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Identifying and combating counterfeit drugs Expert Rev. Clin. Pharmacol. 1(3), 333–336 (2008)

Albert I Wertheimer, PhD, MBA Professor, School of Pharmacy, Director, Center for Pharmaceutical Health Services Research, Temple University, Philadelphia, PA 19140, USA; and 3307 No. Broad Street, Philadelphia, PA 19140, USA Tel.: +1 215 707 1291 Fax: +1 215 707 8188 [email protected] temple.edu

“It should be possible for a joint and combined effort by practitioners, their professional societies, patients, regulatory agencies and manufacturers to make life very difficult for pharmaceutical product counterfeiters… ” What used to be a minor problem in distant lands, the sale of counterfeit drugs, is today a real problem in western Europe and North America, especially as drug prices have increased and the counterfeiting of these products looks ever more attractive. Sales of counterfeit drugs are estimated at 10% of all pharmaceutical commerce worldwide. Healthcare professionals and consumers, as well as legitimate manufacturers, can fight back with some basic tools and techniques to make drug counterfeiters think twice about this market. It appears that most counterfeits are produced in Asia and brought into patient homes from purchases made while abroad and from internet pharmacies. Practitioners should be vigilant regarding very minor changes in drug appearance or effectiveness and not automatically assume treatment failures are due to a lack of compliance. Identifying & combating counterfeit drugs

Until very recently, the presence of counterfeit drugs was a problem found exclusively in lesser developed countries. However, with increasing prices of pharmaceutical products and new means of smuggling, the existence of counterfeit pharmaceutical products is today a worldwide menace. The WHO estimates that approximately 10% of all drugs in international commerce are counterfeit. Of course, these numbers hide the more specific truth that the extent of counterfeiting may be up to 50 or 60% of the drugs on the market in some of the lowest

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capacity countries and it is very likely to be perhaps only approximately 1% in North America, the UK, western Europe, Australia, New Zealand, Japan and some other highly developed nations [1]. Worldwide sales for the pharmaceutical industry in 2005 totaled US$602 billion, up approximately 7% from the 2004 figure [2]. This figure is approximately 25% of the total healthcare sector and is rising at an average annual growth rate of nearly 9%. The market is expected to reach US$938 billion in 2008 [101].

“…with increasing prices of pharmaceutical products and new means of smuggling, the existence of counterfeit pharmaceutical products is … a worldwide menace.” As one may see, these are very large numbers and, clearly, they attract the criminal element. It is difficult to avoid seeing counterfeit Rolex watches and Luis Vuitton purses, along with other highfashion clothing items and jewelry at stalls and bazaars around the world. While the sale of fake haute couture violates the law and deprives the trademark owner of some revenues, it can be argued that such crimes are insignificant compared with the sale of worthless pharmaceutical products, especially to poor patients around the world who may have to borrow money to buy these products, only to find them ineffective. Imagine the mother having to stretch the very limited family budget in a sub-Saharan African country to purchase drugs for the baby’s

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high fever, only to find that the drug not only had no beneficial effect on the baby's health status but, unfortunately, the prolonged high fever caused serious and permanent irreversible damage, or even death. In the USA, the exact number of counterfeit medicines is unknown in precise terms. What is known is that the number of counterfeits is rising. In 2004 there were 58 cases of counterfeit drugs reported, which was approximately double the 30 cases reported in 2003 [102]. The International Federation of Pharmaceutical Manufacturers Association reported a 30% increase in the number of countries experiencing counterfeiting incidents, from 67 countries in 2004 to 89 countries in 2005. This small number of reported cases is merely the tip of the iceberg as there must be many more cases that are either undetected or unreported.

“The WHO defines a counterfeit medicine as one that is deliberately and fraudulently mislabeled, with respect to identity and source.” The WHO defines a counterfeit medicine as one that is deliberately and fraudulently mislabeled, with respect to identity and source. Counterfeiting can apply to both branded and generic products, and counterfeit products may include products with the correct ingredients, with the wrong ingredients, without active ingredients, with an incorrect quantity of the active ingredient or with fake packaging [3]. The US FDA has stated that drug counterfeiting poses a significant public health and safety concern. Patients are denied treatments that could save their lives or are subjected to substandard therapies that may jeopardize and delay their recovery. In either case patients’ health is put at risk. Substandard drugs are a separate but related additional problem. They may be drug products sold by legitimate and licensed manufacturers where batches failing quality tests are released for sale, instead of being reworked or destroyed. It is thought that the substandard drug problem is even larger than the counterfeit problem but it has been studied less and there is far less information regarding this problem. As the prices of pharmaceuticals have increased over time, these goods make attractive targets for counterfeiters. They have high unit values and are made with only modest difficulty. As they are small and not particularly fragile, they are easily shipped and hidden. The manufacture of proper medications, such as tablets, requires a number of not very common skills to produce a tablet that has consistent bioavailability characteristics. However, the manufacture of tablet-like products is quite common throughout the world, as seen in the candy industry, for example. To counterfeit a common or popular pharmaceutical tablet dosage form, one needs only to manufacture a tablet of the approximate same size, shape and color. Packaging and labeling are not normally problems as standard bottles from numerous international commercial sources are available and modern digital printing techniques,

