin Pharm 2016; 38(2):191–4. DOI: 10.1007/s11096-016-0249-x
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21. Fox ER, Birt A, James KB, Kokko H, Salverson S, Soflin DL. ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. Am J Health Syst Pharm 2009; 66(15):1399–406. DOI: 10.2146/ajhp090026
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22. Yang C, Wu L, Cai W, Zhu W, Shen Q, Li Z et al. Current Situation, Determinants, and Solutions to Drug Shortages in Shaanxi Province, China: A Qualitative Study. PLoS One 2016; 11(10):e0165183. DOI: 10.1371/journal.pone.0165183
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23. Bogaert P, Bochenek T, Prokop A, Pilc A. A Qualitative Approach to a Better Understanding of the Problems Underlying Drug Shortages, as Viewed from Belgian, French and the European Union’s Perspectives. PLoS One 2015; 10(5):e0125691. DOI: 10.1371/journal.pone.0125691
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24. Iyengar S, Hedman L, Forte G, Hill S. Medicine shortages: A commentary on causes and mitigation strategies. BMC Med 2016; 14(1):124. DOI: 10.1186/s12916-016-0674-7
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25. Bochenek T, Abilova V, Alkan A, Asanin B, Miguel Beriain I de, Besovic Z et al. Systemic Measures and Legislative and Organizational Frameworks Aimed at Preventing or Mitigating Drug Shortages in 28 European and Western Asian Countries. Front Pharmacol 2017; 8:942. DOI: 10.3389/fphar.2017.00942 26. Bocquet F, Degrassat-Theas A, Peigne J, Paubel P. The new regulatory tools of the 2016 Health Law to fight drug shortages in France. Health Policy 2017; 121(5):471–6. DOI: 10.1016/j.healthpol.2017.03.007 27. COST: European Cooperation in Science and Technology. European Medicines Shortages Research Network - addressing supply problems to patients (Medicines Shortages); 2015. Available from: URL: http://www.cost.eu/COST_Actions/ca/CA15105. (last accessed: April 30, 2018)
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28. AESGP, EAHP, EAEPC, EFPIA, EIPG, GIRP et al. Joint Supply Chain Actors Statement on Information and Medicinal Products Shortages; 2017. Available from: URL: http://www.medicinesforeurope.com/news/joint-statement-on-shortages/. (last accessed: April 30, 2018).
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29. Bundesinstitut für Arzneimittel und Medizinprodukte, Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM). Jour Fixe zu Liefer- und Versorgungsengpässen; 2016. Available from: URL: https://www.bfarm.de/DE/Arzneimittel/Arzneimittelzulassung/Arzneimittelinformationen/Liefereng paesse/jourfixe/_node.html. (last accessed: April 30, 2018)
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30. Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM (Federal Institute for Drugs and Medical Devices). Pressemitteilung Nr. 8/17: BfArM erweitert Informationsangebot im Zusammenhang mit Lieferengpässen; 2017. Available from: URL: http://www.bfarm.de/SharedDocs/Pressemitteilungen/DE/2017/pm8-2017.html. (last accessed: April 30, 2018)
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31. McLaughlin M, Kotis D, Thomson K, Harrison M, Fennessy G, Postelnick M et al. Effects on patient care caused by drug shortages: a survey. J Manag Care Pharm 2013; 19(9):783–8. DOI: 10.18553/jmcp.2013.19.9.783
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32. Beck JC, Chen B, Gordon BG. Physician approaches to drug shortages: Results of a national survey of pediatric hematologist/oncologists. World J Clin Oncol 2017; 8(4):336–42. DOI: 10.5306/wjco.v8.i4.336
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33. Caulder CR, Mehta B, Bookstaver PB, Sims LD, Stevenson B. Impact of Drug Shortages on Health System Pharmacies in the Southeastern United States. Hosp Pharm 2015; 50(4):279–86. DOI: 10.1310/hpj5004-279
A
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34. Heiskanen K, Ahonen R, Karttunen P, Kanerva R, Timonen J. Medicine shortages—a study of community pharmacies in Finland. Health Policy 2015; 119(2):232–8. DOI: 10.1016/j.healthpol.2014.11.001
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Figure and Table legends Figure 1: Drugs prone to shortages with negative consequences for patients. Reports by community (A) and hospital pharmacies (B) were analyzed and depicted as bar chart according to the 1st level of the Anatomical Therapeutic Chemical (ATC) classification system. In total,
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n=360 community and n=26 hospital pharmacies responded. Ten of the brand names provided by community pharmacies were not taken into consideration due to the impossibility to
A
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ED
M
A
N
U
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conclusively code the active substance.
21
22
A ED
PT
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U
N
A
M
Table 1: Drug shortages in everyday pharmacy practice. Frequency of drug shortages (A) and estimated proportion of treatment shortages (B), as stated by community and hospital pharmacies, respectively. Data is shown in relation to given rates within the past three months.
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Table 1. A and B A) Frequency of drug shortages (within past 3 months)
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Respondents [n (%)]
7
(19.4)
< 5 times
133
(27.6)
9
(25.0)
5 – 10 times
136
(28.2)
12
(33.4)
11 – 15 times
50
1
(2.8)
7
(19.4)
U
(11.4)
N
55
A
Never
(10.4)
ED
> 15 times
108
Hospital pharmacies (n=36)
M
Community pharmacies (n=482)
(22.4)
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B) Proportion of treatment shortages of drug shortages
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Community pharmacies (n=399)
No treatment
Hospital pharmacies (n=33)
13
(3.3)
1
(3.0)
≤ 25%
325
(81.4)
30
(91.0)
26 - 49%
32
(8.0)
1
(3.0)
≥ 50%
29
(7.3)
1
(3.0)
A
shortage
23
Table 2: Negative effects on patient safety. Occurrence of given consequences for outpatient and inpatient care due to drug shortages (multiple answers possible). The narration of each individual free text answer is not depicted. Table 2.
