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Comparative Analysis of Drug Shortages in the US and Germany (2016 – 2023)

Published online by Cambridge University Press:  22 October 2024

Emanuel Nussli ,
Miquel Serra-Burriel  and
Kerstin N. Vokinger
Emanuel Nussli
Affiliation:
UNIVERSITY OF ZURICH, ZURICH, SWITZERLAND.
Miquel Serra-Burriel
Affiliation:
UNIVERSITY OF ZURICH, ZURICH, SWITZERLAND.
Kerstin N. Vokinger
Affiliation:
UNIVERSITY OF ZURICH, ZURICH, SWITZERLAND.
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Abstract

This article analyzes trends in drug shortages in the US and Germany, the largest pharmaceutical market in Europe, between 2016 and 2023. It assesses the commonalities and differences between the countries in terms of active substances in shortage, time duration in shortage, and cyclic trends.

Keywords

Drug ShortagesU.SGermanyPublic Health
Type
Columns: Health Policy Portal
Information
Journal of Law, Medicine & Ethics , Volume 52 , Issue 2: Defining Health Law for the Future: A Tribute to Professor Charity Scott , Summer 2024 , pp. 488 - 497
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.
Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of American Society of Law, Medicine & Ethics

Drug shortages are a public health threat that may delay, and sometimes even deny, critically needed treatment for patients.Reference Mazer-Amirshahi and Fox1 They have been an increasing source of discussion and challenge over the past years. Recent survey results published by the National Comprehensive Cancer Network in June 2023 showed that 93% of cancer centers did not have enough supplies of carboplatin for their patients and 70% had cisplatin shortages,2 with at least 100,000 patients affected in the US.Reference Gourd3

In the past decade, governments developed policies with the goal to overcome the problem of drug shortages. For example, the Food and Drug Administration Safety and Innovation Act (FDASIA) was enacted in 2012, which requires manufacturers to notify the US Food and Drug Administration (FDA) of changes in the production of drugs that may help the FDA in its efforts to prevent and mitigate shortages.4 Nonetheless, drug shortages are still a threat to patients and healthcare systems.

Previous studies focused on the causes of and possible solutions for drug shortages,Reference Hernandez, Hershey and Donohue5 often with a focus on specific drugs, therapeutic areas or countries affected by shortages.6 Empirical work focused mainly on single countries or on a short time period.Reference Ravela7 Thus, trends in drug shortages over a longer time period as well as potential commonalities and differences between countries remain unclear. This information, however, is important to develop effective and sustainable measures and policies.

To guide policymakers with the goal to address the challenge of drug shortages successfully and sustainably, we analyzed trends in drug shortages in the US and Germany, the largest pharmaceutical market in Europe, between 2016 and 2023. More specifically, we assessed commonalities and differences between the countries in terms of active substances in shortage, time duration in shortage and cyclic trends.

Methods

Study cohort

We used the public databases of the American Society of Health-System Pharmacists (ASHP) and the German Federal Institute for Drugs and Medical Devices to identify all drug shortages as well as the packages in shortage between 1 January 2016 (starting date for public data of drug shortages in Germany) and 31 July 2023 in the US and Germany.8 The database of the ASHP has also been used as a reference for previous studies focusing on drug shortages.9 We then aggregated the drugs on active substance level. For each identified active substance, we extracted the start and end dates of shortage. For active substances with more than one drug that were in shortage at the same time, these drugs were considered as one active substance shortage.

Both countries define shortage similarly, and list those drugs in the databases of the ASHP and the German Federal Institute for Drugs and Medical Devices. In the US, shortage is defined as a period of time when the demand or projected demand within the United States exceeds the supply.”10 In Germany, a shortage is given when the supply is expected to be disrupted more than two weeks or if the demand exceeds the supply.11

Therapeutic areas of the active substances were categorized based on the World Health Organization’s Anatomic Therapeutic Classification system. Active substances indicated for treatments addressing more than one therapeutic area, were classified to the therapeutic area with the most treatment indications of the respective active substance.

Statistical Analysis

Descriptive statistics was applied to assess trends in shortages. A linear regression model with heteroskedasticity and autocorrelation consistent standard errors (HAC) was used to infer trends in shortages in the US and Germany. To test for seasonal patterns, we conducted an analysis of variance to assess whether shortages were uniformly distributed across all months.

We used R, version 4.3.1 (R Project for Statistical Computing) for all statistical analyses.

Results

Amount, Therapeutic Areas, and Duration of Shortages

Our study cohort included in total 699 distinct active substances in shortage between 2016 and 2023. Of these, 247 (35.3%) active substances were in shortage only in the US, 296 (42.4%) only in Germany, and 156 (22.3%) in both, the US and Germany (Table), with a total of 403 (=247+156) distinct active substances in shortage in the US and 452 (=296+156) in Germany. When counting each occurring shortage spell separately, this amounted to 618 shortages in the US and 812 in Germany.

