Institute of Cardiology, Department of Cardiovascular Medicine, Catholic University, Largo F. Vito 1, 00168 Rome, Italy
* Corresponding author. Tel: +39 6 30154187; fax: +39 6 3055535. E-mail address: felicita.andreotti{at}iol.it
This editorial refers to Comparative analysis of the activity and content of different streptokinase preparations
by P. Hermentin et al., on page 933
How can consumers and health professionals be sure that the drugs they use are safe and effective? A drug that has been approved for clinical use has undergone thorough evaluation during phase I studies (pre-clinical and dose-finding) and during phase II and phase III randomized trials that test defined regimens of the new drug against a reference treatment in medium and large patient-year groups. This well-codified process provides information on the short- and mid-term safety and efficacy of the drug and forms the basis for approval by regulatory authorities. However, once the medication reaches the open market, it is more difficult to carry out a systematic and long-term evaluation. In this phase (phase IV), pharmaceutical assessment relies on a combination of government-sponsored vigilance, spontaneous reports, and epidemiological monitoring.
The sensational withdrawal of rofecoxib (dictated by a significant increase in the incidence of myocardial infarction and stroke) as late as 5 years after its approval has raised questions concerning contemporary methods of monitoring the long-term safety of available drugs.13 Indeed, some of the present measures of phase IV surveillance contain internal conflicts that hinder the very actions they are meant to perform. For instance, current regulations provide for the withdrawal of a drug by the same agency that approved its initial marketing or for the report of drug-related adverse events by the manufacturer of the drug itself.1 These arrangements do not favour impartial decisions, as they entail that the agency be ready to recognize its own failure and that the company voluntarily limit its income.1 Greater awareness of these pitfalls is prompting external and independent assessments of marketed pharmaceuticals in order to improve drug safety.1
But there is still another, largely neglected aspect of post-marketing control aimed at curbing the manufacture and trade of substandard or counterfeit medications. This form of vigilance should check the drug's identity, chemical integrity, physical stability, and biological activity, and exclude the possible damaging effects of inappropriate handling, packaging, and storage. Counterfeit or substandard medicines are more common in developing countries,4,5 where disease burdens are high and public resources insufficient to ensure effective monitoring. The magnitude of the phenomenon is considerable. Indeed, the World Health Organization (WHO) estimates that up to 10% of the world's drug trade25% in developing countriesconsists of fakes that are sold around the world.4,5 Drugs that treat serious diseases such as malaria, tuberculosis, autoimmune deficiency syndrome (AIDS), or other infections are more often the object of counterfeits.4,6 In the Democratic Republic of Congo, a country plagued by both civil war and AIDS, antidepressant medications are sold as antiretroviral drugs.6 The origin of these frauds is either local or from external countries, reflectingin the latter caseinternational networks of illegal trade and drug supply.5 Control of this phenomenon clearly constitutes a global challenge.
Streptokinase (SK) belongs to one of a few dozen contemporary groups of life-saving drugs. It is used to treat one of the most common and suddenly fatal maladies of our society: acute myocardial infarction (AMI). Evidence that this bacteria-derived fibrinolytic agent given intravenously to patients with AMI reduced deaths and myocardial dysfunction, compared with placebo, came about almost 20 years ago.7 Nowadays, optimal treatment of patients with AMI calls for primary percutaneous coronary interventions, but intravenous thrombolysis is next best whenever interventional cardiology is not available. SK compared with alteplase causes fewer intracranial haemorrhages8 and is 510 times less expensive than the newer lytic agents. Thus, despite evidence of a slightly lower efficacy when compared with the accelerated alteplase dosing, SK ranks among WHO's essential medications.9 As for all lytics, the narrow therapeutic range of SK reflects a fine balance between its efficacy, in terms of coronary recanalization, and the risk of causing major bleeds. Strict calibration of the protein's activity is mandatory and must be stated in the manufacturer's label.
