Counterfeit Drugs
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《新英格兰医药杂志》
In May 2002, thousands of vials of Procrit (epoetin) 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. In the spring of 2003, there were reports that some Lipitor (atorvastatin) pills tasted bitter, caused a burning sensation on the tongue, and were too large. In February 2004, several Web sites sold unsuspecting consumers contraceptive patches, under the Ortho Evra brand name, that contained no active ingredient. These incidents were determined to involve counterfeit drugs, resulted in the recall of thousands of pills and vials, and forced manufacturers to make costly changes in the labeling and packaging of the drugs to ensure that patients received the authentic product. Were these isolated events or the warning signs of an impending public health nightmare?
Although it is hard to obtain accurate data, the proportion of drugs in the U.S. marketplace that are counterfeit is believed to be small — less than 1 percent. Given that more than a billion pills are sold in this country every year, however, it is possible that millions may be counterfeit. The number of investigations of possible counterfeit drugs by the Food and Drug Administration (FDA) has jumped from 5 per year in the 1990s to more than 20 per year since 2000. Reports from Asia, Africa, and South America indicate that 10 to 50 percent of prescription drugs in certain countries may be counterfeit. In India, the number of counterfeit drugs is so high that the Indian parliament is expected to pass a bill authorizing the death penalty for drug counterfeiters.
In the United States, counterfeiters generally target high-volume and high-cost drugs, particularly injectables, treatments for human immunodeficiency virus infection and AIDS, and psychiatric medications. Recent examples of drugs that have been counterfeited include Lipitor, Procrit, Neupogen (filgrastim), Viagra (sildenafil), and Zyprexa (olanzapine). Experience shows that many counterfeiters are so well funded and sophisticated that security experts employed by manufacturers of the authentic products often have difficulty distinguishing authentic drugs from fake drugs by sight: both the packaging and the pills or liquid look identical.
Although there have been few reports of serious adverse events, the number of treatment failures attributable to counterfeit drugs in the United States is unknown. There may be more serious side effects and even deaths due to counterfeit drugs in other countries, where counterfeiters have targeted treatments for malaria and other infectious diseases.
Few physicians or patients know what happens to drugs from the time they are manufactured to the time they are dispensed at a pharmacy. Typically, manufacturers ship pharmaceuticals to wholesale distributors, who then ship them directly to hospitals or retail pharmacies. However, not infrequently, drugs can travel a much more circuitous route before reaching the dispenser. For example, wholesalers may sell drugs to other wholesalers (to fill shortages or unload overstocked items) or to repackagers (to move drugs from bulk to unit-of-use containers), and it is not unusual for multiple transactions to occur before drugs are purchased by the dispensing pharmacy. These multiple transactions can provide a means for counterfeit drugs to enter the supply chain.
Counterfeit drugs can be introduced successfully into the legitimate drug supply if the seller conceals the drugs' origin and the purchaser accepts without question the seller's representation of the product. Typically, counterfeiters commingle counterfeit product with authentic product and either fail to give purchasers a pedigree (a statement of origin containing information about all previous transactions) or give them a fake pedigree. Commingling makes it easier to pass off counterfeit drugs as authentic and increases the counterfeiter's profit.
The Prescription Drug Marketing Act was written, in part, to address the problems of counterfeit drugs. The act was signed into law in 1988 and amended in 1992. It requires state licensure for drug wholesalers and requires a pedigree to be provided by those wholesalers who are not considered "authorized distributors" of the products of a given manufacturer. (The definition of an authorized distributor is somewhat controversial: there is disagreement about who designates a wholesaler as authorized and how formal that designation must be.) Unfortunately, the effectiveness of the Prescription Drug Marketing Act in combating counterfeit drugs has been limited. Implementation of its pedigree requirements has been problematic, and until recently, filling out a brief application and paying a nominal fee were sufficient to meet most state licensure standards. Moreover, because of a lack of funding, many states are unable to conduct regular inspections of wholesalers to ensure that they are in compliance with, among other things, requirements regarding storage, handling, and record keeping. The minimal requirements for state licensure, the lack of inspections, and the historical practice of wholesalers' transacting of business on the basis of a handshake have been cited as reasons why some counterfeit drugs make their way to pharmacies and patients.
Moreover, there are currently substantially smaller state and federal criminal penalties for counterfeiting drugs than for other types of counterfeiting. For example, counterfeiting a trademark on a prescription-drug label is punishable by up to 10 years in prison, whereas counterfeiting the drug itself is punishable by a maximum of 3 years in prison. Given these penalties and the current regulatory environment, there is growing concern that the numbers of counterfeit drugs in the United States may increase substantially in the near future.
In a recent report based on the work of an internal task force, the FDA identified several key elements of any effort to secure the nation's drug supply.1 One element is the adoption by all 50 states of the revised model rules released by the National Association of Boards of Pharmacy to strengthen the state licensure requirements for wholesale distributors. These revisions include requirements for corporate background checks, beefed-up pedigree requirements, and increased criminal penalties similar to those recently adopted by the state of Florida.