In the US, most active substances in shortage were indicated to treat diseases of the nervous system, followed by infectious diseases, metabolic disorders and cardiovascular diseases. In Germany, most active substances in shortage were indicated to treat diseases of the nervous system, followed by infectious diseases, oncologic disorders and cardiovascular diseases (Table, Figure S1).

Mean duration of shortages was 23.5 months in the US compared to 9.2 months in Germany (Table, Figure S2).

Overall Time Trends and Cyclic Trends of Shortages

The number of active substances in shortage increased in the US and in Germany over time, on average by 7 active substances per year in the US and by 21 active substances per year in Germany ( Figure 1 ). No substantial changes in shortages between the targeted therapeutic areas were observed between 2016 and 2023 (Figure S3).

Table 1 Amount and duration of active substance shortages in the US and Germany by therapeutic area.

Figure 1 Number of active substances in shortage in the US and Germany (2016 – 2023).

When focusing on the active substances that were in shortage in both countries at the same time (US and Germany), a mean increase of 4.3 active substances per year (p<0.001) was observed from 2016 to 2023 (Figure S4a). Moreover, the proportion of shortages that occurred in both countries relative to the total shortages in both countries increased on average by 1.35% (p<0.001) per year from 2016 to 2023 (Figure S4b).

In both countries, a seasonal cyclic pattern of shortages of active substances was observed, more pronounced in Germany compared to the US. We observed an increase of shortages at the beginning of the year with a peak in May in the US (8.8% of all shortages in the US) and June in Germany (9.5% of all shortages in Germany). A decrease followed with the fewest shortages in August in the US (8%) and in September in Germany (7.3%), followed again by an increase of shortages of active substances in both countries until to the end of the year ( Figure 2 ). The seasonal pattern was significant (p<0.001 US, p<0.001 Germany), i.e., the shortages were not uniformly distributed across months.

Figure 2 Cyclic trends in active substance shortages in the US and Germany.

Among the total of 403 active substances in shortage in the US, 252 (62.5%) were once in shortage, 98 (24.3%) were twice in shortage, 43 (10.7%) were three times, nine (2.2%) were four times, and one (0.2%) active substance was five times in shortage between 2016 and 2023. Of the total of 452 active substances in shortage in Germany, 231 (51.1%) were once in shortage, 114 (25.2%) were twice, 71 (15.7%) were three times, 28 (6.2%) were four times, five (1.1%) active substances were twice and three (0.7%) active substances were six times in shortage ( Figure 3 ). In median, active substances were twice in shortage between 2016 and 2023, both in the US and Germany.

Figure 3 Number of active substance shortage cycles in the US and Germany.

Discussion

Between 2016 and 2023, the number of active substances in shortage increased in the US and even more so in Germany, however, the proportion of active substances that were in shortage in both countries over this time period was less than a quarter. Mean duration of shortage was almost two years in the US and less than a year in Germany. Both countries had a similar seasonal cyclic pattern of shortages–an increase at the beginning of the year with a peak in late Spring, followed by a decrease until late Summer. Of the active substances in shortage, approximately one third in the US and half in Germany were more than once in shortage.

While the COVID-19 pandemic may have resulted in constraints in the global drugs supply change,12 the pandemic likely does not explain all the shortages since the increase in shortages was already observed prior to the pandemic and studies have outlined additional causes for shortages, including too low prices, increase in demand, or quality issues and technical problems.Reference Biedermann13 The increasing number of shortages over the past years is an indicator that the past and current policies and measures aiming at overcoming the challenge of shortages have not been sufficient. In September 2023, the Biden Administration highlighted action steps taken by the FDA to tackle cancer drug supply issues and to help mitigate and prevent impacts to patients. For example, the FDA has worked closely with manufacturers to help identify opportunities to increase manufacturing capacity, and exercised enforcement discretion for a manufacturer to import cisplatin from a Chinese facility.14 While this may be a successful short-term measure, our findings indicate that short-term measures may not be sufficient.

The findings indicate that the problem of drug shortages worsened over the past years in the US and Germany. When implementing new sustainable measures, a way forward in the oversight of the supply chain and the forecast of the demand of drugs could be to pay particular attention to the seasonal pattern and to drugs that have been in shortage more than once to prevent shortages of these drugs in the future.

Mean duration for shortages was almost 2.5 times longer in the US compared to Germany (23.5 months vs 9.2 months). For example, epinephrine, an active substance indicated among other things for treatment of allergic reactions (including anaphylaxis), was more than eight years in shortage in the US and approximately five months in Germany. By contrast, other active substances were for a shorter time in shortage. For example, gabapentin was two months in shortage in the US, and three times with different durations (three months, 7 months, 1.5 years) in shortage in Germany. These findings indicate the variation in the duration of shortages, with a mean duration in the US and Germany that exceeded an acute cyclic phase. Also the published report in March 2023 by the Senate Committee on Short Supply outlined that between 2021 and 2022, the average drug shortage lasted approximately 1.5 years, with more than 15 drugs that have been in shortage for over a decade.15

