Patients' lives at risk from substandard drugs say heart specialists

April 18, 2005

Global action is needed to counter the dangers of substandard life-saving drugs that are putting patients' lives and health at risk, according to heart specialists writing in the new (19 April) issue of Europe's leading cardiology journal, the European Heart Journal.

In an editorial [1], Drs Felicita Andreotti and Filippo Crea said that raising awareness that poor quality drugs exist may cause patients excessive worry, but lack of vigilance could generate distrust by consumers and professionals.

"It is essential to bring the issue to public attention as a first step in reinforcing surveillance," said Dr Andreotti of the Institute of Cardiology at the Catholic University Medical School in Rome, Italy.

The editorial was prompted by the findings of a German research team [2] testing the quality of batches of streptokinase [3] - a clot-busting (fibrinolytic) drug widely used in the emergency treatment of heart attacks.

Dr Peter Hermentin and his team from ZLB Behring GmbH in Marburg - one of the companies manufacturing streptokinase - tested 16 streptokinase preparations (21 samples) for the streptokinase activity, using a validated assay, and found that only three (including their own) matched the minimum fibrinolytic requirements of the European Pharmacopaeia, the European authority on quality and safety of medicines. The activity of the remainder varied from 86% of the claim on the label right down to just a fifth. European Pharmacopaeia demands activity of 90-111%. There were also differences in composition and purity.

Said Dr Hermentin: "The dose of fibrinolytic agents such as streptokinase must be carefully controlled to maximise therapeutic activity while avoiding adverse effects. Too low a dose won't restore blood flow in the artery and too high a dose could cause a bleed in the brain.

"While we analysed only one sample from most of the batches - albeit testing more than one vial and using two assays in most cases -and therefore can't generalise from our results, there are potentially serious clinical implications. The discrepancy between claimed and actual activity of many streptokinase preparations could cause life-threatening situations in severely ill patients." Dr Andreotti said that streptokinase belonged to one of a few dozen contemporary groups of life-saving drugs and that it was used to treat one of the most common and suddenly fatal medical scenarios - acute myocardial infarction (heart attack). It ranked among the World Health Organization's essential medications and, like all fibrinolytics, there was a fine balance between efficacy in restoring blood flow to the heart and the risk of causing major bleeds. Strict calibration of the activity was mandatory and must be stated on the manufacturer's label.

"I found it astonishing that only three of the 21 formulations tested - 14.3% - were reported to meet the minimum requirements of the European Pharmacopoeia," she said.

"How can consumers and health professionals be sure that the drugs they use are safe and effective?" she queried. Regulatory approval was based on short and medium term safety and efficacy as demonstrated through clinical trials. But, once a drug reached the open market, systematic long-term evaluation was more difficult, with assessment relying on a combination of government-sponsored vigilance, spontaneous reports and epidemiological monitoring.

Present arrangements were not fully adequate and did not always favour impartial decisions, she said, relying, for instance, on withdrawal by the same agency that approved the initial marketing, or on reports by the manufacturers. Also, current post-marketing control to curb the making and trading of substandard or counterfeit medicines was insufficient.

"The WHO estimates that up to a tenth of the world's drug trade and a quarter in developing countries consists of fakes. Controlling this phenomenon clearly constitutes a global challenge."

Dr Hermentin's team's test on the streptokinase products, which were on the market in some non-EU European countries, Brazil, India, Jordan, China and Pakistan[4], found that the streptokinase activity ranged from 20.8% to 107% of the claims on the label.

"This significant discrepancy was our most striking finding, although we don't know the history of the samples prior to purchase, which may be relevant, and we can't exclude previous improper handling or storage. Nor do we know which activity assay the manufacturers used and whether these would meet pharmacopoeial standards."

Dr Andreotti said that it was a drawback that only one sample per batch had been tested and she pointed out that the product produced by the authors' company had an exemplary profile. However, the data in the study appeared reliable and were backed by another report from an independent academic institution using rigorous analysis methods.

She detailed 10 steps [5] to be considered to reinforce and improve surveillance.

"It's essential that we acknowledge the problem of counterfeit and substandard drugs and recognise it without embarrassment. It is a serious problem, particularly in the case of life-saving medications used to treat common diseases. When administered correctly within the first hour from the onset of a heart attack an effective dose of streptokinase can cut the risk of dying by over a quarter. A heart attack can strike suddenly, unpredictably, indiscriminately, in one's own country or when travelling abroad. Regardless of whereabouts, it would be a pity if emergency treatment were useless. Getting this right is a global responsibility."
1 Substandard life-saving drugs: a global concern. European Heart Journal. Vol 26 No 9, pages 858-860.
2 Comparative analysis of the activity and content of different streptokinase preparations. European Heart Journal. Vol 26 No 9, pages 933-940.
3 Streptokinase: One of a group of thrombolytic drugs (fibrinolytics or clot-busters) used in the emergency treatment of heart attacks. They work by rapidly dissolving fibrin, a stringy protein that binds a blood clot together, thus restoring normal blood flow to the affected area.
4 Subsequent to the research paper being submitted for publication a sample from Poland was also found to be deficient in streptokinase activity. No deficient samples were found in countries with strict regulatory procedures e.g. the USA, Canada and the pre-expansion EU countries. Tests such as those performed in the authors' laboratories are not routine for non-specialised institutes as they need experience, equipment and validation.
5 The 10 steps include: international exchange of information, better information for consumers and professionals, using radio frequency or other unique traceable tags on products, improving the chain of inspection, displaying assay methods on labels, stricter licensing requirements for distributors, tougher penalties against illegal manufacture and distribution, replacing self-reporting with independent external assessment, and making national government funds available through WHO to fight poor quality drugs.

PDF of research paper available from Josie Bate on request.
Please acknowledge the European Heart Journal as a source in any articles

Contact: (media inquiries only)
Josie Bate: +44 (0)20 8255 1988 Mobile: +44 (0)7971 101404

Margaret Willson [after 25 April]
Tel: +44(0)1536 772181 Mobile: +44(0)7973 853347

ESC Press & PR Office (for independent comment)
Name: Camilla Dormer Tel: +33 (0)4 92 94 86 27 Fax: +33 (0)4 92 94 86 69

European Society of Cardiology

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