Counterfeit drugs appear to be “all the rage.” For some time there have been problems with counterfeit antimalarials, as I learned when I studied in Bangkok at the Asian Tropical Medicine Course in 2006. The practice was common in Asia, causing serious problems with increasing resistance to antimalarials there, as well as in Africa, where counterfeit medications are rife.
Malaria killed 781,000 in 2010. According to the World Health Organization (WHO), there were 216 million cases of malaria in 2010; 81% of these were in the WHO African Region, with 91% of malaria deaths occurring there, primarily in children under 5 years of age (who comprise 86% of the victims) and pregnant women. Because of increasing resistance to the standard antimalarial, chloroquine, WHO had recommended use of artesunate containing products. These are made from Artemisia annua and are far more expensive, as the plant is relatively scarce.
While efforts by both governmental and private sector institutions to eliminate counterfeiting have had some success, the problem is ongoing, and perhaps increasing. News of counterfeiting appears regularly. Last week about $182,000 worth of fake medicines for diabetes, high blood pressure, and cancer were seized in China, and almost 2,000 people were arrested.
“Fake” drugs—currently known formally as “Spurious/falsely-labeled/falsified/counterfeit (SFFC) medicines,” can take various forms, as that cumbersome name suggests. These have been deliberately mislabeled, but may well have some sort of active drug—but not necessarily that which it should have. Sometimes toxic chemicals are even substituted for the real medicine. Rather than fraud, other drugs might instead be “substandard,” lacking in the correct dosage due to factory errors, or from being stored improperly, or being out of date.
Magnitude of the problem
According to the Center for Medicine in the Public Interest, about 30% of brand-name drug sales in developing countries are counterfeit.
India’s Business Standard reports that counterfeits in India comprise about 20% of the total pharma market, and largely involves popular brands of drugs for coughs and colds, vitamins, and symptomatic treatment of acute illnesses. They claim that 8-10% of a drug’s production cost goes to efforts to stymie counterfeiting.
In contrast, according to the World Health Organization (WHO) only about 1% of the medicines sold in developed (i.e. Australia, Canada, Japan, New Zealand, the United States of America, and most of the European Union) markets are fake.
Data as to the magnitude of this problem had been scarce. Cockburn et al. realistically suggested “that many pharmaceutical companies and governments are reluctant to publicize the problem to health staff and the public, apparently motivated by the belief that the publicity will harm the sales of brand-name products in a fiercely competitive business. For those who like pharma scandals, their paper offers detailed examples, a là “The Constant Gardener,” of pharmaceutical companies trying to bury their problems quietly.
Since 2003, the companies have been more forthcoming, having agreed to report problems promptly to the FDA. And since 2006, there has been an International Medical Products Anti-Counterfeiting Taskforce — IMPACT—including pharmaceutical manufacturers, NGOs, regulatory and enforcement agencies.
Thus, it was more of a shock to consumers to learn that the United States was vulnerable to these problems. First, in 2008, was the scandal over tainted batches of heparin, a blood-thinner that had been imported from China. That adulterant caused a number of deaths and allergic reactions. More recently, a counterfeit version of a widely used cancer drug, Avastin, was distributed throughout the U.S. last winter. This fake did not contain the active medicine, so patients missed their chemotherapy for a period of time. Drugs purchased over the internet are particularly at risk of being counterfeit.
Approaches to detect counterfeiting
A major impediment to the elimination of counterfeit medications has been the difficulty of rapidly and inexpensively determining whether a medication is authentic or not. A number of different approaches are being undertaken to identify fake drugs.
Colorimetric assays were used to identify artesunate, which turned yellow, from the fakes, which were colourless. But then the counterfeit drug was modified to contain trace amounts of artesunate in order to trick colorimetric assays. That was a successful ploy.
Holograms were developed for packaging of artesunate. The sophistication of the counterfeiters was impressive—in Bangkok, Dr. Paul Newton (of the Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration in Laos) showed us packaging with holograms that was very much like the real artesunate drug and could readily pass casual visual inspection.
One newer approach is the use of radio-frequency identification (RFID) tracking system, somewhat akin to bar coding on packages. Another approach, being taken in India, is to have unique PIN numbers on packets of drugs. A unique identifier number is revealed on a scratch-off card. A buyer can then SMS (Short Message Service, or text message) this code number to the provider to verify the drug’s authenticity via a free product like Sproxil’s Mobile Product Authentication™ (MPA).