Not only the mean duration for shortages was different between the US and Germany, but also the specific active substances in shortage with less than a quarter in shortage in both countries. One possible explanation could be the different drug prices in the US and Germany. The OECD outlined in its report on drug shortages that unsustainably low prices may influence commercial decisions and put drug supply at risk.16 For example, pegaspargase, a drug initially approved in 1994 by the FDA for treatment of leukemia, was only in shortage in Germany but not in the US. The price for this drug was substantially lower in Germany than in the US (approximately USD 4,464/ml in the US and USD 244/ml in Germany) when it was first in shortage in Germany in 2022. By contrast, cisplatin, a cancer drug initially approved in the US in 1978 and widely used in the treatment of many tumors, was only in shortage in the US but not in Germany in our study period. The unit price for cisplatin was approximately 46% higher in Germany compared to the US (approximately USD 0.4/mg in the US and USD 0.6/mg in Germany) when it was first in shortage in the US in 2015. However, an in-depth empirical analysis is necessary to understand the effect of prices on drug shortages and whether this may also explain differences across countries.

Approximately one third and half of all active substances in shortage were at least twice in shortage in the US and Germany, respectively, between 2016 and 2023. For example, methotrexate, an active substance indicated for treatment of different diseases, including lymphoblastic leukemia, non-Hodgkin lymphoma or rheumatoid arthritis, was three times in shortage both in the US and Germany, or valproate (indicated for treatment of seizures), which was four times in shortage in the US and Germany. Both in the US and Europe, different studies and reports by agencies have proposed the importance of improving the visibility into the drug supply chain, a stronger oversight of the end-to-end supply chain and the reporting of the discontinuances, interruptions and amount of drugs manufactured as well as the forecasting of demand.17 When incorporating these important measures, a particular attention and a priority could be paid to the drugs that have been in shortage more than once in the past to prevent shortages of these active substances in the future.

Limitations

We aggregated the shortages on active substance level and not drug level. We believe that this level of information is sufficient to show relevant trends in shortages over time and between the two countries.

Differences between the US and Germany may occur when deciding whether a substance should be listed as in shortage. Due to the very similar definitions outlined in both countries for shortages, it can be assumed that the classification of active substances as “in shortage” is, in general, congruent between both countries.

Conclusion

Between 2016 and 2023, the number of active substances in shortage increased in the US and even more in Germany. Mean duration of shortage was almost two years in the US and less than a year in Germany. Both countries had a similar seasonal cyclic pattern of shortages — an increase at the beginning of the year with a peak in late Spring, followed by a decrease until late Summer. Of the active substances in shortage, approximately one third in the US and half in Germany were in shortage more than once.

The findings indicate that the problem of drug shortages worsened over the past years in the US and Germany. When implementing new sustainable measures, a way forward in the oversight of the supply chain and the forecast of the demand of drugs could be to pay particular attention to the seasonal pattern and to drugs that have been in shortage more than once to prevent shortages of these drugs in the future.

Note

Funding

This study was funded by the Swiss National Science Foundation (SNSF, grant number PCEP1_194607).

Appendix

Figure S1 Pattern of active substance shortages by therapeutic area.

Figure S2 Distribution of active substances in shortage by duration.

Figure S3 Number of active substances in shortage over time by therapeutic area.

Figure S4 Temporal trend in shortages of active substances in shortage in both countries (US and Germany).

Legend

(a) depicts the temporal trend in shortages of active substances in both, the US and Germany;

(b) depicts the temporal trend in shortages of active substances in both, the US and Germany in percent relative to the total number of active substances in the US and Germany combined.

Footnotes

About This Column

Aaron Kesselheim serves as the editor for Health Policy Portal. Dr. Kesselheim is the JLME editor-in-chief and director of the Program On Regulation, Therapeutics,And Law at Brigham and Women’s Hospital/Harvard Medical School. This column features timely analyses and perspectives on issues at the intersection of medicine, law, and health policy that are directly relevant to patient care. If you would like to submit to this section of JLME, please contact Dr. Kesselheim at [email protected].

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Figure 0

Table 1 Amount and duration of active substance shortages in the US and Germany by therapeutic area.

Figure 1

Figure 1 Number of active substances in shortage in the US and Germany (2016 – 2023).

Figure 2

Figure 2 Cyclic trends in active substance shortages in the US and Germany.

Figure 3

Figure 3 Number of active substance shortage cycles in the US and Germany.

Figure 4

Figure S1 Pattern of active substance shortages by therapeutic area.

Figure 5

Figure S2 Distribution of active substances in shortage by duration.

Figure 6

Figure S3 Number of active substances in shortage over time by therapeutic area.

Figure 7

Figure S4 Temporal trend in shortages of active substances in shortage in both countries (US and Germany).Legend(a) depicts the temporal trend in shortages of active substances in both, the US and Germany;(b) depicts the temporal trend in shortages of active substances in both, the US and Germany in percent relative to the total number of active substances in the US and Germany combined.