Three general types of Internet pharmacies sell prescription drugs directly to consumers. First, some Internet pharmacies operate much like traditional drugstores, selling a wide range of prescription drugs and requiring consumers to submit a prescription from their physicians before their orders are filled. In some instances, these Internet pharmacies are affiliated with traditional chain drug stores. Second, other Internet pharmacies may sell a more limited range of drugs, often specializing in certain lifestyle medications, such as those that treat sexual dysfunction or assist in weight control. These Internet pharmacies typically require consumers to fill out an online medical history questionnaire in place of a traditional examination by a physician, and issue a prescription after a physician affiliated with the pharmacy reviews the questionnaire. Still other Internet pharmacies dispense drugs without a prescription. In the United States, the practice of pharmacy is regulated by state boards of pharmacy, which establish and enforce standards intended to protect the public. State boards of pharmacy also license pharmacists and pharmacies. To legally dispense a prescription drug, a licensed pharmacist working in a licensed pharmacy must be presented a valid prescription from a licensed health care professional. The requirement that drugs be prescribed and dispensed by licensed professionals helps ensure patients receive the proper dose, take the medication correctly, and are informed about warnings, side effects, and other important information about the drug. Under the Federal Food, Drug, and Cosmetic Act (FDCA), as amended, FDA is responsible for ensuring the safety, effectiveness, and quality of domestic and imported drugs. To do so, FDA establishes standards for the safety, effectiveness, and manufacture of drugs that must be met before they are approved for the U.S. market. To gain approval, a drug manufacturer must demonstrate that a drug is safe and effective, and that the manufacturing methods and controls that will be used in the specific facility where it will be manufactured meet FDA standards. The same drug manufactured in another facility not approved by FDA—such as a foreign- made version of an approved drug—may not be sold legally in the United States. Drugs are subject to other statutory and regulatory standards relating to purity, labeling, manufacturing, and packaging. Failure to meet these standards could result in a drug being considered adulterated or misbranded and therefore illegal for sale, which could result in FDA enforcement action. The FDCA requires that drugs be dispensed with labels that include the name of the prescriber, directions for use, and cautionary statements, among other things. A drug is considered misbranded if its labeling or container is misleading, or if the label fails to include required information. Prescription drugs dispensed without a prescription are also considered misbranded. In addition, if a drug is susceptible to deterioration and must, for example, be maintained in a temperature-controlled environment, it must be packaged and labeled in accordance with regulations and manufacturer standards. Drugs must also be handled to prevent adulteration, which may occur, for example, if held under unsanitary conditions leading to possible contamination. FDA-approved drugs manufactured in foreign countries, including those sold over the Internet, are subject to the same requirements as domestic drugs. Further, imported drugs may be denied entry into the United States if they “appear” to be unapproved, adulterated, or misbranded, among other things. While the importation of such drugs may be illegal, FDA has allowed individuals to bring small quantities of certain drugs into the United States for personal use under certain circumstances. Internet pharmacies pose challenges for regulators. State boards of pharmacy in many states have reported difficulty identifying Internet pharmacies located outside of their borders and have limited ability and authority to investigate and act against pharmacies that do not comply with state pharmacy laws when they are identified. In 2000, nearly half of the state boards had identified consumer complaints against Internet pharmacies or reported problems with Internet pharmacies not complying with state pharmacy laws. Additionally, state medical boards have reported receiving complaints about physicians prescribing drugs over the Internet without performing an examination of the patient. Federal agencies have taken steps to stop the illegal sales of prescription drugs and other substances by Internet pharmacies. For example, FDA has taken enforcement actions against Internet pharmacies; the Department of Justice has prosecuted Internet pharmacies and physicians for dispensing medications without a valid prescription; and DEA has investigated Internet pharmacies for illegal distribution of controlled substances. We were able to obtain the majority of prescription drugs we targeted for purchase from a wide variety of domestic and foreign Internet pharmacies without providing a prescription. Five U.S. and all 18 Canadian pharmacies from which we obtained drug samples required a patient-provided prescription, whereas the remaining 24 U.S. and all 21 other foreign pharmacies from which we obtained samples either provided a prescription based on an online medical questionnaire or had no prescription requirement. Although we obtained samples of most of the drugs we targeted for purchase, some drugs, such as those with special safety restrictions and