counterfeit drugs: Mitigating a macroeconomic pandemic

Available online at www.sciencedirect.com

Research in Social and Administrative Pharmacy 5 (2009) 4–16

Review Article

Safeguarding against substandard/counterfeit drugs: Mitigating a macroeconomic pandemic Albert I Wertheimer, Ph.D., M.B.A.a,*, Jeremiah Norris, B.S.b a

Temple University, School of Pharmacy, 3307 No. Broad Street, Philadelphia, PA 19140, USA b Center for Science in Public Policy, Hudson Institute, Washington, DC, USA

Abstract Background: Counterfeiting and the sale of substandard pharmaceutical products can no longer be ignored. At 10% of global trade, counterfeiting is affecting many countries, causing serious downstream expenses and resource shortages. Objective: To describe the nature and impact of drug product counterfeiting and substandard product sale and to present strategies that may have value in ameliorating these phenomena. Methods: A literature review was conducted, supplemented by interviews of key leaders/experts in the field and the search of relevant web sites. All of the data were combined, integrated, and coordinated to present the complete picture of this problem. Results: In addition to known corruption in some of the least developed countries, the trail through developed countries was detected. This report identifies means to detect faulty products and describes efforts toward resisting and ending these corrupt practices. Conclusions: Counterfeit drugs, if not stopped, can be responsible for a macroeconomic pandemic where major portions of some populations may be too ill to work and where the health sector resources are completely overwhelmed, as with the case of HIV/AIDS. Ó 2009 Elsevier Inc. All rights reserved. Keywords: Counterfeit drugs; Substandard drugs; Prevention; Vigilance; Economic consequences; Fake HIV/AIDS drugs

If substandard and counterfeit drug use is not curbed, economies which are now fragile can crack under the burden of unfunded future liabilities. This is not just a health emergency; it is a macroeconomic pandemic in the making.

Introduction The subject of substandard/counterfeit drugs has taken on a new dimension of concern within

the international health community. It now recognizes that their use leads to drug resistance and mutations of the virus, particularly in AIDS treatment. Many prominent members of the public health community have commented on the dangers that counterfeit drugs pose. The Chief Executive Officer of the U.S. Pharmacopeia was quoted in a New York newspaper as saying ‘‘there are likely to be few faster ways to induce resistance to current AIDS drugs than by treating

* Corresponding author. Tel.: þ1 215 707 1291; fax: þ1 215 707 8188. E-mail address: [email protected] (A.I. Wertheimer). 1551-7411/09/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.sapharm.2008.05.002

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patients with counterfeit/substandard drugs.’’1 Professors of medicine and pharmacology from the Stanford Medical School and Trinity College said in the Financial Times: ‘‘Drug concentrations that are too low can cause the therapy to fail and, equally important, promote the emergence of resistant forms of the infectious agent . this failure can compromise the response of the patient to other medicines in the future.’’2 Lesser treatment standards through the use of substandard/counterfeit drugs make a difference to patients’ outcomes. Drs. Luc Montagnier and Robert Gallo, codiscovers of the AIDS virus, have written on this phenomenon: ‘‘if compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in drug-resistant HIV mutants whose spread will only exacerbate the epidemic.’’3 It is no understatement to say, therefore, that substandard/counterfeit drug products pose a serious threat to public health and quality of care. They can induce drug resistance or further damage a patient’s health. These consequences fall disproportionately on the poor because they are more likely to purchase such drugs as they seek the lowest possible price. Patients receiving ineffective treatments may be at risk of unexpected side effects; and what is worse, may never be cured of their otherwise treatable diseases. By failing to assign a proper value to the consequences of illegal drug use, policy makers drastically underestimate the direct costs involved by the sequential increases in the number of chronically sick people, leading to a surge in unfunded future liabilities of unknown dimensions. The indirect costs remain largely out of public view at first, but soon escalate as societies face unanticipated pressures on public expenditures. However, as important as the public health consequences are, the increased use of these drugs poses an even broader macroeconomic problem for poor countries. The simplest consequence is that scarce foreign exchange is wasted on worthless drugs. More fundamentally, the economic productivity of the society is adversely affected. As the economic status of the patients weakens along with their health, they eventually become wards of the state. Their ill health and shorter life expectancy results in long-term economic and societal losses. Worker productivity for the country is diminished and the community is impoverished because of decreased productivity, adding to the circle of poverty. For example, in African

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countries where AIDS is an epidemic and counterfeited drugs are rampant, lack of effective medicines not only increases fatal drug-resistant HIV, but also inhibits economic development. The phenomenon of substandard/counterfeit medicines is a worldwide threat to patients in need of safe and effective medicines. Already in the 1980s, the World Health Organization (WHO) collected sporadic confidential reports on pharmaceutical counterfeiting, but apparently little was accomplished. Counterfeiting is more likely an occurrence with products of relatively high value. Pharmaceuticals usually have relatively high prices, higher than basic foods or detergents where there is not sufficient potential profit for the producer or seller of counterfeit or substandard products. In countries where regulation of the health system is weak, there is an increased opportunity for corruption. Unfortunately, this description fits approximately 40-50 of the countries and territories in existence today. A number of nations that have gained their independence from previous colonial powers during the past 40 years have had other priorities than establishing a system of food and drug protection. Some countries do have legislation in place but do not have the resources or resolve to enforce their laws and regulations. As part of the Global Corruption Report 2006, Cohen stated that ‘‘corruption in the pharmaceutical supply chain can take many forms: products can be diverted or stolen at various points in the distribution system; officials may demand ‘fees’ for approving products for facilities, for clearing customs procedures, or for setting prices; demand for favors may be placed on suppliers as a condition for prescribing medicines; and counterfeit or other forms of sub-standard medicines may be allowed to circulate.’’4 The WHO reports that an estimated 10% of the global market for medicines is counterfeit. In developing countries the problem is bigger, estimated as high as 25-50%.5,6 The pharmaceutical industry total global sales for 2005 were US $602 billion, up 7% from 2004.4 This figure is around 25% of the health-care sector and is rising at an average annual growth rate of 8.8%; the market is expected to reach US $938 billion in 2008.8 In the United States, the exact number of counterfeit medicines is unknown, but rising. Some 58 counterfeit drug cases were reported in 2004, nearly double the 30 cases in 2003.9 The International Federation of Pharmaceutical

