Drug shortages and ensuring the quality of medicine

Published in: Volume 7 / Year 2013 / Issue 1
Category: Conference Report
Page: 38-40
Visits: 2245 total, 1 today

Abstract:
Drug shortages are a growing problem worldwide. Patients find themselves without access to life-saving medicines, and susceptible to threats from illegal or substandard alternatives. The problem is a complex one and there is not a single solution. International cooperation between all stakeholders is key.

The scale of the problem

Drug shortages are an increasing worldwide phenomenon: in 2010, 178 drugs were in short supply; in 2011 this had increased to 230; and by 2012 there were 350 drugs in short supply. It is expected the figures for 2013 with trepidation, see Figure 1 [1-5].

*Figure 1 pending to upload.

In 2012, a survey of European hospital pharmacists to investigate the prevalence of shortage problems and their impact on patient care. Of 300 respondents in over 27 countries, 63% reported that the shortages were a weekly, and sometimes a daily problem, and 77% of respondents considered that the problem had grown worse in the past year.

Announcing the results at a reception in the European Parliament on access to medicines, EAHP stated that ‘These headline results confirm that the shortages problem is widespread, doesn’t respect national borders, and urgently requires attention.’[6].

The drugs involved
Shortages affect drugs for many disease areas, particularly oncology, anti-infectives, and diseases of the cardiovascular and central nervous systems.

Up to 22 oncology drugs, some needed by patients on a daily basis, are affected by shortages including caelyx (pegylated liposomal doxorubicin), methotrexate, and carboplatine [7].

Where in the world
Drug shortages are greatest in developing countries, but increasing in developed countries, see Figure 2. Online businesses provide easy access to low-cost counterfeit and substandard drugs, and stricter regulations are needed to ensure safety. The EU pharmaceutical industry lost an estimated Euros 10.5 billion in 2010 as a result of counterfeits.

*Figure 2 pending to upload.

In developing countries, more than a third (37%) of drugs are substandard. As many as 500,000 patients died after taking a counterfeit malaria treatment in sub-Saharan Africa, while 88 patients died in Haiti after taking liquid paracetamol that included a poor-quality excipient.

Falling standards

Drugs affected by shortages fall into two main categories: substandard and counterfeit. Substandard drugs, either branded or generic, are made by authorized companies, but fail to meet accepted standards. They can be low in quality, purity or strength, they may be contaminated or insufficiently stable, or have inadequate packaging.

Standards set by regulatory authorities in developed countries are generally higher than those in developing countries. Authorities in developing countries have limited resources, so manufacturers may adjust the quality of their products depending on the country they are selling to. Drugs destined for international aid and development programmes are often exempted from regulatory control. There is also a lack of degradation testing in hot or humid conditions.

Unlike substandard drugs, counterfeit drugs are the result of deliberate criminal activity. They imitate branded or generic drugs and may or may not contain the correct ingredients.

The rise of counterfeiting
Counterfeiting is an increasing worldwide phenomenon. In 2011, 15% of all drugs sold worldwide were counterfeits. In some Asian and African countries this can rise to 50%.

The impact of drug shortages
Drug shortages affect patients, physicians and nurses, authorities and the pharmaceutical industry. In a survey of 206 US board-certified oncologists in 2012, 40% said that in previous year (2011) a patient had died sooner due to drug shortages, 60% said cancer had progressed faster, and 80% said patients had more financial burden [8, 9].

Reasons for drug shortages

Drug supplies can be halted by natural disasters, war and blockades. Raw materials are also at risk, with 80% coming from just China and India. Quality concerns have meant that, from July 2013, all non-EU raw materials need a good manufacturing practice (GMP) certificate.

Global crises
The economic downturn has affected drug supplies. In Greece, some companies have stopped supplying hospitals following non-payment of bills [10]. Some pharmacists in Spain have to wait more than six months for government payment, so cannot restock. The effect of the downturn also affects developing countries, with a decrease in overseas aid from developed countries.

Manufacturing
Drug shortages can result from manufacturing difficulties. In 2011, Ben Venue Laboratories in the US, which produced different branded cancer drugs stopped this in favour of producing generic drugs. Consequently, access to several drugs, including Caelyx, was limited throughout 2012 [11].