narcotics, were available from fewer sources or were more difficult to obtain. We obtained 1 or more samples of 11 of the 13 drugs we targeted, both with and without a patient-provided prescription. In total, we placed 90 orders—each with a different Internet pharmacy in the United States, Canada, and other foreign countries—and received 68 samples. Drug samples we received from other foreign pharmacies came from Argentina, Costa Rica, Fiji, India, Mexico, Pakistan, Philippines, Spain, Thailand, and Turkey. Most of the drugs—45 of 68—were obtained without a patient- provided prescription. These included drugs for which physician supervision is of particular importance due to the possibility of severe side effects, such as Accutane, or the high potential for abuse and addiction, such as the narcotic painkiller hydrocodone. (See table 2.) Although most of the samples we received were obtained without a patient- provided prescription, prescription requirements varied. Five U.S. and all 18 Canadian pharmacies from which we obtained drug samples required the patient to provide a prescription. The remaining 24 U.S. pharmacies generally provided a prescription based on a general medical questionnaire filled out online by the patient. Questionnaires requested information on the patient’s physical characteristics, medical history, and condition for which drugs were being purchased. Several pharmacy Web sites indicated that a U.S.-licensed physician reviews the completed questionnaire and issues a prescription. The other foreign Internet pharmacies we ordered from generally had no prescription requirements, and many did not seek information regarding the patient’s medical history or condition. The process for obtaining a drug from many of these pharmacies involved only selecting the desired medication and submitting the necessary billing and shipping information. (See table 3.) While we obtained samples of most of the drugs we targeted for purchase on the Internet, certain drugs were more widely available and easier to purchase than others. The top selling drugs Celebrex (a pain reliever), Lipitor (a cholesterol-lowering drug), Viagra (a medication for male sexual dysfunction), and Zoloft (an antidepressant) were available from multiple pharmacies. We placed 10 orders for each of these four drugs with little difficulty. Other drugs were available from fewer sources or were more difficult to obtain. Some of our orders for drugs with special safety restrictions were more closely scrutinized. For example, one order we placed for Accutane was declined by a U.S. pharmacy. Accutane is an acne medication that may cause birth defects and serious mental disturbances leading to suicide among some users. The pharmacy indicated that it declined our order because the physician was not included on a national registry of qualified prescribers. Similarly, one U.S. and one Canadian Internet pharmacy declined our order for Clozaril. According to its manufacturer, patients taking Clozaril, an antipsychotic medication, must have ongoing blood tests to monitor for the development of a fatal blood disorder that can occur during treatment. The U.S. pharmacy that declined our order indicated that Clozaril should not have been offered for sale on its Web site, and the Canadian pharmacy indicated that more stringent prescription requirements prevented it from dispensing the drug to patients outside of Canada. Narcotic pain medications—OxyContin, Percocet, and Vicodin—were also less readily available. Despite extensive searching of Internet pharmacy sites, we found few that sold these drugs without a prescription. Other factors also hindered our ability to purchase these drugs. For example, some pharmacies that advertised the narcotics did not actually sell them. Rather, they attempted to substitute a different, often less potent and nonnarcotic drug once the order was placed. In addition, several pharmacies that offered narcotics required payment by means that were beyond our scope, such as check, bank transfers, or “e-gold” exchanges. We were able to place orders for the generic version of Vicodin at several U.S. pharmacies; however, some of these pharmacies required not only an online medical questionnaire, but also a telephone consultation with a pharmacy-designated physician in order to obtain a prescription. Finally, we were able to place only one order for a drug purporting to be OxyContin, and only after locating the source by paying a membership fee and joining an Internet pharmacy drug club, which referred us to the site. We identified several problems associated with the handling, FDA-approval status, and authenticity of the 21 drug samples we received from other foreign Internet pharmacies. None included required pharmacy labels that provided patient instructions for use, and few provided warning information. Thirteen were shipped improperly, were packaged unconventionally, or arrived damaged. Manufacturers reported that most of the samples they reviewed at our request from other foreign pharmacies were not approved by FDA for the United States—although most had a comparable chemical composition to the product we ordered—and 4 were either counterfeit products or otherwise not comparable to the product we ordered. While most of the samples received from Canadian Internet pharmacies were unapproved for the U.S. market, they otherwise had a comparable chemical composition, and the samples from U.S. and Canadian pharmacies exhibited few problems otherwise. Table 4 summarizes the problems we identified among the 68 samples we received. None of the 21 