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Manufacturers Association (IFPMA) reported a 32% increase in the number of countries experiencing counterfeiting incidents, from 67 countries in 2004 to 89 in 2005.10 The Center for Medicines in the Public Interest predicts that counterfeiting will reach $75 billion globally in 2010. It offers no estimates for the societal cost of substandard drug use. The pending macroeconomic pandemic With or without the use of substandard/counterfeit drug products, a single disease entity, HIV/ AIDS, is consuming an inordinate amount of donor funds. Even when the use of antiretroviral drugs (ARVs) can be assured on the basis of confirmed quality, safety, and efficacy, drug resistance is forcing a new issue onto the donor agenda. The reason for this is that for a certain cohort of those initiated in treatment, in the best of medical environments, drug resistance will set in on an annual basis. For instance, the ‘‘United Kingdom has systematically registered increases in resistance in different surveys, recording 17 percent in the 20012003 period. Spain has reported an importantly high rate of 21.4 percent between 1996 and 1998. When data from Europe are analyzed as a whole, a rate of 11 percent has been reported.’’11 In Brazil, a country with a good medical and health-care system, it is estimated that for patients under treatment for more than 2 years with the triple dose combination, 44% of them become drug resistant and thus have to be moved to a second line therapy.12 An added problem comes when there are coinfections and morbidity. In India, ‘‘several studies have shown relatively high prevalence of HIV-1 and HIV-2 coinfectionsdas high as 33 percent in some states.’’ This means that patients’ treatment regimens become restricted to highly specific and more expensive ARV therapies because of inherent resistance to lower priced drugs.13 There is not sufficient data yet to determine if these high levels of drug resistance are due to substandard/counterfeit drugs, or to resistance naturally occurring. But it is known that the former will accelerate the onset of drug resistance and mutation of the virus. The use of substandard/counterfeit drugs will add both to the health and financial burden of the developing world. ‘‘The effect of either inadequate drug formulation or content leads to a subtherapeutic dose and the development of drug

resistance of infectious agents. The consequences of this are obvious: 1) relatively cheap drugs will become ineffective, 2) the loss of such drugs will require new drugs development, which will be more expensive and will further disadvantage patients in the developing countries, 3) the selection of drug resistant pathogens will lead to increased morbidity, mortality and a significant burden on developing regions of the world.’’14 The average price for procuring an ARV from a manufacturer is under $300 per person per year. What, then, accounts for the high cost of patient treatment? Conventional wisdom stated that the price of medicines was the barrier to access for the poor. In May 2006, WHO put that notion to rest when it published a report on the price, availability, and affordability of chronic disease medicines. One of its major findings is the following: ‘‘Taxes and duties levied on medicines, as well as the mark-ups applied, frequently contribute more to the final price than the actual manufacturers’ price does.’’ Further on in this report, WHO comments that government mark-ups often price drugs out of reach for the poor.15 On July 24, WHO/Geneva publicly stated in a Reuters News Dispatch that price was no longer the main barrier to AIDS treatment. Instead, WHO is now saying that the lack of medical and health-care infrastructure is the main problem in treatment. One side effect of this statement is an acknowledgment that patients are being treated with ARVs in systems that lack laboratories to confirm diagnosis, or monitoring capabilities to follow patients through their regimens. Without proper infrastructure, the macroeconomic pandemic only spreads faster. The estimates by WHO in 2003 were inaccurate, and the one by UNAIDS Joint United Nations Program on HIV/AIDS in 2005 may be as well. The fact is that the global health community has had little prior experience in exercises to cost out patient care for AIDS. It is, though, the kind of information that ministries of finance need to make forward-looking projections. They have to be concerned not only about HIV/ AIDS, which is threatening to consume ever increasing shares of Official Development Assistance (ODA), but also with this new burden of chronic diseases that will affect their national productivity and international competitiveness. Unquestionably, the trade in substandard/ counterfeit drugs is responsible for increasing drug resistance among some of the world’s most deadly infectious diseases, including malaria,

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tuberculosis (TB), and HIV/AIDS. The reason is that these medicines contain incorrect levels of a drug’s active ingredient, causing the weaker strains of the causal agent to be killed off while allowing the drug-resistant strains to multiple and adapt. A 2004 study found that 53% of the antimalarials being sold in Southeast Asia contained incorrect levels of the active ingredient. The percentages are even worse in Africa, where in many countries more than half their chloroquine tablets are ineffective. In Nigeria, it is estimated that as much as 85% of their malaria drugs are ineffective. The result is that deaths from malaria have doubled over the last 20 years as substandard therapy has caused the disease to become resistant to a succession of drugs, possibly even artemesin, the most recent and promising antimalarial.16 ‘‘One study found that 31 percent of anti TB drugs in Botswana are substandard, contain a toxic ingredient or do not contain any active ingredient.’’17 All the good that is being done by competent public health workers and well-meaning donors is in danger of being undone by those who profit at the expense of vulnerable people. If donors and recipients are unable to control the use of these products for 3 main diseases, there is little likelihood that they would be able to do better for a wide range of much more expensive chronic diseases. Thus, in spite of the billions of dollars being targeted at HIV/AIDS, TB, and malaria, rather than ameliorating the status of sick people through the provision of safe drugs, the presence of so much money may be attracting the worst elements of global society who are mindlessly setting in motion a macroeconomic pandemic. The consequences of the pandemic At present, the direct cost for the therapies required in the treatment of communicable and noncommunicable diseases is the equivalent of an undersea earthquake; and the indirect cost to societies in the developing world is the oncoming tsunami wave of unanticipated financial obligations and unfunded liabilities, exacerbated now by the wide-spread infiltration of substandard/counterfeit drugs. The Sloan School of Management at the Massachusetts Institute of Technology has conducted 2 studies on the indirect costs due to lost work productivity and absenteeism, both for individuals and employers. In the first study, it looked at the cost of depression in the workplace,