Big business
Similarly, mergers and acquisitions in the pharmaceutical industry can halt drug production. Alongside this, ‘lean management’ can mean that companies are less able to deal with sudden increases in demand, because they do not hold sufficient stock.

Regulatory issues
Older manufacturing sites face regulatory hurdles. When Genopharma lost its licence to produce Purinethol, Lanvis, Aleran and Novaban for GSK and Novartis, due to GMP issues in 2012, it also lost is licence to distribute the stock that it had. So a shortage happened despite sufficient product.

Government pricing policies can make it challenging for drug companies. A series of pricing policies saw the price of Eloxatin (oxaliplatin) 50 mg in Belgium drop from Euros 200 per vial in 2008 to Euros 54 in 2012, and probably lower this year. In Denmark, under the so-called Kiwi model, the drug manufacturer offering the lowest price wins the national contract for a given period, after which point procurement begins again in order to stimulate further price concessions. Monopolisation and favouritism for local manufactures can also lead to drug shortages.

Deathly competition
Drug shortages also follow extreme competition, where multiple companies make the same drug. In Belgium, for example, there are 13 competitors for gemcitabine and irinotecan. Discounts of up to 95% of official price have been made to get a portion of the market.

Parallel imports
When the price of a drug has been reduced following interference by the authorities in country A, but not reduced in a neighbouring country B, it becomes profitable to export drugs from A to B. As a result of this situation, termed parallel imports, there is a reduced supply of drugs in A. It is also likely that wholesalers in B limit their stocks in order to avoid being left with unsold stock and expired products, leading to reduction of stock in B.

Speculation
Drugs are considered as ‘sales’ goods, priced according to ‘offer versus demand’. Some drug companies and wholesalers create an artificial drug shortage in order to avoid national tenders, put pressure on authorities and obtain a higher price from government, hospital or patient.

Ethical issues
Drug shortages raise many ethical challenges. Take a situation where two patients need a drug, but there is only enough for one. Aside from the question of which patient ‘deserves’ the drug, there is the temptation to buy drugs from an unapproved source. Once drugs are acquired from the ‘grey market’, the integrity of the drug supply chain is disrupted, creating artificially high or low pricing, often involving substandard or counterfeit drugs.

What can be done?

There is no magical solution to the issue of drug shortages. It cannot be solved by a single partner, country or region. More commitment and ‘common sense’ from all partners is mandatory.

There are already legal initiatives in the US [12] and some EU countries to create national databases, but these will need to consult with one another in order to be warned of upcoming shortages. Similarly, industry and regulatory authorities must provide early warnings of any intention to withdraw a product.

Industry’s role
Industry must stop looking at short-time winners, and commit to a more stable business model. Companies should step into tender business only if they can provide assurance they will maintain the supply chain. Companies must renew and upgrade production facilities in time, and not wait until an inspection service shuts them down. If they decide to outsource production or distribution, it remains their responsibility to assure the quality and capacity of production or distribution.

Pharmacists
Likewise, pharmacists must buy wisely, and not necessarily the cheapest. Drugs should be chosen for their stability, quality and reliability. A commitment for longer periods will, within reason, ensure a more stable business model. Drugs should not be hoarded, and it is essential that drugs are not bought from the grey zone.

The hospital team
The multidisciplinary team within a hospital has responsibility for managing drug supply and allocation decisions. It is important that these decisions are made in full view, and that they are communicated with all stakeholders effectively.

Authorities
Authorities need to apply uniform quality for all products regardless of where they will be used—at home, abroad or as part of an overseas aid programme. New manufacturing sites should be allowed for the sake of short-supply drugs (without compromising on quality), while more stringent but reasonable standards should be imposed for in-house production. There is a need for globalization of a single GMP quality standard [13].

Complex procedures for drug approval need to be simplified and shortened, leading to more refined regulation addressing manufacturing problems without aggravating drug shortages. Imports should be allowed into a country if that country has a shortage of a particular drug (an imperative that was illegal in Belgium until April 2012). Healthy competition should be encouraged within limits—from an agreed minimum to a maximum level.