prescription drug samples we received from other foreign Internet pharmacies included a dispensing pharmacy label that provided patient instructions for use, and only 6 of the samples came with warning information. Lack of instructions and warnings on these drugs leaves consumers who take them at risk for potentially dangerous drug interactions or side effects from incorrect or inappropriate use. For example, we received 2 samples purporting to be Viagra, a drug used to treat male sexual dysfunction, without any warnings or instructions for use. (See fig. 1.) According to its manufacturer, this drug should not be prescribed for individuals who are currently taking certain heart medications, as it can lower blood pressure to dangerous levels. Additionally, 2 samples of Roaccutan, a foreign version of Accutane, arrived without any instructions in English. (See fig. 2.) As noted, possible side effects of this drug include birth defects and severe mental disturbances. Compounding the concerns regarding the lack of warnings and patient instructions for use, none of the other foreign pharmacies ensured patients were under the care of a physician by requiring that a prescription be submitted before the order is filled. We observed other evidence of improper handling among 13 of the 21 drug samples we received from other foreign Internet pharmacies. For example, three samples of Humulin N were not shipped in accordance with manufacturer handling specifications. Despite the requirement that this drug be stored under temperature-controlled and insulated conditions, the samples we received were shipped in envelopes without insulation. (See fig. 3.) Similarly, 6 samples of other drugs were shipped in unconventional packaging, in some instances with the apparent intention of concealing the actual contents of the package. For example, the sample purporting to be OxyContin was shipped in a plastic compact disc case wrapped in brown packing tape—no other labels or instructions were included, and a sample of Crixivan was shipped inside a sealed aluminum can enclosed in a box labeled “Gold Dye and Stain Remover Wax.” (See fig. 4.) Additionally, 5 samples we received were damaged and included tablets that arrived in punctured blister packs, potentially exposing pills to damaging light or moisture. (See fig. 5.) One drug manufacturer noted that damaged packaging may also compromise the validity of drug expiration dates. Among the 21 drug samples from other foreign pharmacies, manufacturers determined that 19 were not approved for the U.S. market for various reasons, including that the labeling or the facilities in which they were manufactured had not been approved by FDA. For example, the manufacturer of one drug noted that 2 samples we received of that drug were packaged under an alternate name used for the Mexican market. The manufacturer of another drug found that 3 samples we received of that drug were manufactured at a facility unapproved to produce drugs for the U.S. market. In all but 4 instances, however, manufacturers determined that the chemical composition of the samples we received from other foreign Internet pharmacies was comparable to the chemical composition of the drugs we had ordered. Two samples of one drug were found by the manufacturer to be counterfeit and contained a different chemical composition than the drug we had ordered. In both instances the manufacturer reported that samples had less quantity of the active ingredient, and the safety and efficacy of the samples could not be determined. Manufacturers also found 2 additional samples to have a significantly different chemical composition than that of the product we had ordered. All 47 of the prescription drug samples we received from Canadian and U.S. Internet pharmacies included labels from the dispensing pharmacy that generally provided patient instructions for use and 87 percent of these samples (41 of 47) included warning information. Furthermore, all samples were shipped in accordance with special handling requirements, where applicable, and arrived undamaged. Manufacturers reported that 16 of the 18 samples from Canadian Internet pharmacies were unapproved for sale in the United States, citing for example unapproved labeling and packaging. However, the samples were all found to be comparable in chemical composition to the products we ordered. Finally, the manufacturer found that 1 sample of a moisture-sensitive medication from a U.S. pharmacy was inappropriately removed from the sealed manufacturer container and dispensed in a pharmacy bottle. We observed questionable characteristics and business practices of some of the Internet pharmacies from which we received drugs. Most, but not all, involved other foreign pharmacies. These included pharmacies that accepted payment but did not provide the drugs ordered, shipments of drugs with questionable return addresses, pharmacies that obscured details about the drugs sold, and pharmacies that were under investigation by regulatory agencies. We ultimately did not receive six of the orders we placed and paid for, suggesting the potential fraudulent nature of some Internet pharmacies or entities representing themselves as such. The six orders were for Clozaril, Humulin N, and Vicodin, and cost over $700 in total. Five of these orders were placed with non-Canadian foreign pharmacies and one was placed with a pharmacy whose location we could not determine. We followed up with each pharmacy in late April and early May of 2004 to determine the status. Three indicated they would reship the product, but as of June 10, 2004, we had