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along with contemporary scanners, are able to reproduce a virtually identical label that can require real expertise to differentiate from the legitimate product. Given the nature, increasing size, scope and severity of this problem, it is fair to ask what is being done about this menace? The FDA inspects ports of entry into the USA and equivalent, counterpart agencies conduct similar surveillance in other developed countries. Such port inspections rarely turn up large quantities of imported counterfeit pharmaceutical products on a regular basis. Nevertheless, these inspections continue to make the importation of such products more difficult and serve as a deterrent. In the USA, a law was enacted in 1975 that essentially eliminated the gray market. This legislation required that the buyer of pharmaceuticals be aware and knowledgeable of the seller and have access to information on the history or pedigree of the product. In essence, this closed the door to diversion among different channels, reimportation and sales through other middlemen. Those early efforts were probably effective since they prevented rogue sellers slipping in to legitimate shipments some amount of counterfeit product. Such schemes would be very difficult to detect. Manufacturers have not stood still and are not taking this attack on their reputation and profitability lying down. Some require their purchasers, usually wholesalers, to sign exclusive purchase agreements, through which the buyer agrees to purchase that firm’s products only from the firm itself, directly. This strategy shuts out the opportunity for some foul play. Some pharmaceutical manufacturers have not stopped there and have become more aggressive in their fight against counterfeits. They have hired investigators who attempt to trace the pharmaceutical fakes back to their point of origin and then to work with local authorities to shut those manufacturers down.

“To counterfeit a common or popular pharmaceutical tablet dosage form, one needs only to manufacture a tablet of the approximate same size, shape and color.” It has been reported that India leads all countries in producing and exporting counterfeit medicines, with perhaps as much as 35% of worldwide counterfeit drug sales coming from India. Nigeria is thought to come in second with over 20%, followed by Pakistan with 13%. China and other Asian countries make up most of the remaining production. Another recent report indicated that China has approximately 500 illegal medicine manufacturers. Counterfeit medicines are a similar problem in Latin America, where it is understood that Mexico is a source of some products en route into the USA [4]. In all of the countries where counterfeit pharmaceuticals are manufactured, there is a lack of strong and effective regulatory authority or policing and, therefore, there are numerous opportunities for corruption. In low-income countries it is a rather simple chore to pay a very much underpaid civil servant

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Identifying and combating counterfeit drugs

inspector to ‘look the other way’, especially since if the inspector chooses not to cooperate, serious physical harm can befall the inspector or his family. Healthcare providers and their respective professional associations are also able to contribute to the fight against counterfeit pharmaceutical products. Practitioners can and should be educated to be vigilant for even the most insignificant difference in the appearance of the label, packaging or actual characteristics of the dosage form itself. If any discrepancy is seen, the manufacturer should be contacted, as well as the FDA. It is common for the healthcare provider to assume that there is a lack of patient compliance (adherence) with the medication regimen when treatment goals are not reached. A situation such as this would routinely result in the patient being scolded about not taking the medication as prescribed and forfeiting the optimal value of the treatment. Otherwise, the physician may elect to modify the therapy using a higher dose of the drug, assuming that the previous dosage was not sufficient to resolve the problem. However, a third hypothesis must now be kept in mind and considered when a treatment failure is observed; perhaps the problem does not lie with patient behavior but rather with the fact that the patient was taking an ineffective product. The most obvious recourse for the physician would be to prepare a new prescription with instructions for the patient to take that prescription to a totally different pharmacy in the hope that their supply of that drug product may have come through a different channel and had not been compromised. Today, it might be appropriate for a physician or pharmacist who learns of dissatisfaction with a medication to ask exactly where the current bottle being used was purchased. Some surprising answers should be expected.

“Practitioners can and should be educated to be vigilant for even the most insignificant difference in the appearance of the label, packaging or actual characteristics of the dosage form itself.” Counterfeit pharmaceuticals enter the supply chain or distribution system through one of only a small number of means. One of the most common avenues today is through the purchase by American consumers of pharmaceuticals from offshore pharmacies via the internet. That it has the Canadian flag in the background on its website offers no guarantee that that pharmacy is located in Canada or has anything to do with Canada. It may well be that the operators of that website are persons in Nigeria or Botswana or elsewhere, and it is totally and completely impossible for the regulatory authorities to keep track of all of the packages of medications that are mailed into the USA every day. It would be a good assumption that a large proportion of these are not the legitimate products people are hoping to receive. A second avenue involves tourists and Americans visiting other countries bringing back medications purchased in those countries. Just as there is a culture of corruption in a large number of countries, it is very likely that

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some of these tourists or visitors may return to the USA with counterfeit products that they had purchased abroad. A third avenue involves criminal groups, gangs and other organized parties that smuggle pharmaceuticals or purses and watches and other items into the USA and bribe persons who are employed along the distribution system to insert some of those products into legitimate shipments.

