Ensuring a sustainable supply of drugs for anaesthesia and peri‐operative care

Drug shortages are increasingly common problems in anaesthesia and intensive care practice. They may be precipitated by an increase in demand or by a reduction in supply, the latter of which may involve the unavailability of an ingredient, problems with the manufacturing process, or commercial decisions about where to market available drugs. A shortage of propofol in the USA was precipitated by a recall after manufacturing difficulties and legal liability concerns after negligent misuse by clinicians 1. The US Food and Drugs Administration (FDA) maintains a register of current drug shortages (see http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050792.htm). Twenty-nine of the 91 drugs recorded as being in short supply in 2011 were drugs used in anaesthesia and intensive care. Sterile injectables are particularly vulnerable; from a baseline of 20–40 shortages reported to the FDA each year, 2009 saw 72 shortages and 2010 saw 132 2. In many instances, the cause of discontinued manufacture is difficulty complying with regulatory standards and remedial requirements imposed by government agencies. President Obama issued an executive order in October 2011 directing the FDA to take steps to prevent and reduce current and future disruptions in the supply of ‘lifesaving’ medicines. He identified a particular risk for cancer drugs and drugs used in anaesthesia 3. A Bill submitted to the House of Representatives on 31 January 2012 is the first step in implementing the Drug Shortage Prevention Act of 2012. It mandates the creation of a Critical Drug List, and defines a Critical Drug as one that is both medically necessary and vulnerable to shortage because of problems with manufacture or sourcing of ingredients 4. Table 1 illustrates the different meanings of the terms ‘essential’, ‘necessary’ and ‘critical’ that have been used in relation to drugs. After a series of problems at a manufacturing plant in Montreal earlier this year, Canadian anaesthetists experienced a critical shortage of drugs for anaesthesia, leading to the cancelation of some elective surgery 7. A publicly-available database of drug shortages has recently been launched by Health Canada 8, and Table 2 shows some drugs used in anaesthetic practice that were listed during June and July 2012. The Department of Health (DoH) engaged with the Association of the British Pharmaceutical Industry (ABPI) 9 and the British Generics Manufacturers Association 10 in 2006 to agree Best Practice Guidelines about notification of shortages. The Pharmaceutical Price Regulation Scheme of 2009 (PPRS) is the current mechanism that the DoH uses to give the NHS access to medicines at controlled prices. Since then, the pharmaceutical market has undergone changes that appear to threaten the supply chain, and the UK Government claims to be in regular dialogue with industry to mitigate the risks. Traditionally, manufacturers make their products available to full-line wholesalers who hold stocks for competitive supply to pharmacies. In order to protect their profitability, some manufacturers are now taking on the role of wholesaler, in a model known as reduced wholesale an arrangements, or supplying their products direct to pharmacy. Such arrangement is claimed to protect the patient from counterfeit drugs and protect the supply of medicines. In these models, manufacturers decide the stock production levels and wholesalers or pharmacies have to manage the downstream demand. The role of hospital pharmacies to hold enough stock of anaesthetic and peri-operative drugs to manage fluctuations in supply and demand conflicts with Quality and Service Improvement Tools promoted by the NHS Institute for Innovation and Improvement. The first two of the Seven Lean Wastes are overproduction ‘just-in-case’ and holding inventory because supply is unreliable 11. According to Simon Burns, Minister of State for Health: “Suppliers may use their own distribution arrangements, including a direct to pharmacy model and quotas providing they continue to meet the legal requirements to ensure, within the limits of their responsibility, the appropriate and continued supply of medical products to pharmacies so that the needs of patients are met.” 12. A challenge for the NHS is that the European market for drugs is often more profitable to UK manufacturers, but the Minister claims that export license holders in the UK are under a duty “within the limits of their responsibilities, to ensure appropriate and continued supplies…”. At a meeting between the Medicines and Healthcare products Regulatory Agency (MHRA) and the DoH in November 2009, increase in the export of medicines from the UK was identified as a major contributor to supply problems, jeopardising patient care in the UK, and a reminder of the DoH's ethical and legal resposibilities was published 13. The All-Party Pharmacy Group recently concluded that export of drugs manufactured in the UK to other EU countries is still the major cause of shortages, and was critical of the attitudes of ‘those responsible for the medicines supply chain’ 