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a highly treatable disease, as are many chronic diseases. Although both studies are somewhat dated, there are nonetheless indicative of the problem that the developing world is now facing. Of the 11 million who suffered from depression in the study year, 7.8 million, or about 72% of all sufferers, were estimated to be in the labor force. In 1990, the total costs for depression as an affective disorder were $44 billion. Of this amount, only $12.4 billion was for direct treatment costs. Morbidity costs due to reductions in productivity and from excess absenteeism while at work totaled $24 billion. The mortality costs due to suicide came to $7.5 billion. The second study, published in November 2000, looked at lost work productivity and absenteeism among parents of children with asthma, a disease affecting as many as 5% of the U.S. population. Multivariate statistical methods were used to analyze a de-identified retrospective data set covering nearly 6000 workers in the same data entry occupation, employed at the same firm, over the period January 1993-June 1995. On average, workers experienced a 12% reduction in daily work productivity at the beginning of an episode of their children’s asthma care. In terms of prevalence and economic terms, asthma poses an enormous burden. Its annual cost burden, estimated to exceed $6 billion in the United States is likely to be understated due to the difficulty in objectively measuring certain indirect costs.18 A perspective on substandard/counterfeit drugs This problem is not one that is exclusive to the developing world. When the U.S. Bureau of Customs and Border Protection uses its existing enforcement tools to intercept illegal drug shipments at ports of entry through random checks, in one-third of the cases, it cannot even identify the country of manufacture. And, when the country was identified, the product itself could not always be specified.19 More recently, beginning in January of 2006, the Bureau intercepted substantial shipments of counterfeit Tamiflu attempting to enter via the San Francisco and Newark International Airports. As these are random checks, one has to wonder at the volume of counterfeit drugs, which manage to evade authorities entering the United States. A point to be highlighted in this example is that the authority charged with protecting the American public from the importation of substandard/counterfeit drugs is not one that has

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public health responsibilities, for example, the Food and Drug Administration (FDA), or the Department of Health and Human Services. It is recommended that a mix of strategies be used to identify counterfeit and substandard drugs. It would seem that key components in this mix would be:  Random testing of specimens of drugs, to be outsourced to any of the world’s 3 pharmacopeias: the European Pharmacopeia, U.S. Pharmacopeia, and the Japanese Pharmacopeia. Testing can be by samples sent via FedEx, or on-site inspections. Back up could be provided by WHO Certified Laboratories, which work closely with the Official Medicines Control Laboratories throughout the world.  Establishment of the policy for on-site preliminary testing of random batches of imported drugs.  Creation of a Watch List of manufacturers whose products were unsatisfactory, with transfer of the listed names to WHO and disqualification from World Bank supported purchases for a period of 5 years. According to the WHO, ‘‘A counterfeit medicine is 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 correct ingredients, with wrong ingredients, without active ingredients, with incorrect quantity of the active ingredient, or with fake packaging.’’20 The U.S. FDA states ‘‘drug counterfeiting poses a significant public health and safety concern.’’21 Patients are denied treatments, which could save their lives or are subjected to substandard therapies that jeopardize and delay their recovery. The patient’s health is put at risk. It has been reported that India leads all countries in producing and exporting counterfeit medicines. As much as 35% of worldwide counterfeit sales come from India. Nigeria comes second with 23.1%, followed by Pakistan with 13.3%. Other Asian countries excluding India and Pakistan account for 14.6%.22 All of the countries where counterfeits are manufactured lack strong regulatory authorities or policing, and therefore there are more opportunities for corruption. An early example of counterfeiting in the United States was Procrit (Epoetin Alfa; Ortho Biotech, Raritan, NJ). In May 2002, thousands of vials of Procrit labeled as containing 40,000 units were found to contain only 2000 units, and

later that year other vials of Procrit were found to contain nothing but Miami tap water, which could have resulted in infections.23 In the 2002 WHO report on the quality of medicines in developing countries, it was reported that substandard and counterfeit drugs are common in many countries; over half are antibiotics, antimalarials, and other anti-infectives. In 2001, China had roughly 500 illegal medicine manufacturers and Laos around 2100 illegal medicine sellers.1 Counterfeit medicines are also a problem in Latin America. Mexico is a major global source of counterfeit medicines, with the trade standing at an estimated value of US $650 million per year equal to 10% of total drug sales in the country.24 The term ‘‘substandard medicines’’ covers:  Counterfeit drugs, which are deliberately and fraudulently mislabeled with respect to identity and/or source; counterfeit medicines are manufactured and sold illegally, and by entities other than those indicated on the drug package and label;  Genuine drugs produced by legitimate manufacturers that do not meet the recognized quality and purity standards used by that manufacturer or the regulatory authorities. If a medicine, upon laboratory testing in accordance with the official pharmacopoeia specifications, fails to meet those specifications, it is classified as substandard.25 The most common source of substandard medicines is bad batches: batches of a drug that failed one or more tests, that should have been destroyed or otherwise properly disposed of, but which fell into the hands of unscrupulous persons who offered them for sale to often unsuspecting parties. The other major source is improper storage, usually at elevated temperature and humidity, which has accelerated the decay of the active ingredients. Although a product should be effective up to its stamped or printed expiration date, which is usually 2 or 3 years past manufacture, a shipment sitting in the sun for 2 months at a harbor in Sub-Saharan Africa waiting for customs clearance probably has little remaining effectiveness. Also, medicines are sold after the expiration date is reached which, depending on storage conditions, might result in a substandard product. In summary, substandard medicines contain microbial contamination, or have too much or too little active ingredient, if any, contributing to