Authorities must enforce production of essential drugs, ensuring strategic centralized safety stocks. Essential drugs cannot be taken out of production unless a valid alternative is available or if the formulation and production specifications are made public.

A fair minimum and maximum price must be set for every drug. A drug’s patented period needs to reflect the research expenses invested and its benefits to patients and the healthcare system. Authorities must also allow reimbursement for imported drugs so that patients and/or hospitals do not have extra costs.

The drug supply must be protected by revoking the marketing licences of companies that fall short of production and/or quality goals.

Authorities need to implement a financial compensation duty for multi-drug disruption from the same manufacturer or distributor. Above all, they must take strong action against counterfeit or substandard drugs, and against artificial drug shortages and speculation.

International organizations

There is clearly a role for the WHO in dealing with drug shortages [14]. WHO has prepared a list of essential drugs in developing countries, and is working with Médicins Sans Frontières to ensure that manufacturing sites make these drugs available to those who need them.

WHO also needs to be more involved in discussions around essential drug provision in developed countries. Limited resources mean that one vial of the chemotherapy agent fluorouracil (5FU) is sold for less than three Euros. This means it is not profitable to make 5FU in Germany, perhaps WHO can step in to resolve this issue.

Conclusion

The final solution to solving problems of counterfeit, substandard drug and drug shortages is far from certain, but lies somewhere between:

  • The ideal situation of a more ethical and common sense model of non-profit healthcare long-term business in cooperation with all partners on an international scale for the interest of the patient we all claim to serve.
  • The more realistic situation, not just focussing on low prices, but on how to create a win–win situation for all. Starting with ourselves over hospital policies, regional/ governmental commitment and value for money business models.

The Fresenius Kabi satellite symposium ‘Drug shortages and ensuring the quality of medicine’ was presented by Johan Vandenbroucke, Senior Pharmacist Production, University Hospital Gent, Belgium; at the 18th European Association of Hospital Pharmacists Congress in Paris, France, on 14 March 2013.

This article is abstracted by Dr Bea Perks, Editor, from the information presented during the satellite symposium.

References

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2. GaBI Online—Generics and Biosimilars Initiative. Management of drugs shortages[www.gabionline.net].Mol,Belgium:ProPharmaCommunications International; [cited 2013 March 26]. Available from: http://www. gabionline.net/Generics/Research/Management-of-drugs-shortages/
3. US FDA. A review of FDA’s approach to medical product shortages. [homepage on the Internet]. 2011 Oct 31 [cited 2013 Mar 26]. Available from: http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/ reports/ucm277755.pdf
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8. Gatesman ML, et al. The shortage of essential chemotherapy drugs in the United States. N Engl J Med. 2011;365(18):1653-5.
9. Mulcahy N. Drug shortages are speeding cancer deaths, survey says. Medscape. 2012 Feb 02. Available from: www.medscape.com/viewarticle/ 757980
10. GaBI Online—Generics and Biosimilars Initiative. Greece drug shortages [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2013 Mar 26]. Available from: http://www.gabionline.net/Pharma-News/Greece-drug-shortages/
11. del Campo JM. Trabectedin + pegylated liposomal doxorubicin (PLD) is back. Eur J Oncol Pharm. 2013;7(1):14-6.
12. GaBI Online—Generics and Biosimilars Initiative. FDA issues drug shortage draft guidance [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2013 Mar 26]. Available from: http://www.gabionline.net/Guidelines/FDA-issues-drug-shortage-draft-guidance/
13. European Medicines Agency [homepage on the internet]. Reflection paper on medicinal product supply shortages caused by manufacturing/ Good Manufacturing Practice Compliance problems. 2012 Nov 22 [cited 2013 Mar 26]. Available from: www.ema.europa.eu/docs/en_ GB/document_library/Other/2012/11/WC500135113.pdf
14. Gray A, Manasse HR. Shortages of medicines: a complex global challenge. Bulletin of the World Health Organization. 2012;90:158-158A. doi:10.2471/BLT.11.101303

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