“It is not really possible to totally eradicate pharmaceutical counterfeiting, but it is possible to make the future production, shipping, smuggling and distribution of these products … complex…” The culprits can get away with these crimes because one physician may see only one or two isolated cases of this treatment failure at very different time periods and not give consideration to any larger pattern or trend. However, when the manufacturer or regulatory agency begin receiving reports of treatment failures for specific products, which may also be in certain limited areas, there is reason for suspicion and investigation. Similarly, when one or several patients report that, recently, a medication they had been taking for some time had a different odor or taste, or that the color, weight or even the manufacturer’s markings were slightly different, that should evoke suspicion of a counterfeit product and appropriate reports should be made. Sudden causation of gastritis or any other side effect related to the dosage form may be an additional clue that something is amiss. Another option for the physician is to switch to a different brand of the same medication in the hope that counterfeits of that second product are not available, and getting the patient to report on the effectiveness of the new and substitute product. A number of strategies are applicable to fighting this problem. Radio-frequency identification (RFID) chips have been used inside the cap or under the label on bottles of pharmaceutical products. These RFID chips may be programmed with the batch number or some other identifying letters or numbers so that when the bottle is scanned, one may tell whether it is genuine or not. Another technology that has been used successfully in some other industries is to laser etch a batch number, serial number or some other identifying number on the glass or plastic container beneath the label on the bottle itself. If there is any question concerning possible inactivity, it is easy to look under the label to see whether there is an etched number that is correct for that product, batch and expiration date. There is some discussion regarding the addition of tracer substances to pharmaceutical tablets, capsules and liquids. Use of these tracers could be identified by parties that had the appropriate detector apparatus and it could, therefore, be ascertained almost immediately whether a product was genuine or not, based upon the presence or absence of such a tracer material. Flourescent materials are ideal. The strategy may not be adopted in the near future or at all because the sense at the regulatory agency is that it would be necessary to repeat clinical trials to make certain that the tracer elements incorporated into

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the tablet did not have a deleterious effect on the availability of the drug or that it might complex or combine with the active ingredient making it unavailable for effective therapy. Such clinical trials would be costly and lengthy, and it is not likely that any manufacturers would choose to undertake this investment with a product that did not have many additional years of further patent protection and where there was a reasonable assurance that it would continue to be a high-volume, popular and profitable seller in the marketplace. Another strategy that holds promise would be to register and control the sale of tablet presses and capsule-filling machines, as well as the excipients that are used in tablet and capsule manufacture. In this way, it would be possible to keep track of the owners of such equipment and the location of equipment capable of manufacturing pharmaceutical tablets and capsules. We see something similar with the restricted over-the-counter (nonprescription) sales of ephedrine-containing decongestants, since ephedrine may be used to manufacture methamphetamine. Advanced and intricate holograms may be attached to the carton and label on the bottle that provide information for that specific product and packet size. While holograms may be copied, not every counterfeiter has access to such sophisticated equipment. It is not really possible to totally eradicate pharmaceutical counterfeiting, but it is possible to make the future production, shipping, smuggling and distribution of these products so complex, difficult, time consuming and costly that the perpetrators may elect to find a simpler area for their future exploits. In fact, there are several other points of vulnerability against drug counterfeiters that may be used by the authorities. Almost always, counterfeiters are paid in cash since checks and most other negotiable financial instruments are easy to trace. It is not practical to send back to India or to the factory in any country 3

References 1

2

Howard Zucker. Combating counterfeit drugs: building effective international collaboration. World Health Organization, Rome, Italy 16 February 2006. International Pharmaceutical Federation, (FIP). Statement of policy on counterfeit medicines. FIP 63rd World Congress. Sydney, Australia, 5–9 September 2003.

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thousands of pounds of US$5 bills. Such shipments are difficult to hide or disguise and are most inconvenient. Banks or other legitimate businesses are needed to ‘launder’ the proceeds and convert them for eventual electronic transfer back to the bank accounts of the producers. Following the path of the money can be an effective anticounterfeiting strategy. Counterfeiters will not remain very enthusiastic about future production if the money from past work does not find its way back to them on a regular and dependable basis. Pharmaceutical products are not the only products counterfeited. Perhaps the original item counterfeited still remains one of the principal areas of this criminal behavior, the counterfeiting of currency or paper money. In recent times, we find counterfeiting present in the area of fine arts, especially with paintings and sculptures, in the market of airplane replacement parts, in the entertainment industry with music CDs and movie DVDs, with wines and, of course, expensive watches, designer clothing and purses. It should be possible for a joint and combined effort by practitioners, their professional societies, patients, regulatory agencies and manufacturers to make life very difficult for pharmaceutical product counterfeiters making them turn their attention back to watches or purses.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

WHO. World Health Organization counterfeit drugs: report of the International Workshop on Counterfeit Drugs, HO/DRS/CFD98.1, Geneva, Switzerland 26–28 November 1997. Norris J. Don’t blame parents. The New York Sun, 28 August 2003.

Websites 101

Meghna Mehta, B-191, World pharmaceutical market, BCC research www.bccresearch.com/biotech/B191.html

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IFPMA, quality and counterfeiting www.ifpma/org/issues/issues_quality.aspx

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Identifying and combating counterfeit drugs.

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