14. The strengthening of the Pound against the Euro may lead to fewer exports to the EU, but there is a view that the DoH could be more pro-active in protecting patients from drug shortages. Clearly, the current informal approach to ensuring an uninterrupted supply of essential medicines is not working. The NHS National electronic Library for Medicines monitors the literature for articles about drug shortages 15 and the MHRA has an excellent webpage promoting the safe use and management of medicines and medical devices in anaesthesia 16, to which professionals may sign up for email alerts, but there is currently no drug shortage reporting or listing page. We believe that a UK Drug Shortages Record, similar to the Canadian database 8, would be a useful tool to forewarn the profession of national supply problems and to monitor the outcome of efforts to reduce such occurrences. The first step is to create a National Essential Medicines List for Anaesthesia and Peri-operative Care. Such a list would usefully be a more extensive list than that included in the report of the World Health Organization's 18th Expert Committee on the Selection and Use of Essential Medicines 17 and it could be focused on the needs of patients in a modern NHS. Guidance on the process has been proposed 18. The National Essential Medicines List could also flag those medicines that are critical insofar as they are vulnerable to shortage. Intravenous solutions pose a special challenge, as practitioners sometimes express preferences for container systems which then become the criterion for choice. Glass bottles are still used for some products, but have been largely superceded by polyvinyl chloride (PVC) containers which are cheap and probably safe, in spite of long-standing concerns that they may pose a health risk or environmental hazard. The main cause for concern is the plasticiser di(2-ethylhexyl) phthalate (DEHP) 19, 20. Conversion to PVC-free containers is inhibited by an initial lack of economy of scale that has given PVC such an advantage. A debate and consensus among UK anaesthetists and intensivists about preferred container materials would enable suppliers to make the necessary investments to deliver cost-effective intravenous products in PVC-free containers if that is what is wanted 21. Alongside the National List there is a need to develop a schedule of priority indications to be implemented when essential drugs are in short supply, to ensure that patients who would be most disadvantaged by unavailability of the drug are protected. In addition, a list of alternatives, with notes on patient safety issues in using them, should be created. A nudge' approach, fashionable amongst behavioural economists, might be taken to guide optimal prescribing at an early stage when shortages are announced 22. Vivid, point-of-care reminders can be created to prompt prescribers to consider alternatives. Where institutional protocols exist, these can be modified to change the default drug choice. Education must include specific consideration of the risks of prescribing errors of dose, contraindications, side-effects, etc, when substituting drugs with which the prescriber is less familiar. Ideally, audits will be immediately initiated to monitor the consequences of shortages as they occur. As an example of good practice, intensivists in Boston were able to show that restricted use of propofol sedation during a period of shortage did not adversely effect patient outcome 23. The profession and the public need to engage in agreeing an open and transparent contingency plan for protecting emergency work and reducing elective surgery when anaesthesia resources become a limiting factor. Such plans must include the independent sector, which must not be allowed to use its buying power to obtain preferential access to affected drugs for paying patients. With an agreed National List in place, professional groups could discuss with the DoH the steps to be taken to prevent future shortages. We question whether the Best Practice Guidelines of 2006 and the PPRS are adequate for today's changing market, and suggest we need a better system for reporting discontinued manufacture and alerting providers of healthcare to imminent and ongoing shortages. Government agencies will need sufficient powers and resources to monitor and protect the supply chain of essential drugs, and this may require legislation. Consideration should be given to maintaining a centrally-funded contingency stockpile of essential anaesthetic and peri-operative drugs for the NHS. A global problem of essential drug shortages is emerging, and UK anaesthetists will have to work with Government and with the DoH to ensure continuity of supply to protect our patients from avoidable inconvenience, morbidity and mortality in future. No external funding declared. KF is a member of the Association of Anaesthetists of Great Britain & Ireland (AAGBI) Council, and Chairman of its Safety Committee. TW is a member of the AAGBI Council. These views represent the authors' opinions, and are endorsed by the Safety Committee of the AAGBI.

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