not received the shipments. Three others did not respond to our inquiry. We determined that at least eight of the return addresses included on samples we received from other foreign Internet pharmacies were shipped from locations that raise questions about the entities that provided the samples. For example, we found a shopping mall in Buenos Aires, Argentina, at the return address provided on a sample of Lipitor. Authorities assisting us in locating this address found it impossible to identify which, if any, of the many retail stores mailed the package. The return address for a sample of Celebrex was found to be a business in Cozumel, Mexico, but representatives of that business informed authorities that it had no connection to an Internet pharmacy operation. Finally, the return addresses on samples of Humulin N and Zoloft were found to be private residences in Lahore, Pakistan. Certain practices of Internet pharmacies may render it difficult for consumers to know exactly what they are buying. Some non-Canadian foreign Internet pharmacies appeared to offer U.S. versions of brand name drugs on their Web sites, but attempted to substitute an alternative drug during the order process. In some cases, other foreign pharmacies substituted alternative drugs after the order was placed. For example, one Internet pharmacy advertised brand name Accutane, which we ordered. The sample we received was actually a generic version of the drug made by an overseas manufacturer. About 21 percent of the Internet pharmacies from which we received drugs (14 of 68) were under investigation by regulatory agencies. The reasons for the investigations by DEA and FDA include allegations of selling controlled substances without a prescription; selling adulterated, misbranded, or counterfeit drugs; selling prescription drugs where no doctor-patient relationship exists; smuggling; and mail fraud. The pharmacies under investigation were concentrated among the U.S. pharmacies that did not require a patient-provided prescription (9) and other foreign (4) pharmacies. One Canadian pharmacy was also included among those under investigation. Consumers can readily obtain many prescription drugs over the Internet without providing a prescription—particularly from certain U.S. and foreign Internet pharmacies outside of Canada. Drugs available include those for which patients should be monitored for side effects or where the potential for abuse is high. For these types of drugs in particular, a prescription and physician supervision can help ensure patient safety. In addition to the lack of prescription requirements, some Internet pharmacies can pose other safety risks for consumers. Many foreign Internet pharmacies outside of Canada dispensed drugs without instructions for patient use, rarely provided warning information, and in four instances provided drugs that were not the authentic products we ordered. Consumers who purchase drugs from foreign Internet pharmacies that are outside of the U.S. regulatory framework may also receive drugs that are unapproved by FDA and manufactured in facilities that the agency has not inspected. Other risks consumers may face were highlighted by the other foreign Internet pharmacies that fraudulently billed us, provided drugs we did not order, and provided false or questionable return addresses. It is notable that we identified these numerous problems despite the relatively small number of drugs we purchased, consistent with problems recently identified by state and federal regulatory agencies. In commenting on a draft of this report, FDA generally agreed with our findings and conclusions and made suggestions to clarify or expand upon its contents (see app. II). FDA commented that, while the draft report noted Internet pharmacy Web sites purported or appeared to be from various countries, the draft did not demonstrate that the drug samples we received were actually sent from those countries, such as by discussing return addresses and postmarks on the samples. FDA suggested we indicate the methods we used to determine the samples’ origins. We modified the report to indicate that we determined the location of the Internet pharmacy Web sites from which we received drug samples based on information contained in the pharmacy Web sites and the return addresses and postmarks on the packages we received. FDA also commented that our finding that certain unapproved drugs were chemically equivalent to the brand name products we ordered was misleading. FDA noted that chemical equivalence testing may not always determine whether a drug is comparable in all respects to the FDA- approved drug and therefore fully therapeutically equivalent. We relied on manufacturers to determine whether the drug samples we received were comparable to their own FDA-approved brand name version of the drug, and manufacturers conducted a range of tests to make this determination. Nevertheless we modified the final report to note the potential limitations to chemical equivalence testing. FDA also made several observations about the practices of Internet pharmacies and provided technical comments, which we incorporated where appropriate. We also provided a draft of this report to DEA for technical comments and to ensure information we reported did not compromise its ongoing investigations. The agency responded that it had no comments. Finally, we provided segments of the draft report to the manufacturer of each drug sample we received. Each manufacturer reviewed the segments of the draft report relating to its own product(s), and provided technical comments, which