Fraudulent and Substandard Medicines - Uppsala Monitoring Centre

EDITORIALDrug Saf 2011; 34 (6): 445-4480114-5916/11/0006-0445/$49.95/0ª 2011 Adis Data Information BV. All rights reserved.Fraudulent and Substandard MedicinesGetting Away with Murder?I. Ralph EdwardsUppsala Monitoring Centre, Uppsala, SwedenSeveral women have bled to death after childbirthbecause the oxytocin used was totally inactiveand there was no emergency blood and othernecessary facilities to hand. A nurse who complainedto the authorities about this had threatsto her life; no official record exists of this.Now, the US FDA is worried about the lessregulated area of so-called ‘dietary supplements’or herbal remedies that could be contaminated byallopathic drugs or dangerous compounds, andthey have recently issued a warning about suchrisks. [1] For the most part, developed countries donot see much of a problem with licensed medicines,although occasionally very clever fraudulent drugsdo get into the supply chain for allopathic medicines,escaping notice even where the most sophisticatedlabelling is used and where quality assuranceis good. The warning includes the following:‘‘Among the substances found in productsthat are marketed as dietary supplements andthat contain hidden or deceptively labeled ingredientsare: The active ingredients in FDA-approved drugsor their analogues (closely-related drugs). Other compounds, such as novel syntheticsteroids, that do not qualify as dietaryingredients.Where FDA investigations have discoveredtainted products marketed as dietary supplements,the agency has issued warning letters andconducted seizures and criminal prosecutions.FDA has also alerted consumers to hundredsof products with these often deceptively labeledand harmful ingredients, including more than80 products marketed for sexual enhancement,more than 70 products marketed for weight loss,and more than 80 products marketed for bodybuilding.’’[1]Such products can be bought in shops and,overwhelmingly, via the Internet. A recent editorialin Drug Safety was about using the Internetfor communication, particularly as a potentialsource for information about harm from medicines.[2] It was noted that free communicationdoes not make it easy to find complete information;even though it may be available, it does notguarantee its quality. To sell a medicine on theInternet certainly does not guarantee its quality,nor does it ensure that it will be used properly.On the whole, the involvement of health professionalshas not always resulted in particularlygood medicine use, but it does seem that it addsdanger to sell products without direct healthprofessional advice and that the drugs either donot work or are contaminated by potentially dangerousmaterials. This is even more significantwhen ‘dietary supplements’, etc., are regarded bymany as ‘safe’.The European Alliance for Access to SafeMedicines gives advice about counterfeit medicinesand buying on the Internet. [3] As an illustrationof the dangers of buying on the Internet,there were reports about 5 years ago of very strikingvirilization of very young children, male andfemale, caused by topical application of bodybuildingsteroids to the father’s arms or chest thatrubbed off onto their child when he or she wascuddled. The particular reason for this anecdotewas that since these products were not licensedmedicines and there was no control over Internetselling, nothing could be done about it. Havethings changed significantly? Well just check on

Fraudulent and Substandard Medicines 447tenth most frequent adverse reaction in the WHOAdverse Drug Reactions database. It is now ninthmost common. Nearly all countries contributesuch reports. The trouble is that we do not oftenknow the reason for such a report, which mightresult from a drug interaction; adherence failures;prescription, dispensing and other medicationerrors. It must be significant that we have suchreports since they are not strictly reports of adversereactions – by older definitions anyway –but someone is clearly concerned enough to reportto an authority with the power to help them.We know that medicines do not work for everypatient, but there must be some suspicion of anunusual problem for reporters to bother to sendin a report. It seems likely that the only place inmany countries where anyone can report such aconcern about a product is to the pharmacovigilancecentre.There seems to be an important public healthreason to do something with these reports, otherthan file them – but what? I have learned a coupleof things from underresourced countries, bothfirst hand and also confirmed by others. Patientsnotice things and want to report them, but theyare frequently put off by narrow-minded professionals.It is clear that when someone reports thattheir tablets have turned to powder in the bottlein which they were bought that there is a problem;if soluble tablets fail to dissolve there is aproblem; if a different looking frusemide tabletfails to produce diuresis, there is probably aquality problem. These are actual examples ofreports to pharmacovigilance centres; they affectthe safety of patients and it is our responsibility tofollow them up or refer them to those who can doit more easily. But the last example, of the mostcommon single term related to drug inefficacy inVigibase (medicine ineffective), is challenging inpharmacovigilance circles for two reasons: Sudden failure of effect, for example, in apatient receiving frusemide is fairly unusual,and a knowledgeable health professional seeingsuch a report should hear some warningbells in the background. However, in someplaces the reports are entered into a databasewithout being seen by a broadly trained healthprofessional, so that professional backgroundknowledge cannot be applied and, furthermore,relevant information for this situation(e.g. change of brand of medicine) is notobtained. The second issue is that, in some therapeuticareas at least, unless the numbers of the reportsare very large, an investigation on ‘medicineineffective’ would not cause much reason forspecial attention. For example, I ranged thereports of ‘medicines ineffective’ in descendingorder and 14 of the top 50 reports related toantivirals, most used in the treatment of HIV/AIDS. We know that these antivirals havebeen subjects of counterfeiting but unless thereis a report-by-report analysis it is unlikely thatsubstandard products would stand out in adisease area where treatment failures ofindividual medicines are relatively high.So, is there more that we can do? Firstly, Ithink our colleagues in resource-poor settings aremore likely to find substandard and fraudulentmedicines, and we should be very aware of theirexperiences. With overall proportionally less reportscoming in, and less focus on new drugs, theyview more broadly and deeply the implicationsof each case report than colleagues in developedsettings. They will also see more instances ofproblems that pass by the resource-limited drugregistration facilities and control in those countries.Sharing their knowledge with the rest of theworld is indeed a good way to go.At the Uppsala Monitoring Centre, in consideringhow we might be able to help usingVigibase, we have come up with the followingproposal, which has just been examined in a pilotstudy, funded by the EU FP7 project. The primarydefining criteria around substandard products(and for antibiotic resistance) are for clustersof reports of ineffectiveness to occur in time and/or place. This can be examined in a variety ofways, but one way is to use disproportionality.Simple in concept, the challenges are to be able togroup appropriate Medical Dictionary for RegulatoryActivities (MedDRA Ò ) terms and to optimallycircumscribe a ‘cluster’. From this pilotstudy, several subgroups were examined, and theability to find substandard products was confirmed.Examples are levothyroxine, where thereª 2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)