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questionable effectiveness. Of 325 substandard drug reports, 60% had no active ingredient, whereas the remainder had incorrect amounts or other problems. In a 6-country study of TB medicines, 13% of single drugs and 21% of fixed dose combination samples were substandard.26 In Thailand, substandard medicines amount to 8.5% of those on the market.27 Causes of counterfeit drugs The growing worldwide problem of counterfeiting has been attributed to many causes. For instance, developing countries simply lack capabilities to assess the quality, efficacy, and safety of new drugs. Access to medicines that are safe and effective for developing countries is crucial to control and eradicate AIDS, malaria, TB, and other rampant diseases. Those countries lacking sound regulatory authorities to assess medicines rely on the U.S. FDA or the European Medicines Evaluation Agency to make decisions. The absence or nonenforcement of regulations or a culture of corruption acts as a magnet for counterfeit and substandard drug sales. A further consideration is price controls on medicines. Tariffs and taxes on medicines may encourage patients to seek traditional medicines or cheap counterfeit medicines. In Congo, Morocco, and Zimbabwe, for instance, tariffs and taxes are 39.5%, 18.3%, and 22.5% respectively.28 This practice is a source of revenue for governments, but at substantial financial cost and serious health consequences to their citizens. A summary of the extent of the problem, and its causes, was presented by the WHO in Rome in 2006.29 The demand for medicines is not likely to decrease and final users are generally unable to tell the difference between real and fake. In many countries, there are no social security or health insurance systems. Patients are forced to pay for medicines from their own limited resources and this leads them to look for cheaper products on the street. Some governments deny that the problem exists, refusing to admit that counterfeit medicines circulate in their country. Equally, some companies are hesitant to make public the discovery of counterfeit versions of their products. The cost of the growing problem Quantification of the growing problem of counterfeit and substandard medicines is difficult

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because there are not many studies measuring direct cause and effect. Estimates of the cost in terms of death, growing resistance to effective treatments, and inability to work, are sketchy. But, the available studies suggest that the consequences are enormous. Some examples are illustrative.  During a meningitis epidemic in Niger in 1995, over 50,000 people were inoculated with fake vaccine, resulting in 2000 deaths.30  In Nigeria, the country with the second most counterfeit medicines, the Pharmaceutical Society of Nigeria reported that 70% of the medicines in circulation were counterfeit and that most are imported from India, China, Pakistan, Egypt, and Indonesia.31  A study in Nigeria regarding access to drugs for HIV/AIDS reported the impact of fake and substandard drugs. Some 12.8% of cases taking counterfeit drugs led to adverse reaction and fatalities; 52.9% resulted in resistance to drug therapy; 10% led to therapeutic failure of spurious drugs; 48.2% resulted in increased severity; and 34.2% of patient taking counterfeit drug developed complications.32 In summary, as stated by Dr. Howard Zucker from the WHO in a speech in Rome in February 2006 ‘‘. counterfeit drugs lead to a loss of confidence in the entire health system, they affect the image of manufacturers, pharmacists, doctors and government institutions alike.’’33 This is certainly true for the real victims of counterfeiting, the sick people in need of medications. They believe that they are receiving a genuine, approved medicine, while, in fact, that is not the case. Corruption: a shadow over pharmaceuticals worldwide It is an irony of sorts that pharmaceuticals, the most highly regulated of industries, should be tied to some of the worst corruption on earth. Yet neither crime nor corruption is new, and it is difficult to tell whether our greater awareness of corruption surrounding the pharmaceutical sector is a product of more effective and instant worldwide communications, or occurs because many societies are no longer afraid or constrained to speak about crimes, scandals, and stigmatized behaviors, or whether there is a real increase in the number and scope of corrupt activities. Part of the problem is that there is a culture of corruption in many countries where behaviors of

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entitlement are acceptable. Those behaviors are either prohibited or unacceptable in many other countries. Norris refers to this problem when he writes of the ‘‘endemic corruption present in a number of African countries.’’34 Perhaps little can be done about cultural traditions in general, but protecting the public from counterfeit and substandard drugs should be an achievable goal, worldwide. A problem cannot be successfully overcome until it is characterized and known. Cohen in her report, Corruption and Pharmaceuticals: Strengthening Good Governance, lists the core decision points in the pharmaceutical system. Each of these points, listed in Table 1, is a potential portal for corrupt activities. Some figures exist on the magnitude of the cost of corruption in the health-care system. In 2003, the World Bank estimated that around $1 trillion was paid in bribes alone in developed and developing countries.35 In the world economy at large, the total value of trade in counterfeit goods is currently estimated at $US 450 billion, representing between 5% and 7% of total global trade.17 To measure progress against corruption, a metric is needed to enable measurement of any change. Cohen et al in 2002 in Costa Rica developed the first pharmaceutical system corruption assessment tool.36 It functions through the use of questionnaires designed to assess the

vulnerability of each decision point in the pharmaceutical system. The tool asks whether a system is guided locally or centrally; what institutions are involved in pharmaceutical procurement; and how committees are selected for the drug selection process. The overall model is: MonopolyðMÞ þ DiscretionðDÞ  AccountabilityðAÞ  TransparencyðTÞ ¼ Corruption Results are reported on a 0-10.0 scale where: 0.0-2.0 is considered extremely vulnerable and 8.110.0 is considered minimally vulnerable to corruption. Once a corruption score is calculated, different appropriate policies are possible. Some prefer to work in minimally vulnerable countries where successful programs are most easily established, and then tackling harder countries later, using their successes as examples of what is achievable. Others try to reach success in the most difficult cases the extremely vulnerable countries. The first U.S. response to the concern that Americans were at risk from counterfeit, adulterated, substandard, or expired medicines was the 1988 Congressional passage of the Prescription Drug Marketing Act (PDMA) aimed at ensuring the integrity of the prescription drug supply.

Table 1 Pharmaceutical system decision points Registration

Selection

Procurement

Distribution

Service delivery

Efficacy

Determine budget

Receive and check drugs with order

Consultation with health professional

Labeling

Access morbidity profile

Determine model of supply/distribution needs and resources Reconcile needs and resources

In patient care

Marketing

Determine drug needs to fit Morbidity profile

Develop criteria for tender Issue tender

Ensure appropriate transportation and delivery to health facilities Appropriate storage

Cost-benefit analysis of drugs Consistency with WHO criteria

Evaluate bids

Use Warnings Full registration Reevaluation of older drugs

Source: Transparency International.