Respondents [n (%)]
(n=399)
224
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M
administered Discontinuation of treatment
Life-saving treatment was delayed or
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denied
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Medication error occurred when
U
Less suitable dosage form was
(54.9)
N
219
(56.1)
(n=33)
24
(72.7)
21
(63.6)
A
Less suitable drug was prescribed
Hospital pharmacies
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Community pharmacies
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Consequences for patient safety
103
(25.8)
2
(6.1)
60
(15.0)
13
(39.4)
80
(20.1 )
7
(21.2)
241
(60.4)
6
(18.2)
75
(18.8)
7
(21.2)
using the alternative medicine
A
Adverse effect on patients’ adherence Others (free text answers)
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Table 3: Countermeasures to overcome possible shortages. Community and hospital pharmacists were given a selection of logistic, pharmaceutical and pharmacotherapuetic solutions. Data is shown in relation to given rates within the past three months (never, <5 times, 5-10 times, 11-15 times, >15 times).
Countermeasures taken by pharmacists
never
< 5 times
5–10 times
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Respondents [n (%)]
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Table 3.
11–15 times
> 15 times
N
U
Dispensing a substitute for the originally prescribed drug (covered by a rebate contract)
41 (10.5)
4 (1.0)
Hospital
236 (60.7)
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2 (6.9)
7 (24.1)
4 (13.8)
13 (44.8)
45 (11.8)
97 (25.4)
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(n=29)
3 (10.4)
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(n=389)
pharmacies
35 (9.0)
73 (18.8)
M
pharmacies
A
Community
Contacting other pharmacies (also subsidiaries)
A
Community pharmacies
34 (8.9)
113 (29.6)
93 (24.3)
(n=382)
25
Hospital pharmacies
11 (45.8)
7 (29.2)
5 (20.8)
1 (4.2)
0 (0)
(n=24)
Community 6 (1.5)
98 (25.0)
121 (30.9)
12 (54.5)
3 (13.6)
1 (4.6)
(n=392)
U
Hospital
110 (28.1)
1 (4.6)
5 (22.7)
N
pharmacies
57 (14.5)
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pharmacies
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Obtaining drugs from pharmaceutical companies instead wholesalers
A
(n=22)
M
Purchasing directly from alternative pharmaceutical company
pharmacies
153 (45.1)
(n=339)
PT
ED
Community
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Hospital
pharmacies
0 (0)
82 (24.2)
57 (16.8)
13 (3.9)
34 (10.0)
1 (3.2)
10 (32.3)
5 (16.1)
15 (48.4)
A
(n=31)
Importing medicinal products in accordance with § 73 (3) of the German Drug Law (AMG) Community 211 (61.7)
110 (32.1)
14 (4.1)
pharmacies
26
3 (0.9)
4 (1.2)
(n=342) Hospital pharmacies
3 (9.7)
22 (71.0)
3 (9.7)
1 (3.2)
2 (6.4)
(n=31)
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Preparing an extemporaneous product (compounding)
pharmacies
271 (80.4)
57 (16.9)
4 (1.2)
12 (44.4)
13 (48.2)
2 (7.4)
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Community 0 (0)
U
(n=337)
0 (0)
0 (0)
A
N
Hospital pharmacies
5 (1.5)
M
(n=27)
ED
Consulting prescribing physician for an alternative prescription
pharmacies
60 (15.3)
96 (24.5)
64 (16.3)
167 (42.6)
1 (3.6)
6 (21.4)
6 (21.4)
3 (10.7)
12 (42.9)
5 (1.3)
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(n=392)
PT
Community
Hospital
A
pharmacies (n=28)
Increase stockpiling
27
Community pharmacies
20 (5.2)
114 (29.6)
102 (26.6)
46 (12.0)
102 (26.6)
0 (0)
4 (12.5)
9 (28.1)
6 (18.8)
13 (40.6)
(n=384)
pharmacies
A
CC E
PT
ED
M
A
N
U
SC R
(n=32)
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Hospital
28
S0168-8510(18)30466-4 https://doi.org/10.1016/j.healthpol.2018.09.005 HEAP 3974
To appear in:
Health Policy
Received date: Revised date: Accepted date:
23-5-2018 19-7-2018 6-9-2018
Please cite this article as: Said A, Goebel R, Ganso M, Zagermann-Muncke P, Schulz M, Drug shortages may compromise patient safety: results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists, Health policy (2018), https://doi.org/10.1016/j.healthpol.2018.09.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Drug shortages may compromise patient safety: results of a survey of the reference pharmacies of the Drug Commission of German Pharmacists
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André Saida,*, Ralf Goebela, Matthias Gansoa, Petra Zagermann-Munckea, b, Martin Schulza
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Author’s details:
[email protected]
Ralf Goebela, RPh, PhD
[email protected]
Matthias Gansoa, RPh, PhD
[email protected]
Petra Zagermann-Munckea, b, RPh, PhD
[email protected]
Prof. Martin Schulza, RPh, PhD, FFIP, FESCP
[email protected]
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Author affiliations: a
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André Saida,*, RPh, PhD
Drug Commission of German Pharmacists (AMK),
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Department of Medicine; ABDA – Federal Union of German Associations of Pharmacists,
b
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Unter den Linden 19–23, 10117 Berlin, Germany ABDATA Pharma-Daten-Service, Avoxa – Mediengruppe Deutscher Apotheker GmbH,
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Apothekerhaus Eschborn,
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Carl-Mannich-Straße 26, 65760 Eschborn, Germany
*Corresponding author: Dr. André Said, Drug Commission of German Pharmacists (AMK), Department of Medicine; ABDA – Federal Union of German Associations of Pharmacists, Unter den Linden 19–23, 10117 Berlin, Germany;
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Phone: +49 30 40004-552, -514; Email: [email protected]
Submission statement: The authors certify that the data in the manuscript are original and the
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manuscript is not under consideration elsewhere. All authors contributed significantly to the publication and have read and approved the manuscript as well as its submission to Health
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Policy.