Research just presented at a meeting of the American Chemical Society shows great promise for detecting fakes more quickly, including in low resource settings.
Chemistry professor Toni Barstis and her team at Saint Mary’s and Notre Dame in Indiana have developed a paper analytical device or PAD to detect Panadol, an overseas brand of acetaminophen (Tylenol), often used to adulterate other medications because it provides some symptomatic relief of pain and fever, thereby fooling patients into believing the drug is effective. Their technique relies on a color change when the paper, swiped over the pill in question, is dipped in water—rather like a litmus test.
Dr. Facundo M. Fernández and colleagues at Georgia Institute of Technology are using a different approach, with an ambient mass spectrometry technique. This works by breaking down the compound into individual components, and the mass of the molecules is used to identify individual chemicals. Although more complex, this technique has the advantage of having both qualitative and quantitative detection modes, as well as identifying specific adulterants. They are also working on an ion mobility spectrometry application for screening samples in the field. Detailed analysis is important because, as Dr. Fernandez noted, that they have found specimens containing poisons, like benzene, and an antimalarial that contained sildenafil (Viagra) instead. Dr. Newton has found fakes containing pollen; analysis of the pollen has revealed that counterfeit drugs found in Africa originated in Asia.
While any harm from a counterfeit or adulterated drug is infuriating, as an Infectious Disease physician and someone interested in social justice issues, I was especially appalled at the extent of counterfeit antibiotics. As noted by Newton, “Counterfeit “lifestyle” drugs and those for chronic conditions are more commonly found in richer countries, whereas counterfeit anti-infectives are more common in poorer, tropical countries.” Counterfeit anti-infectives containing no active ingredient ranged from common antibiotics (such as erythromycin or quinolones) to antiretrovirals (drugs to treat HIV), meningococcal vaccine (to prevent deadly meningitis), and antivirals such as Tamiflu. Treating a life-threatening infection with a placebo results in death, and is unconscionable. WHO expert, Professor Pierre Ambroise-Thomas aptly characterizes it: “Counterfeiting is more than a criminal act. Manslaughter is perfectly justified to describe such an act although some prefer calling it simply murder.” From a public health perspective, the most frightening counterfeits were those for tuberculosis and HIV, where inactive or substandard drugs can result in continued infectivity and rapid spread to others or cause the rapid emergence of drug resistance. Similarly, counterfeit antimalarials have probably contributed to the emergence of resistance to artesunate, the most effective agent, leaving many at risk of death, as there may be no other effective therapy.
Solutions are a long way off, but there has been notable progress made.
Pharma shows increased recognition that openness to the problem and notification of the public is not only the appropriate response, but will likely reduce their liability and is otherwise in their self-interest.
Governments and enforcement agencies are showing increased cooperation and working together more via WHO Impact.
And new sophisticated technologies are being developed to allow earlier recognition of counterfeit drugs and that hopefully can be used successfully in resource poor areas of the world; Fernandez’ group is developing a prototype of a simpler model. But I like Dr. Newton’s proposal the most:
“The increased provision of free or inexpensive medicines for key diseases would undercut the counterfeiters and reduce the criminal financial incentive. Counterfeit and substandard medicines are a component of the problem of insufficient access to essential drugs in many of the world's poorer countries. The expense and desirability of artemisinin derivatives, the shift in antimalarial treatment policy to this class of drugs in Africa, and the shortage of the raw material creates a very dangerous situation…The provision of free or inexpensive antimalarials, with international financial support, could be the key to prevent widespread counterfeiting of anti-infectives. Organisations funding treatments should include monitoring of drug quality as an integral part of their programmes and facilitate the removal of ineffective antimalarials, which patients should have no need for, from the marketplace when effective drugs are available through the public and private sector.” The same could be said for medications to meet other critical public health concerns, as TB.
As long as there is lax enforcement and easy money to be made, counterfeit drugs will likely be a growing problem. Perhaps we should, instead, make it a humanitarian and public health priority.
Molecules to Medicine banner © Michelle Banks
Poster - WHO — IMPACT International Medical Products Anti-Counterfeiting Taskforce
Rapid dye test image - Mike Green, CDC, via Paul Newton
Hologram - Cockburn and Newton, PLoS medicine