Award supplier Determine contract terms Monitor order Make payment Quality assurance

Good inventory control of drugs

Dispensing of pharmaceuticals Adverse drug reaction monitoring Patient compliance with prescription

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PDMA sought to exclude all prescription drugs from unknown sources. After several modifications, the PDMA also requires unauthorized distributors to certify, in writing, the source and place where the medicines were obtained. This written statement of prior sales or pedigree must include the date of the transaction and the names and addresses of all parties to the transaction.37 American initiatives have impact elsewhere, among other reasons because the U.S. FDA is trusted around the world; many countries look up to the FDA for direction and advice on registration and approval of medicines. Aiming to reduce drug counterfeiting in 2003, an internal FDA Counterfeiting Drug Task Force was established with the goal of enhancing safeguards to protect the nation’s drug supply from counterfeit drugs. The Task Force met with the Secret Service, U.S. Customs and Border Protection Service, Department of Justice, the Bureau of Engraving and Printing, and with several pharmaceutical manufacturers, wholesalers, pharmacy associations, and consumer groups. The FDA’s final report in 2004 identified 6 areas that require combined public and private measures to be successful in preventing counterfeit medicines. The 6 critical areas are as follows:  Securing the actual drug product and its packaging;  Securing the movement of the product as it travels through the U.S. drug distribution chain;  Enhancing regulatory oversight and enforcement;  Increasing penalties for counterfeiters;  Heightening vigilance and awareness of counterfeit drugs; and  Increasing international collaboration. The executive summary of the report makes specific recommendations including the following: ‘‘The adoption and common use of reliable track and trace technology is feasible in 2007, and would secure the integrity of the drug supply chain by providing an accurate drug ‘pedigree,’ which is a secure record documenting that the drug was manufactured and distributed under safe and secure conditions.’’38 The FDA recommends that rather than the paper pedigree, a track and trace technology (Radio Frequency Identification, RFID) would produce the electronic pedigree which will stay with the drug from manufacturing to the wholesalers, to the retailers, and finally to the intended patient. This technology will make it possible to document the source of the medicine,

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the number and kinds of transactions between the initial sale by the manufacturer, and the final purchase by the end user. The FDA is encouraging the industry for voluntary adoption of the technology. The FDA also recommends:  Use of authentication technologies for pharmaceuticals, which have been sufficiently perfected so that they can now serve as a critical component of any strategy to protect products against counterfeiting. Authentication technologies include inks, holograms, tags, chemical markers, and other technologies that might develop over time.  Adoption and enforcement of strong, proven anticounterfeiting laws and regulations by states.  Working with the National Association of Boards of Pharmacy in its efforts to develop and implement revised state rules for licensure of wholesaler drug distributors.  Increased criminal penalties to deter counterfeiting and more adequately punish those convicted.  Adoption of secure business practices by all participants in the drug supply chain.  Development of a system that helps ensure effective reporting of counterfeit drugs to the agency and that strengthens FDA’s rapid response to such reports.  Creation of a Rapid Alert System (RAS) precisely to add to the necessity of a quick response when a counterfeit is suspected.  Education of consumers and health professionals about the risks of counterfeit drugs and how to protect against these risks.  Collaboration with foreign stakeholders to develop strategies to deter and detect counterfeit drugs globally. In 2005, the WHO developed the ‘‘Rapid Alert System’’ (RAS), a mechanism serving as a rapid alert for WHO member states and partner organizations for combating counterfeit drugs in the Western Pacific Region. When counterfeit medicines are detected in the region and reported through the RAS, relevant authorities are alerted immediately and actions are taken.39 The WHO has developed the WHO Certification Scheme on the quality of pharmaceutical products to assist countries ensure the quality of imported products. The Certification Scheme is a standardized administrative mechanism that makes it possible to ascertain the regulatory status of a product in the exporting country, the value of

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which depends on the capabilities of the regulatory authority in the exporting country to effectively do the regulatory work.40 The features of the Certification Scheme include actions at the national and international levels to fight counterfeit medicines:  Appropriate legislation and penal sanctions: a clear legal definition of counterfeit medicines is needed and also sanctions that fit the crime.  International harmonization: at present even the definition of a counterfeit medicine varies from country to country.  Sufficient administrative and regulatory capacity: coordination action at the local level between health authorities, police, customs, and judiciary institutions to ensure proper regulation, control, investigation, and prosecution.  International information networks: to monitor the traffic of goods, exchange information, issue alerts from country to country.  Streamlined distribution channels: to ensure effective monitoring of manufacture, importation, and distribution of medicines. International monitoring of ‘‘extraterritorial’’ zones: at present these are excluded from normal regulatory oversight.  Evaluation of medicine prices: excessive price gaps or extremely high prices, may lead to people to seek cheaper alternatives.  Increased public information: patients, dispensers, and doctors have a right to know if there are suspect goods on the market and the risks involved.  Low- or high-tech solutions: technology can accelerate lengthy legal and administrative processes to provide faster solutions. European countries are taking national initiatives to prevent the counterfeiting of drugs. For example the German Pharma Health Fund (GPHF), an initiative of the research-based pharmaceutical companies in Germany, has developed a test methodology designed to protect people in developing countries against the consequences of drug counterfeiting. The GPHF-Minilab R was developed in cooperation with the School of Pharmacy at the University of Bonn and the Department of Tropical Medicine at the Medical Mission Institute in Wuerzburg. This is a simple 4-stage method, using physical and chemical analysis techniques that enable identification of substandard or counterfeited pharmaceuticals.41