Highlights
Drug shortages represent a constant challenge for pharmacists in everyday practice.
Community and hospital pharmacists confirmed negative consequences for patient
A
N
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treatment.
Pharmacists attempt to counteract imminent or current shortages to ensure patient
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safety.
Pharmacists seek for early, comprehensive and valid information on drug shortages.
Germany now implements mandatory reporting obligations on shortages of specific
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drugs.
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Abstract
Drug shortages are a complex problem and of growing concern. To evaluate implications of drug shortages in terms of outpatient and inpatient safety, the Drug Commission of German Pharmacists surveyed its two nationwide reference pharmacy networks: 865 community and 54 hospital pharmacies.
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Participants were asked to complete a six-question online survey, covering relevance and challenges of drug shortages in everyday practice as well as consequences for patient safety. Answers were given in the context of the last three months prior to the survey. In total, 482 community (56%) and 36 hospital pharmacies (67%) participated. Occurrence of drug shortages were confirmed by 88.6% of community and 80.6% of hospital
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pharmacies. Thus, for example, a substitute was dispensed more than 15 times (60.7% of
community, 44.8% of hospital pharmacies) during the 3-month-period. Comparing community
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and hospital pharmacies, differences in the incidence or severity of consequences for patient safety were apparent. Community pharmacies mainly confirmed adverse effects on patients’ medication adherence (60.4%) and treatment discontinuation (25.8%). A delay or deny of a
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life-saving treatment (39.4%) was largely reported by hospital pharmacies. Medication errors
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were reported by 20.1% of the community and 21.2% of the hospital pharmacies, respectively.
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adequate treatment for patients.
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Taken together, sustainable solutions are needed to counteract drug shortages and to ensure
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Keywords Drug shortages . Pharmacy . Drug Commission of German Pharmacists . Patient
Introduction
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safety . Germany . Survey
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A rising number of studies on drug shortages have been published in the recent years, highlighting its growing issue of concern on health and wellbeing of patients (1–6). So far, there is no universally accepted definition on medicine or drug shortages. Acknowledging the
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increasing number of shortages and stock-outs of medicines and vaccines, the WHO proposed draft definitions on a global level in 2016 (7). According to the German Federal Institute for Drugs and Medical Devices (“Bundesinstitut für Arzneimittel und Medizinprodukte”, BfArM), the term delivery shortage (“Lieferengpass”) equals drug shortages in the context of this publication and refers to an interruption in the normal volume of supply lasting more than two 3
weeks, or a significant increase in demand which cannot be adequately met (8). Moreover, when appropriate drug treatment is compromised due to the non-availability of therapeutic alternatives,
a
delivery
or
drug
shortage
translates
into
a
treatment
shortage
(“Versorgungsengpass”).
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Hence, drug shortages cause serious issues related to patient care and pose challenges for healthcare professionals (9–13). The duty of pharmacists is to ensure a continuous and adequate treatment for patients. Problems underlying drug shortages with negative effects on patient
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safety, as viewed from a pharmacists’ perspective, therefore determines a critical aspect to understand the current situation and the arising implications of shortages in pharmacy practice.
AMK) represents
an
independent
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Deutschen Apotheker”,
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In this context, the Drug Commission of German Pharmacists (“Arzneimittelkommission der national
institution
of
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pharmacovigilance (14). The AMK is organised within the ABDA - Federal Union of German
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Associations of Pharmacists (“ABDA - Bundesvereinigung Deutscher Apothekerverbände e.
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V.”), which is the umbrella organization of all pharmacists and community pharmacies in Germany. The AMK collects, assesses and evaluates risks of medicinal products, reported by
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German pharmacies, as defined by § 63 of the German Medicinal Products Act (“Arzneimittelgesetz”, AMG). The AMK records and processes each individual case report and
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forwards it to the competent authorities, enhancing information flow within and towards healthcare professionals. The documentation of adverse events or compromised patient safety due to drug shortages is an important tool to illustrate the current concerns. However, the well-
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known limitation of a spontaneous reporting system is the distinct underreporting, making it virtually impossible to generate comprehensive data on the current implications of drug shortages in pharmacies (15). To overcome those restrictions, the AMK has established a nationwide network of reference pharmacies. In case of specific questions in the context of pharmacovigilance, the AMK is able 4
to launch a survey to get access to comprehensive data on the topic of interest. With respect to the possible issues caused by drug shortages in pharmacy practice, the AMK carried out a survey to elucidate the relevance and issues of drug shortages from the perspective of both, community and hospital pharmacists. The aim of the survey was to determine similarities and/or differences in respective consequences of inpatient and outpatient safety. In addition, specific
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countermeasures taken by community and hospital pharmacies were enquired. To the best of our knowledge, this is the first study to provide comparative data on drug shortages in German
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community and hospital pharmacies on a nationwide level. Materials and methods
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The AMK reference pharmacy network
N
The network of reference community pharmacies was first established in 1978 and constitutes
A
an effective tool for AMK-initiated pharmacovigilance surveys. The network of reference
M
hospital pharmacies was established in 2013. Reference pharmacies are appointed by the 17 State Chambers of Pharmacists and thus, are distributed throughout Germany. For the
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nomination as a reference pharmacy some quality criteria apply: The community or hospital pharmacy has to verify an established quality management system, a high commitment in the
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areas of education and advanced vocational training as well as an affinity for digital
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correspondence (email, Internet). The AMK network comprises pharmacies of various sizes (in terms of both staff and turnover) and geographical locations (urban, rural, peripheral and border regions). For 2017, the ABDA listed overall 19,748 community and 379 hospital pharmacies
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in Germany. With 865 community and 54 hospital pharmacies at the time of the survey, the AMK reference network comprised about 4.4% of all community and 14.3% of all hospital pharmacies in Germany (16). Upon appointment, the selected reference pharmacy is asked to accept the terms of the agreement to participate in surveys initiated by the AMK. However, pharmacies have the option of not responding to selected questions or complete surveys. 5
Available characteristics of the AMK community and hospital reference pharmacies are provided in Supplementary material 1. Online Survey A survey was developed using the Survey Monkey online tool (Dublin, Ireland). The questions
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were compiled, evaluated and reviewed by the AMK (Supplementary material 2). An email was sent to all reference pharmacies with a brief preamble on the topic of drug shortages and a link
inviting them to participate in the six-questions-survey. The survey was launched on October
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24, 2016 and concluded on December 5, 2016, with an additional email to community pharmacies on November 4, 2016 to encourage participation. No personal identifying
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information was collected.