Another element is the continued development and implementation of secure business practices by various stakeholders. For example, several manufacturers have said that they will sell their drug products only to wholesalers who agree to purchase them only directly from the manufacturer and that they will publish the names of those wholesalers on their Web sites. The Healthcare Distribution Management Association, a trade association representing wholesalers, recently released a due-diligence checklist that it says should be used by a wholesaler conducting business with another wholesaler. As conditions for membership, the association is requiring licensure and verification of security measures being used to protect the drug supply.
Perhaps the most important element in ensuring a safe drug supply will be the attachment of radio-frequency identification tags containing a unique electronic serial number (the electronic product code, or EPC) to every bottle of drugs intended for sale in the United States. Each EPC will be irreversibly written by the manufacturer and will be associated with drug-specific information that will be kept in a secure data base. Thus, the EPC should permit the tracking and tracing of the item from the point of manufacture to the point of dispensing (providing an unimpeachable pedigree) and be virtually impossible to counterfeit. EPCs will also allow for easier inventory control, recalling of products, and assurance that patients get the right prescriptions; eventually, it may enable patients to determine precisely where their drugs have been and the environmental conditions in which they have been stored from manufacture to final purchase. Although it may be 2007 before these tags are in common use for drugs, they are currently in commercial use on consumer products such as jeans and perfume and are being tested on pharmaceutical products.
In addition to track-and-trace technology, sophisticated forms of authentication technology, similar to those used in the United States on the new $20 bill, may be appropriate for certain products, especially those most likely to be counterfeited. However, they are expensive and can ultimately be defeated by well-financed, sophisticated counterfeiters, so manufacturers will have to determine the appropriateness of their use on a product-by-product basis.
It will take time for the U.S. drug supply to be secured effectively, but physicians and patients can take some immediate steps to minimize the risk of exposure to counterfeit drugs. In an effort to help physicians stay informed about counterfeit drugs in the marketplace, organizations representing health care professionals and consumers have joined the FDA in creating a "counterfeit alert network" that will be used to send alerts about counterfeit drugs. In addition, physicians should tell their patients to contact them if they have any unusual reactions or side effects or if a prescription drug appears, tastes, or smells abnormal; in turn, physicians should rule out the use of counterfeit drugs whenever a patient has an atypical adverse reaction, unusual side effect, or unexplained treatment failure. Finally, the MedWatch program for the voluntary reporting of adverse events and other problems related to drugs, medical devices, and dietary supplements has been expanded to include the reporting of suspected counterfeit drugs.
Source Information
From the Food and Drug Administration, Rockville, Md.
References
Combating counterfeit drugs: a report of the Food and Drug Administration. Rockville, Md.: Food and Drug Administration, February 2004. (Accessed March 3, 2004, at http://www.fda.gov/oc/initiatives/counterfeit/report02_04.html.)(Paul M. Rudolf, M.D., J.D)
Although it is hard to obtain accurate data, the proportion of drugs in the U.S. marketplace that are counterfeit is believed to be small — less than 1 percent. Given that more than a billion pills are sold in this country every year, however, it is possible that millions may be counterfeit. The number of investigations of possible counterfeit drugs by the Food and Drug Administration (FDA) has jumped from 5 per year in the 1990s to more than 20 per year since 2000. Reports from Asia, Africa, and South America indicate that 10 to 50 percent of prescription drugs in certain countries may be counterfeit. In India, the number of counterfeit drugs is so high that the Indian parliament is expected to pass a bill authorizing the death penalty for drug counterfeiters.
In the United States, counterfeiters generally target high-volume and high-cost drugs, particularly injectables, treatments for human immunodeficiency virus infection and AIDS, and psychiatric medications. Recent examples of drugs that have been counterfeited include Lipitor, Procrit, Neupogen (filgrastim), Viagra (sildenafil), and Zyprexa (olanzapine). Experience shows that many counterfeiters are so well funded and sophisticated that security experts employed by manufacturers of the authentic products often have difficulty distinguishing authentic drugs from fake drugs by sight: both the packaging and the pills or liquid look identical.
Although there have been few reports of serious adverse events, the number of treatment failures attributable to counterfeit drugs in the United States is unknown. There may be more serious side effects and even deaths due to counterfeit drugs in other countries, where counterfeiters have targeted treatments for malaria and other infectious diseases.
Few physicians or patients know what happens to drugs from the time they are manufactured to the time they are dispensed at a pharmacy. Typically, manufacturers ship pharmaceuticals to wholesale distributors, who then ship them directly to hospitals or retail pharmacies. However, not infrequently, drugs can travel a much more circuitous route before reaching the dispenser. For example, wholesalers may sell drugs to other wholesalers (to fill shortages or unload overstocked items) or to repackagers (to move drugs from bulk to unit-of-use containers), and it is not unusual for multiple transactions to occur before drugs are purchased by the dispensing pharmacy. These multiple transactions can provide a means for counterfeit drugs to enter the supply chain.