we incorporated as appropriate. As agreed with your office, unless you publicly announce this report’s contents, we plan no further distribution until 30 days after its issue date. At that time, we will send copies to the Acting Commissioner of FDA, the Administrator of DEA, and others upon request. In addition, this report will be available at no charge at the GAO Web site at http://www.gao.gov. Please call Marcia Crosse at (202) 512-7119 or Robert Cramer at (202) 512- 7455 if you have any questions. Another contact and other major contributors are listed in appendix I. Major contributors to this report were Margaret Smith, Corey Houchins- Witt, Andrew O’Connell, Ramon Rodriguez, Julian Klazkin, Helen Desaulniers, Robert Copeland, and Harold Lewis. The General Accounting Office, the audit, evaluation and investigative arm of Congress, exists to support Congress in meeting its constitutional responsibilities and to help improve the performance and accountability of the federal government for the American people. GAO examines the use of public funds; evaluates federal programs and policies; and provides analyses, recommendations, and other assistance to help Congress make informed oversight, policy, and funding decisions. GAO’s commitment to good government is reflected in its core values of accountability, integrity, and reliability. 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Summary: As the demand for and the cost of prescription drugs rise, many consumers have turned to the Internet to purchase drugs. However, the global nature of the Internet can hinder state and federal efforts to identify and regulate Internet pharmacies to help assure the safety and efficacy of products sold. Recent reports of unapproved and counterfeit drugs sold over the Internet have raised further concerns. GAO was asked to examine (1) the extent to which certain drugs can be purchased over the Internet without a prescription; (2) whether the drugs are handled properly, approved by the Food and Drug Administration (FDA), and authentic; and (3) the extent to which Internet pharmacies are reliable in their business practices. GAO attempted to purchase up to 10 samples of 13 different drugs, each from a different pharmacy Web site, including sites in the United States, Canada, and other foreign countries. GAO determined whether the samples contained a pharmacy label with patient instructions for use and warnings on the labels or the packaging and forwarded the samples to their manufacturers to determine whether they were approved by FDA and authentic. GAO also confirmed the locations of several Internet pharmacies and identified those under investigation by regulatory agencies. GAO obtained most of the prescription drugs it targeted from a variety of Internet pharmacy Web sites without providing a prescription. GAO obtained 68 samples of 11 different drugs--each from a different pharmacy Web site in the United States, Canada, or other foreign countries, including Argentina, Costa Rica, Fiji, India, Mexico, Pakistan, Philippines, Spain, Thailand, and Turkey. Five U.S. and all 18 Canadian pharmacy sites from which GAO received samples required a patient-provided prescription, whereas the remaining 24 U.S. and all 21 foreign pharmacy sites outside of Canada provided a prescription based on their own medical questionnaire or had no prescription requirement. Among the drugs GAO obtained without a prescription were those with special safety restrictions and highly addictive narcotic painkillers. GAO identified several problems associated with the handling, FDA approval status, and authenticity of the 21 samples received from Internet pharmacies located in foreign countries outside of Canada. Fewer problems were identified among pharmacies in Canada and the United States. None of the foreign pharmacies outside of Canada included required dispensing pharmacy labels that provided instructions for use, few included warning information, and 13 displayed other problems associated with the handling of the drugs. For example, 3 samples of a drug that should be shipped in a temperature- controlled environment arrived in envelopes without insulation. Manufacturer testing revealed that most of these drug samples were unapproved for the U.S. market; however, manufacturers found the chemical composition of all but 4 was comparable to the product GAO ordered. Four samples were determined to be counterfeit products or otherwise not comparable to the product GAO ordered. Similar to the samples received from other foreign pharmacies, manufacturers found most of those from Canada to be unapproved for the U.S. market; however, manufacturers determined that the chemical composition of all drug samples obtained from Canada were comparable to the product GAO ordered. Some Internet pharmacies were not reliable in their business practices. Most instances identified involved pharmacies outside of the United States and Canada. GAO did not receive six orders for which it had paid. In addition, GAO found questionable entities located at the return addresses on the packaging of several samples, such as private residences. Finally, 14 of the 68 pharmacy Web sites from which GAO obtained samples were found to be under investigation by regulatory agencies for reasons including selling counterfeit drugs and providing prescription drugs where no valid doctor- patient relationship exists. Nine of these were U.S. sites, 1 a Canadian site, and 4 were other foreign Internet pharmacy sites. In commenting on a draft of this report, FDA generally agreed with its findings and conclusions.