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Domains of interest
A
The survey focused on the occurrence and frequency of drug shortages and the proportion of
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treatment shortages (drug shortage with no therapeutic alternative available), possible
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consequences for patient safety, and countermeasures taken by pharmacists to remedy drug shortages. In addition, the following topics were addressed: the sources of information on drug
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shortages as well as an explicit example of drugs, whose shortage had a negative impact on patient safety. The participants were asked to answer in the context of the last three months
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prior to the survey. All answers given are based on reference pharmacies’ estimations and judgements. All questions were multiple choice, except for the exemplarily mentioned drugs subjected to shortages in the past. For some questions, multiple answers were allowed and/or
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additional free text answers were possible. Statistical Analyses Descriptive statistics were compiled for each question. The data were resumed into two datasets, for community pharmacies and hospital pharmacies, respectively, and analysed using Microsoft Office Excel 2016 (Microsoft, Redmond, WA, USA). 6
Results Relevant number of drug shortages reported by pharmacies In total, 482 community pharmacies and 36 hospital pharmacies participated in the survey (response rates of 56% and 67%, respectively). Nearly 90% of the community pharmacies and over 80% of the hospital pharmacies confirmed that they had experienced drug shortages at
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least once in the last three months which had (or could have had) consequences for the patients’ health. More than 20% even stated that this had happened more than 15 times during that period
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(Table 1, A). However, not every drug shortage has critical implications for patients. Things get particularly problematic when delivery shortages translate to treatment shortages, where
appropriate drug treatment is compromised due to the non-availability of therapeutic
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alternatives. Indeed, the vast majority of community pharmacists (81.4%) and hospital
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pharmacists (91.0%) defined up to 25% of drug shortages as treatment shortages (Table 1, B).
A
Around 15% of community pharmacies and 6% of hospital pharmacies estimated that the
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adequate drug supply as under threat.
M
proportion of treatment shortages was even higher. Only 3% of pharmacists did not yet see
Challenges for pharmacists and consequences for patients
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Pharmacies were additionally asked about direct consequences of drug shortages. Predefined
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answers included safety-related observations, such as medication errors or discontinuations, whereas individual free text answers were also possible (Table 2). Typical consequences for the patients depended on whether drug shortages occurred in community or hospital
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pharmacies. Most pharmacists admitted to having given patients less suitable drugs (54.9% of community and 72.7% of hospital pharmacies) or dosage forms (56.1% of community and 63.6 % of hospital pharmacies) as a result of shortages. While at 20.1% and 21.2%, the incidence of medication errors reported by community and hospital pharmacies, respectively, was nearidentical, 39.4% of hospital pharmacists believed that the shortage either denied patients a life7
saving treatment or at least delayed it, compared to 15.0% of community pharmacists. In contrast, at 25.8%, the rate of discontinuation reported by community pharmacies was far higher than the 6.1% described by hospital pharmacies. Moreover, 60.4% of community pharmacists vs. 18.2% of hospital pharmacists asserted that the use of substitute drugs had adverse effects
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on medication adherence. With regard to additional free text answers (n=75 of community pharmacies, n=7 of hospital
pharmacies), an increased risk of documentation errors or of incorrect conversion of dosages
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was reported in isolated cases (n=3), as was a significant increase in the time and costs associated with obtaining medications (n=7). Some pharmacists also lamented the increase in
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patient anxiety associated with supply shortages (n=13), which could in some cases lead to
N
complete loss of confidence in the supplying pharmacy despite the increased time and effort
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expended by pharmacists (n=3). In total, only ten pharmacies reported having observed no
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negative consequences.
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Countermeasures
Pharmacists were asked to specify how often they had resorted to a predefined selection of
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logistic, pharmaceutical and pharmacotherapeutic solutions listed in the survey (Table 3).
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Community pharmacies (60.7%) and hospital pharmacies (44.8%) had dispensed a substitute for the originally prescribed drug, covered by a rebate contract. Hence, a (bio-)equivalent product in terms of the international non-proprietary name (INN), formulation and dosage,
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more than 15 times in the last three months. Approximately half of the reference pharmacies stated that they had contacted other pharmacies (including subsidiaries) to enquire about the availability of medicines due to shortages up to 10 times within three months. Logistical measures play an important role for pharmacies. Nearly all community pharmacies (98.5%) stated that they had occasionally obtained drugs from pharmaceutical companies instead of their wholesaler. All hospital pharmacies also confirmed that they had made direct purchases from 8
alternative pharmaceutical companies in order to remedy a shortage. Approximately 90% of hospital and 48% of community pharmacies also imported medicinal products on at least one occasion in accordance with § 73 (3) of the AMG. Dispensing pharmacies tried to counteract supply shortages by preparing extemporaneous products (compounding). Hence, 48.2% of hospital and 16.9% of community pharmacies reported having prepared up to four products
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during the specified period. In addition, 42.6% of community and 42.9% of hospital pharmacies
alike consulted the prescribing physician for an alternative prescriptions. Nearly all community
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(94.8%) and all hospital pharmacies stated that they had increased their stockpiles to prevent shortages at least once during the specified period.