Hermentin et al.9 (from Aventis Behring GmbH) compare the in vitro fibrinolytic activity of 16 different SK preparations available on the world market. In five cases, the same commercial product was tested from two different batches, yielding a total of 21 evaluations. The merchandise was produced by 11 manufacturers (including Aventis Behring) based in six countries: Korea, Germany, Sweden, India, China, and Cuba. Three packages were labelled as recombinant. One distributor was European, whereas the other 16 were located in India, Pakistan, Brazil, China, and Jordan. The fibrinolytic activity of each sample was measured by an in vitro, soluble-phase, chromogenic-substrate assay, calibrated against a WHO SK international standard.
Astonishingly, only three of the 21 formulations (14.3%) are reported to have activities between 90 and 111% of the value declared on the label, in accordance with the minimum requirements of the European pharmacopoeia.9 The activities of the other 18 are ranked <90%, with eight <50%, and the three recombinant preparations <40%. The authors then compared the migration pattern of each product on native and reducing sodium dodecyl sulfate polyacrilamide gel electrophoresis. The results suggest variations in the ratio between SK and its stabilizer (human albumin) and heterogeneity in the region attributable to SK, presumably caused by impurities, chemical alteration, or protein degradation. For six preparations that showed an abnormal migration pattern in the SK region, sequencing of the 15 N-terminal amino acid residues is reported to produce sequences coinciding with that of Streptococcus pyogenes SK in only two cases.
A methodological drawback of the work by Hermentin et al.9 (which the authors acknowledge) is the assessment of only one sample per batch of SK, limiting the generalizability of the results. Moreover, the authors have a direct interest in publicizing their findings, as the SK formulation produced and distributed by their employer showed an exemplary profile in their analyses. Despite these limits, the data by Hermentin et al.9 appear reliable, as they are supported by another report, from an independent academic institution, using rigorous methods of analysis, which also describes marked differences in the activity of five commercially available SK formulations.10
How does one tackle the problem of substandard medications? It has been argued that increasing the awareness of poor quality drugs may cause patients to worry excessively about whether the medicines they are taking are genuine.5 On the other hand, lack of vigilance may generate a lack of trust in both consumers and professionals.1 Bringing the issue of substandard medications to public attentionas the article by Hermentin et al. doesis an essential first step towards reinforcing current methods of surveillance. A further indispensable step is to accept that the problem of counterfeit drugs really exists and to recognize it without embarassement. Finally, several actions, adapted to the local needs, should be discussed. They include: (i) exchanging information and establishing collaborations between national and international organizations (e.g. WHO and Interpol) that control marketed drugs;11 (ii) informing consumers and health professionals of the risks of counterfeits and providing them with simple instructions (e.g. the telephone number of a national agent) to report suspect cases;11 (iii) labelling medications with radio frequency or other unique identification tags to trace the drug from the point of manufacture to the point of dispensing;11 (iv) improving the inspection of all steps of the drug distribution chain, from manufacturers to consumers; (v) performing regular chemical analyses on local and imported products; (vi) requesting that the method(s) used to assess a drug's activity be stated on the product label; (vii) stricter licensing requirements for drug distributors;11 (viii) introducing tougher penalties against illegal drug manufacture and distribution;11 (ix) replacing procedures favouring self-denial (in this case, the report of counterfeit medications by agencies responsible for controlling fraud) with external and independent quality assessements of marketed drugs; and (x) making national government funds available through the WHO to fight poor quality drugs within individual countries.4
The presence of counterfeit or substandard drugs on the world market represents a serious problem, particularly in the case of life-saving medications used to treat common diseases. When administered correctly and promptly, an effective dose of SK can reduce the risk of dying of AMI by >25% when compared with placebo.7 AMI can strike suddenly, unpredictably, indiscriminately, in one's own country, and when travelling abroad. Regardless of whereabouts, it would be a pity if emergency treatment were useless. Getting this right is a global responsibility.
Footnotes
References
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