The European Medicines Agency (EMEA) is a decentralized body of the European Union with headquarters in London.42 It began its activities in 1995 and its main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. EMEA coordinates the evaluation and supervision of medicinal products throughout the European Union. Its Committee of Experts on Pharmaceutical Questions includes an ad hoc Group on Counterfeit Medicines, which developed a form in 2004 as a tool for sharing and transmitting information on counterfeit medicines in an easy and systematic way. Some countries outside Europe have also been making efforts. Nigeria under the leadership of Dr. Dora Akunyili of the Nigerian Food and Drug Administration, NAFDAC, has implemented successful strategies and safeguards in the fight against counterfeit medicines. Studies show a reduction of over 80% in the presence of fake drugs in Nigeria in 2004 from what it was in 2001. Among other strategies, NAFDAC was restructured and the Port Inspection and Enforcement department provided help to the agency to effectively tackle the problems resulting from inspections gaps and poor enforcement activities. In addition, NAFDAC embarked on a massive campaign to create awareness of the problem of counterfeit medicines at several levels from highschool children to the general public using various media outputs. NAFDAC stopped the importation of fake drugs from the countries of production to Nigeria by putting in place administrative guidelines, which include the following:  A factory must be good manufacturing practices (GMP) certified before it can export drugs to Nigeria.  NAFDAC officials must inspect factories anywhere in the world before they register or renew registration for their drugs.  NAFDAC has appointed analysts in India and China who recertify any drug from the 2 countries before importation to Nigeria.  For drugs imported from any country, NAFDAC requires mandatory preshipment information.  Since February 2003, banks insist on NAFDAC clearance before processing financial documents for drug importers. At the beginning of 2006, the SafeMeds Alert System of the Partnership for Safe Medicines, a coalition of patient, physician, pharmacist,

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university, industry, and professional organizations, has become a part of the FDA’s Counterfeit Alert Network.43 The SafeMeds Alert System broadcasts e-mail alerts about counterfeit medicines from government health agencies. The adoption of electronic track and trace (e-pedigree) technology will not only help to ensure the effectiveness and safety of medicines but also support brand loyalty and help inventory tracking. Regulators, pharmaceutical manufacturers, distributors, and wholesalers believe that RFID is the best way to track and trace products and to develop and authenticate an electronic pedigree. Other security features are in place to authenticate brands since although a pedigree might be authentic; a producer needs to make sure the product is not counterfeit. A RFID chip sealed in a nontransferable environment will store and transfer data, which is read by RFID readers. This technology is used in many industries; for example, Wal-Mart uses it already. Some pharmaceutical manufacturers have started using the technology as well. Pfizer is attaching RFID tags to each bottle of Viagra tablets (sildenafil citrate; Pfizer, Inc, New York, NY, USA) to ensure that the product is genuine.44 In March 2006, GlaxoSmithKline began attaching a RFID device to bottles of its triple-combination ARV Trizivir shipped to the United States as part of a pilot project that aims to fight counterfeiting of the drug.45 The pharmaceutical industry has been active through the IFPMA, which has spoken up in many national and international conferences voicing their concern about the global trade in counterfeit medicines. The Pharmaceutical Security Institute (PSI) was established in 2002 with 14 major pharmaceutical company members. It is a nonprofit, membership corporation based in Washington with a branch in London. PSI now includes 22 pharmaceutical companies from different countries and maintains a close affiliation with the IFPMA. An evaluation of counterfeiting strategies The path of a counterfeit or substandard medicine is normally long and complex. Tablets, capsules, or other dosage forms must be manufactured and packaged. Then, the finished products must be transported and smuggled into a country, inserted into the distribution system, and sold. Then money must retrace that path in reverse. These multiple steps offer numerous

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opportunities for interventions aimed at deterrence, prevention, education, surveillance, and eradication of the counterfeit drug trade. All interventions must be in collaboration with local and international organizations, private industry, and law enforcement to combat the problem of drug counterfeiting globally. Collaborative efforts between all relevant parties are key for this complex and growing problem of counterfeit medicines. Manufacturing Empty gelatin capsules come from a limited number of suppliers. It could be possible to require the sale of capsules only to licensed, registered pharmaceutical manufacturers. Similarly, tablets cannot be produced without tablet punches. These are matched top and bottom dies that when pressed together compact the powder to produce the final shape of a tablet. Tablet die production is a very highly skilled task that is available from a very limited number of sites, which can be monitored or their sales records scrutinized. High-speed tableting machines are made by only a few manufacturers mainly in Germany, Italy, and China. International guidelines could be prepared to limit sales of these machines to factories registered by their respective Ministry of Health. Certain other components and ingredients are used in pharmaceutical production, where suppliers could receive incentives to send reports to an international agency, or local government department. Tablets use vast quantities of magnesium stearate and sorbitol. Drug factories use granulating equipment, flat bed dryers, and powder blenders. Sales of these items could be restricted. Shipping Accountability must be increased. It is probably easy for a clandestine counterfeit drug factory to label its cartons ready for shipment, as pet supplies or garden nutrients and have some inspector approve or accept that paperwork. Perhaps, corruption may be reduced with multiple levels of approvals by multiple independent checkpoints by different persons. Also, it would be reasonable to have cargo and custom inspectors undergo training to reiterate the importance of integrity in their work and the relationship

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between their job performance and position/salary upgrades. Additionally, empathy lectures might be required for all civil servants, where they would be exposed to the concept that when someone offers you money to look the other way, they may be doing something improper that could even harm your own child or family someday. Finance All of the ingredients, bottles, labels, transportation, commissions, bribes, cartons, and packaging must be paid for with money that comes back from sales. Legitimate pharmaceutical enterprises rarely deal with cash. They are more likely to receive payment through electronic transfers or checks. Therefore, inspectors should be educated to be suspicious if they spot large amounts of cash or cash bank deposits. Distribution To tighten the channels of distribution and thereby prevent an entry way for counterfeit medicines, it would seem reasonable to require licensure of wholesalers and distributors. It would also be helpful to provide a career ladder for employees, so that a clean record would be rewarded and personal financial situations would not be so desperate that workers feel forced into accepting bribes and engaging in other corrupt practices. Tracking shipments can be accomplished through an accompanying pedigree form (which can be very easily counterfeited) and or with the use of technology; namely the RDIF chip inserted into a bottle or sealed inside a carton. The WHO devised a program with Certificates for Drugs in International Commerce. In essence, the exporting country authorities certify that the drugs shipped meet appropriate specifications in the jurisdiction where they were manufactured. Buyers should be suspicious if a shipment arrives without the certificate. It must be noted that the certificate itself can be counterfeited or forged so its presence cannot be a guarantee of a highquality, legitimate shipment. Upon arrival, the recipient must check the appearance of the contents and packaging. This simple observational procedure can often spot fake products when something does not look quite right. Sampling of the received shipment is a good idea in theory, but has numerous obstacles. Many