U
Systemic anti-infectives are often affected by shortages
N
Pharmacies which stated that they had been affected by drug shortages were asked to provide a
A
specific example of a drug, where the shortage had a negative impact on patient safety. In total,
M
360 community pharmacies and 26 hospital pharmacies complied (Figure 1). Here, systemic
hospital pharmacies.
ED
anti-infectives accounted for a significant proportion of drug shortages in both, community and
PT
Drugs most commonly reported by community pharmacies were beta-blockers (metoprolol),
CC E
with a total of 130 mentions. In addition, there were 35 reports of metamizole (dipyrone), which made it the most commonly cited analgesic, and, together with fluspirilene (n=11), quetiapine (n=3) and St. John’s Wort (n=6), formed the bulk of CNS active substances. Community
A
pharmacies also mentioned 28 times anti-diabetic drugs, especially liraglutide (n=9), dapagliflozin (n=9) and empagliflozin (n=4).” Other drug classes included chemotherapy drugs such as melphalan (n=2), thyroid hormones (levothyroxine, n=4), platelet aggregation inhibitors such as ticagrelor (n=7), urological drugs
9
(solifenacin, n=4) or drugs against obstructive airway diseases (salmeterol/fluticasone, n=10, salbutamol (albuterol), and vilanterol). Beside systemic anti-infectives such as piperacillin/tazobactam (n=39), daptomycin, streptomycin, or sultamicillin, hospital pharmacies mainly mentioned electrolyte solutions
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(potassium chloride, n=3), haematological agents (n=2), chemotherapy drugs such as melphalan or oxaliplatin, and thyroid hormones (levothyroxine, n=4).. Other drug classes
included gynaecological drugs, neuromuscular blocking agents (mivacurium, n=2), opioid
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anaesthetics (remifentanil, n=2), antiparasitic drugs (metronidazole), and antidotes such as 4dimethyl-aminophenol (4-DMAP) or calcium folinate.
U
Pharmacies keep up to date
N
Community and hospital pharmacies use reports issued by the Federal Authorities (BfArM,
A
www.bfarm.de: 29.1% and 36.4%, Paul-Ehrlich Institute (PEI), www.pei.de: 39.4% and 30.3%
M
of community and hospital pharmacies, respectively). The website of the European Medicines
ED
Agency (EMA, www.ema.europa.eu) seems far less known or relevant. Only 5.5 % of community and 15.2% of hospital pharmacies resort to the latter when searching for information
PT
on drug shortages. The vast majority of community pharmacists use information from pharmaceutical wholesalers (94.0%), pharmaceutical companies (84.5%), or the pharmacy
CC E
press (53.6%). For hospital pharmacies, information from wholesalers (24.2%) and the pharmacy press (33.3%) plays a less prominent role than that supplied by pharmaceutical companies. All hospital pharmacies stated that they obtained information on drug shortages
A
directly from manufacturers. Further sources of information cited (n=26 and n=14 of community and hospital pharmacies, respectively) included colleagues from other pharmacies (n=9), purchasing communities (n=6), medical sales representatives (n=2), and even social media (n=2).
10
Discussion Findings from the survey This survey of AMK reference pharmacies was conducted to provide details of the current challenges of drug shortages in everyday pharmacy practice from the perspective of both,
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community and hospital pharmacies. The provided insights into current implications of inpatient and outpatient safety, together with the countermeasures taken by pharmacists, are
SC R
valuable data to understand the current limitations in German drug supply.
While measures such as drug imports, purchasing directly from (alternative) pharmaceutical
U
companies, phone calls to prescribers for alternative prescription, preparation of
N
extemporaneous products (compounding) or larger stockpiles can assure drug supply for
A
individual patients, they involve considerable time and effort (18, 19). Higher financial costs
M
should also be taken into account. Moreover, drug substitution, usually with alternative therapeutics made by other manufacturers, requires a high level of professional expertise, inter-
ED
professional cooperation and intensive patient counselling (20, 21). For instance, the import of medicinal products according to § 73 (3) AMG requires an order received from individual
PT
persons in a small quantity and is only allowed, when no drug for the therapeutic indication in
CC E
question, which is identical in terms of the active substance and comparable in terms of the strength, is available in Germany. Recordings taken by pharmacists comprise e.g. the name and batch number of the imported drug, the name and address of the prescribing physician as well
A
as the patient, and also special instructions for the use of the imported drug, given to the patient for safety reasons. This survey shows that medication errors, treatment discontinuations or delaying of vital treatments due to drug shortages are far from uncommon. Pharmacists frequently confirmed their occurrence at least once within the period of three months prior to the survey. Although 11
the setup of a multiple-choice questionnaire did not quantify the total number of negative effects, it allows a direct comparison of implications of drug shortages for outpatient and inpatient safety. Here, a discontinuation of treatment most likely refers to the non-availability of a therapeutic alternative, independent of the medical indication. A delay or denial of a life-
anti-cancer drugs, and thus has the most significant impact on patient safety.
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saving treatment implies a shortage of a live-saving medication, e.g. emergency medicine or
Differences in the incidence of life-threatening drug shortages and in patient medication
SC R
adherence, attributed to the use of substitutes, may be explained by the characteristics of hospital and community settings. The illnesses of inpatients tend to be more serious and
U
associated with a higher likelihood of complications. However, the hospital setting also means
N
that the use of drug substitutes can be supervised by qualified healthcare personnel.