448 Edwardswere reports of inefficacy in a cluster found over a3-year period; malfunction of an adrenaline (epinephrine)pre-filled auto-injector; and counterfeitLipitor Ò (atorvastatin). In the pilot study, specialattention has been given to all antibacterials, selectedbecause of the combined problems of counterfeitproduct and drug resistance. In spite of themethodological challenges, when reports were arrangedaccording to maximum disproportionality,the top candidates quickly yielded two case clusterswhere there was some information in case narrativesthat the antibiotic was not of poor quality,and in one an index case of resistance was mentioned.No such reassurance was available forthree other clusters, which then raises the suspicionof substandard medicines; two of these instanceshave subsequently been confirmed.Apart from help from the case narrative, itseems likely that clusters based on brand namesrather than generic names would be more likelyto be counterfeit. Those with patterns of appearancein Vigibase linked geographically, bothtogether in time and by the brand marketing territories,might also be more suspect.As always, the more and better the informationon the report, the more effective the analysis.Given the extent, persistence and seriousnessof fraudulent and substandard products, thereseems to be no excuse for any group that thinks itmay have access to useful data to fail to makegood use of this data. Dr Dora Akunyili, ex-General Director of Nigeria’s National Agencyfor Drug and Food Administration has said ‘‘Counterfeitdrugs are murder y’’ [9] If not murderousin intent, to knowingly manufacture counterfeitdrugs could well be regarded as manslaughter,given the virtual certainty that someone will diebecause a necessary drug does not work. Whowants to be an accessory to that?AcknowledgementsThe author has no conflicts of interest to declare that aredirectly relevant to the content of this editorial.References1. US FDA. Consumer updates: a history of action and advicefor consumers [online]. Available from URL: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm236774.htm[Accessed 2011 Mar 30]2. Edwards IR, Lindquist M. Social media and networks inpharmacovigilance: boon or bane? Drug Saf 2011; 34 (4):267-713. The European Alliance for Access to Safe Medicines: informationfor patients [online]. Available from URL: http://www.eaasm.eu/Information_for_patients [Accessed 2011Apr 15]4. Purchase testosterone patch. The layman’s guides to steroids:‘‘y real no bull facts on steroid use, explained in layman’sterms by one of the world’s top anabolic steroid experts’’[online]. Available from URL: http://www.nobullcollection.com/44/purchase-testosterone-patch.html [Accessed 2011Mar 30]5. Sole Nazz House. Malaysia bodybuilding supplementshop [online]. Available from URL: http://solenazz.blogspot.com/2010/08/sole-detox-foot-patch-house-sale.html[Accessed 2011 Mar 30]6. WHO. Combating counterfeit drugs: building effective internationalcollaboration, 16-18 February 2006 – Rome,Italy [online]. Available from URL: http://www.who.int/medicines/counterfeit_conference/en/index.html [Accessed2011 Mar 30]7. WHO. Counterfeit medicines: the silent epidemic [online].Available from URL: http://www.who.int/mediacentre/news/releases/2006/pr09/en/ [Accessed 2011 Mar 30]8. Kaiser Health News. Counterfeit drugs become growing problem[online]. Available from URL: http://www.kaiserhealthnews.org/Daily-Reports/2010/September/13/Fake-Drugs.aspx[Accessed 2011 Mar 30]9. BBC. One woman’s war with fake drugs [online]. Availablefrom URL: http://news.bbc.co.uk/1/hi/programmes/this_world/4656627.stm [Accessed 2011 Mar 30]Correspondence: Professor I. Ralph Edwards, UppsalaMonitoring Centre, Stora Torget 3, Uppsala S-75320,Sweden.E-mail: ralph.edwards@who-umc.orgª 2011 Adis Data Information BV. All rights reserved. Drug Saf 2011; 34 (6)