Counterfeit drugs can be introduced successfully into the legitimate drug supply if the seller conceals the drugs' origin and the purchaser accepts without question the seller's representation of the product. Typically, counterfeiters commingle counterfeit product with authentic product and either fail to give purchasers a pedigree (a statement of origin containing information about all previous transactions) or give them a fake pedigree. Commingling makes it easier to pass off counterfeit drugs as authentic and increases the counterfeiter's profit.
The Prescription Drug Marketing Act was written, in part, to address the problems of counterfeit drugs. The act was signed into law in 1988 and amended in 1992. It requires state licensure for drug wholesalers and requires a pedigree to be provided by those wholesalers who are not considered "authorized distributors" of the products of a given manufacturer. (The definition of an authorized distributor is somewhat controversial: there is disagreement about who designates a wholesaler as authorized and how formal that designation must be.) Unfortunately, the effectiveness of the Prescription Drug Marketing Act in combating counterfeit drugs has been limited. Implementation of its pedigree requirements has been problematic, and until recently, filling out a brief application and paying a nominal fee were sufficient to meet most state licensure standards. Moreover, because of a lack of funding, many states are unable to conduct regular inspections of wholesalers to ensure that they are in compliance with, among other things, requirements regarding storage, handling, and record keeping. The minimal requirements for state licensure, the lack of inspections, and the historical practice of wholesalers' transacting of business on the basis of a handshake have been cited as reasons why some counterfeit drugs make their way to pharmacies and patients.
Moreover, there are currently substantially smaller state and federal criminal penalties for counterfeiting drugs than for other types of counterfeiting. For example, counterfeiting a trademark on a prescription-drug label is punishable by up to 10 years in prison, whereas counterfeiting the drug itself is punishable by a maximum of 3 years in prison. Given these penalties and the current regulatory environment, there is growing concern that the numbers of counterfeit drugs in the United States may increase substantially in the near future.
In a recent report based on the work of an internal task force, the FDA identified several key elements of any effort to secure the nation's drug supply.1 One element is the adoption by all 50 states of the revised model rules released by the National Association of Boards of Pharmacy to strengthen the state licensure requirements for wholesale distributors. These revisions include requirements for corporate background checks, beefed-up pedigree requirements, and increased criminal penalties similar to those recently adopted by the state of Florida.
Another element is the continued development and implementation of secure business practices by various stakeholders. For example, several manufacturers have said that they will sell their drug products only to wholesalers who agree to purchase them only directly from the manufacturer and that they will publish the names of those wholesalers on their Web sites. The Healthcare Distribution Management Association, a trade association representing wholesalers, recently released a due-diligence checklist that it says should be used by a wholesaler conducting business with another wholesaler. As conditions for membership, the association is requiring licensure and verification of security measures being used to protect the drug supply.
Perhaps the most important element in ensuring a safe drug supply will be the attachment of radio-frequency identification tags containing a unique electronic serial number (the electronic product code, or EPC) to every bottle of drugs intended for sale in the United States. Each EPC will be irreversibly written by the manufacturer and will be associated with drug-specific information that will be kept in a secure data base. Thus, the EPC should permit the tracking and tracing of the item from the point of manufacture to the point of dispensing (providing an unimpeachable pedigree) and be virtually impossible to counterfeit. EPCs will also allow for easier inventory control, recalling of products, and assurance that patients get the right prescriptions; eventually, it may enable patients to determine precisely where their drugs have been and the environmental conditions in which they have been stored from manufacture to final purchase. Although it may be 2007 before these tags are in common use for drugs, they are currently in commercial use on consumer products such as jeans and perfume and are being tested on pharmaceutical products.
In addition to track-and-trace technology, sophisticated forms of authentication technology, similar to those used in the United States on the new $20 bill, may be appropriate for certain products, especially those most likely to be counterfeited. However, they are expensive and can ultimately be defeated by well-financed, sophisticated counterfeiters, so manufacturers will have to determine the appropriateness of their use on a product-by-product basis.
It will take time for the U.S. drug supply to be secured effectively, but physicians and patients can take some immediate steps to minimize the risk of exposure to counterfeit drugs. In an effort to help physicians stay informed about counterfeit drugs in the marketplace, organizations representing health care professionals and consumers have joined the FDA in creating a "counterfeit alert network" that will be used to send alerts about counterfeit drugs. In addition, physicians should tell their patients to contact them if they have any unusual reactions or side effects or if a prescription drug appears, tastes, or smells abnormal; in turn, physicians should rule out the use of counterfeit drugs whenever a patient has an atypical adverse reaction, unusual side effect, or unexplained treatment failure. Finally, the MedWatch program for the voluntary reporting of adverse events and other problems related to drugs, medical devices, and dietary supplements has been expanded to include the reporting of suspected counterfeit drugs.
Source Information
From the Food and Drug Administration, Rockville, Md.
References
Combating counterfeit drugs: a report of the Food and Drug Administration. Rockville, Md.: Food and Drug Administration, February 2004. (Accessed March 3, 2004, at http://www.fda.gov/oc/initiatives/counterfeit/report02_04.html.)(Paul M. Rudolf, M.D., J.D)