A
The number of negative consequences, given in this study largely relied on pharmacists’
M
estimations and predictions rather than measured facts or data. However, pharmacists in
ED
Germany are obliged to report risks of medicinal products and (potential) negative implications for patient safety via the spontaneous reporting system. As an independent national institution
PT
of pharmacovigilance, the AMK records and processes each individual case report and forwards it to the competent authorities. However, reports referring explicitly to consequences of drug
CC E
shortages are currently underrepresented. Considering the pharmacists’ examples of a drug prone to shortages, with potential (negative)
A
consequences for patient safety, differences between community and hospital pharmacies in the therapeutic indications of the drugs concerned were expected. In fact, a number of drug classes are known to be prone to shortages (17). But for the survey, only systemic anti-infectives accounted for a significant proportion of drug shortages in both settings. However, in community pharmacies, systemic anti-infectives were less likely to be antibiotics, with vaccines against infectious diseases (n=57) accounting for 85% of the total. 12
Moreover, it cannot be said with certainty whether the above mentioned examples indeed met the criteria of the BfArM. The German definition of a drug shortage comprises an interruption in the normal volume of supply lasting more than two weeks, or a significant increase in demand which cannot be adequately met. In May 2017, only six of all the active substances mentioned by pharmacies were explicitly listed in the BfArM report on current drug shortages: 4-DMAP,
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calcium folinate, levothyroxine, melphalan, piperacillin/tazobactam and remifentanil. In contrast, 49 of the 57 vaccines mentioned in the survey were also listed in the April 2017 and
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past drug shortage reports of the PEI.
The BfArM has published reports on its website on current shortages of medicines for human
U
use in Germany since 2013. However, the majority of pharmacists use information from
N
pharmaceutical wholesalers, pharmaceutical companies or the pharmacy press. At the time of
A
the survey, the reports provided by BfArM relied solely on information voluntarily submitted
M
by marketing authorization holders. The federal authority had no further information regarding the supply status of the listed drugs, and no way of verifying the accuracy of the data. In
ED
addition, the only drug shortages recorded at the time were those for which information was specifically requested by the healthcare community. These included prescription drugs
PT
predominantly used for the treatment of severe to life-threatening diseases, and for which no
CC E
alternative therapeutics are available. The PEI issues reports on shortages of human vaccines. Alternative therapeutics are listed when available and otherwise, recommendations are issued by the Standing Committee on Vaccination at the Robert Koch Institute (RKI).
A
General reflections to improve the situation The reasons for drug shortages are manifold and usually due to manufacturing problems, pricing or recalls; they can also be demand-related (22). Processes such as drug development, approval, production and distribution are all subject to high quality standards. Shortages often result from quality deficiencies or (serious) industrial accidents in production facilities. Where product 13
recalls mandated by the authorities come into play, e.g. due to deficiencies in the abovementioned processes, it also becomes necessary to assess the potential impact of these measures on patient care. In the absence of alternative therapeutics and as long as there are no immediate risks to patients, abrupt market withdrawals might be avoided in order to prevent serious
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treatment shortages. Drug shortages are especially noticeable when only a few manufacturers are in charge of the
global supply of the agents concerned (23). The pricing of new and older drugs is also held
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responsible. When early assessments fail to reveal an additional benefit, marketing
authorization holders (MAH) sometimes take new drugs off the German market (“opt-out”). In
U
contrast, older drugs (no longer under patent protection) are subject to constant pricing
N
pressures. As a result, production and sale in Europe is no longer attractive for the manufacturer,
A
which can give rise to new monopoly situations resulting from license sales worldwide.
ED
in Germany and throughout Europe.
M
Problems with manufacturers who have a monopoly are thus quick to impact the care of patients
Thus, a stimulation in decision making, attributed to drug shortages, is urgently needed. In order
PT
to prevent drug shortages and ensure a consistent supply of medicines, current measures should be expanded and adapted, and controls integrated into the processes involved. This requires the
CC E
cooperation of the full spectrum of professionals, institutions, organisations and agencies involved in the healthcare system both at the national and international levels (24–26).
A
In fact, in Europe several networks are currently addressing supply problems to patient safety. In the framework of the COST Action CA15105, 26 EU member states aim to achieve clarity on disruption causes, to simulate decision making and to reflect on best coping practices (27). In addition, a joint supply chain actors’ statement on information and medicinal products shortages was recently published by the Pharmaceutical Group of the European Union (PGEU)
14
and other European stakeholders, representing manufacturers of medicinal products, parallel distributors and pharmaceutical wholesalers (28). In Germany, on the occasion of the German Pharma Dialogue, it was therefore agreed to dedicate a “Jour Fixe” to drug delivery and shortages attended by the Federal Authorities and
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healthcare professionals, with the participation of the AMK. This “Jour Fixe” has been monitoring and assessing the supply situation since the third quarter of 2016 (29).
SC R
In the course of the activities, a list of relevant drugs potentially sensitive to shortages was
acquired and might be helpful in ensuring their specific and continued supply in the future. These include prescription drugs or drug combinations whose supply is relevant to the entire
U
population (usually no orphan drugs), as well as active substances at high risk of shortage. The
N
latter are supply-relevant medicinal products for which only one marketing authorization
A
holder, only one manufacturer with final clearance or only one active substance manufacturer
M
is available. Thus, drugs at high risk of shortage are subject to particularly close regulatory
ED
monitoring. The current lists of supply-relevant active substances and those at high risk of shortage have been available on the homepage of the BfArM website since early May 2017
PT
(30). Both lists are subject to monitoring, regular updates and further development by the
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federal authorities with respect to the supply situation. The system, whereby shortage reports by the pharmaceutical industry are voluntary, should be supplemented by mandatory reporting obligations, as confirmed by the outcomes of our survey.