countries do not have a well staffed or equipped lab to permit quantitative and qualitative tests. Also, test reagents may expensive and frequently out of stock. Laboratory personnel may not be trained on some of the latest techniques and there is always the possibility that lab personnel have been corrupted and for a fee will report that tests results were satisfactory, when that might not have been the actual result. Other indirect strategies are also called for. They include:  Harsh penalties and example setting when corrupt practices have been discovered as a possible deterrent.  Establishment of a Pre-Qualification list, where manufacturers are asked to submit samples of their products and a trusted lab assays them. Manufacturers that pass are placed on an approved purchase source list, if they agree to supply export certifications and purchase a bond or place funds in escrow to pay penalties if their products are ever found to be substandard.  Establishment of an International Database searchable by aid agencies, NGOs, Ministries of Health, missions, and other drug purchasers. The site would list the identity and locations of sources of discovered counterfeit and substandard products from all reports throughout the world. It may be unrealistic to think that drug counterfeiting and the sale of substandard drugs can ever be totally eliminated, but it is a realistic and achievable goal to reduce these practices to a much smaller enterprise. That can happen only through a multiphased, coordinated, international campaign against counterfeiting. A systematic approach of detection, eradication, and information dissemination is needed. When there is no safe haven for sellers of these unsafe, ineffective medicines, and when RASs are used successfully to inform everyone concerned, there is a good chance that the practice would become too troublesome, costly, dangerous, and unprofitable to attract counterfeiters and others who would intentionally sell substandard drug products. Conclusion When used wisely, drugs are a material contribution to the quality of life, human dignity, and self-esteem of individuals, and when successfully used provide employment and a focus for a future

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orientation, instead of desperation, revolution, and strife. Persons with assets that might be endangered are probably less likely to be bellicose toward neighboring countries. Indeed, industrialization makes that neighboring country a hopedfor market for industrial production. With the worldwide prevalence of HIV/AIDS, malaria and TB, now accompanied by the onslaught of chronic diseases, it seems a reasonable expectation that many development projects will involve the purchase large quantities of pharmaceuticals. There is little point in funding a hydroelectric plant if the adults in a community are too ill to staff it or there are too few able bodied persons to work in the industries that should logically develop in an area of reasonably priced, abundant electrical power. Therefore, the use of pharmaceuticals will be needed to control symptoms of chronic diseases, because they are generally acknowledged as the most cost-effective means to achieve that goal. Control of disease with pharmaceuticals, the availability of clean, potable water, and the eradication of poverty (enabling families to eat properly, for example) are the 3 key components to advancing life in the least developed countries. We cannot underestimate the resourcefulness and skills of the parties that sell counterfeit and substandard drugs. Counterfeit Rolex wristwatches may be found in nearly every city in the world. That ‘‘industry’’ has conquered worldwide distribution challenges while maintaining a level of secretive practices. This level of distribution and market penetration must be countered. If the massive quantities of drugs purchased are carefully scrutinized to weed out counterfeit and substandard products, the remaining market may be too small to make it attractive to most criminals to enter. That would be a huge victory.

References 1. Jeremiah Norris. Don’t blame patents. The New York Sun. August 28, 2003. 2. Terrence Blaschke. Generic drugs for HIV/Aids is good news, but manufacturing standards must be monitored. Financial Times. October 6, 2003. 3. Gallo RC, Montagnier L. Prospects for the future. Science 2002;298:1730. 4. Cohen J. Summary sheet: corruption in the pharmaceutical sector. Transparency International. Available at: http://www.globalaging.org/health/world/2006/ world%20HE%20Feb1%20Pharma%20corruption %20(phcorrupt).pdf. Accessed 14.04.06.

15

5. World Health Organization, Fact Sheet no.275, Substandard and Counterfeit Medicines. Available at: http://www.who.int/mediacentre/factsheets/2003/ fs275/en/. Accessed 16.04.06. 6. U.S. Food and Drug Administration. Counterfeit drug task force interim report. Available at: http:// www.fda.gov/oc/initiatives/counterfeit/report/interim_ report; October 2003. Accessed 14.04.06. 7. IMS Health. (Ip-health) now $602 billion in annual sales: IMS World Pharmaceutical Market Summary 3/2006. Available at: http://lists.essential.org/piper mail/ip-health/2006-April/009337.html. Accessed 03. 05.06. 8. Meghna Mehta. B-191 World Pharmaceutical Market, BCC Research. Available at: http://www.bccre search.com/biotech/B191.html. Accessed 02.05.06. 9. Scott Gottlieb. Speech before Parental Drug Association Conference, March 3, 2006. Available at: http://www.fda.gov/oc/speeches/2006/pda0303html. Accessed 13.04.06. 10. IFPMA, quality and counterfeiting. Available at: http:// www.ifpma/org/issues/issues_quality.aspx. Accessed 13.04.06. 11. Debrework Zewdie. AIDS Resist Adher June 2004; 18(suppl 3):10–11. 12. Robert Redfield. Presentation to the Children’s AIDS Fund. Washington, DC; May 10, 2004. 13. International Treatment Preparedness Coalition. Missing the target: off target for 2010: how to avoid breaking the promise of Universal Access. Available at: http://www.aidstreatmentaccess.org/itpcupdate final.pdf; May 24, 2006. Accessed 30.05.06. 14. Michele Forzley. Combating counterfeit drugs, World Health Organization, Geneva, Sept 2005 p. 7. 15. World Health Organization. Price, Availability, and Affordability: An International Comparison of Chronic Disease Medicines. Geneva: World Health Organization; May 2006. 16. Wyatt Yankus. Counterfeit Drugs: Coming to a Pharmacy Near You. American Council on Science and Health; July 2006. 17. Michele Forzley. Combating counterfeit. p. 8. 18. Berndt ER, Finkelstein S. Loss of work productivity due to illness and medical treatment. J. Occup and Environ Med 1999;41:949. 19. Statement of Jason P. Ahern. U.S. House of Representatives, Committee on Energy and Commerce. The Safety of Imported Drugs. December 13, 2005. 20. WHO. World Health Organization Counterfeit Drugs: Report of the International Workshop on Counterfeit Drugs. HO/DRS/CFD98.1. Geneva, Switzerland: WHO; November 26–28, 1997. 21. USFDA. Counterfeit drug task force interim report. Available at: http://www.fda.gov/oc/initiatives/counter feit/report/interim_report. Accessed 14.04.06. 22. Francis PA. National Programme to Counter Fake Drugs. Editorial, Pharmabiz.com. Available at: http:// www.Pharmabiz.com/article/detnews.asp?articleid¼ 123288sectionid-47. Accessed 16.04.06.

