Medicines shortages

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Contents

Introduction

WHO has historically defined good availability of medicines as a priority health matter[1][2], reflecting that , medicine shortages are a global healthcare problem. There is evidence for little transparency as to the true cause of medication shortages at the end user and prescriber level[3]. Presumably sometimes this is because the cause is a human decision that might be embarrassing in hindsight. Indeed in most economies there is no requirement for say a manufacturer of an essential medicinal product to have redundancy and excess supply capacity. Indeed most have indirect and direct disincentives to such an approach in the supply chain. Significant medicines shortages have become routine in most health economies, and increasingly are affecting the supply of routine emergency drugs[4].

Reasons for shortages

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  • Supply side:
    • Natural disasters (eg 2011 Eastern Japanese earthquake caused nationwide drug shortage including basics such as levothyroxine[5])
    • Manufacturing problems
    • Raw material shortages
    • Non-compliance with regulatory standards
    • Packaging shortages
    • Parallel distribution
    • Product discontinuation
    • Industry consolidation (mergers and acquisitions)
    • Limited manufacturing capacity
    • Just-in-time inventories
    • Market manipulation
    • Market shifts
    • Launches of new competitors
    • New formulations
    • Patent expiry
    • Rationing/quotas
    • Creating efficiency as opposed to resilience
  • Demand side:
    • Unexpected demand
      • Epidemics
      • Another drug shortage resulting in substitution
    • Purchasing efficiency as opposed to resilience
  • Sovereign issues:
    • Financial crisis
    • Exchange rate

Medicines shortages can be caused by multiple reasons interacting to produce[3][6]:

  • Raw ingredient supply issues
    • Monopoly ingredient supply is particularly problematical
    • Again monopoly manufacturing with only one production facility is particularly problematic
    • The complexity of manufacturing some medicines such as therapeutic antibodies mean that world wide only one or two manufacturing facilities may exist
    • Batch production
  • Size of market
    • Smaller markets will have greater problems given
      • The complex technology behind many medicines
      • They are also if separately regulated a burden for a manufacturer to meet local regulatory requirements
      • Less negotiating power of the purchaser
  • Market manipulation
    • Either by a monopoly supplier, cartel, monopoly user or cartel of users
    • Drug tendering as for biosimilars can indirectly cause supply issues[7]
  • Distribution issues
    • Monopoly, cartel or locking in contracts
    • Transport disruption
    • Just in time stock management increases risk (and has been implemented enthusiastically in Europe in the last decade as a response to economic pressures[8])
  • Price issues
    • Worldwide this is a most important issue limiting supply of more recently developed effective medications to the whole world population

Serious supply chain disruption usually results from major incidents, industrial or user consolidation or political decisions. Medicines supply chain issues are managed routinely in all health economies so they tend only to be noticed by patients when one or more of these factors are in play. Such routine issues result from exchange rate movements, regulatory enforcement and market manipulation.

The reasons for drug shortages in the third world are very similar to those found in the first world[9]

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  • In 2018 there was a shortage of normal immunoglobulin for intravenous use. This reflected worldwide demand increases, value for money contracting changes by the effectively monopoly user and manufacturing plant issues, despite multiple suppliers in a mature market. The multiple factors interacted to produce a relatively sudden crisis just before a major contract change.
  • Instability in the supply chain for generic medications increased markedly during 2017 and by November was at the worse level since records began.

Commonest causes

  • 37% Quality: Manufacturing Issues[12]
  • 27% Raw Materials
  • 27% Quality: Delays/Capacity
  • 5% Increased demand
  • 2% Loss of manufacturing site
  • 2% Product discontiuation

Impact

Some medicines shortages are very frustrating because they result from behaviours that may be regarded by many as unethical such as marked changes upwards in medicine pricing. They certainly consume a fair amount of health service resource in addressing[13][14]. The time frame of resolution of multiple drug shortages suggests a political dimension with possible correlations with political pressure to resolve the issue in such areas as injectables for critical care[15]. Shortages of one medicine might result in a less than optimal substitution that for example with antibiotics might increase antimicrobial resistance and cause more side effects. Multiple patients with chronic conditions such as Parkinson's disease and epilepsy have lost control of their condition due to medicines shortages.

Solutions

There is no doubt that coordinating centralised systems can help. However as these can get politicised and be underfunded they can create their own distortions. Indeed many shortages are caused by manipulation around the edges of regulations to maximise profit or challenging prices by centrally publicly funded organisations in an existing functioning competitive market. Global solutions suggested by WHO include:

  • Shifting political focus to patient-centred care
  • Appropriate infrastrucure including communication
  • Training
  • Manipulating the global market to increase production
  • Encouraging not-for-profit organisations (NGOs) to create a worldwide accessible buffer stock

Other solutions include:

  • Variable pricing of medicines based on health gain
  • Universal quality control
  • Creation of national/international reporting systems

Recognition of the importance of loss of regulatory approval is usually built into the system, despite it being the most important cause of shortages. It is dealt with often, as with other solutions by ensuring supply chain resilience. Any global supply chain now involves between 10 to 100 parties so disruption has become statistically likely. Systems with resilience have redundancy at all levels. The most severe impact on the Eastern Japanese earthquake of 2011 was where a global supply chain company provided more than 60% of a key component, at secondary level from plant(s) within the earthquake zone.