A
Pursuant to the German “Care Provision Strengthening Act”, federal authorities will be given the opportunity to request information on sales and prescription volumes straight from pharmaceutical manufacturers. Hospital pharmacies will be able to order appropriate quantities of imported drugs in order to improve acute patient care. Pharmaceutical companies are required to inform hospitals as soon as they become aware of shortages of prescription drugs intended for inpatient care. 15
Since early May 2017 and regardless of mandatory drug shortage reporting in hospitals, as recommended by the “Jour Fixe”, the BfArM now requires marketing authorization holders to report drug shortages involving active substances whose supply has been subject to shortages in the past. This obligation likewise applies to supply-relevant drugs for which three or fewer MAH, manufacturers with final clearance or active substance manufacturers are registered in
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the German Federal Drug Information system.
The extent to which the new reporting requirements will achieve timely reporting of delivery
SC R
and supply shortages or even prevent them remains to be seen. While the AMK welcomes the
obligation to report, it also encourages the prompt, comprehensive and transparent notification of community pharmacies with regard to foreseeable short- and longer-term drug shortages on
N
U
the national and international level.
A
Limitations
M
The response rates of 56% and 67%, respectively, increase the potential risk of bias,
ED
overestimating the impact of drug shortages on patient safety. Selected answers such as the estimated number of treatment shortages may be subject to distortion, as they were mostly based
PT
on subjective impressions. Therefore, scientific caution is advised when interpreting the results. The AMK network of reference pharmacies comprises, however, a large number of pharmacies
CC E
of various sizes and geographical locations. In addition and compared to other surveys, the response rate and the number of participating pharmacies were high (31–34).
A
Since the survey was conducted a month-long, it might be a difference if a pharmacist completed the survey at the beginning or end of the time frame, due to the dynamic nature of drug shortages. However, instead of narrowing the observation period, participants were asked to answer in the context of the last three months prior to the survey, allowing a comprehensive analysis of trends and differences between pharmacies and care settings.
16
Conclusion This study is the first to provide comparative figures on the effect of drug shortages from the perspective of both, German community and hospital pharmacies. This survey shows that
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pharmacists depend on early, comprehensive and valid information on the respective matter to initiate specific countermeasures and may specify best coping practices. The question remains
if e.g. the recently introduced mandatory reporting obligations for MAH or an intensified
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monitoring by the federal authorities in Germany, can pave the way to ensure consistent drug
N
U
supply for patients in future.
A
Funding: This research did not receive any specific grant from funding agencies in the public,
ED
Declarations of interest: none
M
commercial, or not-for-profit sectors
A
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PT
Acknowledgments: We thank all AMK reference pharmacies who participated in this survey.
17
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19. Weerdt E de, Simoens S, Casteels M, Huys I. Time Investment in Drug Supply Problems by Flemish Community Pharmacies. Front Pharmacol 2017; 8:568. DOI: 10.3389/fphar.2017.00568
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20. van Mil JW, Westerlund T, Brown L, Chen TF, Henman M, Hersberger K et al. Medical care and drug-related problems: Do doctors and pharmacists speak the same language? Int J Clin Pharm 2016; 38(2):191–4. DOI: 10.1007/s11096-016-0249-x
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21. Fox ER, Birt A, James KB, Kokko H, Salverson S, Soflin DL. ASHP Guidelines on Managing Drug Product Shortages in Hospitals and Health Systems. Am J Health Syst Pharm 2009; 66(15):1399–406. DOI: 10.2146/ajhp090026
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22. Yang C, Wu L, Cai W, Zhu W, Shen Q, Li Z et al. Current Situation, Determinants, and Solutions to Drug Shortages in Shaanxi Province, China: A Qualitative Study. PLoS One 2016; 11(10):e0165183. DOI: 10.1371/journal.pone.0165183
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24. Iyengar S, Hedman L, Forte G, Hill S. Medicine shortages: A commentary on causes and mitigation strategies. BMC Med 2016; 14(1):124. DOI: 10.1186/s12916-016-0674-7
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25. Bochenek T, Abilova V, Alkan A, Asanin B, Miguel Beriain I de, Besovic Z et al. Systemic Measures and Legislative and Organizational Frameworks Aimed at Preventing or Mitigating Drug Shortages in 28 European and Western Asian Countries. Front Pharmacol 2017; 8:942. DOI: 10.3389/fphar.2017.00942 26. Bocquet F, Degrassat-Theas A, Peigne J, Paubel P. The new regulatory tools of the 2016 Health Law to fight drug shortages in France. Health Policy 2017; 121(5):471–6. DOI: 10.1016/j.healthpol.2017.03.007 27. COST: European Cooperation in Science and Technology. European Medicines Shortages Research Network - addressing supply problems to patients (Medicines Shortages); 2015. Available from: URL: http://www.cost.eu/COST_Actions/ca/CA15105. (last accessed: April 30, 2018)
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28. AESGP, EAHP, EAEPC, EFPIA, EIPG, GIRP et al. Joint Supply Chain Actors Statement on Information and Medicinal Products Shortages; 2017. Available from: URL: http://www.medicinesforeurope.com/news/joint-statement-on-shortages/. (last accessed: April 30, 2018).
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30. Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM (Federal Institute for Drugs and Medical Devices). Pressemitteilung Nr. 8/17: BfArM erweitert Informationsangebot im Zusammenhang mit Lieferengpässen; 2017. Available from: URL: http://www.bfarm.de/SharedDocs/Pressemitteilungen/DE/2017/pm8-2017.html. (last accessed: April 30, 2018)
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33. Caulder CR, Mehta B, Bookstaver PB, Sims LD, Stevenson B. Impact of Drug Shortages on Health System Pharmacies in the Southeastern United States. Hosp Pharm 2015; 50(4):279–86. DOI: 10.1310/hpj5004-279
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ED
34. Heiskanen K, Ahonen R, Karttunen P, Kanerva R, Timonen J. Medicine shortages—a study of community pharmacies in Finland. Health Policy 2015; 119(2):232–8. DOI: 10.1016/j.healthpol.2014.11.001
20
Figure and Table legends Figure 1: Drugs prone to shortages with negative consequences for patients. Reports by community (A) and hospital pharmacies (B) were analyzed and depicted as bar chart according to the 1st level of the Anatomical Therapeutic Chemical (ATC) classification system. In total,
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n=360 community and n=26 hospital pharmacies responded. Ten of the brand names provided by community pharmacies were not taken into consideration due to the impossibility to
A
CC E
PT
ED
M
A
N
U
SC R
conclusively code the active substance.