16

Wertheimer & Norris/Research in Social and Administrative Pharmacy 5 (2009) 4–16

23. Rudolf PM and Bernstein IB in Medical Biology: On Counterfeit Drugs. Science Week. Available at: http://www.scienceweek.com/2004/sc040910-4.htm. Accessed 13.04.06. 24. Transparency International. The Global Coalition Against Corruption. Global Corruption report 2006. Corruption in the Health Sector: Seeking the Cure. Feb 1, 2006. Transparency International USA and the Center for Global Development presented the launch of the ‘‘Transparency International Global corruption Report 2006.’’ Available at: http://www. cgdev.org/doc/event%20docs/transcript_2.1.06.pdf. Accessed 16.04.06. 25. Nurses for patient safety: targeting counterfeit and substandard medicines. Available at: http://www. inc.ch/indkit2005.pdf. Accessed 12.04.06. 26. Latin America battles counterfeiting drugs threat. Daily International Pharmacy Alert: Washington Business. Information 2006;2(292). 27. Cohen. Summary sheet: corruption in the pharmaceutical sector. Transparency International. Available at: http://www.globalaging.org/health/world/2006/world %20HE%20Feb1%20Pharma%20corruption%20 (phcorrupt).pdf. Accessed 14.04.06. 28. AllAfrica.com. Ghana: governments make us sick. Ghana Chronicle. Available at: http://www.allaafrica. com/stories/200604070596.html. Accessed 17.04.06. 29. WHO. Combating counterfeit drugs: building effective international collaboration. Declaration of Rome. February 18, 2006. 30. A health tomorrow? Health system facts & trends affecting business decision today. World Business Council for sustainable development. Available at: http://www.wbcd.ch/DocRoot/fcktkuiQcizhGxbL 60v0/healthfacts_pdf. Accessed 16.04.06. 31. Abiodun Raufu. India agrees to help Nigeria tackle the import of fake drugs. Available at: Br Med J http://www.bmj.bmjjournals.com/cgi/content/full/ 326/7401/7234-d; June 7, 2003. Accessed 16.04.06. 32. Kristin Paterson, Olatubosum Obileye. Access to Drugs for HIV/AIDS and Related Opportunistic Infections in Nigeria. Washington, DC: USAID. Available at: http://www.policyproject.com/pub/countryreports/ NIG_ADI.pdf; September 2002. Accessed 17.04.06. 33. Howard Zucker MD. Combating Counterfeit Drug: Building Effective International Collaboration. Rome, Italy: World Health Organization. Available at: http://www.who.int/medicines_technologies/media/ Combating-Counterfeit-Drugs2006_Speech-by-Dr-

34.

35.

36.

37. 38.

39.

40.

41.

42.

43.

44.

45.

Howard-Zucker.pdf; February 16, 2006. Accessed 30.06.06. TopeAkinwande. Lethal ‘Cures’ Plague Africa. Available at: World Press Rev http://www.world press.org/Africa/1749.cfm; February 2004. Accessed 13.04.06. Hank McKinell. Address the United Nations Global Compact Leaders Summit on countering corruption. Available at: http://www.pfizer.com/pfizer/are/news_ releases/2004pr/mn_2004_0624.jsp; June 24, 2004. Accessed 19.04.06. Cohen J, Montoya JC, et al. Corruption and Pharmaceuticals: Strengthening Good Governance. Brown Bag Lunch Seminar. Washington, DC: World Bank; April 4. 2006. Public Law 100-293. Prescription Drug manufacturing Act. April 22, 1988. FDA. Combating counterfeit drugs: a report of the Food and Drug Administration. Available at: http:// www.fda.gov/oc/initiatives/counterfeit/report02_04. html. Accessed 11.04.06. WHO Regional Office for the Western Pacific, Essential Drug Medicines Policy. Available at: http://www. wpro.who.int/NR/rdonlyres/C7BFA66C-64CF-41099254-484FE520D944/0/EDMP_June05.pdf. Accessed 12.04.06. Bale HE, Jr. Counterfeit medicines: the role of industry and pharmacists. IFPMA News. Available at:http:// www.ifpma.org/News/EspeechDetail.aspx?nID¼25. Accessed 12.04.06. The GPHF-Minilab. Protection against counterfeit and substandard pharmaceuticals. German Pharma Health Fund. Available at: http://www.gphf.org/web_ en/projekte/minilab/index.htm. Accessed 13.04.06. Council of Europe. Specific projects: counterfeit medicines. Available at: http://www.coe.int/T/E? Social_Cohesion/soc-sp/Public_Health/Pharma_and_ Medicine/Spec. Accessed 03.05.06. SafeMedicines.org. Available at: http://www.safemedicines.org/resources/001883.html. Accessed 24. 04.06. Pfizer using RFID to Fight Fake Viagra. RFID J. Available at: http://www.rfidjournal.com/article/ articleview/2075/1/1. Accessed 12.04.06. GSK to tag antiretroviral drug Trizivir bottles shipped to US with tracking device in pilot project to prevent counterfeiting. Available at: http://www/ kaisernetwork.org/Daily_reports/rephiv-recent.cfm? dr_cat¼1&show¼yes; March 24, 2006. Accessed 16. 04.06.