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Central FDA action at a time of consistent political process reduced medication shortages ten fold between 2011 and 2016. A specific task force approach was necessary[12] Case studies may be of interest:

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  • A shortage of iv furosemide in 2012 did not lead to a increase in long term heart failure mortality[16]. In-patient morbidity is likely to have increased given later evidence[17].

References

  1. Creese A, Gasman N, Mariko M: World Health Organization—The World Medicines Situation. WHO/EDM/PAR/2004.5
  2. Promoting access, quality and innovation to save and improve lives. Essential Medicines and Health Products WHO 2016
  3. a b Heiskanen K, Ahonen R, Kanerva R, Karttunen P, Timonen J. The reasons behind medicine shortages from the perspective of pharmaceutical companies and pharmaceutical wholesalers in Finland. PLoS ONE. 2017 ; 12(6):e0179479.(Electronic-eCollection) (Link to article – subscription may be required.)
  4. Hawley KL, Mazer-Amirshahi M, Zocchi MS, Fox ER, Pines JM. Longitudinal Trends in U.S. Drug Shortages for Medications Used in Emergency Departments (2001-2014). Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2016 Jan; 23(1):63-69.(Print-Electronic) (Link to article – subscription may be required.)
  5. [http://journals.sagepub.com/doi/abs/10.1177/0092861512448569 Mori J, Hasui K, Tanimoto T et al. Drug Shortages After the Eastern Japan Earthquake: Experiences in a Tertiary Referral Center Therapeutic Innovation & Regulatory Science 2012]
  6. Fox ER, Sweet BV, Jensen V. Drug shortages: a complex health care crisis. Mayo Clinic proceedings. 2014 Mar; 89(3):361-373.(Print) (Link to article – subscription may be required.)
  7. Dranitsaris G, Jacobs I, Kirchhoff C, Popovian R, Shane LG. Drug tendering: drug supply and shortage implications for the uptake of biosimilars. ClinicoEconomics and outcomes research : CEOR. 2017 ; 9:573-584.(Electronic-eCollection) (Link to article – subscription may be required.)
  8. a b An Evaluation of Medicines Shortages in Europe with a more in depth review of these in France, Greece, Poland, Spain, and the United Kingdom 2013 Birgli Ag 2013
  9. Walker J, Chaar BB, Vera N, Pillai AS, Lim JS, Bero L, Moles RJ. Medicine shortages in Fiji: A qualitative exploration of stakeholders' views. PloS one. 2017 ; 12(6):e0178429.(Electronic-eCollection) (Link to article – subscription may be required.)
  10. 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.(Electronic-eCollection) (Link to article – subscription may be required.)
  11. Vogler S, Paris V, Ferrario A, Wirtz VJ, de Joncheere K, Schneider P, Pedersen HB, Dedet G, Babar ZU. How Can Pricing and Reimbursement Policies Improve Affordable Access to Medicines? Lessons Learned from European Countries. Applied health economics and health policy. 2017 Jun; 15(3):307-321.(Print) (Link to article – subscription may be required.)
  12. a b Causes of medication shortages FDA 2012
  13. De Weerdt E, De Rijdt T, 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.(Electronic-eCollection) (Link to article – subscription may be required.)
  14. Rinaldi F, de Denus S, Nguyen A, Nattel S, Bussières JF. Drug Shortages: Patients and Health Care Providers Are All Drawing the Short Straw. The Canadian journal of cardiology. 2017 Feb; 33(2):283-286.(Print-Electronic) (Link to article – subscription may be required.)
  15. Mazer-Amirshahi M, Goyal M, Umar SA, Fox ER, Zocchi M, Hawley KL, Pines JM. U.S. drug shortages for medications used in adult critical care (2001-2016). Journal of critical care. 2017 Oct; 41:283-288.(Print-Electronic) (Link to article – subscription may be required.)
  16. Tan VS, Nash DM, McArthur E, Jain AK, Garg AX, Juurlink DN, Weir MA. Impact of Injectable Furosemide Hospital Shortage on Congestive Heart Failure Outcomes: A Time Series Analysis. Can J Cardiol. 2017 Nov;33(11):1498-1504. Epub 2017 Sep 12.doi: 10.1016/j.cjca.2017.09.003.
  17. Matsue Y, Damman K, Voors AA, Kagiyama N, Yamaguchi T, Kuroda S, Okumura T, Kida K, Mizuno A, Oishi S, Inuzuka Y, Akiyama E, Matsukawa R, Kato K, Suzuki S, Naruke T, Yoshioka K, Miyoshi T, Baba Y, Yamamoto M, Murai K, Mizutani K, Yoshida K, Kitai T. Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure. J Am Coll Cardiol. 2017 Jun 27;69(25):3042-3051. doi: 10.1016/j.jacc.2017.04.042