21
22
A ED
PT
CC E
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SC R
U
N
A
M
Table 1: Drug shortages in everyday pharmacy practice. Frequency of drug shortages (A) and estimated proportion of treatment shortages (B), as stated by community and hospital pharmacies, respectively. Data is shown in relation to given rates within the past three months.
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Table 1. A and B A) Frequency of drug shortages (within past 3 months)
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Respondents [n (%)]
7
(19.4)
< 5 times
133
(27.6)
9
(25.0)
5 – 10 times
136
(28.2)
12
(33.4)
11 – 15 times
50
1
(2.8)
7
(19.4)
U
(11.4)
N
55
A
Never
(10.4)
ED
> 15 times
108
Hospital pharmacies (n=36)
M
Community pharmacies (n=482)
(22.4)
PT
B) Proportion of treatment shortages of drug shortages
CC E
Community pharmacies (n=399)
No treatment
Hospital pharmacies (n=33)
13
(3.3)
1
(3.0)
≤ 25%
325
(81.4)
30
(91.0)
26 - 49%
32
(8.0)
1
(3.0)
≥ 50%
29
(7.3)
1
(3.0)
A
shortage
23
Table 2: Negative effects on patient safety. Occurrence of given consequences for outpatient and inpatient care due to drug shortages (multiple answers possible). The narration of each individual free text answer is not depicted. Table 2.
Respondents [n (%)]
(n=399)
224
ED
M
administered Discontinuation of treatment
Life-saving treatment was delayed or
PT
denied
CC E
Medication error occurred when
U
Less suitable dosage form was
(54.9)
N
219
(56.1)
(n=33)
24
(72.7)
21
(63.6)
A
Less suitable drug was prescribed
Hospital pharmacies
SC R
Community pharmacies
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Consequences for patient safety
103
(25.8)
2
(6.1)
60
(15.0)
13
(39.4)
80
(20.1 )
7
(21.2)
241
(60.4)
6
(18.2)
75
(18.8)
7
(21.2)
using the alternative medicine
A
Adverse effect on patients’ adherence Others (free text answers)
24
Table 3: Countermeasures to overcome possible shortages. Community and hospital pharmacists were given a selection of logistic, pharmaceutical and pharmacotherapuetic solutions. Data is shown in relation to given rates within the past three months (never, <5 times, 5-10 times, 11-15 times, >15 times).
Countermeasures taken by pharmacists
never
< 5 times
5–10 times
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Respondents [n (%)]
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Table 3.
11–15 times
> 15 times
N
U
Dispensing a substitute for the originally prescribed drug (covered by a rebate contract)
41 (10.5)
4 (1.0)
Hospital
236 (60.7)
PT
2 (6.9)
7 (24.1)
4 (13.8)
13 (44.8)
45 (11.8)
97 (25.4)
CC E
(n=29)
3 (10.4)
ED
(n=389)
pharmacies
35 (9.0)
73 (18.8)
M
pharmacies
A
Community
Contacting other pharmacies (also subsidiaries)
A
Community pharmacies
34 (8.9)
113 (29.6)
93 (24.3)
(n=382)
25
Hospital pharmacies
11 (45.8)
7 (29.2)
5 (20.8)
1 (4.2)
0 (0)
(n=24)
Community 6 (1.5)
98 (25.0)
121 (30.9)
12 (54.5)
3 (13.6)
1 (4.6)
(n=392)
U
Hospital
110 (28.1)
1 (4.6)
5 (22.7)
N
pharmacies
57 (14.5)
SC R
pharmacies
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Obtaining drugs from pharmaceutical companies instead wholesalers
A
(n=22)
M
Purchasing directly from alternative pharmaceutical company
pharmacies
153 (45.1)
(n=339)
PT
ED
Community
CC E
Hospital
pharmacies
0 (0)
82 (24.2)
57 (16.8)
13 (3.9)
34 (10.0)
1 (3.2)
10 (32.3)
5 (16.1)
15 (48.4)
A
(n=31)
Importing medicinal products in accordance with § 73 (3) of the German Drug Law (AMG) Community 211 (61.7)
110 (32.1)
14 (4.1)
pharmacies
26
3 (0.9)
4 (1.2)
(n=342) Hospital pharmacies
3 (9.7)
22 (71.0)
3 (9.7)
1 (3.2)
2 (6.4)
(n=31)
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Preparing an extemporaneous product (compounding)
pharmacies
271 (80.4)
57 (16.9)
4 (1.2)
12 (44.4)
13 (48.2)
2 (7.4)
SC R
Community 0 (0)
U
(n=337)
0 (0)
0 (0)
A
N
Hospital pharmacies
5 (1.5)
M
(n=27)
ED
Consulting prescribing physician for an alternative prescription
pharmacies
60 (15.3)
96 (24.5)
64 (16.3)
167 (42.6)
1 (3.6)
6 (21.4)
6 (21.4)
3 (10.7)
12 (42.9)
5 (1.3)
CC E
(n=392)
PT
Community
Hospital
A
pharmacies (n=28)
Increase stockpiling
27
Community pharmacies
20 (5.2)
114 (29.6)
102 (26.6)
46 (12.0)
102 (26.6)
0 (0)
4 (12.5)
9 (28.1)
6 (18.8)
13 (40.6)
(n=384)
pharmacies
A
CC E
PT
ED
M
A
N
U
SC R
(n=32)
IP T
Hospital
28